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AUTOIMMUNITY &IMMUNOTOLERANCE.pptx
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- 2. INTRODUCTION:- An inappropriateresponse of the immune system against self-components is termed as autoimmunity. Sometimes the damage to self-cells or organs is caused by antibodies; in other cases,T cells are the culprit. can be divided into two broad categories:- Organ-specific diseases. Systemic autoimmune diseases. Affect 5%–7% of the human population.
- 3. Organ-Specific Autoimmune Diseases Inthis type, 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. Some Autoimmune Diseases Are Mediated by Direct Cellular Damage. Whereas some Autoimmune Diseases Are Mediated by Stimulating or Blocking Auto- Antibodies.
- 4. Autoimmune Diseases by DirectCellular Damage These diseases occur:- when lymphocytes /antibodies 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). Function of the organ declines.
- 5. EXAMPLES OF DirectCellular Damage autoimmunity:- A:-HASHIMOTO’STHYROIDITIS :- Auto-Antibodies are formed to a number of thyroid proteins, including thyroglobulin and thyroid peroxidase, both of which are involved in the uptake of iodine. sensitizedTH1 cells specific for thyroid antigens are also produced in addition to auto-antibodies.
- 6. B:-AUTOIMMUNE ANEMIAS:- They includepernicious anemia, autoimmune hemolytic anemia, and drug-induced hemolytic anemia. a. Pernicious anemia is caused by auto-antibodies to intrinsic factor, a membrane-bound intestinal protein on gastric parietal cells. b. Autoimmune hemolytic anemia is caused by auto-antibody to RBC antigens, triggering complement mediated lysis or antibody- mediated opsonization and phagocytosis of the red blood cells.
- 7. c. One formof autoimmune anemia is drug- induced: when certain drugs such as penicillin or the anti-hypertensive agent methyldopa interact with red blood cells, the cells become antigenic by having IgG auto-antibodies present on the red cells.
- 8. C:-GOODPASTURE’S SYNDROME:- Auto-antibodiesspecific 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 buildup of complement split products
- 9. D:-INSULIN-DEPENDENT DIABETES MELLITUS:- ActivatedCTLs migrate into an islet and begin to attack the insulin producing cells. Local cytokine production during this response includes IFN-,TNF-, and IL-1. Auto-antibody production can also be a contributing factor in IDDM.
- 10. The firstCTL infiltration and activation of macrophages, frequently referred to as insulitis is followed by cytokine release and the presence of auto-antibodies, which leads to a cell-mediated DTH response. The subsequent beta-cell destruction is thought to be mediated by cytokines released during the DTH response and by lytic enzymes released from the activated macrophages.
- 11. . Auto-antibodiesto beta cells may contribute to cell destruction by facilitating either antibody-plus-complement lysis or antibody- dependent cell-mediated cytotoxicity (ADCC).
- 12. Stimulating/Blocking Auto- Antibodies autoimmunity:- In some autoimmune diseases, antibodies act as agonists, binding to hormone receptors in lieu of the normal ligand and stimulating inappropriate activity.This usually leads to an overproduction of mediators or an increase in cell growth. Conversely, 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.
- 13. Examples:- A:-GRAVES’ DISEASE:- Apatient with Graves’ disease produces auto-antibodies that bind the receptor for TSH and mimic the normal action ofTSH, activating adenylate cyclase and resulting in production of the thyroid hormones. UnlikeTSH, however, long-acting thyroid- stimulating (LATS) auto-antibodies are not regulated that overstimulate the thyroid.
- 14. B:- MYASTHENIA GRAVIS:- Blocking auto-antibodies are produced that bind the acetylcholine receptors on the motor end-plates of muscles, blocking the normal binding of acetylcholine and also inducing complement mediated lysis of the cells. Ultimately, the antibodies destroy the cells bearing the receptors.
- 15. Systemic Autoimmune Diseases:- Insystemic 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 hyperactiveT 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.
- 16. EXAMPLES:- A:-Systemic Lupus Erythematosus Affectedindividuals may produce auto- antibodies to a vast array of tissue antigens, such as DNA, histones, RBCs, platelets, leukocytes, and clotting factors Auto-antibody specific for RBCs and platelets, for example, can lead to complement- mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively.
- 17. When immunecomplexes 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.
- 18. Excessive complementactivation in patients with severe SLE produces elevated serum levels of the complement split products C3a and C5a, which may be three to four times higher than normal. C5a induces increased expression of the type 3 complement receptor (CR3) on neutrophils, facilitating neutrophil aggregation and attachment to the vascular endothelium.
- 19. B:-Multiple Sclerosis Auto reactiveTcells are produced that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers. The cerebrospinal fluid of patients with active MS contains activatedT lymphocytes, which infiltrate the brain tissue and cause characteristic inflammatory lesions, destroying the myelin.
- 20. C:-Rheumatoid Arthritis A groupof auto-antibodies called rheumatoid factors is produced 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.
- 21. Mechanisms for T-cell– mediatedautoimmunity:- A:-Release of Sequestered Antigens Can Induce autoimmune Disease. The induction of self-tolerance inT cells results from exposure of immature thymocytes to self antigens and the subsequent clonal deletion of those that are self-reactive. Any tissue antigens that are sequestered from the circulation, and are therefore not seen by the developingT cells in the thymus, will not induce self-tolerance. Exposure of matureT cells to such normally sequestered antigens at a later time might result in their activation.
- 22. B:- Molecular MimicryMay Contribute to Autoimmune Disease A number of viruses and bacteria have been shown to possess antigenic determinants that are identical or similar to normal host- cell components. This proposes that a pathogen may express a region of protein that resembles a particular self-component in conformation or primary sequence.
- 23. C:- Inappropriate Expressionof Class II MHC Molecules Can Sensitize Auto reactiveT Cells Certain agents can induce some cells that should not express class II MHC molecules to express them. For example, theT-cell mitogen phyto hemagglutinin (PHA) has been shown to induce thyroid cells to express class II molecules. In vitro studies reveal that IFN- also induces increases in class II MHC molecules on a wide variety of cells, including pancreatic beta cells, intestinal epithelial cells, melanoma cells and thyroid acinar cells.
- 24. D:-Polyclonal B-Cell ActivationCan Lead to Autoimmune Disease 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 ofTH cells. If B cells reactive to self- antigens are activated by this mechanism, auto- antibodies can appear.
- 25. Treatment of Autoimmune Diseases Immunosuppressive drugs (e.g., corticosteroids, azathioprine, and cyclophosphamide) are often given with the intent of slowing proliferation of lymphocytes.The 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 theT- cell receptor; thus, they inhibit only antigen- activatedT cells while sparing non activated ones.
- 26. Another therapeutic approachthat has produced positive results in some cases of myasthenia gravis is removal of thymus. Patients with Graves’ disease, myasthenia gravis, rheumatoid arthritis, or systemic lupus erythematosus may experience short-term benefit from plasmapheresis. In this process, plasma is removed from a patient’s blood by continuous-flow centrifugation.The blood cells are then resuspended in a suitable medium and returned to the patient. Plasmapheresis has been beneficial to patients with autoimmune diseases involving antigen-antibody complexes, which are removed with the plasma.
- 27. T-CellVaccination Is aPossibleTherapy. Peptide Blockade of MHC Molecules Can Modulate Autoimmune Responses. Monoclonal Antibodies May Be Used toTreatAutoimmunity When antigens are administered orally, they tend to induce the state of immunologic unresponsiveness called tolerance.
- 28. IMMUNO TOLERANCE RESPONSE:- Immunetolerance refers to the state of a biological system where there should be an immune response but there is none. Tolerance refers to a state of specific unresponsiveness to a specific antigen or failure to mount an immune response to an antigen It is an active response to a particular epitope and is just as specific as an immune response
- 29. Immune tolerance isinduced by prior exposure to that antigen. This does not necessarily mean total lack of immune response. Antigens that induce tolerance are called tolerogens.
- 30. TYPES OF IMMUNETOLERANCE SELF VS NON-SELF:- Immunological ‘self’ implies to all epitopes encoded by the individual’s DNA. All others are considered non-self.
- 31. Ways to preventresponding self Ag Five possible ways- 1. Self-reactive cells may be deleted at certain stages of development. 2. Self-reactive cells may be unable to respond. 3. Self-reactiveT cells may ignore self Ags. 4. Response to self Ag may be supressed if the Ag is in a privileged site. 5. Tolerance can be maintained by immune regulation.
- 32. o Which ofthese mechanisms would work depends on • The stage of maturity of the lymphocyte • The affinity of the receptor for the self Ag • The nature of the Ag • Concentration of the lymphocyte • Tissue distribution of lymphocyte • Pattern of expression of lymphocyte.
- 33. The kinds oftolerance o Tolerance is classified into 1. Central tolerance: Tolerance ofT or B cells induced in during development in the primary lymphoid organs (the bone marrow for B cells and the thymus forT cells). 2. Peripheral tolerance: Induced in other tissues and lymph nodes. o The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.
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- 35. Other mechanisms ofCentral Tolerance o Clonal arrest:Thymocytes that express auto reactiveT-cell receptors are prevented from maturation. o Clonal energy: Autoreactive cells are inactivated, rather than deleted. o Clonal editing: Autoreactive cells are given second or third chance to rearrange aTCR gene. o Clonal deletion is probably the most common mechanism responsible for thymic negative solution.
- 36. Factors that promote tolerance oFetal exposure o High doses of antigen o Long-term persistence of antigen in the host o Intravenous or oral introduction o Absence of adjuvants (compounds that enhance the immune response to antigen). o Low levels of costimulation o Presentation of antigen by immature or unactivated antigen-presenting cells(APCs)
- 37. Escape from central tolerance oTwo factors contribute to this 1. Not all self-antigens are expressed in the central lymphoid organs where negative selection occurs, and 2. There is a threshold requirement for affinity to self antigens before clonal deletion is triggered.
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- 39. Central Tolerance o Tolerancebegins when IgM appears on B cell o Eliminate approximately 90% of the self- reactive B cell pool o Different mechanisms 1. Receptor editing 2. Clonal deletion 3. Clonal energy