basic immunology notes

Immunology Dr.M.Kannan 2012-13

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III B.Sc., Microbiology Immunology Immuno tolerance

One of the remarkable characteristics of the normal immune system is that it is

capable of reacting to an enormous variety of microbes, but it does not react against

each individual's own (self) antigens. This unresponsiveness to self antigens, also

called immunologic tolerance, is maintained despite the fact that the mechanisms by

which lymphocyte receptors are expressed are not inherently biased to produce

receptors for nonself antigens. In other words, lymphocytes with the ability to

recognize self antigens are constantly being generated during the normal process of

lymphocyte maturation.

Immunologic Tolerance Significance and Mechanisms

Immunologic tolerance is a lack of response to antigens that is induced by

exposure of lymphocytes to these antigens. When lymphocytes with receptors for a

particular antigen are exposed to this antigen, any of three outcomes is possible (Fig.

1). The lymphocytes may be activated, leading to an immune response; antigens that

elicit such a response are said to be immunogenic. The lymphocytes may be

functionally inactivated or killed, resulting in tolerance; antigens that induce tolerance

are said to be tolerogenic.

Immunologic tolerance to different self antigens may be induced when

developing lymphocytes encounter these antigens in the generative lymphoid organs,

called central tolerance, or when mature lymphocytes encounter self antigens in

peripheral tissues, called peripheral tolerance (Fig. 2).

The Central tolerance is a mechanism of tolerance only to self antigens that

are present in the generative lymphoid organs, namely, the bone marrow and

thymus. Tolerance to self antigens that are not present in these organs must be

induced and maintained by peripheral mechanisms.


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Figure 1 Consequences of the encounter of lymphocytes with antigens. Naive

lymphocytes may be activated to proliferate and differentiate by immunogenic

antigens. Tolerance is induced when tolerogenic antigens induce functional anergy

(unresponsiveness) or apoptosis. Leading to an inability of the cells to again respond

to the same antigen even in an immunogenic form. Some antigens are ignored by

lymphocytes, resulting in no response, but the lymphocytes are capable of

responding to the same antigen in an immunogenic form


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Figure 2 Central and peripheral tolerance to self antigens. Immature lymphocytes

specific for self antigens may encounter these antigens in the generative lymphoid

organs and are deleted (central tolerance). Mature self-reactive lymphocytes may be

inactivated or deleted by encounter with self antigens in peripheral tissues (peripheral

tolerance) В lymphocytes are shown here, but the same processes occur with T

lymphocytes as well.


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Primary and Secondary Responses to Antigens The immune system reacts to an antigen by studying the levels of antibodies

in serum over time (figure 3). This level is expressed quantitatively as the titer, or

concentration of antibodies. Upon the first exposure to an antigen, the system

undergoes a primary response. The earliest part of this response, the latent period, is marked by a lack of

antibodies for that antigen, but much activity is occurring. During this time, the

antigen is being concentrated in lymphoid tissue, and is being processed by the

correct clones of B lymphocytes.

As plasma cells synthesize antibodies, the serum titer increases to a certain

plateau and then tapers off to a low level over a few weeks or months. When the

class of antibodies produced during this response is tested, an important

characteristic of the response is uncovered. It turns out that, early in the primary

response, most of the antibodies are the IgM type, which is the first class to be

secreted by naive plasma cells. Later, the class of the antibodies (but not their

specificity) is switched to IgG or some other class (IgA or IgE).

When the immune system is exposed again to the same immunogen within

weeks, months, or even years, a secondary response occurs. The rate of antibody

synthesis, the peak titer, and the length of antibody persistence are greatly increased

over the primary response.

The rapidity and amplification seen in this response are attributable to the

memory B cells that were formed during the primary response. Because of its

association with recall, the secondary response is also called the anamnestic response. The advantage of this response is evident: It provides a quick and potent

strike against subsequent exposures to infectious agents. This memory effect forms

the basis for giving boosters additional doses of vaccine to increase the serum titer.


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Figure 3

THE STAGES IN ORIGIN, DIFFERENTIATION, MATURATION, ACTIVATION AND DIFFERENTIATION OF B CELL

Development generally follows a similar general pattern in both types of

lymphocytes (figure 4). Starting in embryonic and fetal stages, stem cells in the yolk

sac, liver, and bone marrow give rise to immature lymphocytes that are released into

the circulation. Because these undifferentiated cells cannot yet react with antigens,

they must first undergo developmental changes at some specific anatomical location.

This maturation occurs along two separate lines that will characterize all future

responses. The fully mature B and T lymphocytes are released and ultimately take up

residence in various lymphoid organs. Lymphocyte differentiation and

immunocompetence are basically complete by the late fetal or early neonatal period.


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Specific Happenings in B-Cell Maturation The site of B-cell maturation was first discovered in birds, which have an organ

in the intestine called the bursa. In human certain bone marrow sites that harbor

stromal cells. These huge cells nurture the lymphocyte stem cells and provide

hormonal signals that initiate B-cell development. As a result of gene modification

and selection, hundreds of millions of distinct B cells develop.

These naive lymphocytes “home” to specific sites in the lymph nodes, spleen,

and gut-associated lymphoid tissue (GALT), where they adhere to specific binding

molecules. Here they will come into contact with antigens throughout life. In addition

to having immunoglobulins as surface receptors, a fully differentiated B cell has a

distinctively rough appearance under high magnification, with numerous microvillus

projections.

Figure 4


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Specific Happenings in T-Cell Maturation The maturation of T cells and the development of their specific receptors are

directed by the thymus gland and its hormones. Due to the complexity of T-cell

function, there are at least seven classes of T-cell receptors or markers, termed the

CD cluster (abbreviated from cluster of differentiation CD1, CD2, etc.). Some

receptors recognize antigen molecules bound to cells on MHC receptors; others

recognize receptors on B cells, other T cells, and macrophages.

Like B cells, T cells also migrate to lymphoid organs and occupy specific sites.

Additional characteristics typical of mature T cell are smaller and fewer microvilli

under high magnification and the property of rosette formation when mixed with

normal sheep red blood cells. It has been estimated that 25X109 T cells pass

between the lymphatic and general circulation per day.

ENTRANCE AND PROCESSING OF ANTIGENS AND CLONAL SELECTION Antigen Processing and Presentation Reorganization of foreign protein antigens by a T cell requires that peptides

derived from the antigen be displayed within the cleft of an MHC molecule on the

membrane of a cell. The formation of these peptide-MHC complexes requires that a

protein antigen be degraded into peptides by a sequence of events called antigen processing. The degraded peptides then associate with MHC molecules within the cell

interior, and the peptide-MHC complexes are transported to the membrane, where

they are displayed (antigen presentation). Class I and class II MHC molecules

associate with peptides that have been processed in different intracellular

compartments.

Class I MHC molecules bind peptides derived from endogenous antigens

that have been processed within the cytoplasm of the cell (e.g., normal cellular

proteins, tumor proteins, or viral and bacterial proteins produced within infected cells).

Class II MHC molecules bind peptides derived from exogenous antigens that are


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internalized by phagocytosis or endocytosis and processed within the endocytic

pathway.

Having reviewed the characteristics of lymphocytes, let us now examine the

properties of antigens, the substances that cause them to react. An antigen (Ag) is a

substance that provokes an immune response in specific lymphocytes. The property

of behaving as an antigen is called antigenicity.

The term immunogen is another term of reference for a substance that can

elicit an immune response. To be perceived as an antigen or immunogen, a

substance must meet certain requirements in foreignness, shape, size, and

accessibility.

The Role of Macrophages: Antigen Processing and Presentation In most immune reactions, the antigen must be further acted upon and

formally presented to lymphocytes by special macrophages or other cells called

antigen-processing cells (APCs). One of the most prominent APCs is a large dendritic cell that engulfs the

antigen and modifies it so that it will be more immunogenic and recognizable to

lymphocytes. After processing is complete, the antigen is moved to the surface of the

APC and bound to the MHC receptor so that it will be readily accessible to the

lymphocytes during presentation (figure 5).

Presentation of Antigen to the Lymphocytes and Its Early Consequences

For lymphocytes to respond to the APC-bound antigen, certain conditions

must be met. T-cell-dependent antigens, usually protein based, require recognition

steps between the macrophage, antigen, and lymphocytes. The first cells on the

scene to assist the macrophage in activating B cells and other T cells are a special

class of helper T cells (TH).

This class of T cell bears a receptor that binds simultaneously with the class II

MHC receptor on the macrophage and with one site on the antigen. Once

identification has occurred, a cytokine, interleukin-1 (IL-1), produced by the


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macrophage, activates this T helper cell. The TH cell, in turn, produces a different

cytokine, interleukin-2 (IL-2) that stimulates a general increase in activity of

committed B and T cells.

A few antigens can trigger a response from B lymphocytes without the

cooperation of macrophages or T helper cells. These T cell- independent antigens

are usually simple molecules such as carbohydrates with many repeating and

invariable determinant groups. Examples include lipopolysaccharide from the cell wall

of Escherichia coli and polysaccharide from the capsule of Streptococcus

pneumoniae. Because so few antigens are of this type, most B-cell reactions require

helper T cells.

Figure 5


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ACTIVATION OF B LYMPHOCYTES: CLONAL EXPANSION AND ANTIBODY PRODUCTION The immunologic activation of most B cells requires a series of events (figure 7):

1. Clonal selection and binding of antigen. In this case, a precommitted B cell of a particular clonal specificity picks up the

antigen itself or is presented with the antigen by the macrophage complex so

that the antigen is bound to the B-cell receptors. At the same time, the

MHC/Ag receptor on the B cell is bound to the TH cell, thereby ensuring self

recognition.

2. Instruction by chemical mediators. The B cell receives developmental signals from macrophages and T cells

(interleukin-2 and -6) and various other growth factors, such as IL-4 and -5.

3. The combination of these stimuli on the membrane receptors causes a

signal to be transmitted internally to the B-cell nucleus (Fig 6).

4. This event triggers B-cell activation. An activated B cell undergoes an

increase in DNA synthesis, organelle bulk, and size in preparation for entering

the cell cycle and mitosis. 5. Clonal expansion. A stimulated B cell multiplies through successive mitotic

divisions and produces a large population of genetically identical daughter

cells. Some cells that stop short of becoming fully differentiated are memory cells, which remain for long periods to react with that same antigen at a later

time. This reaction also expands the clone size, so that subsequent exposure

to that antigen provides more cells with that specificity. This expansion of the

clone size accounts for the increased memory response. By far the most

numerous progeny are large, specialized, terminally differentiated B cells

called plasma cells.


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6. Antibody production and secretion. The primary action of plasma cells is

to secrete into the surrounding tissues copious amounts of antibodies with the

same specificity as the original receptor (figure 15.13). Although an individual

plasma cell can produce around 2,000 antibodies per second, production does

not continue indefinitely because of regulation from the Tsuppressor (TS) class

of cells. The plasma cells do not survive for long and deteriorate after they

have synthesized antibodies.

Figure 6


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ACTIVATION OF T LYMPHOCYTES AND HOW T CELLS RESPOND TO ANTIGEN: CELL-MEDIATED IMMUNITY (CMI)

During the time that B cells have been actively responding to antigens, the T-

cell limb of the system has been similarly engaged. The responses of T cells,

however, are cell-mediated immunities, which require the direct involvement of T

lymphocytes throughout the course of the reaction. These reactions are among the

most complex and diverse in the immune system and involve several subsets of T

cells whose particular actions are dictated by CD receptors. All mature T cells have

CD2 (the cause of rosetting), but CD4 and CD8 are found only on certain classes. T

cells are restricted; that is, they require some type of MHC (self) recognition before

they can be activated, and all produce cytokines with a spectrum of biological effects.

T cells have notable differences in function from B cells. Rather than making

antibodies to control foreign antigens, the whole T cell acts directly in contact with the

antigen. They also stimulate other T cells, B cells, and phagocytes.

The Activation of T Cells and Their Differentiation into Subsets

The mature T cells in lymphoid organs are primed to react with antigens that

have been processed and presented to them by macrophages. A T cell is initially

sensitized when antigen is bound to its receptor. By mechanisms not yet fully

characterized, sensitization leads to the final differentiation of the cell into one of four

functionally specialized subsets: helper, suppressor, cytotoxic, or delayed

hypersensitivity T cells (figure 7). As with B cells, activated T cells transform into

lymphoblasts in preparation for mitotic divisions, and they divide into one of the

subsets of effector cells and memory cells that can interact with the antigen upon

subsequent contact. Memory T cells are some of the longest-lived blood cells known

(70 years in one well-documented case).


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T Helper (TH) Cells Helper cells play a central role in assisting with immune

reactions to antigens, including those of B cells and other T cells. They do this

directly by receptor contact and indirectly by releasing cytokines such as interleukin-

2, which stimulates the primary growth and activation of B and T cells, and

interleukins-4, -5, and -6, which stimulate various activities of B cells. T helper cells

are the most prevalent type of T cell in the blood and lymphoid organs, making up

about 65% of this population. The severe depression of this class of T cells (with CD4

receptors) by HIV is what largely accounts for the immunopathology of AIDS.

Figure 7


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Target Cells That TC Cells Can Destroy Include the Following: • Fungi, protozoans, and complex bacteria (mycobacteria).

• Cancer cells. T cells constantly survey the tissues and immediately attack

any abnormal cells they encounter. The importance of this function is clearly

demonstrated in the susceptibility of T-cell-deficient people to cancer.

• Cells from other animals and humans. Cytotoxic CMI is the most important

factor in graft rejection. In this instance, the TC cells attack the foreign tissues that

have been implanted into a recipient’s body.

Other Types of Killer Cells Natural killer (NK) cells are a type of lymphocyte

related to T cells that lack specificity for antigens. They circulate through the spleen,

blood, and lungs and are probably the first killer cells to attack cancer cells and virus

infected cells. They destroy such cells by similar mechanisms as T cells. Their

activities are acutely sensitive to cytokines such as interleukin-12 and alpha and beta

interferon.

MHC Molecules

MHC stands for major histocompatibility complex. This term was coined for a

genetic locus on the short arm of chromosome 6 that proved decisive for rejection or

acceptance of transplanted tissue.

On this multi-gene locus, two main types of transmembrane proteins are

encoded: MHC class I and MHC class II. MHC proteins can be understood as ID-

cards carried by cells to be inspected by T cells in stop and search operations. MHC-I

molecules are ID-cards shown to cytotoxic (CD8+) T cells; MHC-II molecules are

shown to (CD4+) T-helper cells.

MHC I presents an image of all that is being synthesized in the cell.

Normally, that will be self-peptides. In the event of a viral infection, peptides from viral

proteins will appear on MHC I in addition to normal cellular peptides.

MHC II presents extracellular material taken up by antigen-presenting cells

(APC). This is intended to activate CD4+ T cells, mainly helper cells. MHC II is


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therefore expressed by a small minority of cells, mainly "professional" APC: dendritic

cells, macrophages and B cells.

MHC-II molecules, while very similar in overall shape, consist of two equivalent

protein chains, α and β, that are encoded by two separate genes in the MHC.

The MHC Encodes Three Major Classes of Molecules The major histocompatibility complex is a collection of genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans and on chromosome 17 in mice. The MHC is referred to as the HLA complex in humans and as the H-2 complex in mice. Although the arrangement of genes is somewhat different, in both cases the MHC genes are organized into regions encoding three classes of molecules (Figure 9). Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of peptide antigens to TC cells. Class II MHC genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, dendritic cells, and B cells), where they present processed antigenic peptides to TH cells. Class III MHC genes encode, in addition to other products, various secreted proteins that have immune functions, including components of the complement system and molecules involved in inflammation.


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HYPERSENSITIVITY REACTIONS

Hypersensitivity reactions to usually harmless substances are often called

allergies or allergic reactions. Antigens that cause allergic reactions are allergens. Hypersensitivities are categorized according to which parts of the immune response

are involved and how quickly the response occurs. Most allergic or hypersensitivity

reactions fall into one of four major types:

■ Type I: Immediate IgE-mediated ■ Type II: Cytotoxic ■ Type III: Immune complex–mediated ■ Type IV: Delayed cell-mediated

IMMEDIATE (TYPE I) HYPERSENSITIVITY Immediate (Type I) hypersensitivity, or anaphylactic hypersensitivity, typically

produces an immediate response upon exposure to an allergy-inducing antigen (also

known as an allergen). Nonallergic persons do not respond to such antigens.

Anaphylaxis (Greek: ana, ‘‘against,’’ phylaxis, ‘‘protection’’) is an immediate,

exaggerated allergic reaction to antigens.


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The term anaphylaxis refers to detrimental effects to the host caused by an

inappropriate immune response. These effects are the opposite of prophylaxis, the

preventive effects generated by an immune response. Anaphylaxis is the harmful

result of IgE antibodies made in response to allergens. It can be local or generalized

(systemic). Localized anaphylaxis appears as reddening of the skin, watery eyes,

hives, asthma, and digestive disturbances. Generalized anaphylaxis appears as a

systemic life-threatening reaction such as airway constriction or anaphylactic shock,

generalized condition resulting from a sudden extreme drop in blood pressure.

ALLERGEN

Immediate hypersensitivity results from two or more exposures to an allergen.

An allergen is an ordinarily harmless foreign substance (typically a protein or a

chemical bound to a protein) that can cause an exaggerated immunological

response. The first exposure to the allergen produces no visible signs or symptoms.

Allergens include airborne substances such as pollen, household dust, molds, and

dandertiny particles from hair, feathers, or skin. Household dust commonly contains

nearly microscopic mites and their fecal pellets. Other allergens include venoms from

insect stings, antibiotics, certain foods, sulfites, and foreign substances found in

vaccines and in diagnostic or therapeutic materials. Allergens can be introduced into

the body by inhalation, ingestion, or injection

CYTOTOXIC (TYPE II) HYPERSENSITIVITY

In cytotoxic (Type II) hypersensitivity, specific antibodies react with cell surface

antigens interpreted as foreign by the immune system, leading to phagocytosis, killer

cell activity, or complement-mediated lysis. The cells to which the antibodies are

attached, as well as surrounding tissues, are damaged because of the resulting

inflammatory response. Antigens that initiate cytotoxic hypersensitivity typically enter

the body in mismatched blood transfusions or during delivery of an Rh-positive infant

to an Rh-negative mother.


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IMMUNE COMPLEX (TYPE III) HYPERSENSITIVITY

Immune complex (Type III) hypersensitivity results from the formation of

antigen-antibody complexes. Under normal circumstances these large immune

complexes are engulfed and destroyed by phagocytic cells. Hypersensitivity occurs

when antigen-antibody complexes persist or are continuously formed. In type III

hypersensitive reaction is mediated by the formation of immune complexes and the

ensuing activation of complement. Complement split products serve as immune

effector molecules that elicit localized vasodilation and chemotactically attract

neutrophils. Deposition of immune complexes near the site of antigen entry can

induce an Arthus reaction, in which lytic enzymes released by the accumulated

neutrophils and the complement membrane attack complex cause localized tissue

damage.

CELL-MEDIATED (TYPE IV) HYPERSENSITIVITY

Cell-mediated (Type IV) hypersensitivity is also called delayed hypersensitivity

because reactions take more than 12 hours to develop. These reactions are

mediated by T cells—specifically, a type of TH1 cell [sometimes called a delayed

hypersensitivity T (TDH) cell]—not by antibodies. A type IV hypersensitive reaction

involves the cell-mediated branch of the immune system. Antigen activation of

sensitized TH1 cells induces release of various cytokines that cause macrophages to

accumulate and become activated. The net effect of the activation of macrophages is

to release lytic enzymes that cause localized tissue damage.


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Disorders of Immune response

Humans possess a powerful and intricate system of defense, which by its very

nature also carries the potential to cause injury and disease. In most instances, a

defect in immune function is expressed in commonplace, but miserable, symptoms

such as those of hay fever and dermatitis. But abnormal or undesirable immune

functions are also actively involved in debilitating or life threatening diseases such as

asthma, anaphylaxis, rheumatoid arthritis, graft rejection, and cancer.

The immune response have centered on its numerous beneficial effects. The

precisely coordinated system that seeks out, recognizes, and destroys an unending

array of foreign materials is clearly protective, but it also presents another side a side

that promotes rather than prevents disease. It is called immunopathology, the study


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of disease states associated with over reactivity or under reactivity of the immune

response. In the cases of allergies and autoimmunity, the tissues are innocent

bystanders attacked by excessive immunologic functions. In grafts and

transfusions, a recipient reacts to the foreign tissues and cells of another individual.

In immunodeficiency diseases, immune function is incompletely developed,

suppressed, or destroyed. Cancer falls into a special category, because it is both a

cause and an effect of immune dysfunction.

Autoimmunity Usually, the body’s immune system recognizes its self-antigens and deletes

clones of cells that would respond and attack its own tissues. A growing number of

diseases are suspected of being caused by an autoimmune process, however,

meaning that the immune system of the body is responding to the tissues of the body

as if they are foreign. Susceptibility to many of them is influenced by the major

histocompatibility makeup of the patient, and so, not surprisingly, they often occur in

the same family. Autoimmune diseases may result from reaction to antigens that are similar

though not identical to antigens of self. Some bacterial and viral agents try to evade

destruction by the immune system by developing amino acid sequences that are

similar to self-antigens. As a result, the immune system is unable to discriminate

between the agent and self. The immune system may then destroy the substances of

self as well as those of the bacteria or virus. It has been found that the likeness of

amino acid sequences need not be exact for this self-destruction; even a 50%

likeness may lead to an autoimmune response. Autoimmune responses may also

occur after tissue injury in which self-antigens are released from the injured organ, as

in the case of a heart attack. The auto antibodies formed react with heart tissue and

evidence suggests that they can cause further damage.

The human autoimmune diseases can be divided into two broad categories:

organ-specific and systemic autoimmune disease. Such diseases affect 5%–7% of


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the human population. In an organ-specific autoimmune disease, the immune

response is directed to a target antigen unique to a single organ or gland, so that the

manifestations are largely limited to that organ. The cells of the target organs may be

damaged directly by humoral or cell-mediated mechanisms.

HASHIMOTO’S THYROIDITIS In Hashimoto’s thyroiditis, which is most frequently seen in middle-aged

women, an individual produces auto-antibodies and sensitized TH1 cells specific for

thyroid antigens. Antibodies are formed to a number of thyroid proteins, including

thyroglobulin and thyroid peroxidase, both of which are involved in the uptake of

iodine. Binding of the auto-antibodies to these proteins interferes with iodine uptake

and leads to decreased production of thyroid hormones (hypothyroidism).

GOODPASTURE’S SYNDROME In Goodpasture’s syndrome, auto-antibodies specific for certain basement-

membrane antigens bind to the basement membranes of the kidney glomeruli and

the alveoli of the lungs. Subsequent complement activation leads to direct cellular


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damage and an ensuing inflammatory response mediated by a buildup of

complement split products. Damage to the glomerular and alveolar basement

membranes leads to progressive kidney damage and pulmonary hemorrhage. Death

may ensue within several months of the onset of symptoms. Biopsies from patients

with Goodpasture’s syndrome stained with fluorescent-labeled anti-IgG and anti-

C3b reveal linear deposits of IgG and C3b along the basement membranes.

INSULIN-DEPENDENT DIABETES MELLITUS A disease afflicting 0.2% of the population, insulin-dependent diabetes

mellitus (IDDM) is caused by an autoimmune attack on the pancreas. The attack is

directed against specialized insulin-producing cells (beta cells) that are located in

spherical clusters, called the islets of Langerhans, scattered throughout the pancreas.

The autoimmune attack destroys beta cells, resulting in decreased production of

insulin and consequently increased levels of blood glucose.

Systemic Autoimmune Diseases In systemic autoimmune diseases, the response is directed toward a broad

range of target antigens and involves a number of organs and tissues. These

diseases reflect a general defect in immune regulation that results in hyperactive T

cells and B cells. Tissue damage is widespread, both from cell mediated immune

responses and from direct cellular damage caused by auto-antibodies or by

accumulation of immune complexes.

Systemic Lupus Erythematosus Attacks One of the best examples of a systemic autoimmune disease is systemic

lupus erythematosus (SLE), which typically appears in women between 20 and 40

years of age; the ratio of female to male patients is 10:1. SLE is characterized by

fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction.

Multiple sclerosis (MS) is the most common cause of neurologic disability

associated with disease in Western countries. The symptoms may be mild, such as


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numbness in the limbs, or severe, such as paralysis or loss of vision. Most people

with MS are diagnosed between the ages of 20 and 40.

Rheumatoid Arthritis Attacks Joints Rheumatoid arthritis is a common autoimmune disorder, most often affecting

women from 40 to 60 years old. The major symptom is chronic inflammation of the

joints, although the hematologic, cardiovascular, and respiratory

systems are also frequently affected. Many individuals with rheumatoid arthritis

produce a group of auto-antibodies called rheumatoid factors that are reactive with

determinants in the Fc region of IgG. The classic rheumatoid factor is an IgM

antibody with that reactivity. Such auto-antibodies bind to normal circulating IgG,

forming IgM-IgG complexes that are deposited in the joints. These immune

complexes can activate the complement cascade, resulting in a type III

hypersensitive reaction, which leads to chronic inflammation of the joints.

Immunodeficiency Diseases

Components of the immune response system are absent. Deficiencies involve

B and T cells, phagocytes, and complement.

A. Primary immunodeficiency is genetically based, congenital; defect in

inheritance leads to lack of B-cell activity, T-cell activity, or both.

B. B-cell defect is called agammaglobulinemia; patient lacks antibodies;

serious recurrent bacterial infections result. In Ig deficiency, one of

the classes of antibodies is missing or deficient.

C. In T-cell defects, the thymus is missing or abnormal. In DiGeorge syndrome, the thymus fails to develop; afflicted children experience recurrent

infections with eukaryotic pathogens and viruses; immune response is generally

underdeveloped.


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D. In severe combined immunodeficiency (SCID), both limbs of the

lymphocyte system are missing or defective; no adaptive immune response exists;

fatal without replacement of bone marrow or other therapies.

E. Secondary (acquired) immunodeficiency is due to damage after birth

(infections, drugs, radiation). AIDS is the most common of these; T helper cells are

main target; deficiency manifests in numerous opportunistic infections and cancers.

Transplantation Immunology

Transplantation immunology refers to the act of transferring cells, tissues, or

organs from one site to another. The desire to accomplish transplants stems from the

realization that many diseases can be cured by implantation of a healthy organ,

tissue, or cells (a graft) from one individual (the donor) to another in need of the

transplant (the recipient or host). The development of surgical techniques that allow

the facile reimplantation of organs has removed one barrier to successful

transplantation, but others remain.

Immunologic Basis of Graft Rejection

The degree of immune response to a graft varies with the type of graft. The

following terms are used to denote different types of transplants:

Autograft is self-tissue transferred from one body site to another in the same

individual. Transferring healthy skin to a burned area in burn patients and use of

healthy

blood vessels to replace blocked coronary arteries are examples of frequently used

autografts.

Isograft is tissue transferred between genetically identical individuals. In

inbred strains of mice, an isograft can be performed from one mouse to another

syngeneic mouse. In humans, an isograft can be performed between genetically

identical (monozygotic) twins.


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Allograft is tissue transferred between genetically different members of the

same species. In mice, an allograft is performed by transferring tissue or an organ

from one strain to another. In humans, organ grafts from one individual to another are

allografts unless the donor and recipient are identical twins.

Xenograft is tissue transferred between different species (e.g., the graft of a

baboon heart into a human). Because of significant shortages in donated organs,

raising animals for the specific purpose of serving as organ donors for humans is

under serious consideration.

Basics of graft rejection

First and second set reactions When a graft is undergoing rejection for the first time, there is very rapid

invasion by polymorphs and lymphoid cells, including plasma cells. Thrombosis and

acute cell destruction can be seen in three to four days. This “first time” reaction to a

foreign graft is known as the First set reaction.

Second set rejection occurs during subsequent grafting, taken from the

original donor or a related subject. It does not occur if the allograft has been donated

by an entirely unrelated subject with a completely different set of tissue antigens.

(Such grafts are rejected as first set of reactions). The recipient of a second graft

from a donor who has already been rejected, will mount an accelerated rejection of

the second graft. Since T cells are implicated in graft rejection, it demonstrated that

they are primed and retain memory of the first contact with graft antigens.

During rejection humoral antibodies, with specificity for the graft antigens are

produced. Such antibodies are produced in a T cell dependant manner i.e., with T cell

help.

Immune Mechanisms in Graft Rejection Immune mechanisms in graft rejection are best illustrated using rejection of the

grafted kidney as a model.

A. Acute rejection


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Antigen presenting cells (APC) in the grafted tissue provide the primary

stimulus. These MHC Class II-positive cells are mainly dendritic cells and to a lesser

extent - monocytes. These cells are necessary to present antigen in a form that

recipient lymphocytes can recognize. These cells are sometimes called “passenger

cells” since they come along with the graft.

B. Hyperacute rejection Hyperacute rejection occurs within minutes of transplantation and is

characterized by sludging of red cells and microthrombi in the glomerulus. This type

of rejection occurs in individuals with pre existing antibodies to blood group antigens

or in those that are pre sensitized to MHC Class I antigens of the donor, through

blood transfusions. Antigen antibody complexes formed during rejection, fix

complement and complement activation ensues, followed by activation of the clotting

pathway. C. Chronic rejection Chronic rejection occurs months to years after transplantation. It is

characterized by a narrowing of the vascular arterial lumen, owing to growth of

endothelial cells that line the vascular bed.

Tissue typing clinical transplantation

A tissue type test is a blood test that measures substances called antigens on

the surface of body cells and tissues. Checking the antigens can tell if donor tissue is

safe (compatible) for transplant to another person. This test may also be called HLA typing. Antigens can tell the difference between normal body tissue or foreign tissue

(for example, tissue from another person's body). Tissue type helps find the best

match for tissues or blood cells (such as platelets). Sometimes tissue type test is

done to check the autoimmune diseases.

A special pattern of antigens (called tissue type) is present on each person's

cells and tissues. Half of each person's antigens come from (inherited) the mother

and half from the father. Identical twins have the same pattern, but everyone else has

his or her own special pattern. Brothers and sisters have a 1‐in‐4 chance of having an


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identical match. Each person's antigen pattern can be "fingerprinted" through a

tissue type test.

• The closer the match of antigens, the more likely that transplanted tissues or

organs will not be rejected.

• The more similar the antigen patterns are from two people, the more likely it

is that they are related.

Two main antigen groups are used for a tissue type test. Class I has three

classes of antigens (HLA‐A, HLA‐B, HLA‐C) that are found on some kinds of blood

cells. Class II has one class of antigens (HLA‐D) that are found only on certain cells

in the body. There are many different types of antigens in each category.

CANCER IMMUNOLOGY

Cancer: Origin and Terminology In most organs and tissues of a mature animal, a balance is usually

maintained between cell renewal and cell death. The various types of mature cells in

the body have a given life span; as these cells die, new cells are generated by the

proliferation and differentiation of various types of stem cells. Under normal

circumstances, the production of new cells is regulated so that the number of any

particular type of cell remains constant. Occasionally, though, cells arise that no

longer respond to normal growth-control mechanisms. These cells give rise to clones

of cells that can expand to a considerable size, producing a tumor, or neoplasm. A tumor that is not capable of indefinite growth and does not invade the

healthy surrounding tissue extensively is benign. A tumor that continues to grow and

becomes progressively invasive is malignant; the term cancer refers specifically to a

malignant tumor. In addition to uncontrolled growth, malignant tumors exhibit

metastasis; in this process, small clusters of cancerous cells dislodge from a tumor,

invade the blood or lymphatic vessels, and are carried to other tissues, where they

continue to proliferate. In this way a primary tumor at one site can give rise to a

secondary tumor at another site (Figure 1).


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Malignant tumors or cancers are classified according to the embryonic origin of

the tissue from which the tumor is derived. Most (>80%) are carcinomas, tumors that

arise from endodermal or ectodermal tissues such as skin or the epithelial lining of

internal organs and glands. The majority of cancers of the colon, breast, prostate,

and lung are carcinomas. The leukemias and lymphomas are malignant tumors of

hematopoietic cells of the bone marrow and account for about 9% of cancer

incidence in the United States. Leukemias proliferate as single cells, whereas

lymphomas tend to grow as tumor masses. Sarcomas, which arise less frequently

(around 1% of the incidence in the United States) are derived from mesodermal

connective tissues such as bone, fat, and cartilage.

Tumor antigen

The subdiscipline of tumor immunology involves the study of antigens on

tumor cells and the immune response to these antigens. Two types of tumor antigens


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have been identified on tumor cells: tumor-specific transplantation antigens (TSTAs) and tumor-associated transplantation antigens (TATAs). Tumor-specific

antigens are unique to tumor cells and do not occur on normal cells in the body. They

may result from mutations in tumor cells that generate altered cellular proteins.

Tumor-associated antigens may also be proteins that are normally expressed at

extremely low levels on normal cells but are expressed at much higher levels on

tumor cells.


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IMMUNERESPONSE TO TUMOR

THE FUNCTION OF THE IMMUNE SYSTEM IN CANCER A concept that readily explains the detection and elimination of cancer cells is

immune surveillance. Many experts postulate that cells with cancer-causing

potential arise constantly in the body but that the immune system ordinarily discovers

and destroys these cells, thus keeping cancer in check. In some cases, the cancer

may not be immunogenic enough; it may retain self markers and not be targeted by

the surveillance system. It may turn out that most cancers are associated with some

sort of immunodeficiency, even a slight or transient one.

basic immunology notes

Documents

dependent

major histocompatibility

systemic autoimmune

systemic autoimmune

generative

localized

tissue type

mhc class