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Immunopathology

Immunopathology. Immunity. Innate (non-specific, native immunity) Adaptive (acquired, specific) – immunity acquired during life. Immunity. “ Innate” immune system : The host defenses that are not antigen specific Physical barriers Chemical -mechanical barriers

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Immunopathology

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  1. Immunopathology

  2. Immunity • Innate (non-specific, native immunity) • Adaptive (acquired, specific) – immunity acquired during life

  3. Immunity • “Innate” immune system: The host defenses that are not antigen specific • Physical barriers • Chemical -mechanical barriers • Soluble cell surface mediator systems • Antigen non-specific phagocytes(Resident macrophages, neutrophils)

  4. Immunity • “Adaptive”immune system: The host defenses which are antigen specific which involves lymphocytes, B-cells, APC’s & immunoglobulins • Defining features: • Specificity • Memory • Capacity for amplification

  5. Biology of immune system: • Cellular components of immune system start from Hemotopoietic stem cells (HSC) • Embryogenesis – 1 month HSC’s appear in Yolk sac 6 weeks - Liver 2 months- 6 months - bone marrow • 8 weeks- lymphoid stem cells fated to become T-cells circulate to Thymus-differentiate to mature T cells • Lymphoid stem cells fated to become B-cells develop in BM • After maturation in Primary lymphoid organs – They “home” to peripheral lymphoid organs(Lymphnodes, spleen , Mucosa, skin)

  6. CD • The cells of Immune system express vast array of surface molecules important in cellular differentiation and cell to cell communication. • They are referred as CD (nomenclature - Cluster of differentiation numbers , more than 250 have been identified) • These surface molecules are helpful for cellular identity

  7. T cells development in thymus • Thymus has epithelial cells in the cortex, macrophages and dentritic cells in cortico-medullary areas. • When T cells pass thru these areas they are “educated” by the process of positive & negative selection • Involves MHC Class I & II expression in the cells in the thymus

  8. T Lymphocytes • 60 – 70% of peripheral lymphocytes • Paracortical areas of lymph nodes • Periarteriolar sheath in the spleen • T cells Express TCR • Other surface molecules expressed by T cells are CD2, CD3, CD4, CD8, CD11a, CD 28, CD40 ligand

  9. Lymph Node Follicle

  10. TCR complex

  11. TCR • TCR can bind only to membrane bound antigens • Needs 2 signals for activation

  12. CD4+ T Lymphocyte • Master regulator (60% of peripheral T cells) • recognize antigen only in the context of MHC class II antigens on APCs (Class II restricted) • Thru’ cytokines it can influence the function of all other cells of immune system • Two subsets have been recognized • Th1 (T helper 1) • Th2 (T helper 2)

  13. Defense Against Intracellular organisms IL- 2 IFN-g DH, Macrophage Activation, IgG2b Th1 IL- 12 ThP cell IL- 4 IL- 5 IL- 6 IL- 9 IL-10 IL-13 TGFb Defense Against large Extracellular Pathogens, Allergy, Immunoregulation IL- 4 IgE IgG Other Ig Th2

  14. Cytotoxic T cell (CD 8+ TCT) • An effector cell • Recognizes antigens only in the context of MHC Class I antigens present on all nucleated cells (Class I restricted) • Activated CTL kills target cells (i.e., virus infected cell, tumor cells etc.) –cytotoxic • Produces cytokines of Th1 cell type

  15. B Lymphocyte • 10 – 20% of circulating lymphocytes • Bone marrow, Follicular areas of nodal and extra-nodal lymphoid tissue, White pulp of spleen • Express surface immunoglobulin as B cell receptor (usually IgM) • Recognize Ag thru’ BCR • Other surface molecules include complement receptors, FC receptors(CD21), CD 40, CD 20, CD 19 etc. • B cell forms plasma cells on antigenic stimulation

  16. BCR

  17. B & T-cell Interaction

  18. Before binding antigen, B cells contain IgM molecules only. Following antigen binding, when plasma cells are produced, class switching occurs. Class switching refers to a DNA rearrangement changing the heavy chain constant gene in memory cells

  19. APC’s • Macrophages, Dentritic cells, B cells, Endothelial cells & Epithelial cells Macrophages (histiocytes): • Express Class II MHC antigen, complexed with processed, exogenous, particulate antigen • DH – Formation of granulomas • Participate in both innate and adaptive immune system

  20. APC’s • Dentritic cells: • Interdigitating dendritic cell • Nonphagocytic • Express MHC class II, B7-1/7-2 molecules(CD80/86) • Most potent antigen presenting cell for naïve T cells • Widely distributed • In the skin, dentritic cells are called langerhan’s cells • Follicular dendritic cells • Seen within the lymphoid follicles

  21. Natural Killer Cells • 10 – 15% of circulating cells • Also called large granular lymphocytes • They lack TCR or BCR • Express CD2, CD16, CD56. • Can kill tumor cells and virus infected cells without prior sensitization • Participate in ADCC • NK cell induced lysis is inhibited by MHC class I • Secrete TNFa, GM-CSF, IFN-g • stimulated by IL2 and IL15

  22. MHC • MHC or HLA • Located in Ch 6 • Orchestrate cell-cell interactions in immune response • Serve as potent immunogens and targets for transplant rejection • 2 major classes of HLA which are co-dominantly inherited • HLA class I and HLA class II

  23. Class I antigens These antigens are recognized by cytotoxic CD8+T-cells. They are present on all nucleated cells and platelets. They bind & display intracellular proteins (viral antigens) Class II antigens Important in immune cell interaction with CD4+ cells found mainly on APCs (macrophages, B-lymphocytes, dentritic cells) Recognize exogenous antigens MHC

  24. Why are HLA important? • HLA matching is important in transplantation • HLA regulate immune responses • HLA are associated with a variety of diseases, such as HLA B27 with ankylosing spondylitis, or HLA DR 2, DR3, and DR4 with autoimmune diseases

  25. Disorders of Immunity • Hypersensitivity • Immuno-deficiency • Auto-immune disorders

  26. ImmunopathologyDefinition - Type I Reaction • Anaphylaxis or immediate-type hypersensitivity. • IgE mediated • Th2 cells are pivotal in type I reaction. • Accumulation of eosinophils is an important feature.

  27. Type I Hypersensitivity • Primary mediators • Biologic amines (histamine, adenosine) • Chemotactic agents (ECF, NCF) • Enzymes (chymase, tryptase, hydrolases) • Proteoglycans (heparin, chondroitin sulfate) • Secondary mediators • Lipid mediators • Leukotrienes – LTB4, LTC4 and LTD4 • Prostaglandins – PGD2 • PAF • Cytokines – IL1, IL3, IL4, IL5, IL6. TNF, GM-CSF, MIP, eotaxin etc

  28. Type I Hypersensitivity • Has two phases • Initial – within 5 to 30 minutes after exposure and subside within 60 minutes • Late reaction – developing 2 to 8 hours later and lasting for several days (does not need antigenic exposure) • Late phase reaction particularly involves eosinophils

  29. Type I Hypersensitivity • May be systemic. • Anaphylactic shock (after administration of penicillin, enzymes, hormones, antisera, polysaccharides etc). • Within minutes • Itching, skin erythema (Hives – Urticarial lesions) • Contraction of respiratory bronchioles • Laryngeal edema • Abdominal cramps, vomiting, diarrhea, • Shock and even death within an hour • Treatment : Adrenaline, Steroids and Antihistamines

  30. Laryngeal Edema

  31. Urticaria

  32. Localized type I reaction - Atopy • Atopy is genetically determined predisposition to allergy. About 10 % suffer from allergy to pollen, house dust, animal dander, fish etc • 50 % of patients give family history, have higher serum IgE. • urticaria, allergic rhinitis, bronchial asthma, food allergy.

  33. ImmunopathologyDefinition - Type II reaction • Cytotoxic antibodies of IgM or IgG subtype are formed against an antigen on a cell surface, or more rarely, against a component of the extracellular matrix. • There are three mechanisms • complement dependent reactions • Antibody dependent cell-mediated cytotoxicity • antibody mediated cellular dysfunction

  34. Type II Hypersensitivity

  35. ImmunopathologyType II Hypersensitivity Reaction • Complement dependent reactions. • Usually, the binding of the antibody to the cellular antigen causes complement fixation (activation). The membrane attack complex (MAC) of complement then kills the cell. • ADCC. • Type II reactions may also involve NK cells, via antibody-dependent cell-mediated cytotoxicity • Antibody mediated cellular dysfunction. • Additionally, antibodies may bind to receptors and alter function by blocking binding, such as in myasthenia gravis.

  36. Type II Reaction – some examples • Complement dependent reactions • Transfusion reactions • Erythroblastosis fetalis • Autoimmune hemolytic anemia • ADCC • Killing of parasites and tumor cells • Transplant rejection • Cellular dysfunction • Myasthenia gravis • Grave’s disease • Antibodies against Extracellular antigens • Good Pasture’s syndrome –autoantibodies bind to Glomerular & Alveolar BM proteins • Pemphigus Vulgaris – autoantibodies against intercellular proteins (desmosomes)

  37. Pemphigus vulgaris

  38. ImmunopathologyType II Reaction - Goodpasture Syndrome

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