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THE IMMUNE SYSTEM

INNATE IMMUNITY

The components of the innate immune system provide a constant, unchanging system of protection for the healthy individual (Table 4.1). These physical and chemicalbarriers are an essential contribution to good health.

Physical barriers and phagocytesThe intact skin and mucous membranes constitute abarrier to the entry of microorganisms. These agents musttherefore rely on physical damage, such as injuries or insectbites, to gain access to the body. Numerous natural anti-microbial substances also exist that fatally damage micro-organisms. These include unsaturated fatty acids that aresecreted on to the skin, lysozyme that is secreted in tears,and others, including gastric acid. Interferons are a furtherfamily of molecules (a,b,g) that block viral replication andpromote antiviral immune responses.

However, some microorganisms have developed specificattachment and penetration mechanisms to bypass theseinitial defences. An example is rhinoviruses, which pene-trate the respiratory mucosa by first attaching to a cellsurface adhesion molecule ICAM-1 (intercellular adhesionmolecule-1). If microorganisms are successful in breach-ing the physical defences, they are usually phagocytosedand killed by polymorphonuclear leukocytes (PMN) ormacrophages. Some bacteria (e.g. pneumococci) can resistphagocytosis by virtue of their capsules, whereas others(e.g. staphylococci) release toxins that destroy phago-cytes. Whereas some microorganisms can survive withinphagocytic cells (e.g. mycobacteria), giving rise to chronicinfection, most are killed in the phagolysosomes by a com-bination of acid pH, oxygen metabolites (e.g. hydrogenperoxide) and various cytotoxic proteins. However, not allkilling is intracellular, and macrophages or PMN cansecrete toxic molecules in order to kill large targets, e.g.worms (helminths). In the case of viruses and tumours,natural killer (NK) cells also play an essential role.

INTRODUCTION

This chapter describes the components of the immunesystem and their interactions in the defence against infec-tion. It is only intended to provide the reader with suffi-cient basic scientific detail to understand the clinicaldisorders described. Abnormal or inappropriate immuneresponses cause the clinical conditions of immunodefi-ciency and allergy, and these are discussed with an empha-sis on clinical presentation, investigation and management.The principles of autoimmunity, along with conventionaland novel immunosuppressive therapies, are also dis-cussed. Throughout, the chapter highlights how recentadvances in understanding the immune response at a mol-ecular level have had an impact on clinical practice.

The human immune system has developed to combatinfection by a diverse range of potential pathogenic micro-organisms: bacteria, viruses, fungi, protozoa and helminths.It is a complex but effective system comprised of multiplecomponents which have both specific and overlappingfunctions. The immune system is conventionally subclassi-fied into the innate and adaptive components, the essentialfunctions of which are:

• The differentiation of self from non-self;• The recognition of foreign proteins by specific molecules

(antibodies, T-cell receptors);• The recall of previous exposure to specific organisms

and the production of a rapid, more effective responseupon re-exposure.

The last two are characteristic of adaptive immunity.

The immune system 79

Immunodeficiency 85

Hypersensitivity 96

Immunosuppression 102

TABLE 4.1 Innate and adaptive immune systems

Innate Adaptive

Physical protection (skin, mucous membranes)Chemical protection (lysozyme, gastric acid) AntibodyInterferonsPhagocytes LymphocytesComplement

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complement and phagocytes are recognized as primaryimmunodeficiency diseases (PID). In addition, individualelements of the innate system are essential in stimulat-ing the adaptive response during antigen presentation.Although classification into innate and adaptive helps ourunderstanding of the immune response, it is important toremember that these elements are interdependent andfunction as an integrated system.

ADAPTIVE IMMUNITY

The adaptive immune system differs in two importantrespects from the innate, with its characteristics of speci-ficity and memory. The adaptive system responds to theenvironment and ‘remembers’ specific encounters withforeign antigens. The most important cells involved in the adaptive response are lymphocytes (B and T cells).The antigen recognition molecules on the surfaces of B and T cells (antibody and T-cell receptors) confer the specificity of the adaptive system. These molecules recognize and bind to specific antigens through amino acid sequences that are complementary in structure to thetarget antigen. Immunological memory is generated afterthe first antigen exposure (primary response) becauseantigen-specific lymphocytes proliferate and generate anincreased pool of cells. These memory cells, responsive tothe specific antigen, remain relatively inactive until thesame antigen is encountered again (secondary response).Subsequent stimulation of memory cells results in a sec-ondary immune response that is more rapid and quantita-tively greater than the primary response (Fig. 4.2).

LymphocytesLymphocytes originate from stem cells in the bone marrow.B lymphocytes complete their maturation in the bonemarrow, but T lymphocytes require passage through thethymus, where they complete their maturation and educa-tion process. Crucially, it is in the thymus that T cells learnto identify ‘self proteins’, and any autoaggressive T cells are either allowed to die (by apoptosis) or are rendered non-reactive (tolerant). The bone marrow andthymus are referred to as primary lymphoid organs. Thesecondary lymphoid organs include lymph nodes, thespleen, Peyer’s patches, tonsils and adenoids. These arestrategically located to encounter microorganisms enteringthe body through external tissues, blood, gut, and upperairway, respectively. The structure of secondary lymphoidtissue is exemplified by the lymph node, where the cortexcontains mainly B lymphocytes and the paracortex T lymphocytes, whereas antibody-secreting plasma cells arefound in the medulla.

Peripheral blood normally contains 70–90% T cells,5–10% B cells and approximately 1–10% natural killer(NK) cells. A characteristic of lymphocytes is their abilityto ‘traffic’ from peripheral blood into the tissues and secondary lymphoid organs. This property allows lym-

Complement systemA further line of innate defence is the complement system(Fig. 4.1), a cascade of serum proteins which, when acti-vated in succession, mediate three important effects:

• Release of small peptides that stimulate inflammationand attract phagocytes;

• Deposition of the cleavage component (C3b) on micro-bial membranes, which promotes phagocytosis via C3breceptors on phagocytic cells;

• Assembly of complement components (C5–C9) intolytic complexes which puncture cell membranes, causingosmotic death.

This activation ‘cascade’ is triggered by numerous micro-bial surfaces, notably the endotoxins of Gram-negativebacteria, by C-reactive protein (CRP) and mannan-bindinglectin (MBL). Through interactions with antibody, phago-cytes and mast cells, the complement cascade has an impor-tant role in integrating the response to infection.

SummaryThe innate immune system is essential in the defenceagainst infection, and deficiency can result in serious clin-ical consequences. The vulnerability to infection of patientswith severe burns emphasizes the protective value ofnormal skin. As will be described later, specific defects of

CRP andimmune

complexes

Mannanbindinglection

FIG. 4.1 Complement activation pathwaysThe central event in complement activation is cleavage of C3 with the subsequentformation of C5 convertase. The generation of cleavage products (indicated by bluelines) augments the inflammatory response by attracting and activating phagocytesand causing activation and degranulation of mast cells. The deposition of C3b oncellular surfaces to promote phagocytosis is known as opsonization. The terminalpathway components (C5–C9) create the membrane attack complex (MAC) whichcauses osmotic cell lysis.

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phocytes to encounter antigen in almost all physical locations. The lymphoid tissues of the gut, genitourinarytract, breast and lungs behave, to a certain extent,autonomously, in that particular B cells (largely IgA-secreting) and T cells recirculate selectively through them.This recirculation is mediated by the expression of specifichoming receptors and is referred to as the mucosal immunesystem. The result is that primary antigen exposure at onemucosal site will facilitate protective immunity at othermucosal sites.

B cellsThe main function of B cells is antibody production. SomeB cells are stimulated directly by polymeric antigens andthese responses are termed T-independent (e.g. bacterialcapsular polysaccharides). Most B-cell responses arehowever T-cell dependent. For T-dependent responses,B cells are triggered to proliferate by interaction betweentheir surface Ig and the antigen, but they require additionalsignals from T-helper cells in order to differentiate intoplasma cells and secrete antibody. These signals consist ofnon-antigen specific cytokines (particularly IL-4 and -6)and cell–cell-mediated signalling. The interaction of thesecell surface molecules, e.g. gp39 (CD40 ligand, CD40L) onT cells with CD40 on B cells, is essential in facilitatingeffective B-cell antibody production. During T-dependentresponses some proliferating B lymphocytes are retainedin germinal centres instead of differentiating ‘terminally’into plasma cells. These are the memory B cells.

AntibodiesAntibodies are a family of five major classes of moleculewhich have a primary role in combating microorganismsfree in the blood or tissue spaces, primarily viruses in their

extracellular stage, and many bacteria. The antibody orimmunoglobulin (Ig) molecule is ideally suited to its func-tion of promoting the removal of foreign antigens. Its basicstructure is seen in antibodies of the IgG class (Fig. 4.3).The N-terminal half is composed of heavy (H) and light(L) chains and is responsible for binding to antigen (Fabportions). The C-terminal half (Fc), which consists of por-tions of heavy chains, determines the class of antibody andis responsible for the other biological functions of the molecule. The major role of antibody molecules is to bindto microorganisms via the Fab portion, enhancing phago-cytosis, as phagocytes possess Fc receptors. This process of coating microorganisms with antibody is known asopsonization. The basic four-chain structure is preserved inall five classes of immunoglobulin, but each class hascertain characteristics that subserve its specific functions.

• IgG molecules are involved in the activation of com-plement, attachment to phagocytic cells, passage into thetissues and transport across the placenta. The four IgGsubclasses (IgG1, IgG2, IgG3 and IgG4) vary somewhat inthese functions.

• IgM is a large molecule with a pentameric structure. Itis mainly confined to the bloodstream and is very effi-cient at activating complement and agglutinating foreignmaterial because of its 10 antigen-combining sites perpentameric complex.

• IgA is the predominant immunoglobulin class secretedat mucosal sites. It has a dimeric structure and is pro-tected from proteolytic damage by a special polypeptide,the secretory chain (Sc). Sc is produced by the mucosalepithelial cells and acts as a receptor-transporter, bind-ing to and taking the antibody into external sites. IgA can

FIG. 4.2 Primary and secondary antibody responsesPrimary and secondary antibody responses to antigen. This demonstrates thecharacteristics of the adaptive immune response, i.e. specificity and memory. Upon re-exposure to antigen the immune system recognizes the antigen due toimmunological memory. The resulting response has a shorter lag time (lag 2) and a quantitively greater antibody response.

FIG. 4.3 Immunological moleculesV = variable, D = diversity, J = joining, C = constant, HC = heavy chain, LC = lightchain, VH/L = variable region of heavy/light chain, CH1(2,3) = constant region 1(2,3) of heavy chain, CL = constant region of light chain.

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RAG2 largely control the recombination events in lym-phocyte progenitors. Defects or mutations associated withthese genes can profoundly and adversely affect the devel-opment of the immune system.

After gene rearrangement, the B cell does not restorethe germline configuration and daughter cells will retainthis unique rearrangement, ensuring continued antigenicspecificity of that clone and its entire subsequent offspring(progeny). This is the molecular basis of immunologicalmemory, thus maintaining immunological specificity in the clonal progeny. The heavy-chain C gene can, however,change to allow class switching (e.g. IgM–IgG) during theimmune response, as occurs in moving from a primary toa secondary response.

During the life of a B cell, point mutations may occurwithin the variable regions (somatic mutation), resulting in a change of affinity of the antibody molecule. Increasedaffinity for antigen confers a selective advantage to any B cell. This phenomenon results in affinity maturationwhereby, as an immune response progresses, antibody-binding affinity increases. The huge potential diversity (i.e. the ability of humans to respond to a multitude of different foreign antigens) of antibody binding specificity(up to 108 specificities) is thus achieved by a number ofmechanisms:

• Association of different heavy chains with either k or llight chains;

• Association of V genes with different (D) and J genes;• Genetic joining errors;• Somatic mutation.

Genetic differences between antibody molecules areknown as isotypic if they occur in the constant region andas idiotypic if they reside in the hypervariable regions (thesites associated with direct binding to antigen; Fig. 4.3). Theidiotype of an antibody is the portion defining the unique-ness of that variable region, and may include both theantigen-combining site and the adjacent regions. There arealso allelic differences known as allotypes, mainly withinthe C regions, which enable the antibody molecules of different individuals to be distinguished.�1

T cellsThe major effector role of T cells is the elimination ofviruses, fungi and protozoa, but they also act as coordina-tors of the overall adaptive immune response. B and T lym-phocytes are impossible to distinguish by light microscopyand therefore more sophisticated techniques are needed(e.g. flow cytometry) which can identify specific cell type-specific surface antigens (CD antigens). All T cells bear theCD3 antigen, which is associated on the cell surface withthe T-cell receptor (TCR).

Cytotoxic T cells (Tctx) are responsible for killing ab-normal host cells (e.g. virally infected, malignantly trans-formed or transplanted cells) and, in addition to possessingCD3, are also positive for the surface molecule CD8. Theydestroy target cells by several mechanisms, including cellmembrane interactions (such as that of the Fas antigen

therefore survive proteolytic attack in secretions of theeyes, lungs, nose, gut and urinary tract.

• IgE attaches via its Fc region to receptors on mast cells.When two bound IgE molecules are cross-linked byantigen, intracellular signalling results in the release ofmediators from mast cell granules which cause the clinical features of acute allergy.

• IgD is found mainly on B-cell membranes and acts as anantigen receptor. Its soluble form is not thought to havea significant physiological role.

The properties of the various Ig classes and subclasses aresummarized in Table 4.2.

Antibody genesGenes on three different chromosomes code for antibodymolecules. The genes of heavy and light chains are not continuous in the germline, but consist of separate clustersof gene segments separated by non-informative regionscalled introns. The clusters are named according to the part of the immunoglobulin molecule that they encode(Fig. 4.3), i.e. V, variable; D, diversity (heavy chains only);J, joining; and C, constant.

During the development of a B cell, the germline DNAencoding the heavy-chain genes undergoes somatic rear-rangement and recombination such that a complete heavy-chain variable region gene, V–D–J, is assembled. Aftertranscription, RNA is spliced to link the V–D–J segmentwith a C segment to encode a complete heavy chain(V–D–J–C). Once this is accomplished, the light-chaingenes rearrange to encode a complete light chain (V–J–C).Heavy and light chains then link together to form a com-plete antibody molecule. If rearrangement is not success-ful, the developing B cell is aborted. Enzymes(recombinases) encoded by two genes termed RAG1 and

TABLE 4.2 Immunoglobulin structure and function

Class & subclass Structure Major functions*

IgGIgG1 Monomer C & OIgG2 Monomer CIgG3 Monomer C & OIgG4 Monomer O

IgM Pentamer C

IgA Dimer Mucosal protection

IgE Monomer Mast cell activation

IgD Cell surface bound Antigen binding

* C, complement activation; O, opsonization.

MCQ 4.11

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(CD95) with its ligand) and the release of cytotoxic sub-stances: perforins, granzymes and other cytokines.

Helper T cells (Th), in addition to expressing CD3, alsoexpress CD4. It is helpful to remember some of these morecommon CD numbers, as these are important in describ-ing primary immune deficiency states and lymphoprolifer-ative diseases.

The T-cell receptor (TcR, Fig. 4.4)The T-cell receptor is a two-chain (a and b, or g and d) mol-ecule, rather like a shortened immunoglobulin. However,it has a more complicated combining site than antibody,and recognizes linear fragments of small foreign peptidesin combination with molecules of the human leukocyteantigen system (HLA). The TcR-associated CD4 or CD8 molecules determine whether the individual T cellrecognizes antigen in association with class I or class IImolecules. CD8-expressing T cells only recognize antigenwhen it is presented with HLA class I molecules, whereasCD4-expressing T cells are only stimulated by antigen inassociation with HLA class II molecules.

The human leukocyte antigen (HLA) systemsThe HLA system is the major determinant of transplantrejection responses. However, its normal physiologicalfunction is mainly to control cell–cell interactions, par-ticularly within an individual’s own immune response. TheHLA genes lie on the short arm of chromosome 6 and aregrouped into two major sets, referred to as class I and classII. Each set contains three genetic loci that have a largenumber of alleles coding for HLA antigens. The genes forsome complement components and cytokines also lie with-in the same region (the class III region), but their productsare quite unrelated to class I and class II molecules.

Class I molecules consist of a large a chain, and a smallb chain known as b2-microglobulin. b2-Microglobulin isencoded on a different chromosome and shows nosequence variability. Class I antigens (i.e. alleles at the A,B and C loci) are expressed on all nucleated cells (two from

each locus on diploid cells). Class II HLA molecules aretwo-chain (a and b) structures both chains are encoded inthe HLA locus and are polymorphic. Class II antigens(alleles at the DP, DQ and DR loci) are expressed on amore limited range of cells: classic antigen-presenting cells,B lymphocytes and activated T lymphocytes. Class I and II antigens are central to antigen presentation and the generation of an effective immune response.

Knowledge of the HLA alleles expressed by an individ-ual is clearly essential for most organ transplantation. Inaddition, particular HLA types are also known to be asso-ciated with certain diseases (Table 4.3). In some circum-stances the HLA association is so strong as to be helpfulin diagnosis, e.g. HLA B27 and ankylosing spondylitis.

Antigen presentation (Fig. 4.5)Antigen-presenting cells (APC) include macrophages, den-dritic cells of the spleen and lymph nodes, Langerhans’cells of the skin, and B cells. Antigenic fragments are pre-

T cell

a/ba/b

g/dg/d

ClassI/II

CD8/4

APC

= antgen

FIG. 4.4 Interaction of T cell receptor and HLA moleculesThe T cell is ‘restricted’ in that CD8+ T cells only recognize antigen when it ispresented in association with HLA class I molecules. CD4+ cells only recognizeantigen in association with HLA class II molecules.

TABLE 4.3 Major HLA associations

Disease HLA-B HLA-DR

Ankylosing spondylitis 27Rheumatoid arthritis 4SLE 3Celiac disease 8 3IDDM* 8 3,4Hashimoto’s disease 5

* IDDM, insulin-dependent diabetes mellitus.

Class II pathwayClass I pathway

Proteasome

Endosome

Nucleus

Endogenouslysynthesizedpeptides

Exogenouslysynthesized

peptides

b2

β2

RER RER

HLA class II

TAP 1 and 2

Ag

FIG. 4.5 Antigen processing and presentationb2 = b2-microglobulin, TAP = transporter of antigenic peptides, = HLA class 1, = peptide, = HLA class II.WV

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MCQ 4.21

Th-cell activation (Fig. 4.6)CD4+ T-cell activation is dependent on a series of ‘costim-ulatory’ signals consisting of cell–cell surface binding andsoluble cytokines.* The result of these ‘positive signals’ isthe generation of gene transcription factors (such as NFAT– nuclear factor of activated T cells) which ‘switch on’genes (e.g. IL-2 gene) within the T-cell nucleus. Once IL-2is secreted, it acts on both the responding and neighbour-ing cells.

In contrast to CD28, a molecule termed CTLA4 appearsto be crucial in downregulating the T-cell immuneresponse. CTLA4 appears on T cells late in their activa-tion and also binds to B7 molecules (see above), but thisbinding delivers a negative signal to ‘switch off’ respond-ing T cells. Constructs of CTLA4 have recently been usedin clinical trials (phase I and II) to downregulate unwantedT-cell responses in transplantation rejection and in autoim-mune disorders. The increase in understanding of the keysignalling molecules involved in antigen presentation willundoubtedly result in further attempts at therapeuticmanipulation.

Regulation of immune responsesBoth T and B cells are activated by recognition of specificantigens. Effective removal of antigen is therefore animportant physiological endpoint for an immune response.However, the immune system has several additional mechanisms that regulate the nature and intensity of theimmune response:

• Apoptosis (programmed cell death) is now recognizedas an important regulatory mechanism for the disposalof immune cells which have completed their function.

• Anti-idiotype antibodies are directed against the Vregion of the Fab portion (idiotype) of other antibody

sented to T cells in specialized ‘antigen-binding grooves’ in HLA class I and class II molecules. Class I moleculespresent peptides which are endogenously synthesized, e.g.viral proteins in an infected cell, whereas class II moleculespresent peptides from external proteins (e.g. extracellularmicroorganisms) which have been engulfed and degradedto peptides by the APC. There are distinct intracellularpathways involved for class I and class II presentation.

Class II molecules are synthesized within the roughendoplasmic reticulum (RER) and, bound to a second molecule called the invariant chain, are transported to the endosomal compartment. There the invariant chain isreplaced by antigenic fragment and the complex is trans-ported to the cell surface. Class I molecules are also syn-thesized in the RER and are initially anchored on the innersurface of this organelle. Peptide fragments generated incytoplasmic proteasomes are transported into the RER byspecialized transporter proteins TAP-1 and TAP-2 (TAP =transporter of antigenic peptides). The peptide fragmentsthen bind to the class I molecule and this complex associ-ates with b2-microglobulin before being transported to thecell surface (Fig. 4.5).

CD4 T Cell

CD28 B7

ICAM - I LFA -1

LFA - 3

a

b

a b are the chainsof the T cell receptor

CD2CTLA-4 B7

CD4

IL-2 IL-1

IL-2RIL-1R

IL - 1R is receptor for IL-1

APC

HLA class II

= antigen

IL-1 is shown as a

IL-2R is receptor for IL-2

IL-2 is shown as

* In addition to TcR recognition of the HLA/antigenic fragment,the CD4 molecule binds to a non-polymorphic region of the HLAclass II molecule. Several other adhesion molecule pairs (LFA-1/ICAM-1, CD2/LFA-3) link together, strengthening the cellularadhesion. The interaction of a T-cell surface molecule CD28 with B7molecules on APCs is believed to be crucial to T-cell activation, as isthe secretion by the APC of IL-1.

FIG. 4.6 CD4+ cell activation after antigen presentationThe binding of cell surface receptors to their cell-bound or soluble ligands results in a series of positive (+) or negative (–) signals transmitted to the CD4 T cell nucleus.Secretion of IL-2 activates both the secreting T cell and its near neighbours.

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molecules and may block or modulate antibody function.

• A specific T-suppressor cell subset has not been identi-fied in humans. There is, however, increasing evidence,in both animals and humans, that the pattern ofcytokines secreted by CD4+ T cells will preferentiallyinduce either a predominantly cellular or an antibodyresponse. The major cytokines, their actions and poten-tial clinical importance are summarized in Table 4.4.

Prior to activation, most CD4+ T cells are ‘Th0’ (i.e. theyhave the potential to secrete a wide range of cytokines).

After activation, however, there is a preferential commit-ment towards either a Th1 or a Th2 pattern (Fig. 4.7). Th1cytokines are IL-2, IL-12 and IFN-g, favouring a cellularimmune response, whereas Th2 cytokines, favouring anantibody response, are IL-4, IL-5, IL-6 and IL-10. There ismutual suppression between these two dominant patternsof cytokine secretion such that, once a response hasbecome committed in either direction, this pattern willtend to be maintained. It is therefore currently believedthat the ‘suppression’ of immune response seen in certainsituations is the net result of a balance in the type ofcytokines secreted in the microenvironment, rather thanthe function of a single cell type. This is important in under-standing the influence of the immune response on thepattern of clinical diseases such as leprosy (see hypersen-sitivity section).�1

IMMUNODEFICIENCY

Immunodeficiency is classified as primary (where the causeis/was previously unknown) or secondary, where there is arecognized cause for the immune defect, such as cancer,infection, drug treatment, radiotherapy or malnutrition.

PRIMARY IMMUNODEFICIENCY

Understanding of primary immunodeficiency has increasedrapidly over recent years with the identification of specificmolecular lesions in a number of these previously poorlyunderstood conditions. Research into these conditions hasincreased our understanding of the cell biology of theimmune response and led to new diagnostic strategies andexperimental forms of gene therapy in humans.

TABLE 4.4 The major cytokines and their functions

Cytokine Natural source Functions Potential clinical uses

TNF-a and b Macrophages Antitumour, antiviral, vascular damage, PMN Anti-TNF moAb used for rheumatoid arthritis, inflammatory activation, bone resorption, induces IL-1 etc. bowel disease

Interferon-a Macrophages Antiviral Hepatitis B&C, papillomatosis, Kaposi’s sarcoma, hairy cell leukemia, chronic myeloid leukaemia

Interferon-b Fibroblasts Antiviral Multiple sclerosisInterferon-g T cells Antiviral, activates macrophages, increases Multidrug-resistant TB, lepromatous leprosy, visceral leishmaniasis,

mycobactericidal activity IFNgR deficiency, chronic granulomatous disease, hyper-IgE syndrome, chronic mucocutaneous candidiasis

IL-2 T cells Activates T, B and NK cells Melanoma, renal cell carcinomaIL-5 T cells, mast cells Eosinophil growth and activation Anti IL-5 moAb in phase II clinical trials for asthmaIL-6 T cells, fibroblasts, B-cell growth and differentiation; induces

APC, hepatocytes acute-phase responseIL-8 T cells, monocytes Neutrophil activation and chemotaxis IL-8 receptor antagonist in preclinical trials for airway diseaseG-CSF Macrophages Granulocyte growth and maturation Cyclical neutropenia, chemotherapy ‘rescue’

Differentiate

IL-10IL- 4IL- 5IL- 6

IL-12IL-2IFNg

Th 1

Th 2

Th 0

Secrete

Secrete

Activate

Activate

Mutualsuppression

NK

CTX

Mac

Eos

B

FIG. 4.7 T cell differentiationThe blue lines indicate secretion of soluble mediators, the black lines indicatesuppressive activity. For explanation see text.

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monly, they may present with the long-term complica-tions of their condition (e.g. bronchiectasis). They may also present with a combination of clinical features andlaboratory abnormalities that may not initially alert thenon-specialist to the underlying diagnosis (e.g. chronic illhealth, autoimmune phenomena). It is very typical forpatients with PID to suffer a prolonged delay before thecorrect diagnosis is made, despite attending many doctors.During this period of delay they suffer significant morbid-ity and even mortality, and it is therefore essential thatthere is increased awareness of these conditions to allowearlier diagnosis and treatment.

The simple guidelines from the history (Table 4.5) areuseful in determining the most appropriate first line ofimmunological investigation. It is important that investi-gations are used appropriately and that expert advice isavailable, both in the selection of tests and in the inter-pretation of results. The general principles guiding investi-gation for immune deficiency include determining boththat the relevant components of the systems are present,and that they are functionally intact. It is particularlyimportant in the investigation of children that all immuno-logical results are compared to appropriate, age-relatednormal ranges. Increasingly, specific molecular tests areused to confirm diagnoses, and therefore subtler variantforms of immune deficiency are being recognized.

Primary antibody deficiency diseasesX-linked agammaglobulinaemia (XLA/Bruton’s type)Clinical featuresAffected boys usually present between 6 months and 2years of age. There may be a family history of affected malerelatives. The most common complaint is of recurrent bacterial infections (typically Streptococcus pneumoniae orHaemophilus influenzae), usually affecting the respiratorytract, which if untreated lead to bronchiectasis. Boys maypresent with ear or joint infection and some have a non-specific arthropathy that responds to the introduction ofimmunoglobulin replacement therapy. Chronic diarrhoeaand a malabsorption syndrome may occur as a result ofGiardia lamblia infection. A helpful physical sign is theabsence of tonsillar lymphoid tissue or lymphadenopathy.A particular long-term complication in XLA is myco-plasma or ureaplasma arthritis. This is distinct from themore frequent non-specific arthropathy and is difficultboth to diagnose and to treat. XLA patients are also susceptible to enterovirus infection (polio, coxsackie orechoviruses). Oral polio vaccine is therefore contraindi-cated, as it may cause paralysis, and a chronic meningoen-cephalitis may result from coxsackie or echovirus infection.This latter complication has become rarer since the adventof intravenous immunoglobulin therapy, but it still occurseither as a generalized condition or in a more limited form,causing sensorineural deafness. The prevalence of XLA isthought to be approximately 1 in 100000 in the UK, but

Primary immunodeficiency diseases (PID) are sub-classified according to the individual immunological components involved, hence there are antibody, T-cell orcombined deficiencies, as well as phagocytic and com-plement component deficiencies. The defect in each con-dition leads to preferential susceptibility to certain typesof organisms. Typically, antibody deficiency causes suscep-tibility to bacterial infection: T-cell deficiency to viral andfungal infections; and some complement deficiencies tomeningococcal infections. These associations are impor-tant in consideration of the initial immunological differen-tial diagnosis.

What are the characteristics of infection in PID?If the clinical history of infection can be described asserious, persistent, unusual or recurrent (SPUR), thenimmunodeficiency should be part of the differential diag-nosis. ‘Serious’ suggests a potentially life-threatening infec-tion (meningitis or septicaemia). ‘Persistent’ suggests that an infection is particularly resistant to conventionaltherapy. Infections may be ‘unusual’ in terms of site (liver/brain abscess, or osteomyelitis) or organism (Pneumocystis,Aspergillus, Mycobacteria), and these should always raisethe possibility of immune deficiency. Finally, ‘recurrent’infection is particularly important. The child or adult whorepeatedly presents with infection deserves further inves-tigation of his or her immune status. It is difficult to be spe-cific about how many infections constitute a ‘recurrent’problem, and this inevitably involves an assessment of bothfrequency and severity of infection, evidence of organdamage, impact on systemic wellbeing and normal dailyactivity. The ‘10 warning signs of immune deficiency’ are byno means exhaustive, but do give practical guidance on theclinical features that should prompt investigation for PID(Table 4.5)

When to suspect the diagnosis?Patients with PID may present with a history of infectionor with a family history of an affected relative. More com-

TABLE 4.5 Ten warning signs of immune deficiency

1. 8 or more new ear infections/year2. 2 or more serious sinus infections/year3. 2 months antibiotics without effect4. 2 or more episodes of pneumonia within a year5. Failure to thrive6. Recurrent, deep abscesses7. Persistent thrush after 1 year of age8. Need for intravenous antibiotics9. 2 or more deep-seated infections (sepsis, meningitis, cellulitis)

10. Family history of PID

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erswith the advent of molecular testing a milder, previouslyundiagnosed, form is being identified.

InvestigationSerum IgG level is usually less than 2g/L, with serum IgA,IgM and IgE being undetectable. Measurement of IgGsubclasses is not usually helpful. Isohaemagglutinins aretypically absent, as are specific antibodies to previouslyadministered vaccines. Mature B cells are not usuallydetectable in peripheral blood, but T-cell numbers andfunction are normal. Neutropenia may be a feature. In the atypical, less severe, cases immunoglobulin levels aremore variable and low numbers of circulating B cells aredetected (typically in young teenage or adult males). Insuch cases the diagnosis can be difficult and test immu-nization responses to protein and polysaccharide antigens(usually tetanus toxoid and pneumovax II) are veryhelpful. Antigen-specific antibody levels are measuredbefore and 4 weeks after immunization. Results requireexpert interpretation.

The underlying molecular lesion has been characterizedas a defect of the intracellular tyrosine kinase ‘Bruton’styrosine kinase’ (Btk), coded for at X21.3-22. This kinaseis essential for normal B-cell maturation, and B-cell devel-opment is therefore arrested at the pre-B stage. Familyassessment to identify carriers is possible and should beundertaken, with appropriate genetic counselling. Rareautosomal recessive cases occur.

Management of antibody deficiencyReplacement therapy with regular intravenous immuno-globulin (ivIg) is now the standard treatment for primaryantibody deficiency. This lifelong treatment is extremelyeffective in controlling infection, improving quality of lifeand preventing end-organ damage. The usual dose is 400mg/kg, given every 3 weeks. Regular preinfusion serumIgG levels are measured and should be maintained withinthe physiological range (usually >8g/L). Patients con-tribute to their own monitoring by completing diary sheets which record their general wellbeing, frequency ofinfections and antibiotic requirement. Patients must beweighed regularly and appropriate increments in ivIg dosemade, because growth (in children) and weight (in adults)often increases significantly after the initial diagnosis andtreatment. Various ivIg preparations differ in their con-tent. Once a patient is established on a particularproduct, it must not be changed without clear clinical indications.

The main potential side-effect of treatment is reactionto the infusions. This may be related to infusion rate, inter-current infection, or anti-IgA antibodies in IgA-deficientpatients. Transmission of viral infection is now a very smallrisk because of careful viral screening and new antiviralsteps in the production of ivIg from pooled donor sera.Recent advances include self-administration of ivIg athome and the development of subcutaneous administra-tion (scIg), which is of particular value in the very young.Although immunoglobulin replacement is the mainstay of

treatment for antibody deficiency, there are other aspectsof therapy. When respiratory infection occurs, patientsshould be treated over an extended period (usually 10days) with high-dose antibiotics, guided by antibiotic sensitivity. Patients should be encouraged to undertakeregular breathing exercises to assist with expectoration ofsputum, and in those with established lung damage pos-tural drainage should be undertaken daily. Regular assess-ment of pulmonary function is advised; however, ‘routine’use of X-ray and CT examination (e.g. at annual review)is not advised in patients with PID. Many of these con-ditions predispose to a range of malignant diseases, and‘non-essential’ exposure to radiation should therefore beavoided.

Common variable immune deficiency (CVID)/acquired hypogammaglobulinaemiaClinical featuresThis condition usually presents in adults with establishedlung disease or recurrent pyogenic infections. It is verytypical for there to be a diagnostic delay of many years,during which respiratory function has deteriorated.Patients with CVID are at increased risk of autoimmunephenomena, including thrombocytopenia, haemolyticanaemia, malabsorption syndromes and organ-specificautoimmune disease. They have a particular tendency togranuloma formation and may present with lym-phadenopathy or hepatosplenomegaly. The finding oftypical granulomata on imaging may be helpful in estab-lishing the diagnosis. These are usually non-caseating andsteroid responsive, but treatment is not necessary if lesionsare asymptomatic.

A further characteristic complication of CVID isnodular lymphoid hyperplasia (NLH), in which lymphoidtissue of the gut becomes hyperplastic and produces char-acteristic filling defects on small bowel radiology series.NLH is thought to be a prelymphomatous condition, butCVID patients without NLH also have an increased riskof malignancy, particularly of lymphoma. CVID preva-lence is estimated as 2–4 : 100000 in the UK, but is proba-bly underdiagnosed. IgG subclass and specific antibodydeficiencies are thought to be related conditions, and somewill progress to more typical CVID.

InvestigationTotal serum IgG level is usually less than 3g/L; the levelsof IgA and IgM are more variable. The diagnosis can there-fore be difficult, and test immunization as described ininvestigation of XLA is required. In CVID the responsesare poor or absent. Measurement of IgG subclasses is notusually helpful. Peripheral blood lymphocyte subset analy-sis may indicate a reduction in the proportion of CD4+ Tcells that also carry the CD45RA antigen. Lymphocyte-proliferative responses may be reduced. Unlike XLA, asingle genetic defect has not been described for CVID, butB cells from these patients do not develop normally intoplasma cells. It is thought that there is an abnormality ofT-cell regulation of B cells in CVID.

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isolated IgA deficiency, in the absence of such defects, is a relatively benign condition.

IgG subclass deficiencyClinical featuresIgG subclass deficiency is regarded as a part of a spectrumof conditions, including CVID and IgA deficiency. Incommon with IgA deficiency, patients may be asympto-matic or give a typical history of recurrent bacterial infec-tion. The simple identification of a slightly reduced level of an IgG subclass is not sufficient in itself to warrant adiagnosis of significant primary immune deficiency.

IgG subclass deficiency is usually suspected when theclinical history is suggestive of antibody deficiency, buttotal IgG (and other immunoglobulin classes) are normaland other primary antibody deficiencies have beenexcluded. Full immunological assessment is essentialbefore treatment decisions are made.

InvestigationIgG subclass development occurs slowly during early child-hood, and it is therefore important to relate results to thecorrect age-related ranges. Total serum immunoglobulinlevels are usually normal, or may be high if there is a compensatory rise in the level of the non-deficient subclass(usually IgG1). On investigation, T-cell numbers and func-tion (measured by in vitro proliferation assays) are usuallynormal. A failure of specific antibody response to testimmunization would support a diagnosis of clinically significant IgG subclass deficiency.

ManagementNot all patients will require ivIg and a careful assessmentof the clinical history and investigative results is required.As discussed under IgA deficiency, several therapeuticstrategies may be introduced and monitored for evidenceof clinical response.

Specific antibody deficiencyClinical featuresThese patients are particularly susceptible to pneumococ-cal infection, but their total serum IgG and IgG subclasslevels are normal. The clinical features are otherwisetypical of other antibody deficiency syndromes, except thatthe diagnostic delay is likely to be longer because of thesubtlety of the defect.

InvestigationThese patients fail to mount a specific antibody responseto polysaccharideantigens (e.g. Pneumovax II) but respondnormally to protein antigen (e.g. tetanus toxoid). By defini-tion, they will have normal total serum immunoglobulinand IgG subclasses.

ManagementAs for IgG subclass deficiency, the appropriate thera-peutic option for each individual patient is based on a combined assessment of the clinical severity of the defectand the investigative results. The typical clinical features

ManagementCVID patients require immunoglobulin replacementtherapy as for XLA, with the possible addition of steroidsfor symptomatic granulomatous disease. CVID patientswho are deficient in IgA should always be prescribed anivIg preparation that is known to be low in IgA in orderto reduce the risk of infusion reactions (see below).

IgA deficiencyClinical featuresIgA deficiency is the most common primary immune defi-ciency in the UK, with a prevalence of approximately 1 :600. Most people with IgA challenge are identified bychance and are asymptomatic. The challenge is therefore to identify those in whom there is a significant immunedeficiency. The history is crucial because IgA deficiency is known to be associated with an increased risk of pulmonary/sinus infections, allergy, celiac disease, otherautoimmune diseases and malignancy. One must thereforelook carefully for any suggestive clinical features in patientspresenting with incidentally identified IgA deficiency.Furthermore, IgA deficiency can be a feature of some combined immune deficiencies (e.g. ataxia–telangectasia(page 93) and Wiskott–Aldrich syndrome (page 92)), andthere may be clinical features suggestive of these diseases;IgA-deficient patients may form anti-IgA antibodies,which create a high risk of transfusion reactions to IgA-containing blood products. If immunoglobulin replace-ment therapy is required, a product containing the lowestpossible concentration of IgA must be used.

InvestigationIgA deficiency is defined by a laboratory measurement ofserum IgA <0.05g/L. The automated methods used in mostroutine laboratories are not sufficiently sensitive to detectthese levels. Therefore, a routine report of ‘low’ level ofserum IgA does not necessarily indicate a diagnosis of IgAdeficiency. Once IgA deficiency is established, however, thepatient must be fully evaluated to determine whether thereis a clinically significant immune deficiency. A number ofthese patients will have associated IgG subclass deficiencyand/or a failure of antibody responses to test immuniza-tion. If a combined immune deficiency syndrome is suspected, more extensive investigations are required (see ataxia–telangectasia (p. 93) and Wiskott–Aldrich syndrome (p. 93)).

ManagementIt is only the minority of IgA-deficient patients who havea significant history of infection, and usually other labora-tory evidence of immune deficiency (IgG subclass defi-ciency, failure of response to test immunization, combinedimmune deficiency syndromes), who require treatment.Options include prolonged high-dose antibiotics for infec-tious episodes, prophylactic antibiotics, and immunoglobu-lin replacement therapy. Very few patients without IgGsubclass deficiency or failure of immunization responsesrequire immunoglobulin replacement, which suggests that

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ersdescribed will usually indicate a requirement for ivIg;however, equivocal responses to immunization do occur insome individuals who do not require specific therapy.

Transient hypogammaglobulinaemia of infancyClinical featuresAs passively acquired maternal immunoglobulin dis-appears and the infant begins to produce its own immu-noglobulin, there is normally a physiological low level of serum antibody levels between 3 and 6 months of life.In some infants this ‘physiological nadir’ is profound, pro-longed, and associated with bacterial infections. There areno other specific features: this is a diagnosis of exclusionand the clinical priority is to ensure that the child does nothave a primary immune deficiency, such as severe com-bined immune deficiency (SCID, p. 93), X-linked agam-maglobulinaemia (XLA, p. 86) or very early-onsetcommon variable immune deficiency (CVID, p. 87).

InvestigationSerum IgG and IgA levels will usually be below the age-related normal ranges, but IgM levels may be normal andisohaemagglutinins should be detectable. Differentiationfrom primary antibody deficiency may be difficult at thisstage, but it is essential that a primary immune deficiencybe excluded. Close clinical and laboratory monitoring ofsuch infants is required for evidence of emerging antibodyproduction. A diagnosis of transient hypogammaglobuli-naemia can only be made retrospectively when antibodylevels have returned to normal and the baby is clinicallywell.

ManagementDecisions regarding treatment depend on the severity ofthe clinical history. If there are only occasional minor infections, no treatment is indicated. If frequent infectionis causing significant morbidity the range of therapeuticoptions for antibody deficiency should be considered. Ifimmunoglobulin replacement is deemed necessary, despitediagnostic uncertainty, it is essential to observe the patientclosely for signs of recovering endogenous antibody pro-duction. This may be detected by a rise in IgM or IgA levelsin preinfusion testing (intravenous immunoglobulin (ivIg)products do not contain IgM or IgA). Planned withdrawalof ivIg is also possible to allow repeat immunologicalassessment, including test immunization. Withdrawal ofivIg must, however, be for a prolonged period beforeimmunization, as the half-life of IgG in the circulation isapproximately 3 weeks.

Immune deficiency with associated hyper-IgMAetiologyThis is a disorder of T-cell function which prevents IgM-producing B cells from differentiating into IgG-producingplasma cells. The molecular lesion is of the T-cell surfaceprotein gp39 (CD40 ligand/CD40L) and the gene is locatedat Xq26–27. The interaction between B cells (expressingCD40) and T cells (expressing CD40L) is crucial in trig-

gering IgM-producing immunoblasts to differentiate intoIgG-secreting plasma cells.

Clinical featuresAs this is an X-linked condition (although autosomalrecessive cases are reported), affected boys present withrecurrent pyogenic infections related to their hypogam-maglobulinaemia and a commonly associated neutropenia.A typical presentation is with Pneumocystis carinii pneu-monia (PCP) in infancy, which is an unusual infection inantibody deficiency and the susceptibility is probablyexplained by an associated underlying T-cell defect. Thereis also increased susceptibility to cryptosporidial infection,with ascending cholangitis and chronic liver impairment.There is an increased incidence of malignancy, particularlylymphoma and a range of autoimmune diseases.

InvestigationSerum levels of IgG are usually less than 3g/L, but IgMlevels may be up to 10g/L (normally <3g/L). Neutropeniais common, but T-cell numbers and response to mitogensare normal. The failure of CD40L expression on stimulatedT-cells in vitro can help confirm the diagnosis, but mutatedforms of the CD40L gene may not be identified withoutmore sophisticated genetic analysis.

ManagementCommencement of ivIg therapy usually results in normal-ization of both serum IgM and neutrophil counts. The particular susceptibility of these patients to PCP is an indication for primary/secondary prophylaxis with oral co-trimoxazole. Allogeneic bone marrow transplantation isthe definitive treatment in childhood. For those (usuallyolder) patients with established chronic liver disease(probably caused by chronic cryptosporidial infection),combined liver and bone marrow transplantation is nowconsidered. Experience to date is too limited to give definitive statements regarding prognosis.

Complement deficienciesThe complement system is represented in Figure 4.1. Theclinical features of deficiency depend on which part of theactivation cascade is interrupted. The major points will bedescribed.

Individual complement component deficiencyClinical featuresIndividual complement component deficiencies are rare,and in most cases are inherited as autosomal recessive conditions. Classic pathway component deficiency (C1, C2and C4) may present with recurrent bacterial infection orwith immune complex-mediated disorders (‘lupus-like syndromes’). C2-deficient patients are especially prone topneumococcal infection. C3 deficiency is very rare; it isassociated with recurrent bacterial infection. Deficienciesof properdin (X-linked) or the terminal pathway compo-nents C5, C6, C7, C8 and C9 are associated with recurrentneisserial (meningococcal or gonococcal) infection. Any

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CASE STUDY 4.1 RECURRENT INFECTIONAn 11-year-old girl was referredbecause of a history of recurrentinfection. She had been fullyimmunized as an infant. At the age of4 years she had recurrent otitis mediaand underwent surgical insertion oftympanic membrane vents(grommets). These had requiredreinsertion the following year. Shewas well until the age of 9 years,when she presented to hospital withchest pain and pyrexia. Left basalpneumonia was diagnosed and shewas treated as an inpatient. Fourmonths later she presented withrecurrent symptoms. Chest X-rayagain confirmed left basalconsolidation. After antibiotictreatment she was discharged andreturned to school. However, herparents noted that she suffered fromfrequent unexplained pyrexias andpersisting chest pain. Her schoolperformance deteriorated, shecomplained of fatigue and withdrewfrom sporting activities. She had nohistory of allergy or family history ofrecurrent infection. Investigations Hb 11.5g/dL, WCC 9.2 ¥ 109/L, IgG4.59g/L, IgA < 0.07g/L, IgM 0.28 g/L.

Further investigation indicatedIgA < 0.05 g/LIgG subclasses: IgG1 4.5g/L (4.5–9.4);

IgG2 0.4g/L (1.6–5.1); IgG3 0.5 g/L(0.3–1.1); IgG4 0.07g/L (0.01–1.2)

Classic complement pathway (CH50):normal

Nitroblue tetrazolium (NBT):normal

Lymphocyte phenotype: CD4+ T-cellnumbers low. CD45RA expressionvery low on CD4 T cells

Immunization responses: failure toincrease specific antibody levelsafter immunization with tetanustoxoid and Pneumovax II

CT scan of chest: no evidence ofstructural lung damage.A diagnosis of common variable

immune deficiency was reached andtreatment commenced withprophylactic ivIg (400mg/kg threetimes weekly) commenced. The girlmade a rapid response, with acessation of her febrile episodes, nofurther chest infections and asignificant improvement in energylevels. Her school performanceimproved and she re-engaged in hercompetitive sporting activities. Herweight correspondingly increased, tothe extent that her ivIg dose had tobe carefully monitored and increasedappropriately. After 9 months onhospital-based therapy she opted fora home treatment programme. Sheand her mother were trained in allaspects of home infusion therapy byan immunology nurse specialist, andhome therapy, under the guidanceand monitoring of the RegionalImmunology Centre, has beensuccessfully established.

DiscussionThe history of recurrent infection inthis case was probably notremarkable up to the age of 9 years.It is common for children to presentwith otitis media, but tympanicmembrane vents are usually indicatedfor chronic secretory otitis media(‘glue ear’). There may therefore be

some doubt as to the exact diagnosisat the age of 4 years. The episode ofpneumonia at the age of 9 years wassignificant, particularly because of therecurrence 4 months after initialtreatment, and the persisting pleuriticpain and recurrent fevers thereafter.It was therefore appropriate toconsider a primary immunedeficiency and the initialinvestigations by the paediatricianwere abnormal. The total serum IgGwas slightly below the age-relatednormal range, and although IgA wasreported as being, ‘low’, the levelquoted was not low enough toconfirm IgA deficiency. Theadditional investigations undertakenat the immunology clinic confirmedthat the total serum IgA was <0.05g/L and IgG2 subclass was low.The measurement of specific antibodyresponse to immunization confirmeda significant defect in antibodyproduction. Tetanus toxoid is aprotein antigen (T dependent),whereas Pneumovax II ispolysaccharide (T independent).Thus, these two antigens test thefunctional integrity of both the T-dependent and the T-independentresponses. A healthy response shouldresult in a minimum fourfold (usuallymuch greater) rise in specificantibody level.

Because there were low levels ofIgG and IgA, low IgG2 and a failureof normal immunization response, thediagnosis was common variableimmune deficiency (CVID). Thelymphocyte phenotype is notdiagnostic, but the relative reductionin CD4 T cells (and the CD45RAsubset in particular) is typical ofCVID. The clinical presentationdescribed is reasonably typical, withthe exception that the diagnosis wasmade before structural lung damagehad occurred. Presentation in thesecond and third decades of life iscommon, but can be at any age.Usually there is a delay of manyyears from the onset of infection to

Questions1. Give two likely explanations

for her recurrent symptoms.2. Do her preliminary

investigations establish adiagnosis?

3. What further generalinvestigations are indicated?

4. What further immunologicalinvestigations are required?

She was referred to animmunology clinic, where the detailsof history were confirmed and furtherinvestigation undertaken. The historywas suggestive of recurrent bacterialinfection and, with the suggestion ofIgA deficiency, an antibody deficiencysyndrome should be considered asthe most likely diagnosis.

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patient presenting with a recurrence of meningococcalinfection should therefore be investigated for complementdeficiency.

InvestigationInvestigation of the complement system is indicated in anypatient with symptoms of recurrent bacterial (especiallyneisserial) infection, ‘lupus-like’ disorders or angioedema.Total C3 and C4 levels are readily measured, but the mostuseful screening tests for deficiency are the assays that test the functional integrity of the classic and alternativepathways (known as CH50 and AP50, respectively). If anabnormality is detected, further characterization is neces-sary to identify the individual component that is defective.

ManagementThis is dependent on the clinical presentation. For patientswith recurrent bacterial infection, prophylactic antibioticsmay be indicated. For those susceptible to pneumococcaland or neisserial infection, immunization with pneumo-coccal capsular polysaccharide and meningococcal vaccinesis often advised. In some cases intramuscular penicillin iskept at home for early treatment of suspected meningo-coccal disease, and it is advisable for patients to wear amedical warning bracelet. For patients with prominentjoint symptoms, further rheumatological assessment maybe advised.

C1-inhibitor deficiencyDefects of the control protein C1-inhibitor (C1-INH) areinherited in an autosomal dominant manner and causehereditary angioedema. There is a failure of the normalregulation of the classic pathway that results in uncon-trolled activation of complement and kinin pathways inresponse to even minor trauma.

Clinical featuresPatients present with recurrent deep tissue swelling following apparently minor trauma (typically dental treatment). This may affect any part of the body, but is ofmost concern when the airway is compromised. Symptomsusually begin in early adolescence, although late presenta-tion is increasingly recognized. An interesting feature is that attacks may begin, or become more severe, aftercommencement of the oral contraceptive pill, hormonereplacement therapy, or during pregnancy.

Although inherited as an autosomal dominant trait,patients may not give a significant family history as approx-

imately 20% of cases are caused by new mutations in the C1-inhibitor gene. As with other immune defici-encies, there is often a period of diagnostic delay duringwhich patients will have suffered symptoms, often of a life-threatening nature. It is typical for children with this condition to suffer recurrent abdominal pain (caused byintestinal wall swelling), rather than swelling at other sites.In one series, 30% of patients had an undiagnosed rela-tive who had died of laryngeal oedema, 34% had had anunnecessary laparotomy and 10% had had endotrachealintubation or tracheotomy prior to diagnosis.

InvestigationDuring an acute attack there is a characteristic pattern ofserum complement levels which is caused by inefficientand excessive activation of the classic complement pathway.Serum C4 and C2 are low but C3 levels are usually normal. This is a very valuable pointer to the diagnosishereditary angioedema, and measurement of C3 and C4 in any patient with angioedema will help differentiatethis from allergic angioedema. In 85% of cases there is a low level of C1-inhibitor level (usually less than 50% of the lower limit of normal) but in 15% of cases the enzymelevel is normal. This latter group have ‘functional C1-inhibitor deficiency’, the enzyme being present but non-functional.

ManagementProphylactic treatment with androgenic steroids (danazol200–400mg daily, stanozolol 2.5–10mg/day – alternate-daydosage may be possible) or antifibrinolytics (tranexamicacid up to 4g/day) is usually effective. Antifibrinolytics arethe preferred alternative for female patients because of theandrogens’ virilizing side-effects. If laryngeal oedemaoccurs (e.g. after dental extraction) it is life-threatening andrequires emergency intravenous administration of C1-INHconcentrate (1000–1500 units i.v). Patients are advised towear a medical warning bracelet. C1-inhibitor concentrateshould also be given prior to surgical procedures, androutine dental work should only be undertaken in hospital,where laryngeal oedema can be dealt with effectively.

Cellular immune deficiencyBecause of the central role of T cells in coordinating theimmune response, isolated T-cell deficiency is rare. The following will first consider those conditions in which the T-cell defect is the major feature, and then those inwhich a combined defect is more prominent.

CASE STUDY 4.1 CONTINUEDdiagnosis, and during this periodstructural lung damage occurs. IvIgtreatment is proven to preventinfection and its complications, and inthis case a specialist immunologyservice established home therapy for

the child. Home therapy isincreasingly seen as a desirableoption for patients with primaryimmune deficiency, as it reduces theneed for hospital visits that interferewith normal school or work activities.

Integrating treatment into family lifealso empowers the patient andemphasizes that these conditions, likemany other medical conditions, canbe prospectively managed, preventingillness and maintaining good health.

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DiGeorge’s syndromeThis is a rare syndrome associated with a developmentalabnormality of the third and fourth pharyngeal pouches.The full syndrome consists of:

• Abnormal facies with low-set ears, ‘fish-shaped’ mouth,hypertelorism, notched ear pinnae, micrognathia and adownward slant of the eyes;�1

• Hypoparathyroidism (often presenting with neonatalhypocalcaemic tetany);

• Congenital heart disease (particularly aortic archdefects: truncus arteriosus, interrupted arch or Fallot’stetralogy);

• Cellular immune deficiency.

Not all of these clinical features are present in every case,and the immune function usually improves with time.DiGeorge’s syndrome is now recognized as one of a groupof related disorders that share a common genetic lesion.This is usually a deletion at 22q11, and the group of con-ditions is referred to as the CATCH 22 syndrome (cardiacanomalies, abnormal facies, thymic hypoplasia, cleft palateand hypocalcaemia). Other clinical syndromes in thisgroup include velocardiofacial syndrome, Kallman’s syn-drome and Schprintzen’s syndrome. Not all the CATCH 22-associated conditions include immune deficiency.

InvestigationDiagnosis is based on the typical morphological features,associated with recurrent viral or fungal infections such asoral and perineal candidiasis and viral pneumonia. ChestX-ray may show an absent thymic shadow with an abnor-mal cardiac outline (Fig. 4.8). It is usual to find a reducednumber of circulating T cells, but the degree of immuno-logical deficiency is variable and is probably only signifi-cant in approximately 20% of cases identified by othercriteria. Lymphocyte proliferation in response to mitogens(PHA and PMA) may be reduced. Antibody deficiency israre. It is now possible to detect the chromosome 22q11lesion by fluorescent in-situ hybridization (FISH). How-ever, as the range of clinical associations with 22q11 lesionsis wide and the degree of immunodeficiency variable, thesimple demonstration of a 22q11 deletion does not neces-sarily imply that there is clinically important immune deficiency.

ManagementAwareness of the features and early recognition of DiGeorge’s syndrome is important, particularly as theseinfants may be subjected to neonatal cardiac surgery.Calcium levels must be monitored and supplemented asnecessary. All blood transfusions must use X-irradiated (25

Gy/unit) blood only, and live immunizations are con-traindicated (MMR, oral polio vaccine). Antibiotic pro-phylaxis to prevent PCP should be considered. In our unitthis is instituted if the absolute CD4 count is below 0.4 ¥109/L or if there is reduced T-cell proliferation to phyto-haemagglutinin (a T-cell mitogen). In cases with severe cel-lular immune deficiency, bone marrow transplantation issuggested. The place of fetal thymus grafting is still exper-imental, although there have been some recent encourag-ing results showing reconstitution of T cells.

Other cellular deficienciesIsolated T-cell deficiencies occur but are very rare. Thediagnostic approach involves recognizing a suggestivehistory and undertaking both quantitative and functionalassessments of lymphocytes.

Chronic mucocutaneous candidiasis (CMC) affects bothmales and females and presents with chronic candidalinfection of skin and mucous membranes.�2 There may bean associated endocrine deficiency which may precede theimmune deficiency, most commonly hypoparathyroidismor Addison’s disease. There are normal T-cell responses tonon-specific mitogens but a specific failure of proliferativeresponse to candida.

NK cell deficiency is also reported; patients have anincreased susceptibility to herpesviruses. Functionalstudies of NK cells are only performed in specialist centres.

Combined immune deficienciesWiskott–Aldrich syndromeClinical featuresThis X-linked disorder presents in young boys with atypical triad of eczema, thrombocytopenia and recurrent

FIG. 4.8 Di George’s syndromeChest X-ray of a one-week-old female infant with hypocalcaemia and Fallot’stetralogy. Note the abnormal enlarged cardiac outline and absent thymic shadowconsistent with her diagnosis of Di George’s syndrome.

Fig. 4.11 Figs 4.2, 4.3, 4.42

Fig. 4.53 Figs 4.6, 4.74

Figs 4.8,4.95 MCQ 4.36

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ersinfection.�3 Immune deficiency may be mild. There is ahigh frequency of malignant lymphoma in the second andthird decades of life, and severe autoimmune vasculitis orglomerulonephritis may occur. If untreated, death fromone of these causes is usual in the second or third decade.

InvestigationPlatelets are small and have abnormal expression ofsurface glycoproteins (CD43 and gpIb). There are defectsaffecting the cytoskeletal proteins, including actin, andassociated defects of T-cell proliferation. The moleculardefect is mutation of the WASP gene at Xp11.22. Charac-teristically there is a failure of response to polysaccharideantigens and progressive lymphopenia.

ManagementThese patients require careful clinical and laboratoryassessment to establish optimum management. Increas-ingly, affected males are offered bone marrow transplan-tation in early childhood in order to reduce the risk oflong-term complications and increase life expectancy.

Ataxia–telangectasia (AT)Clinical featuresThis progressive neurological and immunological disorderpresents in early childhood with neurological manifesta-tions, including cerebellar ataxia, nystagmus and oculomo-tor dyspraxia. Telangiectases are typically seen on theelbows, conjunctivae and ear lobes.�4 There is a progres-sive, combined immune defect that is variable in itsimmunological features. Patients ultimately develop lym-phoid leukaemia/lymphoma in the second and thirddecades and this, combined with progressive combinedimmune deficiency, is the usual cause of death.

InvestigationThe fundamental lesion is defective DNA repair leading to increased radiosensitivity (such as is seen in other disorders, e.g. Bloom’s syndrome, xeroderma pigmentosa,Nijmegen breakage syndrome). Chromosomal breaks,inversions and translocations are commonly seen at the T-cell receptor, and immunoglobulin gene complexes on chromosomes 7 and 14, respectively. The serum a-fetoprotein is often raised. Heterozygotes for the AT genemutations have an increased risk of developing a numberof malignancies (including breast cancer), and familymembers need to be aware of this. Patients with AT grad-ually develop immune deficiency and, after comprehensiveimmunological investigation at diagnosis, this is confirmedand monitored by regular review of the clinical and labo-ratory features.

ManagementCareful, continuing immunological assessment is essentialin these patients, and treatment is dependent on the degreeof immune deficiency. Patients commonly require ivIg bylate childhood. There is no corrective treatment availablefor the underlying chromosomal instability.

Severe combined immune deficiency (SCID)Clinical featuresThis group of conditions has a number of causes but theclinical features are similar in most cases. By definition,both humoral and cellular responses are impaired orabsent. SCID typically presents early (in the first weeks andmonths of life) with a history of failure to thrive (FTT),unexplained diarrhoea, and recurrent bacterial, viral orfungal infection. Unexplained lymphopenia (<2.8 ¥ 109/L)is often present and should always prompt investigation.Total lymphocyte counts may, however, be apparentlynormal in B-cell-positive variants, T-cell activation defi-ciencies and graft-versus-host disease (GVHD). GVHDmay be related to maternofetal transfusion,where normallyfunctioning maternal lymphocytes attack the immunodefi-cient child. If present, GVHD occurs in the first month oflife with jaundice, typical skin rash �5 and diarrhoea. It mayalso occur as a complication of blood transfusion, and alltransfusions to potentially immunodeficient individualsshould be irradiated (25Gy/unit) to eradicate immuno-competent lymphocytes, the potential inducers of GVHD.

InvestigationWhen SCID is suspected, immunological advice should be sought urgently, with regard to both investigation andimmediate management. In general, serum immunoglobu-lins are low and there is a low lymphocyte count, withdiminished proliferative response to mitogens. Lympho-cyte subset analysis is essential and a range of other inves-tigations is needed to exclude SCID. The molecular basisof many variants of SCID is now recognized: each has aparticular pattern of abnormalities and some of the morecommon are summarized in Table 4.6. Molecular charac-terization allows greater precision in diagnosis and carrierdetection.

ManagementEarly diagnosis, prevention of infection and rapid bonemarrow transplantation (BMT) are all crucial to ensureultimate survival. Delay in making the diagnosis allowscomplications to occur (such as disseminated CMV infec-tion), which reduce the chance of survival. BMT can becurative and, in the UK, is currently performed at twosupraregional centres. With increasing characterization ofthe molecular basis of immune deficiency, it is hoped thatgene therapy will become a practical possibility in thisgroup of disorders.�6

Phagocytic disordersPhagocytes may be defective in numbers or function. Table4.7 summarizes the main disorders, the commonest ofwhich are described below.

Chronic granulomatous disease (CGD)Clinical featuresCGD typically presents in childhood with recurrent, deepabscesses caused by catalase-positive organisms (Staphy-

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may not be abnormal in all cases, and more sensitivescreening techniques have been developed. The moleculardefect is a deficiency of the 91kDa chain of cytochrome b(X-linked CGD) or the 22kDa chain of cytochrome b, orof p47 or p67 cytoplasmic factors (autosomal recessiveCGD). These proteins are all involved in the energy-dependent process of intracellular killing. The definitivetest is to demonstrate a failure of neutrophil-mediated bacterial killing.

ManagementAntimicrobial prophylaxis (usually with co-trimoxazole) is the mainstay of therapy. Prophylactic interferon-g (IFN-g) is not useful prophylactically, but may be a useful adjunctto conventional antibiotic and surgical management ofabscesses. Allogeneic bone marrow transplantation, beforethe development of complications of infection, is now thetreatment of choice for CGD if a suitable donor can befound.

Cyclical neutropeniaClinical featuresThis condition, which may present in childhood or adultlife, is characterized by recurrent abscesses, usually occur-ring at intervals of approximately 3 weeks, although theperiodicity can vary greatly. The neutrophil count is typi-cally <1 ¥ 109/L at times of infection, and the diagnosisshould be suspected if there is clear periodicity to the history. Alternatively, the neutrophil count may be incidentally noted as low on a blood count during acuteinfection.

InvestigationNeutrophil counts should be measured on alternate daysfor a 4-week period and carefully analysed for any evi-dence of a cyclical pattern. A cyclical pattern may also bedetected for other elements, including platelets, and otherleukocytes.

lococcus aureus, Aspergillus, Serratia, Nocardia).�1 Pre-sentation may be with osteomyelitis, unexplained granulo-matous lesions, malabsorption or recurrent pneumonia.New cases have been diagnosed in adulthood. Inheritancemay be X-linked or autosomal recessive.

InvestigationThe diagnosis rests on the demonstration of a failure of theneutrophil respiratory burst. The most common screeningtest of neutrophil function is the nitroblue tetrazolium test(NBT) test, in which normal neutrophils reduce the yellowdye formazan into blue intracellular crystals.�2 This test

TABLE 4.6 The major features of some combined immunodeficiency syndromes

Syndrome Major immunological features Molecular defect Inheritance/associated features

X-linked SCID Immunoglobulin low; T cells low, IL-2 receptor g chain (XL)B cells normal/increased

T-B- SCID Immunoglobulin, T and B cells all low Mutation in RAG1/2 genes (AR)Reticular dysgenesis Immunoglobulin, T and B cells all low Stem cell defect (AR): Anaemia, granulocytopenia, thrombocytopeniaAdenosine deaminase Immunoglobulin low. Progressive Accumulation of (AR): Progressive onset, diagnosis may be delayed intodeficiency fall in T and B cell numbers lymphotoxic metabolites childhood: flared ribsX-linked hyper-IgM IgG low, IgM high, T cell numbers normal Mutation in CD40L gene (XL) Neutropenia, thrombocytopenia, haemolytic anaemia,MHC class II Immunoglobulin normal/low, B Mutations in MHC II (AR)deficiency cells normal, reduced CD4+ cells regulator genesTAP-2 deficiency Immunoglobulin normal/low, B TAP-2 gene mutation (AR) MHC class I deficiency

cells normal, reduced CD8+ cells.

(XL), X-linked; (AR), autosomal recessive.

TABLE 4.7 Examples of phagocytic disorders

Inheritance/associated Phagocytic defect Clinical disorder features

Numbers Cyclical neutropaenia (AR) See textAdhesion Leukocyte adhesion (AR) See text

defect (LAD-1)Chemotaxis Schwachmann’s (AR) Anaemia,

syndrome thrombocytopenia, pancreatic insufficiency, chondrodysplasia

Intracellular killing Chronic granulomatous (XL/AR) See textdiseaseG6PD deficiency (XL) AnaemiaIL-12R & IFNgR (AR) Susceptibility to deficiency mycobacteria and

salmonella. See text

Fig. 4.101 Fig. 4.112 Fig. 4.123

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ersManagementThis is dictated by the clinical severity of the condition.Prophylactic antibiotics may be adequate during times of low neutrophil numbers. In more severe cases, treatmentwith granulocyte colony-stimulating factor is considered.

Leukocyte adhesion deficiency (type 1)Clinical featuresThis is typically a disorder of infancy and childhood.Chronic/recurrent skin ulcers and periodontitis are com-mon. There is characteristically little pus formation and anassociated peripheral blood neutrophilia. There is likely tobe a neonatal history of delayed separation of the cord(>10 days).

InvestigationThere is defective expression of the CD18 (b chain) of theadhesion molecules LFA-1, Mac-1 and CR4. The absentexpression is demonstrated on both lymphocytes andphagocytes by flow cytometry. A second variant, LAD-2, isassociated with defective expression of CD15.

ManagementAntibiotics are the mainstay of therapy. Drug choiceshould be guided by antibiotic sensitivities. Prophylactictherapy may be necessary, depending on the frequency ofinfection. Bone marrow transplantation is necessary forseverely affected individuals.

Interferon-g receptor (IFNgR) deficiencyClinical featuresDefects in the IFNgR (and IL-12 receptor) systems haverecently been identified as important susceptibility factorsfor mycobacterial infection. These conditions have beenidentified in both children and adults. They typicallydevelop infection with poorly pathogenic mycobacteria,salmonella, or the live vaccine Bacille Calmette–Guérin(BCG). There are three types of IFNgR defect identified.Complete deficiency determines a phenotype that is char-acterized by severe and fatal susceptibility to either BCGor disseminated non-tuberculous mycobacterial (NTM)infection. Partial IFNgR-1 deficiency is associated with aless severe clinical defect that may allow disseminatedBCG infection with tuberculoid granulomata or clinicaltuberculosis. Both complete and partial IFN-g deficienciesare inherited as autosomal recessive traits. A functionaldefect of the IFNgR has also recently been described which is characterized clinically by susceptibility to non-tuberculous mycobacteria (NTM) and variable granulomaformation.�3 A notable feature of the cases described todate is that a significant number are initially misdiagnosedas suffering from Langerhans’ cell histiocytosis (LCH),because of the association of fevers, lymphadenopathy,granulomatous ulcers and lytic bone lesions. The conditionis caused by a premature stop codon in the intracellularsignalling domain of IFNgR that reduces the mycobacteri-cidal properties of macrophages. Inheritance of this lasttype is ‘dominant negative’. The affected individuals are

heterozygous for the genetic lesion, but this is clinicallyexpressed as a dominant susceptibility. This is in contrastto most autosomal genetic disorders, in which the normalallele dominates, so that heterozygotes only show a minorclinical abnormality. The prevalence of these conditions isnot yet established.

InvestigationCell surface expression of IFNgR and IL-12R is detectedby flow cytometry. Specialist functional assays of lympho-cyte signalling are necessary to confirm and characterizethe defects. Histologically, complete IFNgR deficiency ischaracterized by a failure to form granulomata, whereaspartial deficiency is associated with good granuloma formation.

ManagementOnce the diagnosis is established, appropriate antimyco-bacterial therapy must be commenced. Experience withadjunctive IFN-g treatment in the partial forms is increas-ing and discussion with specialist centres is advised.

SECONDARY IMMUNODEFICIENCY

Secondary immunodeficiency is much more common thanprimary immune deficiency in clinical practice. It mayoccur as a result of systemic disease, including diabetesmellitus, chronic hepatic and renal failure and systemicmalignancy. Autoimmune disorders may be associated with immune deficiency as a consequence of both disease and treatment. Specific infections are also associated with secondary immune deficiency. The best known ofthese is human immunodeficiency virus (HIV), which leads to the acquired immune deficiency syndrome (AIDS; Chapter 11). HIV causes a progressive loss ofCD4+ T cells and thus disrupts both antibody and cellu-lar responses. Several other infections are associated withimmune suppression. Measles predisposes to bacterialinfection partly through its disruption of phagocytic function. Epstein–Barr virus may occasionally causehypogammaglobulinaemia.

Immunosuppressive drugs are widely used in the treat-ment of cancer and autoimmune disease and are an impor-tant cause of secondary immunodeficiency. When usingthese agents it is essential to monitor treatment carefullyand maintain the lowest level of immunosuppression com-patible with effective treatment. Malnutrition, infectionand other iatrogenic causes, including radiotherapy, arealso important causes of secondary immune deficiency. Themechanisms of secondary immunosuppression are usuallymultifactorial: specific intervention is not usually indicated,but susceptibility to infection must be recognized inpatients who are at risk.

Secondary antibody deficiency may occur in lymphopro-liferative disorders such as multiple myeloma and chroniclymphocytic leukaemia, or in protein-losing states such asnephrotic syndrome or intestinal lymphangectasia. In the

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Fig 4.131

the term allergy is used in a more restricted sense todescribe type 1 hypersensitivity reactions. In this section,we will use the Gell and Coombs classification to illustrateand explain the important clinical conditions associatedwith hypersensitivity reactions. In addition to allergy andautoimmunity, the hypersensitivity mechanisms involvedin the response to infectious agents can influence the clinical manifestations of disease. Furthermore, the mani-pulation of the immune response (e.g. in mycobacte-rial disease) offers new possibilities for therapeutic intervention.

Type I hypersentivityType I hypersensitivity reactions (the major mechanism inallergy) are the result of the immune system reacting tootherwise apparently innocuous antigen (allergen). Themechanism involves:

• Formation of IgE antibody specific to the inducingantigen or ‘allergen’;

• Binding of this antibody (via Fc receptors) to mast cellsand basophils;

• Cross-linking of at least two cell-bound IgE molecules;• Degranulation of mast cells, with release of pre-

formed mediators and the generation of late-phase mediators.

Type II hypersentivityType II hypersensitivity involves the reaction of antibodywith cell surface-bound antigen. This reaction then causesdownstream activation of the complement system, andattraction and activation of phagocytes and mast cells.The effect is to focus inflammatory damage at the site of antibody binding or, in the case of receptor-binding antibodies, to modulate the function of the target organ.This mechanism is especially important in organ-specific

lymphoproliferative disorders, where there is a failure ofantibody synthesis, there is often a history of recurrent bac-terial infection, and in these cases ivIg has been demon-strated to be beneficial. Interestingly, in the protein-losingstates, recurrent infection is not usually a significant clini-cal problem, and antibody replacement therapy is theexception rather than the rule.

Splenectomy is an important cause of secondary immunedeficiency. These patients have a lifelong risk of sudden-onset overwhelming sepsis caused by encapsulated organ-isms. This is related to the important role of the spleen inthe immune response to polysaccharide antigens. Patientsin whom splenectomy is planned should be immunizedwith pneumococcal, meningococcal and Haemophilusinfluenzae type b vaccines. Annual flu immunization is recommended, and travel to malarial endemic areas shouldbe avoided if possible. Patient education regarding therisks of splenectomy is very important, and they should be provided with warning cards or bracelets and advisedto take penicillin early if they develop cough and fever.Prophylactic penicillin V (250mg b.d.) should be given for the rest of the patient’s life. Penicillin-allergic individ-uals should take erythromycin (250mg b.d.). Long-termfollow-up is recommended both to monitor the need forrepeat immunization and to reinforce medical advice.There are also a number of inherited syndromes, many of which are rare, associated with secondary immune deficiency.

HYPERSENSITIVITY

IMMUNOLOGICAL MECHANISMS

In contrast to immunodeficiency syndromes, where theimmune system is underactive, clinical disease may result from inappropriate overactivity. Overactivity of theimmune system is referred to as hypersensitivity. Theimmunological mechanisms that cause hypersentivity weredescribed and classified by Gell and Coombs (Table 4.8).Four types of hypersensitivity are described, each involv-ing different immunological components. In some cases thehypersensitive response is directed at a foreign antigen(e.g. reactions to allergens, blood transfusions, transplantedorgans or infectious agents) and in others it is directed at known ‘self-antigens’ (e.g. in autoimmune diseases).Finally, some hypersensitivity reactions appear to bedirected at unknown antigens (e.g. Wegener’s granulo-matosis). The term hypersensitivity applies to all four typesof reaction in the Gell and Coombs classification, whereas

TABLE 4.8 Classification of hypersensitivity reactions (Gell and Coombs classification)

Type of reaction Effector mechanism Clinical disorders

I IgE, mast cells Allergic rhinitis, urticaria, angiodema

II IgG directed at cell Transfusion reactions, acute surface antigens graft rejection, Graves’

disease, myasthenia gravis, Goodpasture’s syndrome

III Immune complexes Cryoglobulinaemia, SLE, post streptococcal glomerulonephritis

IV CD4+ lymphocytes, Delayed type hypersensitivity, contact eczema, granulomatous reactions

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ersautoimmune disease (Graves’ disease, myasthenia gravis,autoimmune haemolytic anaemia, Goodpasture’s syn-drome), but also in blood transfusion reactions and hyperacute graft rejection.

Type III hypersensitivityType III reactions involve the formation of solubleimmune complexes that circulate in the blood and causedamage at many sites. Formation of immune complexes is part of the normal immune response, and these are normally disposed of via the complement and reticuloen-dothelial systems. Complexes remain in the circulation if they are produced persistently or are inadequately disposed of. Such pathological complexes becomedeposited, typically in the renal glomerulus, in joints andthe skin, causing inflammatory reactions at these sites.The experimental model for immune complex disease is serum sickness, in which nephritis, arthritis and rash typically occur 7–10 days after the injection of foreignprotein. The best examples in human disease includechronic infection (e.g. hepatitis, malaria, streptococci),systemic lupus erythematosus (SLE), inhalation of anti-gens (e.g. farmers lung) and cryoglobulinaemia.�1

Type IV hypersensitivityThis is also known as delayed-type hypersensitivity (typeIV hypersensitivity) because in experimental systems signsdevelop 12 or more hours after antigen exposure. Impor-tantly, the major immunological effectors of type IV reac-tions are T cells, instead of antibody, which mediates thereaction in types I–III hypersensitivity.

CLINICAL DISEASE ASSOCIATED WITH HYPERSENSITIVITY REACTIONS

AllergyClinical allergy is becoming increasingly prevalent inwestern societies: it is estimated that up to 20% of the UKpopulation is now affected by allergy. The symptomsdepend mainly on the nature of the allergen and the siteat which mast cell degranulation occurs. The common clin-ical syndromes are of seasonal or perennial rhinitis, aller-gic asthma, urticaria, oral allergy syndrome, angio-oedemaand anaphylactic reactions. The term atopy is used todescribe a genetic susceptibility, expressed in the clinicaltriad of eczema, allergic rhinitis and asthma, which arecommonly associated in many patients.

DiagnosisThe diagnosis of allergy is often thought to be difficult, butin the majority of cases a thorough clinical history com-bined with relatively simple investigations will prove ade-quate. The history is the most important component, and

one looks for typically allergic symptoms occurring con-sistently after exposure to the same agent, and improve-ment of symptoms during periods of avoidance. Wheredoubt remains, further investigation by skin-prick testingand/or the detection of allergen-specific IgE (e.g. byradioallergosorbent test – RAST) is necessary. Skin-pricktesting is preferred, as it is a rapid, cheap and painless formof in vivo challenge. There are, however, limitations to itsuse, as it should only be undertaken by trained individualsin an environment with full resuscitative facilities avail-able. Specific IgE testing using the RAST test has theadvantage of easy accessibility. Although results correlatewell with skin testing for most allergens, they are notdirectly comparable for every allergen. RAST testingshould not be used as a screening test for allergy. Its useshould be guided by careful clinical assessment.

Allergic syndromesRhinitisClinical featuresSeasonal or perennial rhinitis usually presents little diag-nostic difficulty or need for specific investigation. Thesymptoms of a red, itchy, runny nose with associatedswelling and itchy watery eyes are easily recognized. Ahistory of seasonality and/or key triggering factors willusually indicate the offending allergen.

InvestigationThis is required when the provoking allergen is not clearfrom the history, or when another cause is suspected (Table 4.9).

ManagementThe important elements in management are the avoidanceof, or reduction in exposure to, the allergens and the use ofnasal steroid inhalers, with or without oral antihistamines.The latter are particularly useful in young children, whomay find the use of inhalers difficult. For perennial symp-toms caused by house dust mite patients need to be advisedon how to reduce exposure by modifications to floor cov-erings, bedding, and cleaning and laundering procedures.There is increasing evidence that effective control of nasal

TABLE 4.9 Differential diagnosis of rhinitis

Allergic (aeroallergens)Drug induced (decongestant sprays, cocaine, antihypertensive)VasomotorInfectiousIrritantVasculitisHormonal (pregnancy)CSF rhinorrhoea

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Fig. 4.141

and it is essential that once regular therapy is commencedthe dose is periodically reduced or withdrawn to determinewhether continued treatment is necessary.

Food allergyIgE-mediated allergy to food has been described since the1920s but remains a source of controversy. This is proba-bly because there are exaggerated claims made for boththe prevalence and the effects of food allergy, and the diag-nostic tests that are available have not been reliable. Thereis also confusion between food allergy (an IgE-mediatedphenomenon) and food intolerance, which may have many causes. For patients in whom food allergy is sus-pected a double-blind placebo controlled food challenge(DBPCFC) is the only reliable investigation, but this isavailable in only a few specialist centres at present. Self-reporting of food allergy is common. In one large study theself-reported prevalence was 20%, but actual prevalencewas only 1–2% when confirmed by DBPCFC. Food allergyis often invoked as a potential cause for complex multi-system disorders or obscure symptoms. This is unlikely tobe the case, and in the absence of clear evidence of allergypatients should be encourage to eat a normal diet.

IgE-mediated food allergy may cause symptoms includ-ing urticaria, angioedema, rhinitis, asthma, oral allergy syn-drome, anaphylactic reactions and some gastrointestinalsymptoms (chiefly acute vomiting and/or diarrhoea).Common food allergens include milk, eggs and seafood.Affected children typically become tolerant to these foodsby mid–late childhood. Currently, the most important foodallergy is to peanut – a relatively unknown condition untilthe late 1980s, the prevalence of which has increased con-siderably. Among the UK preschool population it is nowestimated to be as high as 1 :50–100. Nut allergy is differ-ent in many important respects from other food allergies:

allergy in asthmatic patients can improve their overallairway disease. Desensitization is returning to clinical practice for grass and house dust mite allergy, but only specialist units should undertake it.

Urticaria/angioedemaClinical featuresUrticarial lesions are raised red itchy weals (often describedas ‘like nettle stings’) caused by epidermal mast cell activa-tion. Angioedema is non-itchy, non-dependent swellingwhich occurs in the deep dermis. Activation of the kininsystem is important in causing angioedema. It is commonfor both symptoms to occur in the same patient. However,when angioedema occurs in the absence of urticaria,hereditary or acquired deficiencies of C1-esterase inhibitor(C1-INH) should be considered. A number of specific trig-gers for both urticaria and angioedema may be identified(Table 4.10), but in the majority (89–90%) of cases referredto clinics no specific allergic cause is identified. If symptomspersist for more than 6 weeks, this is defined as chronic idiopathic urticaria/angioedema. The natural history isquite variable, with many patients experiencing prolongedremissions between relapses.

InvestigationA thorough clinical history is essential to determine thepattern of symptoms and any associated trigger factors.Screening tests for allergy are not recommended; however,the wide variety of disorders associated with combinedurticaria/angioedema (Table 4.10) may justify furtherinvestigation, including thyroid function tests, full bloodcount, CRP and complement levels. Skin biopsy is helpfulin confirming urticaria pigmentosa and urticarial vasculitis.

ManagementIf an associated medical condition is identified (e.g.hypothyroidism, infection), the urticaria should respond tomanagement of that disorder. In other patients, if attacksare only infrequent oral short-acting antihistamines (e.g.acrivastine 8mg t.i.d.) will be adequate. In most cases,however, daily non-sedating antihistamines are necessary(e.g. fexofenadine, loratadine and cetirizine). If necessary asedating antihistamine can be added at night (e.g. hydrox-izine hydrochloride). Experience with oral disodium chro-moglycate has been disappointing, with the possibleexception of urticaria pigmentosa, in which it has an impor-tant role in management. H2 antagonists (cimetidine andranitidine) are often tried for refractory cases, as is doxepin(an antidepressant with potent antihistamine effects).Urticarial vasculitis often responds to NSAID therapy. Therelapsing, remitting nature of urticaria makes it difficult tobe certain of the efficacy of some of these interventions,

TABLE 4.10 Causes of urticaria/angioedema

IdiopathicAllergic (foods, drugs, hymenoptera venom, contact)Physical (pressure, heat, solar, aquagenic, vibratory)Cold induced (autosomal dominant, cryoprotein)Cholinergic (exercise or heat induced)Adrenergic (stress induced)Vasculitis (hypocomplementaemic urticarial vasculitis)Autoimmune (SLE, antibodies to IgE/FceR1/C1q)Infection (hepatitis B, Helicobacter pylori, EBV, Lyme’s disease, cutaneous larvamigrans, larva currens)Insect bites (papular urticaria)Drug induced (aspirin, ACE inhibitors, opiates, muscle relaxants, andradiocontrast media)HypothyroidismUrticaria pigmentosaSystemic mastocytosisAngiodema/deafness, urticaria (Muckle–Wells syndrome)Malignancy

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ers• It appears to develop in very young children.• Reactions characteristically cause angioedema, often

affecting the larynx, with airway restriction.• Anaphylactic reactions may result from exposure to

even trace amounts of nut.• Indirect exposure may cause life-threatening reactions

in highly sensitive individuals.• Nut allergy appears to be a lifelong problem in the

majority of cases.

Nut allergy is a major challenge facing the medical pro-fession and others who look after children. Success-ful management requires the complete avoidance of allnut-containing foods, and teaching family, friends andschool staff the symptoms and signs of allergic reactions.An emergency medication kit should be available whichincludes both oral antihistamines and injectable adrenaline(epinephrine) (for life-threatening reactions), and patientsare encouraged to wear a medical warning bracelet. Nutallergy has now overtaken bee/wasp sting allergy as themost common cause of anaphylactic reactions occurringoutside hospital.

Development of autoimmunityThe occurrence of hypersensitivity reactions directedagainst self-antigens implies a breakdown in the body’snormal tolerance mechanisms. A number of factors areimplicated in the development of autoimmune reactions,including infection, drugs and chemical exposure and HLAtype. The influence of the hormonal state is undoubted andis exemplified by the increased autoreactivity seen inwomen and the effect of hormonal change (pregnancy andlactation, hormone replacement therapy) on the clinicalmanifestations of disease. Several cellular and molecularmechanisms are recognized as contributing to autoreac-tivity. These include ‘cross-reactivity’, where a pathogen is sufficiently similar to self-antigen that it induces anautoimmune response, e.g. group A b-haemolytic strepto-coccus cross-reacts with cardiac muscle, causing acuterheumatic fever: ‘Molecular mimicry’, wherein a shortgenetic sequence of a pathogen is identical to a self-antigen, has long been postulated as a mechanism forautoimmunity. Mathematical modelling, however, suggeststhat molecular mimicry is likely to be so common as to bethe rule rather than the exception, and thus unlikely to beimportant in disease aetiology. ‘Provision of foreign T-cellepitopes’ implies that foreign antigens containing T-cellepitopes bind to host proteins and stimulate an auto-immune response. This may be one of the mechanismsthrough which drug and chemical exposure causes autoim-mune reactions. The important HLA disease associationshave been summarized in Table 4.3. It should be remem-bered that T cells learn to differentiate self from non-selfantigens during their maturation in the thymus; thus theoccurrence of autoreactive antibodies or lymphocytes represents a breakdown in the normal mechanisms of self-tolerance. One of the crucial mechanisms for eradicationof self-reactive T cells is through programmed cell death

or apoptosis. Patients deficient in the Fas antigen, an essential signalling molecule in normal apoptosis, developcharacteristic clinical features dominated by lymphopro-liferation and autoimmunity,�1 emphasizing the impor-tance of central (thymic) deletion of autoreactive cells.

Autoimmune diseases: classification and diagnosisHuman autoimmune diseases are classified according towhether predominantly a single organ is affected (organspecific) or whether there is multiple organ involvement(non-organ specific). As with any classification system,some conditions fall between these two extremes. Table4.11 lists some common autoimmune diseases in these two categories.

Autoantibody detection is frequently requested in theinvestigation of suspected autoimmune disease. Autoanti-bodies may be primary and directly cause disease (e.g.antiglomerular basement membrane antibodies in Good-pasture’s syndrome, antiacetylcholine receptor antibodies in myasthenia gravis and anti-TSH receptor antibodies inGraves’ disease), but more commonly they are secondaryand are formed as part of the disease process itself (e.g.antinuclear, anti-dsDNA, antismooth muscle, antimito-chondrial antibodies). Detection of a secondary autoanti-body does not necessarily indicate that the patient has an autoimmune disease. ‘False positive’ autoantibodies areassociated with, for example, infection, female gender,increased age and surgical procedures. Determining thesignificance of autoantibody results requires careful clini-cal assessment. It is also important to know the exactpattern of autoantibody detected, its titre (or strength) and

TABLE 4.11 Autoimmune diseases and their associated autoantibodies

Disease Autoantibodies directed against

Hashimoto’s disease Thyroid peroxidaseGraves’ disease TSH receptorPernicious anaemia Intrinsic factor

Gastric parietal cellsAddison’s disease Steroid-secreting cells of adrenal cortexType 1 diabetes mellitus Islet cellChronic active hepatitis Smooth muscleMyasthenia gravis Acetylcholine receptorLambert–Eaton myasthenic Voltage-gated calcium channelsyndromePemphigus DesmosomesGoodpasture’s syndrome Basement membraneSjögren’s syndrome Nuclear antigens (Ro/La)Primary biliary cirrhosis MitochondriaSystemic lupus erythematosus Nuclear antigens (ds DNA, Ro/La, Sm)(SLE) PhospholipidRheumatoid arthritis IgG (rheumatoid factor-IgM class)

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CASE STUDY 4.2 ACUTE ONSET OF SWELLINGA 15-year-old girl presented to herlocal accident and emergencydepartment with an acute onset ofswelling that affected her face. Hereyes were closed, she had swelling ofthe lips, but neither tongue swellingnor difficulty in breathing (Case Fig.4.2.1). She reported eating achocolate bar that contained peanuts4 hours earlier, and a provisionaldiagnosis of nut allergy was made.She was immediately treated with i.v.chlorpheniramine andhydrocortisone. Adrenaline was notadministered but she was admittedfor observation and remained inhospital for 4 days, until hersymptoms had completely resolved.She was discharged home with anadrenaline (epinephrine) self-administration kit and told to readthe package insert to explain its use.

had eczematous patches at her rightwrist, marked dermographism, andrespiratory examination confirmedscattered inspiratory wheeze.Investigations indicated: total IgE 731 kU/L, specific IgE to house dustmite (strongly positive), grass pollen(moderately positive), peanut(negative). Autoantibody screennegative, rheumatoid factor negative,C3 1.38g/L (0.7–1.7), C4 < 0.1g/L(0.13–0.43), CRP 1.5mg/L (<6 mg/L).

Further investigationThe disparity between the low C4and normal C3 levels promptedmeasurement of C1-esterase inhibitorlevels. These were normal (C1-esterase inhibitor 0.52 g/L (0.28–0.5));however, functional assessment ofC1-esterase inhibitor activity was 0%(70–140), indicating a functionallydefective molecule and confirming adiagnosis of C1 inhibitor deficiency(type II).

DiscussionThis case demonstrates an importantdifferential diagnosis that must beconsidered in anyone presenting withangioedema. Although the commoncauses of urticaria/angioedema are aslisted in Table 4.10, C1-esteraseinhibitor deficiency (C1-INHdeficiency) typically causesangioedema but not urticaria. Thispresentation is typical in a number ofrespects of the experience with C1-INH-deficient patients. She wassymptomatic as a child, with somehand swelling and prominentabdominal pain. In her case this wasdiagnosed as abdominal migraine, butthe more likely cause was C1-INHdeficiency-related abdominal pain,which is thought to be caused byangioedema affecting the bowel wall. The development of facialswelling as a teenager is also typical.Attacks commonly become morefrequent and severe after puberty(and during pregnancy), theexplanation for this being the relativechanges in hormonal balanceaffecting C1-inhibitor synthesis fromthe normal allele.

Interestingly, however, the patientdid have an atopic background witheczema and asthma, as well as ahistory of nickel sensitivity. Onexamination she also haddermographism. Thus she wasdemonstrating conditionscharacterized by types 1 and 4hypersensitivity reactions, and thisundoubtedly contributed to the initial

Questions1. How common is peanut

allergy in the UK?2. Was her presentation typical

of nut allergy?3. If she did have peanut allergy,

was her treatment optimal?

Questions4. How does this further history

affect the differentialdiagnosis?

5. Do the investigations rule outnut allergy?

6. What other condition(s)should be considered?

7. Do any of these havesignificantly differenttherapeutic implications?

CASE FIG. 4.2.1 Facial angioedema that ispreventing the patient from opening her eyesor speaking

Further historyHer GP referred her for furtherinvestigation as he felt that she mighthave more than just nut allergy. Adetailed history revealed that she hadsuffered recurrent swelling of herhands since the age of 4 years. Shealso had been investigated forintermittent abdominal pain andpainful knees. She had eczemaaffecting her face and wrists, mildasthma and hay fever. She hadpreviously had positive skin-pricktests to house dust mite and dog andcat dander. She was unable to wearcheap jewellery as this caused a rash.On examination she was obese, she

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erswhether it is of the IgG or the IgM isotype. For example,a significant antinuclear antibody (ANA) would be of hightitre (>1 :80) and IgG class. If the ANA pattern was nothomogeneous (e.g. speckled or nucleolar) this might indi-cate specific subsets of connective tissue disorders (mixedconnective tissue disease, systemic lupus erythematosus,scleroderma). Once an antinuclear antibody is detected,specialist immunology laboratories will further character-ize it according to which nuclear antigen is targeted (Table4.11). Again, this is helpful in the subcategorization of con-nective tissue disorders and the recognition of susceptibil-ity to specific complications (e.g. anti-Ro antibodies andneonatal congenital heart block).

Diseases associated with type IVhypersensitivityContact eczemaThe most common clinical example is nickel hypersensi-tivity. Affected individuals develop an eczematous reactionto nickel-containing jewellery, watches, buttons etc. thatare in prolonged contact with the skin. The reaction isusually confined to the area of contact. Although some-times referred to as ‘nickel allergy’, IgE mechanisms arenot involved in the pathogenesis of this condition. Nickelis absorbed directly through the skin and binds to self-proteins(haptenization).Thisstimulates CD4+T cells, whichare recruited to the area, and there is associated oedemaof the epidermis. This reaction occurs over 24–48 hours andis artificially recreated during ‘patch testing’, which iswidely used to investigate type IV hypersensitivity.

Granulomatous hypersensitivityGranulomatous reactions represent the full developmentof type IV hypersensitivity reactions, in which antigen persists and a focus of inflammation is established. Thetuberculin reaction is a modified, self-limiting form whichoccurs, for example, with the Mantoux and Lepromin tests.

These involve the intradermal injection of M. tuberculosisand M. leprae extracts. The local skin reaction is charac-terized by an area of induration and swelling which ismediated by sensitized lymphocytes. CD4+ lymphocytespredominate and accumulate, along with macrophagesaround blood vessels, with a maximum infiltration at about48 hours. This reaction is focused at the site of foreignantigen in the dermis and is self-limiting, as antigen is progressively degraded and removed.

Where antigen persists, however, granulomatous fea-tures can develop. Granulomas are collections ofmacrophages, some of which form giant cells; othersappear as epithelioid cells. A cuff of small lymphocytes surrounds these. Granulomas may develop in response toforeign antigen (Mycobacterium infections) or as part of a presumed autoimmune response (Wegener’s granulo-matosis, sarcoidosis or CVID). The clinical effects of gran-ulomas depend on the underlying cause, and the number,size and location of the lesions. They may cause signi-ficant destruction and morbidity,e.g.TB in the lungs, or theymay be an incidental finding, e.g. in CVID in the liver.In mycobacterial infection it is recognized that theimmunoregulatory Th1/Th2 response influences the degreeof granuloma formation and indeed the individual’s clinical manifestation of infection. If the response is pre-dominantly of the Th1 phenotype, with activated T cellsproducing IFN-g and IL-2, there is marked granuloma formation and, in the case of leprosy, the clinical pattern is tuberculoid. Tuberculoid leprosy is characterized clini-cally by localized granulomatous lesions which may beasymptomatic and which contain few viable organisms.In lepromatous leprosy there are widespread skin lesionscontaining numerous bacilli but few lymphocytes. Thesepatients have a predominant Th2 phenotypic response tothe organism (Th2 cells secrete IL-4, IL-5 and IL-10) andno clear granuloma formation. Consequently, M. leprae areable to proliferate and disseminate more freely in lepro-matous leprosy, and the patient suffers the systemic effects

CASE STUDY 4.2 CONTINUEDclinical diagnosis in the A&Edepartment of probable allergicangioedema. The importance of thecomplement investigations inangioedema cannot be overestimated.C1-INH deficiency, cryoglobulinaemiaor genetic deficiency of C4 usuallyexplains the finding of very low C4despite normal C3. Thusmeasurement of complement levels isan extremely useful investigation, anda normal C4 during an attack ofangioedema virtually excludes thediagnosis of C1-INH deficiency.

The treatment of acute life-threatening angioedema in thiscondition is very different from thatrequired for allergic angioedema.Life-threatening attacks commonlyoccur after dental work thatprecipitates laryngeal angioedemaand respiratory obstruction.Emergency treatment consists of1000–1500 units C1-INH concentrateintravenously, with close clinicalobservation in hospital. Prophylactictherapy is also considered forpatients with frequent attacks. In this

case the patient was commenced oncyclokapron 500 mg q.i.d., inpreference to androgenic steroids,because of the potential virilizingeffects of the latter. She was alsoprovided with a warning bracelet that gave details both of herdiagnosis and the necessary treatmentin case of an emergency. Familystudies confirmed that her biologicalparents were not affected and thatthis was one of the significantminority of cases caused by a newmutation.

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plantation and autoimmunity enabled reductions in thedoses of corticosteroids required (in this situation they areoften referred to as ‘steroid-sparing agents’). The majorcomplication of long-term use is myelosuppression andimmunosuppression, and a long-term increase in suscepti-bility to malignancies.

AzathioprineAzathioprine is an analogue of the cytotoxic drug 6-mercaptopurine (both are thiopurines) and was originallyintroduced in the 1950s for renal transplant recipients.It now has a major use as a steroid-sparing agent in themanagement of many autoimmune disorders. Thiopurinesblock the synthesis of inosinic acid, the precursor ofadenylic and guanylic acids, and thus impair DNA synthe-sis. Their major cytotoxic effect is on developing T and NKcells, and thus there is a delay before clinical onset ofaction. The most important side-effect is bone marrow suppression. Weekly monitoring of full blood count (FBC)is advised during induction, with 3-monthly FBC duringmaintenance therapy. The patient must be warned ofpotential susceptibility to infection, and any unexplainedillness or clinical suggestion of infection requires thoroughinvestigation and, potentially, withdrawal of treatment. Theusual maintenance dose range is 1–3mg/kg daily.�2

CyclophosphamideThis is one of the most widely used drugs in cancerchemotherapy and is now frequently used in combinationwith corticosteroids in the management of severe autoim-mune conditions, especially systemic vasculitis. As an alky-lating agent it acts by cross-linking DNA strands, therebypreventing normal mitosis. It is particularly toxic to B cells. Side-effects include a dose-dependent neutropeniaand lymphopenia, alopecia and infertility (especially inmales) and, infrequently, haemorrhagic cystitis. Cyclophos-phamide is typically used in combination with pred-nisolone in either oral or intravenous protocols to controlsevere systemic vasculitis. Dosage is determined by diseaseseverity and according to renal function, bone marrowfunction and the patient’s age.

Mycophenolate mofetilMycophenolate mofetil is used in combination with corti-costeroids and ciclosporin in the prophylaxis of renal trans-plant rejection. Mycophenolic acid (MPA) is the activemetabolite and is rapidly produced by hydrolysis afteringestion of the drug. MPA selectively inhibits inosinemonophosphate dehydrogenase (IMPDH), which preventslymphocyte purine biosynthesis. The inhibition of IMPDHcauses a depletion of guanine nucleotides, inhibition ofDNA synthesis, and prevents clonal expansion of both T and B cells. Close monitoring is necessary with weeklyfull blood counts (FBC) for the first month of treatment,2-weekly for the next month, and monthly for the first year of treatment. Its use is currently limited to specialisttransplantation units.

of the infection. Host response in the form of hypersen-sitivity may therefore be advantageous under certain circumstances, and modification of the response by theadministration of exogenous cytokines (e.g. interferon-g)can change the pattern of disease.�1

IMMUNOSUPPRESSION

The rapid development of organ transplantation has beendependent on the availability of effective immunosuppres-sant drugs. An ideal immunosuppressant would be antigenspecific and free of side-effects, but none of the currentlyavailable drugs meets these criteria. The clinical use andrelative merits of the major immunosuppressant drugs areoutlined below, as are some newly emerging immunomod-ulatory strategies.

CorticosteroidsThese drugs have been widely used in the treatment ofautoimmune diseases, malignancy and graft rejection formany years. The immunosuppressant action is difficult to separate from other potent anti-inflammatory actions of steroids. In humans it is mediated mainly through aninhibitory action on monocytes and macrophages, withreduced phagocytic function and diminished IL-1 secre-tion. Although in animals there is a marked lymphocyto-toxic effect, in humans this is only significant againstabnormal lymphocytes, for example in lymphoprolifera-tive disorders, and when used at very high doses. Corticos-teroids are potent immunosuppressants but their majordisadvantage is multiple side-effects; these include weightgain, hirsutism, hypertension, diabetes mellitus, recurrentinfection, growth retardation, osteoporosis, and reducedresponse to physiological stress.

The appropriate dose of corticosteroid is determined bythe individual clinical situation. For the long-term controlof autoimmune disorders an oral dose of <10mg/day prednisolone would be appropriate. In the acute manage-ment of autoimmune haemolytic anaemia, acute glo-merulonephritis or immune thrombocytopenic purpura,1–2mg/kg/day is indicated. In very severe life-threateningsituations, such as systemic vasculitis, pulsed high-dose regimens of 10mg/kg are used (maximum 1000mg).

CYTOTOXIC DRUGS (see Chapter 6)

This group of drugs kills cells capable of self-replicationand they were initially introduced in the treatment ofcancer. Their introduction into the management of trans-

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ersMethotrexateThis drug is used in maintenance treatment of childhoodleukaemias and is increasingly used in the control of anumber of inflammatory diseases, including rheumatoidarthritis, polymyositis, psoriasis, Reiter’s syndrome andgraft-versus-host disease following bone marrow trans-plantation. It also appears to have a role in steroid-dependent asthma, although the exact mode of action inthis condition is unclear. Methotrexate inhibits dihydrofo-late reductase, thus preventing the conversion of folic acidto its active form, tetrahydrofolate. This prevents normalthymidine synthesis and cell division. Side-effects includebone marrow suppression, megaloblastic anaemia, pneu-monitis and mucositis. Long-term drug toxicity is increasedin hepatic impairment. Acute side-effects are partiallyreversible by the administration of folinic acid.

NON-CYTOTOXIC IMMUNOSUPPRESSION

CiclosporinThis relatively recently introduced drug has revolutionizedthe management of post-transplantation patients and isalso finding a place in the management of some auto-immune disorders. A fungal metabolite with a cyclic unde-capeptide structure, it acts to selectively inhibit T-cell activation. The drug binds to cytosolic proteins, calledcyclophilins, which prevent calcium-dependent activationof the IL-2 gene. IL-2 transcription is a crucial event in T-cell activation and thus cyclosporine is a relatively selective immunosuppressant.

Ciclosporin does not cause myelotoxicity but does causea dose-dependent reduction in renal function that must becarefully monitored and differentiated from renal trans-plant failure or rejection. Monitoring of therapeuticplasma levels is essential. Other side-effects include hir-sutism, gingival hyperplasia and seizures. In common withother immunosuppressants there is an increased long-termrisk of lymphoma and skin neoplasia.

Tacrolimus (FK506)This macrolide is not chemically related to ciclosporin buthas a similar mode of action. Its use is currently limited tohepatic and renal transplant patients, although there is evidence to suggest it will have significant clinical impactin autoimmunity. Tacrolimus binds to the cytosolic FK506-binding protein (FKBP), preventing IL-2 gene activation.It has a similar range of side-effects to ciclosporin.�3

NEWER IMMUNOSUPPRESSIVESTRATEGIES

In addition to the pharmacological immunosuppressivedrugs, a number of new immunological therapies areemerging in clinical practice.

Plasma exchange has been available for many years andcontinues to be of value in the acute management of somesevere autoimmune conditions, including Goodpasture’ssyndrome, myasthenia gravis and rhesus disease, in whichautoantibodies are demonstrated to be pathogenic. Plasmaexchange allows the removal of these autoantibodiesacutely but has no proven role in the long-term manage-ment of these conditions.

High-dose ivIg therapy (1–2g/kg) is of proven benefit in autoimmune thrombocytopenia and Kawasaki’s and Guillain–Barré syndromes. Its mode of action is incom-pletely understood, but may involve blockade of Fc recep-tors, disturbance of anti-idiotypic networks, or suppressionof macrophage and/or T-cell activation. This therapy hasspecific side-effects, including aseptic meningitis, acutehaemolysis (when ivIg is uncross-matched) and acute deterioration in renal function. It should therefore only beused for conditions in which clinical benefit is proven byproperly controlled studies.

Monoclonal antibody (moAb) therapy has shownencouraging results in a number of areas of clinical prac-tice. CAMPATH-1 is a humanized mouse anti-CDw52moAb, an antigen which is present on all leukocytes. It hasproved to be of particular value in the treatment of acutegraft rejection and graft-versus-host disease followingbone marrow transplantation. More specifically, anti-CD25moAb (basiliximab), which prevents T-cell activation, hasbeen introduced for the prophylaxis of acute renal rejec-tion. Antitumour necrosis factor (anti-TNF) moAb hasrecently shown promising results in the control of disablingrheumatoid arthritis (RA) and in severe inflammatorybowel disease, especially Crohn’s disease. TNF is believedto have a central role in the pathogenesis of these diseases.

Future clinical developments in this area may followfrom current preclinical studies. ‘Biological immuno-suppressive agents’, including antibodies directed againstcell surface molecules of T, B and antigen-presenting cells,are being studied in models of transplantation and auto-immunity. These models may indicate new modalities for controlling undesirable immune responses throughmodulation of the function of the cell surface signallingmolecules. Antibodies directed against gp39 (CD40 ligand)and CD28 have been demonstrated to overcome renalallograft rejection in a primate system. Human clinicaltrials (phases I and II) of these agents are currently underway. Anti-LFA-1 moAb has also been used to controltransplant rejection. The cell surface molecule CTLA-4,which is known to downregulate T-cell responses, also hasthe potential for therapeutic manipulation. CTLA-4 linkedto immunoglobulin molecules (to prolong its half-life inthe circulation) has been successfully used in clinical trialsto treat psoriasis. In respiratory medicine, IL-8 receptorantagonists are being evaluated in airway disease, and anti-IL-5 moAb is under investigation in the treatment ofasthma. These experiences of ‘biological immunosuppres-sion’ suggest that this will be a major area of therapeuticdevelopment in the coming years, with novel drug devel-

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Janeway C A, Travers P 1997 Immunobiology – the immune systemin health and disease, 3rd edn. Churchill Livingstone,Edinburgh.

Primary immunodeficiency diseases. Report of an IUIS scientificgroup. 1999. Clinical and Experimental Immunology 118 (suppl 1):1–28.

Reeves W G, Todd I 1996 Lecture notes on immunology, 3rd edn.Blackwell Science, Oxford.

Rosen F S, Cooper M D, Wedgewood R J P 1995 The primaryimmunodeficiencies. New England Journal of Medicine333(7):431–440.

Stites D P, Terr A I, Parslow T G 1997 Medical immunology, 9thedn. Appleton and Lange, Connecticut.

opment for a wide range of disorders associated with inappropriate or excessive immune activation.

FURTHER READING

Chapel H M 1994 Consensus on diagnosis and management ofprimary antibody deficiencies. British Medical Journal308:581–585.

Chapel H, Heaney M, Misbah S, Snowden N 1999 Essentials ofclinical immunology, 4th edn. Blackwell Science, Oxford.

Conley M E, Notarangelo L D, Etzioni A 1999 Diagnostic criteriafor primary immunodeficiencies. Clinical Immunology93(3):190–197.

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