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Autoimmunity dwd lect

Principle, etiology,pathogenesis and diseases

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Autoimmunity dwd lect

  1. 1. • 1. Define and discuss autoimmunity 2. Use autoimmune diseases to illustrate mechanisms of autoimmunity 3. Provide you with clinical correlations and applications of the basic principles of immunology 4. To illustrate the spectrum of autoimmune diseases 5. To define pathogenic aspects of autoimmune diseases
  2. 2. • Definition : Autoimmunity is a condition in which body’s own immunologically competent cells or antibodies act against self – antigens resulting in structural or functional damage. Hashimoto’s Thyroiditis Systemic Lupus Erythematosus (SLE)
  3. 3. : Literally, the horror of self-toxicity. • A term coined by the German immunologist Paul Ehrlich (1854- 1915) to describe the body's innate aversion to immunological self-destruction.
  4. 4. • Normally immune system does not react to its own antigens due to protective mechanism called • Any breach in tolerance mechanism predispose to several autoimmune diseases.
  5. 5. is a state in which an individual is incapable of developing an immune response against his/her own tissue antigens. • Mediated by broad mechanisms : 1. Central Tolerance 2. Peripheral Tolerance
  6. 6. : Refers to the deletion of self reactive T & B lymphocytes during their maturation in central lymphoid organs ( i.e. in the thymus for T cells & in the bone marrow for B cells).
  7. 7. During T cell development in thymus, if any self antigens are encountered, they are processed & presented by thymic antigen presenting cells (APCs) in association with self MHC. Any developing T cell that expresses a receptor for such self antigens are negatively selected ( i.e. deleted by apoptosis). Thus the resulting peripheral T cell pool is devoid of self reactive cells.
  8. 8. Immature T-cells migrate from bone marrow to thymus. Interact with self peptide-MHC complexes on thymic epithelium. Double positive(CD4+/CD8+)thymocytes develop T-cell receptors (TCRs) –Only those with low affinity for self- antigens persist (Positive Selection). Cells with dysfunctional TCRs or with very high or no affinity for MHC-self peptide complex undergo apoptosis (Negative Selection). • Positively selected cells then lose either CD4 or CD8 and leave thymus to function in periphery as mature CD4+ or CD8+T-cells
  9. 9. When developing immature B cells in the bone marrow encounter a self antigen during their development, the tolerance is developed by – Many B cells reactivate the machinery of antigen receptor gene arrangement ( genes coding for light chain) so that a different (edited) B cell receptor will be produced which no longer recognizes the self antigen
  10. 10. When developing immature B cells in the bone marrow encounter a self antigen during their development, the tolerance is developed by – After receptor editing, if the B cells again recognize a self antigen, then they are destroyed by subjecting them to apoptosis.
  11. 11. • Several back – up mechanisms occur in peripheral tissues to counteract the self reactivity. It is provided by many mechanisms- Self reactive T cells might never encounter the self antigens which they recognize & therefore may remain in a state of ignorance. Unresponsiveness to antigenic stimulus. The self reactive T cells interact with the APCs presenting the self antigen, but the co stimulatory signal is blocked. The B7 molecules on T cells bind to CTLA – 4 molecules on T cells instead of CD28 molecules.
  12. 12. Self reactive T cells interacting with APCs presented with self antigens, undergo full activation, but might secrete nonpathogenic cytokines & chemokine receptors profile & fail to induce autoimmune response even though are activated. Self reactive T cells are activated on interaction with APCs presented with self antigens. But activation of T cells induces upregulation of Fas ligand which subsequently interacts with the death receptor Fas leading to apoptosis. = AICD.
  13. 13. They down regulate the self reactive T cells through secreting cytokine IL – 10 & transforming growth factor  (TGF - ) or killing by direct cell to cell contact. When immature & tolerogenic dendritic cells capture self antigens for processing, they down regulate the expression of molecules of co stimulatory ligands such as B7 & CD40 molecules or may indirectly induce Treg Cells. Certain self antigens can evade immune recognition by sequestration in immunologically
  14. 14. Certain self antigens can evade immune recognition by sequestration in immunologically privileged sites e.g. corneal proteins, testicular antigens & antigens from brain.
  15. 15. • When the mechanisms controlling and maintaining tolerance function poorly or breakdown, autoimmunity and autoimmune disease can develop.
  16. 16. Normal cells that do not usually express co stimulatory molecules(B7) are induced to do so leading to tissue necrosis & local inflammation. This mechanism postulated in Multiple sclerosis, Rheumatoid arthritis, Psoriasis. Failure of autoreactive T cells to undergo activation induced cell death(AICD). i.e. apoptosis via Fas – Fas ligand can lead to autoimmunity. Seen in Systemic Lupus Erythematosus(SLE). Autoimmunity can result from the loss of T cell mediated suppression of self reactive lymphocytes.
  17. 17. Antibody response to self antigens occurs only when potentially self reactive B cells receive help from T cells. Autoreactive B-cells -Efficient antigen presenting cells (APCs). May present antigen to non- autoreactive T- cells. Part of the cross-reactive antigen has an epitope that normal (non-autoreactive) T cells recognize. This processed antigen is now capable of stimulating T-cells and provides “help” for autoreactive B cells
  18. 18. The sequestrated antigens are viewed as foreign to the immune system as they are never been exposed to the tolerance mechanisms during development of immune system. Injury to the organs lead to release of such sequestrated antigens which are capable of mounting immune response. Spermatozoa & ocular antigens release can cause post vasectomy orchitis & post traumatic uveitis. The self peptides released due to persistent inflammation induce tissue damage ( chronic infection) & are processed & presented by APCs along with microbial peptides. Non specific activation of bystander self reactive TH1 cells leads to cytokine influx which causes an increased infiltration of various non specific T cells at the site of infection.
  19. 19. Some microorganisms share antigenic determinants with self antigens, & induce an immune response against such microbes would produce antibodies that can crossreact with self antigens. • Acute rheumatic fever results due to antibodies formed against streptococcal M protein cross react with cardiac glycoproteins due to antigenic cross reactivity. • Molecular mimicry involving T cell epitopes – Multiple sclerosis where T cell clones reacting myelin basic protein probably would have been induced by reacting against peptides derived from many microbes including viruses.
  20. 20. Several microorganisms & their products are capable of causing polyclonal (i.e. antigen non – specific) activation of T cells or B cells. • Polyclonal T cell activation – Superantigens released from microbes e.g. Staphylococcus aureus polyclonally activate the T cells directly by binding to antigen on non specific V region of T cell receptor. • Polyclonal B cell activation – It can be induced by products of various microbes such as Epstein Barr virus, HIV etc.
  21. 21. • During development of immune system, not all epitopes of an antigen are effectively processed & presented to T cells. There are some non dominant cryptic epitopes which remain sequestrated. Hence T cell clones reacting against such epitopes are not deleted. • Such cryptic epitopes can be released secondary to inflammation at the site of tissue injury, which can induce increased protease production & differential processing of released self – epitopes by APCs.
  22. 22. The administration of drugs or defects in synthesis could result in the modification of a previously tolerated epitope, rendering it antigenic • Not commonly reported • Autoimmune hemolytic anaemia following treatment with methyldopa • Isoniazid may produce arthritis, associated with production of anti-nuclear antibodies. • Procainamide induces anti-nuclear antibodies in a high proportion of patients, with 40% showing clinical signs of SLE
  23. 23. Disease Self antigen present on Type of immune response & important features Autoimmune anemias Autoimmune hemolytic anemia. RBC membrane protein Autoantibodies to RBC antigens trigger compliment mediated lysis or antibody mediated opsonization of the RBCs. Drug induced hemolytic anemia Drugs alter the red cell membrane antigens Drugs such as penicillin or methyldopa interact with RBCs so that cells become antigenic. Pernicious anemia Intrinsic factor( a membrane bound protein on gastric parietal cells) Autoantibodies to intrinsic factor block the uptake of vitamin B12 leads to megaloblastic anemia. Idiopathic thrombocytopenic purpura Platelate membrane proteins (glycoproteins II b – III a or I b – IX) Auto – antibodies against platelate membrane antigens leads to  platelate count. Goodpasture syndrome Renal & lung basement membranes Auto- antibodies bind to basement membrane antigens or kidney glomeruli & the alveoli of the lungs followed by complement mediated injury leads to progressive kidney damage & pulmonary hemorrhage.
  24. 24. Disease Self antigen present on Type of immune response & important features Myasthenia gravis Acetylcholine receptors Blocking type of antibody directed against Ach receptors present on motor nerve endings, leads to progressive weakening of the skeletal muscle. Grave’s disease Thyroid stimulating hormone (TSH) receptor Anti – TSH auto- antibody (stimulates thyroid follicles, leads to hyperthyroid state) Hashimoto’s thyroiditis Thyroid proteins & cells Auto- antibodies & TDTH cells targeted against thyroid antigen leads to suppression of thyroid gland • Seen in middle aged females • Hypothyroid state is produced( production of thyroid hormone). Post – Streptococcal glomerulonephritis Kidney Streptococcal antigen – antibody complexes are deposited in glomerular basement membrane.
  25. 25. Disease Self antigen present on Type of immune response & important features Systemic lupus Erythematosus (SLE) Autoantibodies are produced against various tissue antigens such as DNA, nucleus protein, RBC & platelate membranes. • Age & sex – Women (20 – 40 yrs) are commonly affected female to male ratio 10 :1 • Immune complexes – (self Ag - auto Ab) are formed which are deposited in various organs •Major symptoms Fever, butterfly rash over the cheeks, arthritis, pleurisy, & kidney dysfunction. Rheumatoid arthritis Here a group of auto – antibodies against the host IgG antibodies are produced called RA factor. It is an IgM antibody against the Fc region of IgG Anticitrulinated peptide antibodies (ACPA) are also produced •Age & sex : Women(40 – 60 yrs) affected. • Autoantibodies bind to circulating IgG, forming IgM – IgG complexes that are deposited in the joints & can activate the complement cascade. • Major symptoms – Arthritis( chronic inflammation of joints, begins at synovium, common joints – small joints of hands, feet & cervical spine. • Other features – Hematologic, CVS & RS also frequently affected.
  26. 26. Disease Self antigen present on Type of immune response & important features Sjogren syndrome Ribonucleoprotein (RNP) antigens SS – A (Ro) & SS – B (La) present on salivary gland, lacrimal gland, liver, kidney, thyroid. • Autoantibodies to the RNP antigens SS – A (Ro) & SS – B (La) ; leads to immune mediated destruction of the lacrimal & salivary glands resulting in dry eyes (Keratoconjunctivitis) & dry mouth (xerostomia). Scleroderma (systemic sclerosis) Nuclear antigens such as DNA topoisomerase & centromere present in heart, lungs, GIT, Kidney etc. Helper T cells (mainly) & autoantibody mediated. Excessive fibrosis of the skin, throughout the body. Two types: • Diffuse scleroderma – Autoantibodies against DNA topoisomerase I (anti Scl 70) is elevated. • Limited scleroderma -  Anticentromere antibody, characterized by CREST syndrome - calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, & telangiectasia.
  27. 27. Disease Self antigen present on Type of immune response & important features Seronegative Spondyloarthropathies Sacroiliac joints & other vertebrae. Several types- • Ankylosing spondylitis • Reiter Syndrome • Psoriatic Arthritis •Spondylitis with inflammatory Bowel Disease •Reactive arthritis. Common Characteristics: They present as rheumatoid arthritis like features, but differ from it by: • Association with HLA – B 27 • Pathologic changes begin in ligamentous attachments to the bone rather than in the synovium. • Involvement of the sacroiliac joints and/or arthritis in other peripheral joints. • Absence of RA( hence the name seronegative). • Auto – Ab & immune complex mediated. Multiple sclerosis Brain (white matter) Self reactive T cells produce characteristic inflammatory lesions in brain that destroys the myelin sheath of the nerve fibers; leads to numerous neurologic dysfunctions.
  28. 28. Diagnosed by Coombs test, in which the red cells are incubated with an anti – human IgG antiserum. If IgG autoantibodies are present on the red cells, the cells are agglutinated by the antiserum. Biopsies from the patients are stained with fluorescent – labeled anti – IgG & anti – C3b reveal linear deposits of IgG & C3b along the basement membranes.
  29. 29. is diagnosed by : 1. Detection of autoantibodies against various nuclear antigens by indirect immunofluorescence assay & ELISA based techniques 2. Antinuclear antibody (ANA) : Positive in >90% of cases used as screening method 3. Anti – double stranded DNA (dsDNA): Highly specific, used for confirmation of cases. 4. Anti – Sm antibodies. 5. Lupus band test: It is a direct immunofluorescence test, can detect deposits of immunoglobulins & complement proteins in the patient’s skin. 6. LE cell test: Lupus erythematosus (LE) cell test was commonly used for diagnosis .
  30. 30. Anti Scl 70 antibody is raised, detected by indirect immunofluorescence assay. Is diagnosed by detection of SS- A (or anti Ro) and SS – B (or anti La) antibodies by indirect immunofluorescence assay.