Autoimmune Diseases- MMS

7/27/2019 Autoimmune Diseases- MMS

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Immunotoleranceand

Autoimmune diseases

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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, autoimmunedisease develops.

the immune system has to recognize self-MHC tomount a response against a foreign antigen.

the immune system is constantly challenged todiscriminate self vs non-self and mediate the rightresponse.

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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,

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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.

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Clonal anergy Clonal anergy is the terms used to describe self-reactive T

cells that are not activated because proper co stimulationdoes not occur .

Both T-cell and B-cell clonal deletion fail to eliminate allautoreactive cells The mechanism of clonal anergy involves the

inappropriate presentation of antigen, leading to a failureof interleukin-2(IL-2) production.

Inappropriate presentation is due to a failure of Costimulatory signal, eg. Sufficient amounts of IL-1might not be made, or cell surface proteins, such as CD28on the T cell and B7 on the B cell, might not interactproperly, leading to failure of signal transduction by ras

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Clonal ignorance clonal ignorance refers to self-reactive T cells that areignorant by physical separation from the targetantigens,eg, the blood-brain barrier,

T cells reactive to self-antigen not represented in thethymus will mature and migrate to the periphery

but they may never encounter the appropriate antigenbecause it is sequestered in inaccessible tissues.

Such cells may die out for lack of stimulus.

Auto-reactive B cells, that escape deletion, may not findthe antigen or the specific T-cell help and thus not be

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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 findingthat most autoimmune disease are mediated byantibodies

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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 astimulatory signal-when most of the antigen is bound in complexes with IgG, it

deliver an inhibitory signal to B cells Anti-idiotype antibodiesAs a particular clone of B cells expands in number, and the cells

differentiate to plasma cells, the concentration of the particularidiotype of antibody produced by that clone will increaseenormously.

The idiotype itself will reach concentrations high enough that itcan be recognized as an antigen, and an antibody response againstit 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 Th2cytokine production.

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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 largelylimited to that organ

cells of the target organs may be damaged directly by humoralor cell-mediated effector mechanisms

alternatively, the antibodies may overstimulate or block thenormal function of the target organ

Occur when lymphocytes or Abs bind to cell-membraneantigens, causing cellular lysis and/or an inflammatory responsein the affected organ

Gradually, the damaged cellular structure is replaced byconnective tissue (scar tissue), and the function of the organdeclines

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HASHIMOTOS THYROIDITIS (DTH)

most frequently seen in middle-aged women, anindividual produces auto-antibodies and sensitizedT H1 cells specific for thyroid Ag

characterized by an intense infiltration of thethyroid gland by lymphocytes, macrophages, andplasma cells, which form lymphocytic follicles andgerminal centers

ensuing inflammatory response causes a goiter, orvisible enlargement of the thyroid gland, aphysiological response to hypothyroidism

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AUTOIMMUNE ANEMIAS

include pernicious anemia, autoimmune hemolyticanemia, and drug-induced hemolytic anemia

Pernicious anemia is caused by auto-antibodies tointrinsic factor,

binding of auto-antibody to intrinsic factor blocksthe intrinsic factormediated absorption of vitamin B12.

in the absence of sufficient vitamin B12, which isnecessary 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-mediatedopsonization and phagocytosis of the RBCs

Drug-induced hemolytic anemia when certain drugs such as penicillin or the anti-hypertensive agent methyldopa interact with RBCs thecells become antigenic

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GOODPASTURES SYNDROME auto-antibodies specific for certain basement-membrane

antigens bind to the basement membranes of the kidneyglomeruli and the alveoli of the lungs

subsequent complement activation leads to direct cellulardamage and an ensuing inflammatory response mediated by abuild-up of complement split products

damage to the glomerular and alveolar basement membranesleads 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 basementmembranes

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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 (betacells)

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 theinsulin 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 releaseand the presence of auto-antibodies, which leads to acell-mediated DTH response

subsequent beta-cell destruction is thought to bemediated by cytokines released during the DTHresponse and by lytic enzymes released from theactivated M

Auto-antibodies to beta cells may contribute to celldestruction by facilitating either antibody-plus-complement lysis or antibody-dependent cell-mediatedcytotoxicity (ADCC)

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Autoimmune Diseases Mediated stimulating or blocking auto-Abs

Abs act as agonists, binding to hormone receptorsin the normal ligand and stimulatinginappropriate 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 affectedorgan

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Autoimmune Diseases Mediated stimulatingor blocking auto-Abs Graves Disease:Graves Disease:

Production of auto-antibodies that bind the receptor forTSH and mimic the normal action of TSH, activating

adenylate cyclase and resulting in production of thethyroid hormones

Unlike TSH, however, the autoantibodies are notregulated, and consequently they overstimulate the

thyroid. For this reason these auto-antibodies are called long-

acting 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 byblocking antibodies

auto-antibodies that bind the acetylcholine receptorson 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 rangeof target antigens and involves a number of organs and tissues.

these diseases reflect a general defect inimmune regulation that results in hyperactiveT cells and B cells.

tissue damage is widespread, both from cellmediated immune responses and from directcellular damage caused by auto-antibodies orby accumulation of immune complexes

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Systemic Lupus Erythematosus

which typically appears in women between 20 and 40 yearsof 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 womenthan in Caucasians, although it is not known why this is so.

affected individuals may produce autoantibodies to a vastarray 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 antigensproduces various symptoms.

Auto-antibody specific for RBCs and platelets, for example, canlead to complement-mediated lysis, resulting in hemolyticanemia and thrombocytopenia, respectively

when immune complexes of auto-antibodies with variousnuclear antigens are deposited along the walls of small bloodvessels, a type III hypersensitive reaction develops.

the complexes activate the complement system and generatemembrane-attack complexes and complement split productsthat damage the wall of the blood vessel, resulting in vasculitisand 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 arealso frequently affected

Characterized by production of a group of auto-antibodiescalled rheumatoid factors that are reactive with determinants inthe Fc region of IgG

the classic rheumatoid factor is an IgM antibody with thatreactivity

such auto-antibodies bind to normal circulating IgG, formingIgM-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 tochronic inflammation of the joints.

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Proposed Mechanisms for Induction of

Autoimmunity a variety of mechanisms have been proposed to account forthe T-cellmediated generation of autoimmune diseases

evidence exists for each of these mechanisms, and it islikely that autoimmunity does not develop from a singleevent but rather from a number of different events

susceptibility to many autoimmune diseases differsbetween the two sexes

Hashimotos thyroiditis, systemic lupus erythematosus, multiplesclerosis, rheumatoid arthritis, and scleroderma preferentially

affect women factors that have been proposed to account for this

preferential susceptibility, such as hormonal differencesbetween the sexes and the potential effects of fetal cells inthe maternal circulation during pregnancy

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Sources of Autoimmunity Any tissue antigens that are sequestered from the circulation, and aretherefore not seen by the developing T cells in the thymus, will not induce self-tolerance.

Exposure of mature T cells to such normally sequestered antigens at a latertime might result in their activation

a pathogen may express a region of protein that resembles a particular self-component 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 therabies vaccine.

In the past, the rabies virus was grown in rabbit brain-cell cultures, andpreparations of the vaccine included antigens derived from the rabbit braincells.

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 ownbrain cells, leading to encephalitis.

Cross-reacting antibodies are also thought to be the cause of heart damage inrheumatic fever, which can sometimes develop after a Streptococcus infection

In this case, the antibodies are to streptococcal antigens, but they cross-react withthe heart muscle

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The pancreatic beta cells of individuals with insulin-dependent diabetesmellitus (IDDM) express high levels of both class I and class II MHCmolecules, whereas healthy beta cells express lower levels of class I and donot 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 expressedonly on APCs may serve to sensitize T H cells to peptides derived from the beta cells orthyroid cells, allowing activation of B cells or T C cells or sensitization of T H1 cells againstself-antigens

Other evidence suggests that certain agents can induce some cells thatshould not express class II MHC molecules to express them (PHA)

A number of viruses and bacteria can induce nonspecific polyclonal B-cellactivation 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, auto-antibodies 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 butmerely palliatives,

aimed at reducing symptoms to provide the patient with anacceptable quality of life

for the most part, these treatments provide nonspecificsuppression of the immune system and thus do not distinguishbetween 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, suchdrugs can reduce the severity of autoimmunesymptoms

general reduction in immune responsiveness, however,puts the patient at greater risk for infection or thedevelopment of cancer

A somewhat more selective approach employscyclosporin A or FK506 to treat autoimmunity

these agents block signal transduction mediated by theT-cell receptor; thus, they inhibit only antigen-activated T cells while sparing nonactivated ones

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Autoimmune Diseases- MMS