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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, 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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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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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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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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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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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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