Immunotolerance and Autoimmune diseases

Tolerance
Tolerance is a specific immunologic unresponsiveness antigens that are present during embryonic life are considered self and do not stimulate an immunologic response When the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops. the immune system has to recognize self-MHC to mount a response against a foreign antigen. the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.
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T-Cell Tolerance
T lymphocytes acquire the ability to distinguish self from nonself occurs in the fetal thymus , Clonal deletion It involves the killing of T cells (negative selection) that react against antigens (primarily self MHC proteins) present in the fetus at that time. The self-reactive cells die by a process of programmed cell death called apoptosis. Tolerance to self acquired within the thymus is called central tolerance,

T-Cell Tolerance
tolerance acquired outside the thymus is called peripheral tolerance Peripheral tolerance is necessary because some self reactive T cells are not killed in the thymus, there are several mechanisms involved: some self-reactive T cells are killed some are inhibited Others suppressed by regulatory T cells producing inhibitory cytokines.

Clonal anergy
Clonal anergy is the terms used to describe self-reactive T cells that are not activated because proper co stimulation does not occur . Both T-cell and B-cell clonal deletion fail to eliminate all autoreactive cells The mechanism of clonal anergy involves the inappropriate presentation of antigen, leading to a failure of interleukin-2(IL-2) production. Inappropriate presentation is due to a failure of Costimulatory signal, eg. Sufficient amounts of IL-1 might not be made, or cell surface proteins, such as CD28 on the T cell and B7 on the B cell, might not interact properly, leading to failure of signal transduction by ras proteins.
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Clonal ignorance
clonal ignorance refers to self-reactive T cells that are ignorant by physical separation from the target antigens,eg, the blood-brain barrier, T cells reactive to self-antigen not represented in the thymus will mature and migrate to the periphery but they may never encounter the appropriate antigen because it is sequestered in inaccessible tissues. Such cells may die out for lack of stimulus. Auto-reactive B cells, that escape deletion, may not find the antigen or the specific T-cell help and thus not be activated and die out.
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B cell Tolerance
B cells also become tolerant to self by two mechanisms. Clonal deletion, probably while the B-cell precursors are in the bone marrow clonal anergy of B cells in the periphery. Tolerance in B cells is less complete than in T cells, an observation supported by the finding that most autoimmune disease are mediated by antibodies

Immune Regulation
Regulation of immune responses, which prevents overproduction of antibody or excessive proliferation of T cells and/or B cells, occurs at several levels. Antigen concentration:-As antigen levels decrease during an immune response that successfully eliminates them, there is less of a stimulus for continued proliferation and differentiation of lymphocytes, so immune responses decline. Antibody levels:-Free IgG antibody at high concentrations can suppress immune responses
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Immune Regulation
Antigen-antibody complexes: -When antigen is free, it can bind to B cells and act as a stimulatory signal -when most of the antigen is bound in complexes with IgG, it deliver an inhibitory signal to B cells Anti-idiotype antibodies As a particular clone of B cells expands in number, and the cells differentiate to plasma cells, the concentration of the particular idiotype of antibody produced by that clone will increase enormously. The idiotype itself will reach concentrations high enough that it can be recognized as an antigen, and an antibody response against it will be triggered. This anti-idiotype will usually turn off the immune response of the initial B (or T) cell.
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Helper T-cell subset cytokine regulation

Helper T-cell subset cytokine regulation is one of the most important regulatory mechanisms. Antigen-stimulated helper T cells exist in two distinct subsets, Th 1 and Th2. Each helper subset stimulates one arm of the immune system, and inhibits the other, mainly through secretion of different cytokines. The interferon-y secreted by the Th1 cell inhibits Th2 cytokine production.

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Helper T-cell subset cytokine regulation

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Organ-Specific Autoimmune Diseases

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 cells of the target organs may be damaged directly by humoral or cell-mediated effector mechanisms alternatively, the antibodies may overstimulate or block the normal function of the target organ Occur when lymphocytes or Abs bind to cell-membrane antigens, causing cellular lysis and/or an inflammatory response in the affected organ Gradually, the damaged cellular structure is replaced by connective tissue (scar tissue), and the function of the organ declines

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HASHIMOTOS THYROIDITIS (DTH)

most frequently seen in middle-aged women, an individual produces auto-antibodies and sensitized TH1 cells specific for thyroid Ag characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physiological response to hypothyroidism
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AUTOIMMUNE ANEMIAS
include pernicious anemia, autoimmune hemolytic anemia, and drug-induced hemolytic anemia Pernicious anemia is caused by auto-antibodies to intrinsic factor, binding of auto-antibody to intrinsic factor blocks the intrinsic factormediated absorption of vitamin B12. in the absence of sufficient vitamin B12, which is necessary for proper hematopoiesis, the number of functional mature RBCs decreases below normal
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autoimmune hemolytic anemia

auto-antibody to RBC antigens is formed, triggering complement mediated lysis or antibody-mediated opsonization and phagocytosis of the RBCs Drug-induced hemolytic anemia when certain drugs such as penicillin or the antihypertensive agent methyldopa interact with RBCs the cells become antigenic

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GOODPASTURES 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 damage and an ensuing inflammatory response mediated by a build-up 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 stained with fluorescent-labeled anti-IgG and anti-C3b reveal linear deposits of IgG and C3b along the basement membranes
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INSULIN-DEPENDENT DIABETES MELLITUS

disease affecting 0.2% of the population, caused by an autoimmune attack on the pancreas attack is directed against specialized insulin-producing cells (beta cells) attack destroys beta cells, resulting in decreased production of insulin and consequently increased levels of blood glucose factors important in the destruction of beta cells: activated CTLs migrate into an islet and begin to attack the insulin producing cells local cytokine production during this response includes IFN-, TNF-, and IL-1
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INSULIN-DEPENDENT DIABETES MELLITUS

the first CTL infiltration and activation of macrophages, frequently is followed by cytokine release and the presence of auto-antibodies, which leads to a cell-mediated DTH response subsequent beta-cell destruction is thought to be mediated by cytokines released during the DTH response and by lytic enzymes released from the activated M Auto-antibodies to beta cells may contribute to cell destruction by facilitating either antibody-pluscomplement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC)
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Autoimmune Diseases Mediated stimulating or blocking autoAbs

Abs act as agonists, binding to hormone receptors in the normal ligand and stimulating inappropriate activity this usually leads to an overproduction of mediators or an increase in cell growth. auto-antibodies may act as antagonists, binding hormone receptors but blocking receptor function. this generally causes impaired secretion of mediators and gradual atrophy of the affected organ
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Autoimmune Diseases Mediated stimulating or blocking auto-Abs

Graves Disease: Production of auto-antibodies that bind the receptor for TSH and mimic the normal action of TSH, activating adenylate cyclase and resulting in production of the thyroid hormones Unlike TSH, however, the autoantibodies are not regulated, and consequently they overstimulate the thyroid. For this reason these auto-antibodies are called longacting thyroid-stimulating (LATS) antibodies Symptoms: Goiter (enlarged thyroid) and bulging eyes
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Autoimmune Diseases Mediated stimulating or blocking auto-Abs

Myasthenia gravis: is the prototype autoimmune disease mediated by blocking antibodies auto-antibodies that bind the acetylcholine receptors on the motor end-plates of muscles, blocks the normal binding of acetylcholine and also inducing complement mediated lysis of the cells progressive weakening of the skeletal muscles Affects mainly women treated with drugs or immunosuppressants

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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
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Systemic Lupus Erythematosus

which typically appears in women between 20 and 40 years of age; the ratio of female to male patients is 10:1 characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction more frequent in African-American and Hispanic women than in Caucasians, although it is not known why this is so. affected individuals may produce autoantibodies to a vast array of tissue antigens, such as DNA, histones, RBCs, platelets, leukocytes, and clotting factors
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Systemic Lupus Erythematosus

Interaction of these auto-antibodies with their specific antigens produces various symptoms. Auto-antibody specific for RBCs and platelets, for example, can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively when immune complexes of auto-antibodies with various nuclear antigens are deposited along the walls of small blood vessels, a type III hypersensitive reaction develops. the complexes activate the complement system and generate membrane-attack complexes and complement split products that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis.
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Rheumatoid Arthritis
most often affecting women from 40 to 60 years old major symptom is chronic inflammation of the joints, although the hematologic, cardiovascular, and respiratory systems are also frequently affected Characterized by production of 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.
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Proposed Mechanisms for Induction of Autoimmunity

a variety of mechanisms have been proposed to account for the T-cellmediated generation of autoimmune diseases evidence exists for each of these mechanisms, and it is likely that autoimmunity does not develop from a single event but rather from a number of different events susceptibility to many autoimmune diseases differs between the two sexes
Hashimotos thyroiditis, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and scleroderma preferentially affect women

factors that have been proposed to account for this preferential susceptibility, such as hormonal differences between the sexes and the potential effects of fetal cells in the maternal circulation during pregnancy
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Sources of Autoimmunity
Any tissue antigens that are sequestered from the circulation, and are therefore not seen by the developing T cells in the thymus, will not induce selftolerance. Exposure of mature T cells to such normally sequestered antigens at a later time might result in their activation a pathogen may express a region of protein that resembles a particular selfcomponent in conformation or primary sequence (molecular mimicry) One of the best examples of this type of autoimmune reaction is post-rabies encephalitis, which used to develop in some individuals who had received the rabies vaccine. In the past, the rabies virus was grown in rabbit brain-cell cultures, and preparations of the vaccine included antigens derived from the rabbit brain cells.
In a vaccinated person, these rabbit brain-cell antigens could induce formation of antibodies and activated T cells, which could cross-react with the recipients own brain cells, leading to encephalitis.

Cross-reacting antibodies are also thought to be the cause of heart damage in rheumatic fever, which can sometimes develop after a Streptococcus infection
In this case, the antibodies are to streptococcal antigens, but they cross-react with the heart muscle

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The pancreatic beta cells of individuals with insulin-dependent diabetes mellitus (IDDM) express high levels of both class I and class II MHC molecules, whereas healthy beta cells express lower levels of class I and do not express class II at all Similarly, thyroid acinar cells from those with Graves disease have been shown to express class II MHC molecules on their membranes.
this inappropriate expression of class II MHC molecules, which are normally expressed only on APCs may serve to sensitize TH cells to peptides derived from the beta cells or thyroid cells, allowing activation of B cells or TC cells or sensitization of TH1 cells against self-antigens

Other evidence suggests that certain agents can induce some cells that should not express class II MHC molecules to express them (PHA) A number of viruses and bacteria can induce nonspecific polyclonal B-cell activation
Gram-negative bacteria, cytomegalovirus, and Epstein-Barr virus (EBV) are all known to be such polyclonal activators, inducing the proliferation of numerous clones of B cells that express IgM in the absence of T H cells

If B cells reactive to self-antigens are activated by this mechanism, autoantibodies can appear
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Treatment of Autoimmune Diseases

Aimed at reducing only the autoimmune response while leaving the rest of the immune system intact Current therapies for autoimmune diseases are not cures but merely palliatives, aimed at reducing symptoms to provide the patient with an acceptable quality of life for the most part, these treatments provide nonspecific suppression of the immune system and thus do not distinguish between a pathologic autoimmune response and a protective immune response Immunosuppressive drugs (e.g., corticosteroids, azathioprine, and cyclophosphamide) are often given with the intent of slowing proliferation of lymphocytes
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Treatment of Autoimmune Diseases

By depressing the immune response in general, such drugs can reduce the severity of autoimmune symptoms general reduction in immune responsiveness, however, puts the patient at greater risk for infection or the development of cancer A somewhat more selective approach employs cyclosporin A or FK506 to treat autoimmunity these agents block signal transduction mediated by the T-cell receptor; thus, they inhibit only antigenactivated T cells while sparing nonactivated ones

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