Autoimmunity

Julius Donath and Karl Landsteiner (1904)reported autoantibodies can cause disease by showing that autoantibodies (‘hemolysins’) caused paroxysmal cold hemoglobinuria.

1. Autoimmunity

2. Disorders of Immune system

3. DEFINITION Three requirements to call it Autoimmunity : 1 . The presence of an immune reaction specific for some self antigen or self tissue. 2 . Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance. 3 . The absence of another well-defined cause of the disease.

4. HISTORY Julius Donath and Karl Landsteiner (1904)reported autoantibodies can cause disease by showing that autoantibodies (‘ hemolysins ’) caused paroxysmal cold hemoglobinuria.

5. Introduction Autoimmune diseases is a group of disorders in which tissue injury is caused by humoral ( by auto-antibodies ) or cell mediated immune response (by auto-reactive T cells ) to self antigens . An autoimmune disorder may result in: The destruction of one or more types of body tissue Abnormal growth of an organ Changes in organ function

6. Causes of Autoimmunity

7. Tolerance and Autoimmunity

8. Immune tolerance Definition : Immunological tolerance occurs when an immunocompetent host fails to respond to an immunogenic challenge with a specific antigen. * a state of unresponsiveness specific for a given antigen * It is specific (negative) immune response * It is induced by prior exposure to that antigen * While the most important form of tolerance is non-reactivity to self antigens, it is possible to induce tolerance to non-self antigens. When an antigen induces tolerance, it is termed tolerogen .

9. Immune tolerance * Tolerance is different from non-specific immunosuppression and immunodeficiency. It is an active antigen-dependent process in response to the antigen. * Like immune response, tolerance is specific and like immunological memory, it can exist in T cells, B cells or both and like immunological memory, tolerance at the T cell level is longer lasting than tolerance at the B cell level.

10. TOLERANCE – GENERAL PROPERTIES Immature or developing lymphocyte is more susceptible to tolerance induction than mature one 1.Tolerance to antigens is induced even in mature lymphocytes under special conditions 2.Tolerance of T lymphocytes is a particularly effective for maintaining long-lived unresponsiveness to self antigens

11. Central tolerance: fates of immature self-reactive lymphocytes Induced by antigen in generative lymphoid organs (thymus for T cells, bone marrow for B cells), and high-affinity (“strong”) recognition of the antigens Immature lymphocytes undergo apoptosis upon encounter with antigens (negative selection) Eliminates high-affinity self-reactive (potentially most dangerous) lymphocytes Some self-reactive T cells that encounter self antigens in the thymus develop into regulatory T cells and immature B cells in the bone marrow change their receptors (rendered harmless)

12. Mechanisms of tolerance induction * Clonal deletion – physical elimination of cells from the repertoire during their lifespan * Clonal anergy – downregulating the intrinsic mechanism of the immune response such as lack of costimulatory molecules or insufficient second signal for cell activation * Suppression – inhibition of cellular activation by interaction with other cells: ( Treg – CD4+CD25+ T lymphocytes)

13. Mechanism of tolerance induction Clonal deletion: Functionally immature cells of a clone encountering antigen undergo a programmed cell death, as auto-reactive T-cells are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection).

14. Mechanism of tolerance induction Clonal anergy : * Auto-reactive T cells, when exposed to antigenic peptides which do not possess co-stimulatory molecules (B7-1 or B7-2), become anergic to the antigen. * Recognition of such antigens may lead to signaling block and/or engagement of inhibitory receptors

15. Mechanism of peripheral tolerance Ignorance: Never encounter Self Ag Anergy : unresponsiveness Self reactive T cell interact with APC but co-stimulatory signal blocked Immunomodulatory molecules like CTLA4 binding instead of CD 28 on T cell Phenotypic skewing: after activation via APC (with Self Ag)---Non pathogenic cytokines release Activated self reactive Tcell ---Upregulation of Fas Ligand---apoptosis Regulatory T cells (T REG Cells )-can down regulate self reactive T cell (by IL-10, TGF-b) Sequestration of self Ag: lens protein

16. Antigen can be T olerogen or Immunogens Co-stimulatory molecules play an important role Tolerance is antigen specific

17. Immune tolerance: factors that influence immunity vs. tolerance * The stage of differentiation of lymphocytes at the time of antigen confrontation * The site of encounter * The nature of cells presenting antigenic epitopes * The number of lymphocytes able to respond * Microenvironment of encounter (expression of cell adhesion molecules, influence of cytokines etc.)

18. Immunologically Privileged Sites * Sites in the body where foreign antigens or tissue grafts do not elicit immune responses * These antigens do interact with T cells, but instead of destructive IR they induce tolerance or a response innocent to the tissue Immunosuppressive cytokines such as TGF-beta seem to be resposible for such unusual response * The sites include: brain, eye, testis, uterus (fetus)

19. Failure of tolerance Autoimmunity Failure of Tolerance to protect host from self-reacting lymphocytes Destruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells 3 % to 8 % of individuals in the industrialized world

20. Factors responsible for promoting tolerance High dose of antigen Persistence of antigen Route of administration Adjuvents Low level of co-stimulators Presentation of antigen by immature/ unactivated antigen-presenting cells (APCs)

21. All together Autoimmunity may be due to immunological, Genetic, Viral, Drug induced, & hormonal mechanisms Number of immunological mechanism  all leading to abnormal B or T-cell production. Most instances Diseases by multiple mechanism  difficulty in Rx

22. Mechanisms Antigenic alteration Sequestered Ag Cross reacting foreign Ag Molecular mimicry Polyclonal activation of B cell Altered T or B cell function

23. Antigenic alteration Neoantigen formation Physical- Irradiation, photosensitivity, cold allergy Chemical- Drug induced anemia , Lecopenia , thrombocytopenia Biological injury-Viral infection (infectious mononucleosis etc ) intracellular pathogen

24. Sequestered Ag Sequestered Ag: Self Ab present in closed system not accessible to immune system Lens protein Immunological tolerance not established during foetal life Penetrating injury---leak of lens protein—immune response— injury to other eye

25. Sequestered Ag Sperm Ag—Puberty Mumps---damage to BM seminiferous tubules—immune response--- Orchitis

26. Cross reacting foreign Ag Similary b/w some foreign & Self Ag Indivisual Nerve tissue damage- antirabies immunization of human with neural vaccine of infected sheep brain Streptococcal M protein—heart ms —Heart damage Nephritogenic strain streptococcus-- GN

27. Molecular mimicry Identical peptide sequence in epitopes b/w microorganism & Self Ag HLA B27- Arthritogenic strain of S. flexneri Joint membrane- M. tuberculoisis Myocardium- Coxsackie B virus

28. Polyclonal activation of B cell Ag--- corresponding B cell activation Polyclonal activation of B cells: Chemical (2 ME) Bacterial product (PPD, LPS) Enz (Trypsin) Antibotics (Nystatin) Infection (Mycoplasma, EBV, Malaria)

29. Altered T or B cell function Enhanced Helper T cell ↓↓ Suppressor T cell function Defect in thymus Stem cell development Macrophage function Idiotype-antiidiotype network defect

30. Nature Immunology

31. Initial laboratory evaluation Inflammatory markers Autoantibodies and Immunologic Studies Flow cytometry Cytokine studies Major Histocompatibility Complex (MHC) (human leukocyte antigen (HLA))

32. Initial laboratory evaluation CBC Liver function tests Renal function tests Coagulation studies Urine analysis Inflammatory markers Erythrocyte sedimentation rate (ESR ) C-reactive protein ( CRP) Ferritin Ceruloplasmin Fibrinogen Haptoglobin Albumin

33. 3. Autoantibodies and Immunologic Studies Enzyme-linked immunosorbent assay (ELISA ) Rheumatoid factor (RF) and Anti-nuclear antibody (ANA ) Anti-double stranded DNA (anti-dsDNA ) Anti-extractable nuclear antigen (anti-ENA ) Antineutrophil cytoplasmic antibody (ANCA) [myeloperoxidase (MPO), proteinase-3 (PR3 ) Complement Immunoglobulins (quantitative and qualitative ) Cryoglobulins antiphospholipid autoantibodies ( aPL ) 4. Flow cytometry 5. Cytokine studies 6. Major Histocompatibility Complex (MHC) (human leukocyte antigen (HLA))

34. Localised Organ Specific Diseases

35. Disease Hashimoto’s Ds Enlargement of thyroid Hypothyrodism or Frank myxedma Glandular structure-replacement with lymphoid tissue Ab- to thyoglobulin , acinar colloid, Microsomal Ag, thyroid cell surface components Thyrotoxicosis (Grave’s Ds) ↑↑↑ hormone IgG Ab (to thyroid membrane Ag) act as Long acting thyroid stimulator (LATS) Addison ds Lymphocytic infiltration of adrenal & circulating Ab to Zona glomerulosa Autoimmune orchitis Mumps Lymphocytic infiltration of Testes & circulating Ab to sperm & germinal cell

36. Disease Myasthenia gravis Thyorid lymphoid hyperplasia Numerous germinal center Ab Ach Receptor on myoneural junction of striated Ms---impairment of Ms Contraction Autoimmune Disease of eye Phacoanaphylaxis - Cataract Sx –intraocular inflammation Symathetic ophthamia - Performating injury to one eye Pernicious Anaemia Ab to parietal cell of gastric mucosa- Achlorhydria , Atrophic gastritis Ab to Intrinsic Factor--- Vit B12 def Autoimmune Disease of Nervous system Neuroparalytic accidents following- neural vaccine—Rabies GBS- idiopathic polyneuritis Autoimmune ds of Skin Pemphigus vulgaris- Ab to intracellular adhesion protein desmoglein Bullous pemphigoid- Ab dermoepidermal junction Ab in Dermatitis herpetiformis

37. Variety of AutoAb Nuclei Intracytoplasmic cell constituents LE cell- Neutrophils containing LE Bodies (large pale homogenous body) almost filling cytoplasm Antinuclear Ab (ANA)—Sensitive but not specific Pattern: homogenous, Peripheral, speckled, nucleolar Anti DNA Ab- ds

38. The diagnostic methods of autoimmune diseases includes, • Initial laboratory evolution • Immunological studies • Inflammatory markers • Flowcytometry • Cytokine studies • Major histocompatibility complex

39. Q : Why are autoimmune diseases challenging to diagnose? A: Diagnosis is challenging for several reasons: 1. Patients initially present with nonspecific symptoms such as fatigue, joint and muscle pain, fever, and/or weight change. 2. Symptoms often flare and remit. 3. Patients frequently have more than 1 autoimmune disease. According to a survey by the Autoimmune Diseases Association, it takes up to 4.6 years and nearly 5 doctors for a patient to receive a proper autoimmune disease diagnosis

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