disease of immunity

DISEASES OF IMMUNITY

ROBERTO D. PADUA JR., MD, DPSPDEPARTMENT OF PATHOLOGY

FATIMA COLLEGE OF MEDICINE

The immune system protects the host from invasion by foreign and potentially harmful agents.

Characteristics:1. distinguish self from non-self2. discriminate among potential invaders

(specificity)3. maintain the presence of immune memory

(anamnesis)4. recall previous exposures and mount an

amplified response to them

☻Immune responses can be elicited by a wide range of agents (termed antigens) including microorganisms, chemicals, toxins, drugs, and transplanted tissues

☻Adaptive immunity – immune responses that show antigen specificity and immune memory

☻Innate immunity – does not demonstrate immune memory and lacks the exacting specificity of adaptive immunity

Mechanisms involved in Innate and Adaptive immunity

Innate and Adaptive Immunity

Innate Immunity• Natural or native immunity• Defense mechanisms present even before infection• First line of defense• Components

• Epithelial barriers• Phagocytic cells (PMN’s and Macrophages)• Dendritic cells• NK cells• Several plasma proteins, including the Complement system


Innate Immunity

Two most important cellular reactions

1. Inflammation

phagocytic leukocytes are

recruited and activated to kill microbes

2. Anti-viral defense

mediated by dendritic cells and NK cells

Innate and Adaptive ImmunityInnate Immunity

Pathogen-associated molecular patterns*Microbial structures recognized by leukocytes and epithelial cells

Danger-associated molecular patterns*Molecules released by injured and necrotic cells that are recognized by leukocytes *Pattern recognition receptorsToll-like receptors (TLR’s)


Toll-like Receptors (TLR’s) homologous to the Drosophila protein specific for components of different bacteria

and viruses located on the cell surface and in endosomes

*Recognize and initiate cellular responses

Different TLRs involved in response to different microbial products

Innate Immunity

Epithelia (skin, respiratory, GIT)

provide mechanical barriers to the entry of

microbes

produce anti-microbial molecules = defensins

Innate Immunity

Monocytes and Neutrophils

phagocytes in the blood recruited at the site of infection

monocytes that enter the tissues and mature are called macrophages

Innate Immunity

Dendritic cells

produce type I interferons, anti-viral

cytokines that inhibit viral infection and

replication

Natural killer cells

provide early protection against many viruses

and intracellular bacteria

Innate ImmunityComplement proteins

* activated by binding to microbes using the

alternative and lectin pathways

Innate Immunity

Mannose-binding lectin and C-reactive protein

* coat microbes for phagocytosis and complement activation

Lung surfactant

* protection against inhaled microbes

Adaptive Immunity

consists of lymphocytes and their products, including antibodies

Adaptive Immunity

Cell-mediated (cellular) immunity responsible for defense against intracellular microbes

mediated by T (Thymus-derived) lymphocytes

Humoral immunity protects against extracellular microbes and their toxins

mediated by B (Bone-marrow derived) lymphocytes

and their secreted products antibodies

T Lymphocytes• Generated from immature precursors in the thymus• Mature, naïve T cells enters the circulation, constituting

60-70% of lymphocytes• Found in the paracortical areas of LN and periarteriolar

sheaths of spleen• Each T cell is genetically programmed to recognize a

specific cell-bound antigen by means of an antigen-specific T cell receptor (TCR)

B lymphocytes• Develop from immature precursors in the bone marrow• Mature B cells constitute 10-20% of the circulating

peripheral lymphocytes• Also seen in the LN (superficial cortex), spleen (white

pulp), tonsils, and extralymphatic organs (e.g. GIT)• Recognizes antigen via the B-cell antigen receptor

complex• Has unique antigen specificity derived partly from

somatic rearrangements of immunoglobulin gene

Cytokines

☻ Short-acting soluble mediators

☻ Includes lymphokines, monokines and other polypeptides that regulate immunologic, inflammatory, and reparative host responses

☻ Molecularly defined cytokines - Interleukins

Cytokines

1. Mediate innate (natural) immunity♣ IL-1, TNF, type 1 IFN, IL-6

♣ IL-12 and IFN-γ (innate and adaptive immunity)

2. Regulate lymphocyte growth, activation and differentiation

♣ IL-2, IL-4, IL-12, IL-15 and TGF-B

Cytokines3. Activate inflammatory cells

♣ IFN-γ – macrophages♣ IL-5 – eosinophils♣ TNF and TNF-Β – PMN’s and endothelial cells

4. Affect leukocyte movement (Chemokines)♣ C-C and C-X-C chemokines

5. Stimulate hematopoiesis♣ derived from lymphocytes or stromal cells♣ colony-stimulating factors

CytokinesGeneral Properties

☺produced by different cell types☺pleiotropic actions☺induce effects in 3 ways

1. act on the same cell that produces them (autocrine effect)

2. affect other cells in the vicinity (paracrine effect)3. affect many cells systematically (endocrine effect)

☺mediate their effects by binding to specific high-affinity receptors on their target cells

SUBSETS OF T HELPER CELLS IN RESPONSE TO STIMULI (MAINLY CYTOKINES)

Histocompatibility Molecules☼ Important for the induction and regulation of the immune

response☼ Principal physiologic function is to bind peptide fragments of

foreign proteins for presentation to antigen-specific T cells☼ Encoding genes are found in chromosome 6

MHC or HLA complex☼ Class I and Class II genes encode cell surface glycoproteins

involved in antigen presentation☼ Class III genes encode components of the complement

system

Histocompatibility MoleculesCategories:

1. Class I MHC molecules► expressed on all nucleated cells and platelets► encoded by 3 closely linked loci – HLA-A,

Hla-B, and HLA-C► heterodimer molecules – polymorphic α linked

noncovalently to nonpolymorphic peptide β-2 microglobulin

► CD8 T cells

Histocompatibility Molecules

Categories:

2. Class II MHC molecules

► coded in the HLA-D region (HLA-DP, HLA-DQ, and HLA-DR)

► heterodimer, noncovalently binded α and β chains

► CD4 T cells

Histocompatibility Molecules

HLA and Disease Association

► mechanisms not fully understood

► grouped into the following categories

◘ Inflammatory diseases

◘ Inherited errors of metabolism

◘ Autoimmune disorders

HLA and Disease Association

Disease HLA Allele Relative Risk

Ankylosing spondylitis B27 90

Post-gonococcal arthritis B27 14

Acute anterior uveitis B27 14

Rheumatoid arthritis DR4 4

Chronic active hepatitis DR3 13

Primary Sjogren syndrome DR3 9

Type I diabetes DR3

DR4

DR3/DR4

5

6

20

21-Hydroxylase deficiency BW47 15.0

Disorders of the Immune System

╬ Hypersensitivity reactions

╬ Autoimmune diseases

╬ Immunologic deficiency syndromes

╬ Amyloidosis

Hypersensitivity Reactionsand Tissue injury

۩ Hypersensitivity is a misnomer

۩ These diseases result from normal immune responses

۩ Not Excessive or ‘Hyper’ responses

۩ Classification based on Immunologic Mechanisms

General features of hypersensitivity disorders

~ Both exogenous and endogenous antigens may elicit hypersensitivity reactions

~ The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes

~ Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses

۩ Results in tissue injury or other pathophysiological changes

۩ Occurs when an already sensitized individual is re-exposed to the same foreign substance

۩ May be immediate or delayed

Hypersensitivity Reactions and Tissue Injury

Ensuing tissue injury may be caused by:۩ Release of vasoactive substances۩ Phagocytosis or lysis of cells۩ Activation of inflammatory & cytolytic components of complement system۩ Release of cytokines, proteolytic enzymes and other mediators of tissue injury or inflammation

Hypersensitivity Reactions and Tissue Injury

Immediate (Type I) Hypersensitivity

• A rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen

• The reaction is called an allergy, and the antigen that cause them are termed allergen

• Most are mediated by IgE antibody-dependent activation of mast cells and other leukocytes


~ Anaphylactic type• Occurs within minutes• IgE mediated• Provoked by re-exposure to the same antigen (by

contact, inhalation, ingestion, or injection)• Mediated by antigen binding with antibody previously

bound to mast cells or basophils• Local or systemic


LOCAL ANAPHYLAXIS

♠ Atopy genetically determined predisposition to develop localized anaphylactic reactions to inhaled or ingested allergens

♠ positive family history chromosome 5q31

♠ With higher serum IgE levels compared to general population


Two Phase Reaction♠ Initial response is rapid - 5-30 min after exposure to

antigen (subsides in 60 minutes)◘ Vasodilatation, edema, smooth muscle spasm

♠ Late phase response - 2-8 hrs later◘ Occurs in 50% of patients◘ Infiltration by monocytes, eosinophils, basophils, PMN’s and CD4 T cells◘ With mucosal epithelial damage

Kinetics of the immediate and late-phase reactions

Type I Hypersensitivity

♠ Mast cells in tissues; Basophils circulate

♠ Both contain granules with Inflammatory Mediators

♠ Activated by cross-linking to IgE Fc receptors

Vasodilatation, increased vascular permeability

Smooth muscle spasm

Cellular infiltration


Primary Mediators♠ Preformed and stored in granules

♠ Histamine

♠ Chemotactic factors for eosinophils and PMN’s

♠ Proteases


Secondary Mediators♠ Lipid Mediators

◘ Platelet Activating Factor◘ Arachidonic Acid

☻ Leukotrienes and Prostaglandin

♠ Cytokines◘ TNF-alpha◘ Interleukins 1, 4, 5, 6


۞ Is the result of release of ‘a variety of chemotactic, vasoactive and spasmogenic compounds’


CLINICAL MANIFESTATIONS

♠ Systemic Disorder

♠ Local Reaction


SYSTEMIC ANAPHYLAXIS♠ characterized by vascular shock, widespread

edema, and difficulty in breathing ♠ Hospital setting = Antisera, hormones, enzymes,

polysaccharides, and drugs (penicillin)♠ Community setting = food allergies, insect toxins

♠ Itching, hives, skin erythema within minutes respiratory difficulty or GIT symptoms

♠ Shock and Death can occur within minutes


LOCAL REACTIONS

♠ Affects 10-20% of the population

♠ Skin or Mucosal Surfaces◘ Urticaria (Hives)

♠ Skin and food allergies

♠ Hay fever

♠Atopy - familial predisposition to allergy

Immediate (Type I) HypersensitivityWhat good is it?

☻ Fights Worm infection

☻ EEEEWWWWWW!!!!

IgE and parasites: IgE binds to parasite, then Eosinophil binds

Degranulation!

schistosoma ova

eosinophils

Antibody-Mediated (Type II) Hypersensitivity

♥ Mediated by antibodies directed toward antigens present on the cell surfaces or extracellular matrix

♥ IgG and IgM

♥ Antigenic determinants – intrinsic or exogenous


MECHANISMS:♥ Opsonization and Complement-and Fc Receptor-

Mediated Phagocytosis Cells targeted by antibodies are coated (opsonized) with molecules that make them attractive for phagocytes Activates the complement system producing C3b and C4b deposited on the surface of the cells and recognized by phagocytes (Fc receptors)

Results to the phagocytosis of the opsonized cells and their destruction Complement activation formation of MAC disrupts membrane integrity osmotic lysis of cells

Type II Hypersensitivity Reaction – Opsonization and Complement-and Fc-Receptor Mediated Phagocytosis

Antibody-Mediated (Type II)Hypersensitivity

*Antibody-dependent cellular cytotoxicity (ADCC) does not involve fixation of complement,

requires cooperation of leukocytes

Coated cells with low concentrations of IgG antibody are killed by a variety of effector cells (monocytes, PMNs, eosinophils, and NK cells) bind to the target by their receptors to the Fc fragment of IgG cell lysis without phagocytosis

MECHANISMS:

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Source: Robbins PATHOLOGIC BASIS OF DISEASE 6th ed.

Antibody-Mediated (Type II)Hypersensitivity

• Clinical Conditions1. Transfusion reaction

- cells from an incompatible donor react with and are opsonized by preformed antibody in the host

2. Erythroblastosis fetalis- there is an antigenic difference b/w the mother and the fetus, and antibodies

(IgG) from the mother cross the placenta and cause destruction of RBCs3. Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia

- individuals produce antibodies to their own blood cells which are then destroyed

4. Certain drug reactions- antibodies are produced that reacts with the drug, which may be attached to

the surface of RBCs or other cells

Pathogenic functions of auto-antibodies

------------------------------------------------------------ type II hypersensitivity response- ex: RBC autoantibodies ==> hemolysis

------------------------------------------------------------

C’


♥ Complement-and Fc Receptor-Mediated Inflammation

antibodies deposited in extracellular tissues (basement membrane and matrix activate complement (C5a, C4a, and C3a) recruits PMNs and monocytes release injurious substances (enzymes and reactive O2 intermediates inflammation

Antibody-Mediated (Type II) Hypersensitivity – Complement-and Fc Receptor-Mediated Inflammation


♥ Antibody-Mediated Cellular Dysfunction

Antibodies directed against cell-surface receptors impair or dysregulate function without causing cell injury or inflammation

Antibody-Mediated (Type II) Hypersensitivity – Antibody-Mediated Cellular Dysfunction

An example of type II hypersensitivity

Pathogenic functions of auto-antibodies

------------------------------------------------------------ type II hypersensitivity response- ex: GBM autoantibodies ==> glomerulonephritis Goodpasture’s syndrome

GBM Podocytes

Immune Complex-Mediated (Type III) Hypersensitivity

☻Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition

Immune Complex-Mediated (Type III) Hypersensitivity

♦ Antigen - Antibody Complexes initiate acute inflammation◘ Complement activation and accumulation of PMN’s

♦ Endogenous Antigens – DNA◘ circulating Ag’s present in the blood, or, more commonly, antigenic components of one’s own cells and tissues

♦ Exogenous Antigens - Bacteria, Viruses, Foreign protein, etc.♦ Immune Complexes form in circulation or♦ Antigens are ‘planted’ and IC’s form in situ♦ Can be generalized or localized

Pathogenesis of immune-complex disease

Systemic Immune Complex Disease

Prototype disorder – Acute serum sicknessFrequent sequela to the administration of large amounts

of foreign serum (e.g. horse immune serum for passive immunization)

Pathogenesis (3 phases)

1. formation of Ag-Ab complexes

2. deposition of immune complexes

3. inflammatory reaction at the site of deposition


Two mechanisms causing inflammation at the site of deposition

1. activation of the complement cascade

2. activation of neutrophils and macrophages through their Fc receptors release of pro-inflammatory substances

(prostaglandins, vasodilator peptides, chemotactic substances, lysosomal enzymes, oxygen free radicals)


***Chronic form of serum sickness results from repeated or prolonged exposure to an antigen

***Continous antigenemia is necessary for the development of chronic immune complex disease because complexes in antigen excess are the ones deposited in vascular beds – e.g. SLE


Morphology acute necrotizing vasculitis, with necrosis of vessel wall and intense neutrophilic infiltration

fibrinoid necrosis – smudgy, eosinophilic deposit that obscures the underlying cellular detail affected glomeruli are hypercellular because of swelling and proliferation of endothelial and mesangial cells, accompanied by neutrophilic and monocytic infiltration IF microscopy – granular lumpy deposits of Ig and Complement Electron microscopy – electron-dense deposits along GBM


◘ Tissues affected☼ Kidneys, joints, skin, heart, serosal

surfaces and small vessels

◘ The reason(s) for this specific organ/tissue predeliction is unknown

Vasculitis

Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink “fibrinoid” material.

Fig 5-13 IF

Fig 5-12 EM

Local Immune Complex Disease

♦ LOCAL (ARTHUS REACTION)◘ Localized tissue necrosis from acute

immune vasculitis◘ Can induce experimentally by injecting

antigen into the skin of a pre-sensitized recipient

◘ Local PMN recruitment and fibrinoid necrosis thrombi formation local

ischemic injury

T Cell-Mediated (Type IV) Hypersensitivity

♣ T-Cells are the active agents not Antibodies

☼ Otherwise Type II is very similar to Type IV

♣ Delayed-Type

mediated by CD4+ T cells

♣ Direct Cell Cytotoxicity

mediated by CD8+ T cells

Mechanisms of Delayed Type Hypersensitivity Reactions

Mechanism of Direct T Cell Cytotoxicity

Type IV HypersensitivityDelayed Type

♣ Tuberculin Skin Test (Mantoux Reaction)

♣ Granuloma Formation• Nodular aggregate of Epithelioid Macrophages

surrounded by a rim of lymphocytes• Multinucleated Giant Cells may be present

♣ Persistent organisms that are poorly degraded (tuberculosis)

Type IV Hypersensitivity Delayed Type

♣ “The Type of inflammation characteristic of this Reaction is called Granulomatous Inflammation”

♣ The key cell is the epithelioid macrophage NOT the Giant Cell!!

Formation of granuloma in Type IV Hypersensitivity

GranulomasLow Power

High Power

Langhan’s Giant Cell Picture

Robbins Textbook of Pathology 1971

Type IV - Cell Mediated Delayed Hypersensitivity

♣ TB antigen processing by macrophages • presentation to CD4 T cells sensitized CD4 cells

that remain in the circulation• Re-exposure activation, amplification and

recruitment of Macrophages which cause the majority of tissue damage

• IL-2 and IFN-gamma are the most important cytokines

Type IV - Cell Mediated Delayed Type

♣ Major defense against Tuberculosis & Fungi

Type IV - Cell Mediated Delayed Type

♣ Major defense against Tuberculosis & Fungi

♣ Patients with AIDS have little defense against these organisms due to the extreme decline in CD4 cells

Type IV - T-cell Mediated Cytotoxicity

♣ Sensitized T cell directly kill cells

♣ Major role in Transplant Rejection

♣ Protects against Viral Infections

Type IV - T-cell Mediated Cytotoxicity

♣ CD8 or Cytotoxic T Lymphocytes are the effector cells◘ Lyse target cells

– Perforin release leads to osmotic lysis

– Fas binding leads to apoptosis

◘ Release cytokines e.g. interferon gamma

Key Facts on Hypersensitivity Reactions

~ Type I : IgE/mast cell-mediated liberation of histamine. Local and systemic anaphylaxis.

~ Type II: antibodies bind to cell surface. Damage by complement activation or cellular cytotoxicity, or

may stimulate/block a receptor~ Type III: antigen-antibody complexes, either local or

circulating. Cause damage by activating complement in tissues at site of

trapping of complexes.~ Type IV: T-cell mediated: CD4 cells recruit macrophages; CD8

cells cause cytotoxicity

TRANSPLANT REJECTION

Transplant Rejection

~ Factors enhancing graft survival• ABO blood group compatibility between recipients

and donors• Absence of pre-formed anti-HLA cytotoxic antibodies

in recipients– People must have previous exposure to blood products to

develop HLA cytotoxic antibodies

• Close matches of HLA-A, -B, and –D loci between recipients and donors

Transplant Rejection~ Type of grafts

• Autograft (i.e., self to self)– Associated with the best survival rate

• Syngenetic graft (isograft)– Between identical twins

• Allograft– Between genetically different individuals of the same species

• Xenograft– Between two species

– Example = transplant of heart valve from pig to human


◙ Involves recognition of major histocompatibility antigens (HLA)• The most important HLA presenting cells are the

donor lymphocytes, especially dendritic cells, contained within the graft

• Mediated by: CD8+ & CD4+ T cells


◙ T cells• Lyse graft cells• Attract and activate macrophages• Increase vascular permeability with local

accumulation of lymphocytes and macrophages

Hyperacute Transplant Rejection

◙ Preformed anti-donor antibodies are present• Hx of previous Transplant• Multiparous women• Previous blood transfusions

◙ Circulating antibodies react with the graft

Hyperacute Rejection

~ Pathogenesis• ABO incompatibility or action of preformed anti-HLA

antibodies in the recipient directed against donor antigens in vascular endothelium

• Type II hypersensitivity reaction

Hyperacute Transplant Rejection

◙ Complement fixes, PMN’s arrive

◙ Graft destroyed in MINUTES to hours

◙ This no longer occurs• Much better graft screening

Morphology of Rejection Hyper-acute Rejection

۩۩۩ Widespread arteritis, thrombosis of vessels, and ischemic necrosis

Normal Kidney

~ Microthrombi~ PMN’s

Hyperacute Rejection

Antibody- mediated damage to the blood vessel in a renal allograft. The blood vessel is markedly thickened and the lumen is obstructed by proliferating fibroblast and foamy macrophages.

Acute Rejection

~ Most common transplant rejection~ Reversible reaction that occurs within days to

weeks1) Type IV cell-mediated hypersensitivity

– CD4 T cells release cytokines, resulting in activation of host macrophages, proliferation of CD8 T cells destruction of donor graft cell

– Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury

Acute Rejection

2) Antibody-mediated Type II hypersensitivity reaction

- Cytokines from CD4 T cells promote B-cell

differentiation into plasma cells anti-HLA antibodies attack vessels in the donor graft

- Vasculitis with intravascular thrombosis in recent grafts

- Intimal thickening with obliteration of vessel lumens in older grafts

Acute Rejection

***Acute rejection is potentially reversible with immunosuppressive agents such as cyclosporine (blocks CD4 T-cell release of IL-2), OKT3 (monoclonal antibody against T-cell antigen recognition site and corticosteroids (lymphotoxic)***Immunosuppressive therapy is associated with an

increased risk of cervical squamous cancer, malignant lymphoma, and skin squamous cell carcinoma (most common)

Morphology of Acute Rejection

۞ Onset usually 7-10 days

۞ Detected by slight rise in serum creatinine

۞ Mononuclear cell tubulo-interstitial infiltrate with tubular injury and interstitial edema

۞ Vasculitis is very uncommon

Acute cellular rejection of a renal allograft

R – Intense mononuclear cell infiltrate between the glomerulus and the tubules

L – Tubules undergoing destruction by invading lymphocytes

Chronic Rejection۞ Irreversible reactions that occurs over months to

years۞ Involves continued vascular injury with

ischemia to tissues۞ Dominant histological features

• arterial and arteriolar intimal thickening• thick glomerular capillary walls• tubular atrophy• interstitial fibrosis

۞ Cause is unclear۞ Therapy is ineffective

Schematic representation that lead to the destruction of histo-incompatible grafts

Transplantation of Other Solid Organs

• In heart and liver transplants, unlike kidney transplantation, no effort is made to match HLA antigens in donor and hosts

• This is due to size compatibility requirements &

• The time a liver/heart remains viable is low

Allogeneic Hematopoietic Cell Transplant

Bone Marrow Transplants

~ Graft - versus - host disease and transplant rejection can occur

~ Rejection is mediated by T cells and NK cells

Bone Marrow Transplants Graft - Versus - Host Disease

~ Causes• Potential complication in bone marrow

transplant

• Potential complication in blood transfusions given to patients with a T-cell immunodeficiency and newborns


~ Pathogenesis• Donor T-cells recognize host tissue as foreign and

activate host CD4 and CD8 T cells

~ Clinical Findings• Bile duct necrosis (jaundice)

• Gastrointestinal mucosa ulceration (bloody diarrhea)

• Dermatitis


~ Donor marrow cells recognize host as “Foreign”

~ The host is “rejected”~ Three principal targets:

• Liver• Skin• GI tract

TYPE OF TRANSPLANT

COMMENTS

Cornea Best allograft survival rate

Danger of transmission of C-J disease

Kidney Better survival with kidney from living donor than from cadaver

Bone marrow Graft contains pluripotential cells that repopulate host stem cells

Host assumes donor ABO group

Danger of graft-versus-host reaction and CMV infection

SOME TYPES OF TRANSPLANTS

AUTOIMMUNE DISEASES

Introduction

~ Autoimmunity- immune reaction against “self-antigens” Tissue damage

~ Single organ or multi-system diseases

~ More than 1 auto-antibody in a given disease may occur

~ Common in females

Autoimmunity

~ Three Requirements1. The presence of an immune reaction specific for some

self-antigen or self-tissue

2. Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance

3. The absence of another well-defined cause of the disease

Autoimmunity

~ Clinical manifestations• Variable

Organ-specific disease immune responses are directed against a single organ or tissue

Systemic or generalized diseaseAutoimmune reactions are against widespread antigens

*** Results from loss of self-tolerance

Immune-mediated Inflammatory Disease

~ Diseases mediated by antibodies and immune complexes• Organ-specific autoimmune diseases

• Autoimmune Hemolytic anemia

• Autoimmune thrombocytopenia

• Myastenia gravis

• Graves disease

• Goodpasture syndrome

• Systemic autoimmune diseases• Systemic Lupus Erythematosus (SLE)

• Diseases caused by autoimmunity or by reactions to microbial antigens• Polyarteritis nodosa

Immune-mediated Inflammatory Disease

~ Diseases mediated by T cells• Organ-specific autoimmune diseases

• Type I Diabetes mellitus• Multiple sclerosis

• Systemic autoimmune diseases• Rheumatoid arthritis*• Systemic sclerosis*• Sjogren syndrome*

• Diseases caused by autoimmunity or by reactions to microbial antigens• Inflammatory bowel disease (Crohn disease, Ulcerative colitis)• Inflammatory myopathies

*Antibodies may also play a role in these diseases

Immunological Tolerance~ It is the phenomenon of unresponsiveness to an antigen

as a result of exposure to lymphocytes to that antigen~ Self-tolerance lack of responsiveness to an

individual’s own antigen » Underlies our ability to live in harmony with our cells and

tissues

» Lymphocytes with receptors capable of recognizing self-antigens are being generated constantly eliminated or inactivated as soon as they recognize the antigens

» Mechanisms : Central tolerance and Peripheral tolerance

CENTRAL TOLERANCE

• Negative selection or deletion of self-reactive T and B lymphocytes during their maturation in the central lymphoid organs

T cells

• T lymphocytes that bear high-affinity receptors for self-antigens are negatively selected or deleted undergo apoptosis

• AIRE (autoimmune regulator) – a protein that stimulates expression of some “peripheral tissue-restricted” self-antigens in thymus critical for deletion of immature T cells specific for these antigens

• occur during fetal development

CENTRAL TOLERANCE

B cells

• Also undergo negative selection or deletion

• Receptor Editing – when developing B cells strongly recognize self antigens in the BM reactivate the machinery of antigen receptor gene rearrangement express new antigen receptors not specific for self-antigens

• Failure self-reactive cells undergo apoptosis purging dangerous lymphocytes from the

mature pool

• Occurs throughout life

PERIPHERAL TOLERANCE

• Self-reactive T cells that escape

intra-thymic negative selection are

deleted or muzzled in the peripheral

tissues


Silence potentially autoreactive T and B cells in peripheral tissues

Best defined for T cells

Mechanisms:

1. Anergy

2. Suppression by regulatory T cells

3. Deletion by activation-induced cell death


Anergy

Prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens

T cells – due to absence of co-stimulatory molecules on APCs, such as B7-1 & B7-2

B cells – due to lack of T cell help for antibody synthesis (T cell anergy or down-regulation of surface IgM)

PERIPHERAL TOLERANCESuppression by regulatory T cells

Regulatory T cells plays a major role in preventing immune reactions against self-antigens

CD4 T cells is the best defined regulatory T cells that expresses CD25, the alpha chain of the IL-2 receptor, and a transcription factor of the forkhead family (Foxp3)

***both are required for the development and maintenance of functional CD4+ regulatory

T cells

Mutations in Fox3p result in severe autoimmunity

***cause of autoimmune disease called IPEX (immune dysregulation, polyendocrinopathy,

enteropathy, X-linked)

PERIPHERAL TOLERANCEDeletion by activation-induced cell death

CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis

two mechanisms

1. Expression of a pro-apoptotic member of the Bcl family (Bim), without anti-apoptotic

members of the family, Bcl-2 and Bcl-x

unopposed Bim triggers apoptosis by the mitochondrial pathway

2. Involves the Fas-Fas ligand system

engagement of Fas by FasL induces apoptosis of activated T cells by the

death receptor pathway

MECHANISMS OF IMMUNOLOGICAL TOLERANCE

Mechanism of Autoimmunity

~ Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes

~ These genetic and environmental influences conspire to create an imbalance between control mechanisms that normally function to prevent self-reactivity and pathways that lead to activation of pathogenic effector lymphocytes

Pathogenesis of Autoimmunity

Mechanism of AutoimmunityROLE OF SUSCEPTIBILITY GENES

• Most autoimmune diseases are complex multigenic disorders• HLA genes – affects the negative selection of T cells in the thymus

or the development of regulatory T cells• Non-MHC genes

• PTPN-22 = most frequently implicated in autoimmunity; encodes for the protein tyrosine phosphatase

• NOD-2 = cytoplasmic sensor of microbes; associated with Crohn disease

• Genes encoding the IL-2 receptor (CD25) and IL-7 receptor alpha chain

= control the maintenance of regulatory T cells

Mechanisms of AutoimmunityROLE OF INFECTIONS

• Infections may up-regulate the expression of costimulators on APCs• Results in breakdown of anergy and activation of T cells specific

for the self-antigens• Molecular mimicry

• Microbes may express antigens that have the same amino acid sequences as self-antigens

• Immune responses against the microbial antigens may result in activation of self-reactive lymphocytes

• RHD – antibodies against streptococcal proteins cross-react with myocardial proteins

• Polyclonal B-cell activation• Some viral infections may result in production of autoantibodies• EBV and HIV

POSTULATED ROLE OF INFECTIONS IN AUTOIMMUNITY

Mechanisms of Autoimmunity

RELEASE OF SEQUESTERD ANTIGENS Some antigens are hidden (sequestered) from the

immune system, because the tissues in which antigens are located do not communicate with the blood and lymph.

self-antigens in these tissues do not induce tolerance but fail to elicit immune responses and are essentially ignored by the immune system

Immune-privileged sites – testis, eye, and brain Trauma to these sitesrelease antigenstissue inflammation and

injury

General Features of Autoimmune Diseases

~ Once induced it tends to be progressive, sometimes with sporadic relapses and remissions, and the damage becomes inexorable• Epitope Spreading

• Infections and initial autoimmune response damage tissues, release self antigens and exposed epitopes of the antigens that are normally concealed from the immune system continuing activation of lymphocytes

~ The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response

~ Different autoimmune diseases show substancial clinical, pathologic, and serologic overlaps

Systemic Lupus Erythematosus (SLE)

~ Etiology: Unknown~ Pathogenesis: Failure to maintain self-tolerance due to

polyclonal autoantibodies~ Multisystem: Skin, kidneys, serosal surfaces, joints, CNS

& heart~ Incidence: 1:2500 more common in black Americans;

10X F > M; 2nd- 3rd decades

SLE: Predisposing Factors

~ Genetic factors• 30% concordance in monozygotic twins• Associated w/ HLA-DR 2 & 3 loci

~ Non-genetic factors• Drugs (procainamide, isoniazid, d- penicillamine &

hydralazine) LE like s/s• Androgens protect, estrogens enhance• UV light may trigger

SLE

~ Immunologic factors• B-cell hyper-reactivity caused by excess T-helper

activity• How self-tolerance is lost is not known

MODEL FOR THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Revised Criteria for Classification of SLE

~ Malar rash~ Discoid rash~ Photosensitivity (Photodermatitis)~ Oral ulcers~ Arthritis~ Serositis- Pleuritis; Pericarditis~ Renal disorder

• Persistent proteinuria > 0.5 gms/ day or > 3+ if quantitation not performed, or;

• Cellular casts- red cell, hemoglobin, granular, tubular, or mixed


~ Neurologic disorder- Seizures; Psychosis~ Hematologic disorder

• Hemolytic A with reticulocytosis• PANCYTOPENIA

~ Immunologic disorder: • (+) LE cell prep; • (+) Anti- dsDNA • (+) Anti-Sm• (+) Antiphospholipid antibodies

– Anticardiolipin antibodies– (+) lupus anticoagulant– False-positive serologic test for syphilis

~ ANA

CLINICAL MANIFESTATIONS OF SLE

100

80-90

85

55-85

80-100

60

50-70

25-35

45

35

25

20

15-40

15

15

8th Edition

Multisystem manifestations of Systemic Lupus Erythematosus. SLE affects a wide range of tissues and organ systems

DISCOID RASH


~ Any 4 or more of the 11 criteria present, serially or simultaneously, during any interval of observation = SLE

~ In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE

SLE

~ Antinuclear antibodies• Antibodies to DNA (Classic SLE)• Antibodies to histones (Drug induced SLE)• Antibodies to non- histone proteins bound to RNA• Antibodies to nucleolar antigens

~ ANA test is sensitive, but non specific

SLE

~ Mechanisms of tissue injury• Type III hypersensitivity reactions with DNA-anti-

DNA complexes depositing in vessels

~ LE cell - any phagocytic leukocyte (neutrophil or macrophage) that engulfs denatured nuclei of injured cells (evidence of cell injury and exposed nuclei)

SLE: Morphology

~ BV: Acute necrotizing vasculitis of small arteries or arterioles in any organs

~ Skin: Erythematous maculopapular eruption over malar regions exacerbated by sun-exposure; some

patients have discoid LE with no systemic involvement

» Liquefactive degeneration of basal layer» Interface dermatitis w/ superficial & deep

perivascular lymphocytic infiltrates w/ deposits of immunoglobulins along DEJ

SLE involving the skin.

A. An H & E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema of the dermo-epidermal junction

B. An IF micrograph stained for IgG reveals deposits of Ig along the dermo-epidermal junction

SLE

~ Serosa: Pericardial & pleural serosanguinous exudate

~ Heart: Nonbacterial verrucous endocarditis (Libman-Sacks) multiple warty deposits on any valve

on either surface of leaflets

Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows.

SLE~ Joint: No striking anatomic changes nor deformities, non-

specific lymphocytic infiltrates~ Spleen: Splenomegaly, capsular thickening, and follicular

hyperplasia~ Lungs: Pleuritis and pleural effusions~ CNS: Multifocal cerebral infarcts from microvascular

injury~ Other Organs and Tissues: LE or hematoxylin bodiesnin

the bone marrow or other organs. Lymph nodes may be enlarged with hyperplastic follicles or even demonstrate necrotizing lymphadenitis

Lupus nephritis, focal proliferative type. There are two focal necrotizing lesions in the glomerulus (arrows)

Lupus nephritis, diffuse proliferative type. There is marked increase in cellularity throughout the glomrulus

Immune complex deposition in SLE. IF micrograph of a glomrulus stained with anti-IgG from a patient with diffuse proliferative lupus nephritis.

Immune complex deposition in SLE. Electron micrograph of a renal glomerular capillary loop showing subendothelial dense deposits corresponding to “wire loops” seen by light microscopy. Deposits are also seen in the mesangium.

Lupus nephritis. A glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes.

Rheumatic Fever

~ Etiology: Group A, streptococcal pharyngitis

~ Pathogenesis: antibody cross-react with connective tissue in susceptible individuals Autoimmune reaction (2- 3 wks) Inflammation (T cells, macrophages) Heart, skin, brain & joints

Morphology:

~ Acute RF • Acute Inflammatory Phase

• Heart– Pancarditis

• Skin– Erythema Marginatum

• CNS– Sydenham Chorea

• Migratory polyarthritis

~ Chronic RF• Deforming fibrotic valvular disease

Acute Rheumatic vegetations:

Fish-mouth Mitral stenosis

Rheumatoid Arthritis: Etiology

~ HLA- DR4/ DR1 associated (increased incidence)

~ Incidence: 1% of population; 4th & 5th decades; 3 - 5X F > M

~ 80% of patients with Rheumatoid Factors (Abs against Fc portion of IgG)

Rheumatoid Arthritis: Pathogenesis

~ Precise trigger is unknown~ Activation of T-helper cells cytokines

activate B cells Abs Non-suppurative proliferative synovitis (destruction of articular cartilage & progressive disabling arthritis)

~ Extra-articular manifestations resemble SLE or scleroderma

Multisystem manifestations of Rheumatoid arthritis. Although the initial manifestation is usually arthritis, Rheumatoid disease is a systemic illness.

Rheumatoid Arthritis: Clinical course

~ Symmetrical, polyarticular arthritis~ Weakness, fever, malaise may accompany joint

symptoms~ Stiffness of joints in AM early claw-like deformities~ Anemia of chronic disease present in late cases~ Severely crippling in 15-20 years, life expectancy

reduced 4-10 years~ Amyloidosis develops in 5%-10% of patients

Rheumatoid Arthritis: Morphology

~ Symmetric arthritis of small joints (proximal interphalangeal & metacarpophalangeal

~ Chronic synovitis, proliferation of synovial lining cells (villous projections)

~ Subsynovial inflammatory cells lymphoid nodules~ Pannus- highly vascularized, inflamed, reduplicated

synovium~ Fibrosis & calcification ankylosis~ Synovial fluid contains neutrophils

Rheumatoid Arthritis: Morphology

~ Rheumatoid nodules (25% of patients)• Subcutaneous nodules along extensor surfaces of forearms or

other sites of trauma • Firm, non-tender, up to 2 cm. diameter

~ Dermal nodules with fibrinoid necrosis surrounded by macrophages & granulation tissue

~ Progressive interstitial fibrosis of lungs some cases

Sjogren’s Syndrome: Features

~ Dry eyes (keratoconjunctivitis sicca) & dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands

~ Sicca syndrome- this phenomenon occurring as an isolated syndrome

~ Frequently associated with RA, some with SLE or other autoimmune processes

~ Associated with HLA- DR3

Sjogren’s syndrome: Pathogenesis

~ Primary target is ductal epithelial cells of exocrine glands

~ B-cell hyperactivity hypergammaglobulinemia, ANAs

~ Primary defect is in T-helper cells (too many)

~ Most have anti -SS-A & anti-SS-B Abs

Sjogren’s syndrome: Clinical course~ Primarily in women > 40~ Dry mouth, lack of tears~ Salivary glands enlarged~ Lacrimal & salivary gland inflammation of any cause (including

Sjogren's) is called Mikulicz's syndrome~ 60% w/ other CTD~ 1% develop lymphoma, 10% w/ pseudolymphomas

Sjogren’s syndrome: Morphology

~ All secretory glands can be involved~ Intense lymphoplasmacellular infiltrates~ 2ndary inflammation of corneal epithelium (due to

drying) ulceration & xerostomia~ Can develop respiratory symptoms~ 25% develop extraglandular disease (most with anti-SS-

A) CNS, kidneys, skin & muscles

Systemic Sclerosis (Scleroderma)

~ A chronic disease characterized by1. Chronic inflammation thought to be a result of

autoimmunity

2. Widespread damage to small blood vessels

3. Progressive interstitial and perivascular fibrosis in the skin and multiple organs


~ Etiology: Unknown~ Most common in 3rd- 5th decades~ 3X as frequent in women as in men ~ 95% w/ skin involvement~ Can be Diffuse or Limited


~ Pathogenesis: • Abnormal immune responses

– CD4+ T cells responding to an unidentified antigen accumulates in the skin and release cytokines that activate inflammatory cell and fibroblasts

• Vascular damage– Microvascular disease is consistently present early in the course

of systemic sclerosis and may be the initial lesion

• Collagen deposition

Possible mechanisms leading to systemic sclerosis


~ Diffuse Scleroderma: • Anti-DNA topoisomerase I (Scl-70) is highly specific in 75%

of patients (nucleolar pattern of staining)

~ Limited Scleroderma (CREST): • Anti-centromere pattern in 60%-80% of patients

~ Suggested that microvascular disease may play some role in development of fibrosis

Systemic Sclerosis: Clinical course

~ Raynaud’s phenomenon reversible vasospasm of digital arteries color changes; sensitivity to cold

~ Fibrosis joint immobilization~ Eosphageal fibrosis dysphagia & GI hypomotility

~ Pulmonary fibrosis dyspnea & chronic cough RSHF~ Malignant HPN (hyperplastic arteriolosclerosis) renal

failure~ 35%-70% 10 year survival with Diffuse SS

Systemic Sclerosis: Clinical course

~ CREST (Limited Scleroderma)

Calcinosis

Raynaud’s phenomenon

Esophageal dysmotility

Sclerodactyly (Dermal fibrosis)

Telangiectasia~ Better long-term survival than Diffuse PSS

Multisystem manifestations of Systemic Sclerosis. Systemic Sclerosis affects a wide range of tissues and organ systems, often as a result of vascular obliteration.

The fingers in some patients with Systemic Sclerosis are narrowed, with tight shiny skin. Subcutaneous calcification (calcinosis cutis) can also be seen as white spots on the edges of the fingers.

Systemic Sclerosis: Morphology

~ Skin: fingers & distal extremities then spreads, shows edema & inflammation thickened collagen & epidermal atrophy; subcutaneous calcification (esp in CREST); Morphea- skin fibrosis only

~ GI tract (80% of patients): atrophy & fibrosis of esophageal wall w/ mucosal atrophy, BV thickening

Systemic Sclerosis: Morphology

~ MS: inflammatory synovitis fibrosis joint destruction; muscle atrophy

~ Lungs: interstitial fibrosis (honeycomb) & BV thickening~ Kidneys:

• 66% concentric thickening of vessels• 30% malignant hypertension (fibrinoid necrosis of arterioles)

~ Heart: focal interstitial fibrosis & slight inflammation

Mixed Connective Tissue Disease

~ Used to describe a disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis

~ Characterized serologically by high titers of antibodies to ribonucleoprotein particle-containing U1ribonucleoprotein

Polyarteritis Nodosa and Other Vasculitides

~ Belongs to a group of diseases characterized by necrotizing inflammation of the walls of blood vessels and showing strong evidence of an immunological pathogenetic mechanism

ANTINUCLEAR ANTIBODIES IN VARIOUS AUTOIMMUNE DISEASES

IMMUNODEFICIENCY SYNDROMES

IMMUNODEFICIENCY SYNDROMES~ Primary immunodeficiency disorders

• Almost always genetically determined

• Affect the humoral and/or cellular arms of adaptive immunity or the defense mechanisms of innate immunity

~ Secondary immunodeficiency states• May arise as complications of cancers, infections, malnutrition,

or side-effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases

IMMUNODEFICIENCY SYNDROMES

~ Risk factors for immune disorders• Prematurity• Autoimmune diseases (e.g., SLE)• Lymphoproliferative disorders• Infections (e.g., HIV)• Immunosuppressive drugs (e.g., corticosteroids)

PRIMARY IMMUNODEFICIENCIES

1. X-linked Agammaglobulinemia of Bruton◘ Failure of B-cell precursors ( pro-B cells

and pre-B cells) to differentiate into B cells

◘ maturation stops after the rearrangement of heavy- chain genes; light chains are not produced

◘ the block in differentiation is due to mutations in a cytoplasmic tyrosine kinase – Bruton tyrosinase

kinase (btk)

PRIMARY IMMUNODEFICIENCIESX-linked Agammaglobulinemia of Bruton

◘ seen almost entirely in males but sporadic cases seen in females◘ does not become apparent until about 6 months of life◘ recurrent bacterial infections of the respiratory tract

call attention to the underlying immune defect – H. influenzae, S. pneumoniae, or S. aureus

◘ 35% of children develop arthritis that respond to Ig therapy

◘ SLE and Dermatomyositis occur with increased frequency

◘ Treatment is replacement therapy with Ig


X-linked Agammaglobulinemia of BrutonCharacteristics:

◘ B cells are absent or remarkably decreased and serum classes of all Ig are depressed◘ Germinal centers of LN, Peyer’s patches, the appendix, and tonsils are underdeveloped or

rudimentary◘ there is remarkable absence of plasma cells throughout the body◘ T cell-mediated reactions are entirely normal


2. Common Variable Immunodeficiency

◘ Feature common to all patients is hypogammaglobulinemia, generally affecting all classes of antibody but sometimes only IgG

◘ Diagnosis is based on exclusion of other well-defined causes of decreased antibody synthesis

◘ No evidence of any intrinsic B cell defect


Common Variable Immunodeficiency◘ Clinical manifestations resemble X-linked agammaglobulinemia◘ 20% of patients have recurrent herpesvirus infections◘ Affects both sexes equally◘ Onset of symptoms is later – in childhood or adolescence◘ Histologically, B cell areas of lymphoid tissues are hyperplasplastic◘ Increased incidence of RA, PA, HA, lymphoid malignancy, and gastric cancer (50-fold)


3. Isolated IgA deficiency◘ Affected individuals have extremely low levels of both serum and secretory IgA◘ Most individuals with this disease are completely asymptomatic◘ Mucosal defenses are weakend and infections occur in the respiratory, gastrointestinal and urogenital tracts◘ Symptomatic patients commonly present with recurrent sino-pulmonary infections and diarrhea


Isolated IgA deficiency◘ Basic defect is in the differentiation of IgA B lymphocytes ◘ In most patients, the number of IgA positive B cells

is normal, but only few of these cells can be induced to transform into IgA plasma cells in vitro◘ Serum antibodies to IgA are found in approximately

40% of the patients◘ Fatal anaphylactic reactions occur if transfused with

blood containing normal IgA


4. Hyper IgM Syndrome◘ Affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies◘ A T cell disorder in which functionally abnormal T cells fail to induce B cells to make antibodies of isotypes other than IgM◘ Clinically, male patients with the X-linked form present with recurrent pyogenic infections, susceptible to Pneumocystis carinii pneumonia◘ Serum of patients contains normal or elevated levels of IgM and IgD but no IgA or IgE and extremely low levels of IgG


5. DiGeorge Syndrome (Thymic Hypoplasia)◘ T cell deficiency that derives from failure of development of the 3rd and 4th pharyngeal pouches –

thymus, parathyroids, some clear cells of the thyroid, and ultimobranchial body◘ Variable loss of T cell-mediated immunity, tetany,

congenital defects of the heart and great vessels◘ Appearance of the mouth, ears, and facies maybe

abnormal


DiGeorge Syndrome (Thymic Hypoplasia)◘ Low levels of circulating T lymphocytes and a poor

defense against certain fungal and viral infections◘ Plasma cells are present in normal numbers in lymphoid tissues; depleted in paracortical areas of the

LN and periateriolar sheaths of spleen◘ Ig levels maybe normal or reduced, depending on the

severity of the T cell deficiency


DiGeorge Syndrome (Thymic Hypoplasia)

◘ Partial DiGeorge syndrome – small but histologically normal thymus, T cell function

improves with age

◘ Complete absence of thymus – transplantation of fetal thymus may be of benefit

◘ A component of 22q11 deletion syndrome


6. Severe Combined Immunodeficiency Diseases◘ Involves both humoral and cell-mediated immune responses◘ Affected infants present with oral candidiasis,

extensive diaper rash, and failure to thrive◘ Definitive treatment – bone marrow transplantation


Severe Combined Immunodeficiency Diseases◘ Classic Form – defect in the common lymphoid stem cell◘ X-linked – genetic defect is mutation in the common γ chain

subunit (γc) of several cytokine receptors◘ Autosomal recesive – deficiency of the adenosine deaminase

(ADA) enzyme= leads to accumulation of deoxyadenosine and

its derivatives which are toxic to immature lymphocytes esp. of T cell lineage***histologic findings = small thymus devoid of lymphoid cells


7. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)◘ X-linked recessive disease char. by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection ending in early death◘ Thymus is morphologically normal, but there is progressive

secondary depletion of T lymphocytes in the peripheral blood and in the paracortical areas of LN◘ IgM is low; IgG normal; IgA & IgE elevated◘ The syndrome maps to Xp11.23 – inc. lymphoma◘ Treatment is bone marrow transplantation


8. Genetic Deficiencies of the Complement System◘ Deficiency of C2 is the most common

= inc. incidence of SLE-like disease◘ Deficiency of C3

= serious and recurrent pyogenic infections= immune complex-mediated GN

◘ C5, 6, 7, 8, and 9= increased susceptibility to recurrent neisserial

infections◘ C1 inhibitor deficiency = hereditary angioedema

ACQUIRED IMMUNODEFICIENCY SYNDROME

◘ A retroviral disease characterized by by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations

◘ Second leading cause of death in men 25-44 years old

◘ 3rd leading cause of death in women

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

~ Etiologic agent of AIDS~ Discovered independently by Luc Montagnier of France

and Robert Gallo of the US in 1983-1984~ Former names of the virus include :

• Human T cell Lymphotrophic virus (HTLV-III)

• Lymphadenopathy associated virus (LAV)

• AIDS associated retrovirus (ARV)

***HIV-2 discovered in 1986, antigenically distinct virus endemic in West Africa


◘ Groups at risk of developing AIDS1. Homosexual or bisexual men – over 50%2. Intravenous drug abusers – 20% 3. Hemophiliacs – 0.5%4. Recipients of blood and blood components –

1.0%5. Heterosexual contacts of members of other

high-risk groups – 10%


◘ 2% of all cases occurs under 13 years old, 90% of these resulted from transmission of the virus from mother to child, remaining 10% are hemophiliacs or received blood/blood products

◘ 3 major routes of transmission1. sexual transmission – 75%2. parenteral transmission IV drug users, hemophiliacs, BT3. mother-to-infant transmission


◘ mother-to-infant transmission – pediatric AIDS1. in utero by transplacental spread2. during delivery through an infected birth

canal3. after birth by ingestion of breast milk

☻☻Extensive studies indicate that HIV infection cannot be transmitted by casual personal contact in the household, workplace, or school

☻☻Seroconversion after needle-stick injury – 0.3%


◘ Etiology:

1. HIV-1 – most common type associated with AIDS in the US, Europe, and Central

Africa

2. HIV-2 – West Africa and India


◘ Contents of the viral core1. major capsid protein p242. nucleocapsid protein p7/p93. two copies of genomic RNA4. three viral enzymes – protease, reverse

transcriptase, and integrase۞ p24 most readily detected viral antigen hence the

target for the antibodies used for diagnosis

Schematic illustration of an HIV-1 virion

Pathogenesis of HIV infection

Mechanisms of CD4+ T-cell loss in HIV infection

Multiple effects of loss of CD4 + T cells as a result of HIV infection

Clinical Categories

1>500 cells/uL

2200-499 cells/uL

3<200 cells/uL

Asymptomatic, acute (primary) HIV, or persistent generalized lymphadenopathy

A1 A2 A3

Symptomatic, not A nor C conditions

B1 B2 B3

AIDS, indicator conditions: constitutional disease, neurologic disease, or neoplasm

CDC Classification Categories of HIV infection

Typical course of HIV infection

Algorithm for Serologic Testing for AIDS

AMYLOIDOSIS

AMYLOIDOSIS

◘ Amyloid is a pathologic proteinaceous substance, deposited in between cells in various tissues and organs of the body in a wide variety of clinical settings

◘ Appears as an amorphous, eosinophilic, hyaline, extracellular substances that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells

Amyloid structure

A section of the liver stained with Congo Red

Yellow-green birefringence of the deposits observed under polarizing microscope

AMYLOIDOSIS

◘ Chemical nature- 95% consist of fibril proteins, 5% P component and other glycoproteins- 3 most common amyloid proteins

1. AL (amyloid light chain) – derived from plasma cells and contains Ig light chains

2. AA (amyloid-associated) – non-Ig protein synthesized by the liver

3. Aβ amyloid – found in Alzheimer disease◘ Other biochemical distinct proteins found in amyloid deposits

- Transthyretin (TTR), β2-microglobulin, prion proteins

Types of Amyloidosis1. Systemic

• Similar tissue involvement in both primary and secondary types

• Primary amyloidosis– AL amyloid deposition– Associated with multiple myeloma (30% of cases)

• Secondary (reactive)– AA amyloid– Associated with chronic inflammation (e.g., RA, Tb)

Types of Amyloidosis

2. Localized• Confined to a single organ (e.g. brain)• Alzheimer’s disease

– Aß

– Most common cause of dementia

3. Hereditary• Autosomal recessive disorder involving AA amyloid

(e.g., Familial Mediterranean fever)

AMYLOIDOSIS

~ Pathogenesis• Abnormal folding of proteins, which are deposited as

fibrils in extracellular tissues and disrupt normal function

Proposed mechanisms in the pathogenesis of amyloidosis

Amyloidosis - Morphology

◘ Gross – Affected organs are often enlarged and firm and have a waxy

appearance. - Painting the cut surface with iodine

imparts a yellow color that is transformed to blue violet

after application of sulfuric acid◘ Microscopic – Based almost entirely on its

staining characteristics (Congo Red)


◘ Kidney- most common and potentially the most serious form of

organ involvement- may appear normal in size and color or it may be enlarged

in advanced cases- it may be shrunken and contracted due to vascular

narrowing induced by amyloid deposits- deposited primarily in glomeruli, but also affected are the interstitial peritubular tissue, arteries, and arterioles


◘ Kidney

thickening of the mesangial matrix + uneven widening of the basement membrane of glomerular capillaries capillary narrowing and distortion of glomerular vascular tuft obliteration of capillary lumens masses or interlacing broad ribbons of amyloid

Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid


◘ Spleen- inapparent grossly or may cause moderate to

marked splenomegaly (up tp 800 grams)- Sago spleen deposit limited largely the the

splenic follicles, producing tapioca-like granules on gross inspection

- Lardaceous spleen involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the

early deposits gives rise to large, maplike areas of amyloidosis


◘ Liver- grossly inapparent or cause moderate to marked

hepatomegaly- appears first in the space of Disse encroach on

adjacent hepatic parenchymal cells and sinusoids deformity, pressure

atrophy, disappearance of hepatocytes- Vascular involvement and Kupffer cell

depositions are frequent- Normal liver function is usually preserved


◘ Heart

- may be enlarged and firm, shows no significant changes on cross-section of the myocardium

- deposits begin in subendocardial accumulations and within the myocardium between the muscle fibers expansion pressure atrophy

- conduction system damaged leads to electrocardiographic abnormalities


◘ Other organs- encountered in systemic disease- adrenals, thyroid, and pituitary- GIT

- tongue – tumor-forming amyloid of the tongue- Respiratory tract- Brain – Alzheimer’s disease- Peripheral and Autonomic nerves- median nerve – carpal tunnel syndrome

disease of immunity

Technology