1. Disorders of Immune System - Hypersensitivity Reactions: Immune response to exogenous antigens - Autoimmune diseases: Immune reactions against self antigens - Immune deficiency syndromes Congenital / acquired - Amyloidosis

2. Hypersensitivity reactions - Group of immune reactions resulting from exposure to exogenous antigens - Designed as a protective response but usually results in tissue injury - Caused by mixture of humoral and cell mediated reactions - Classified into 4 types based on immunologic basis

3. Hypersensitivity reactions - Type I (Immediate) hypersensitivity - Type II (antibody mediated) hypersensitivity - Type III (immune complex mediated) hypersensitivity - Type IV (cell mediated) hypersensitivity

4. Type I Hypersensitivity Reaction: - Rapidly developing immunologic reaction - Occurs within minutes of antigen-antibody reaction - Antibody is bound to surface of sensitized mast cells - Antigen is called allergen and reaction is called allergy - Reaction may be localized or systemic - Release of vasoactive and spasmogenic substances

5. Local reaction: Depends on the point of entry of allergen - Localized cutaneous swellings (skin allergy, hives) - Nasal / conjunctival discharge (allergic rhinitis / conjunctivitis) - Hay fever, bronchial asthma (respiratory allergy) - Allergic gastroenteritis (food allergy)

6. Local reaction: Depends on the point of entry of allergen - Localized cutaneous swellings (skin allergy, hives) - Nasal / conjunctival discharge (allergic rhinitis / conjunctivitis) - Hay fever, bronchial asthma (respiratory allergy) - Allergic gastroenteritis (food allergy) Systemic - Follows injection of allergen - Produces state of shock within minutes

8. Elements that participate in Type 1 hypersensitivity: - B and T lymphocytes - Antigen presenting cells - Mast cells & Basophils - IgE antibodies - Chemical mediators

9. Mast cells: - Bone marrow derived, widely distributed in tissues - Contain cytoplasmic membrane bound mediator granules - Have high affinity IgE Fc receptors - Also triggered by complement C5a and C3a (anaphylotoxin) - Responsible for allergic reactions in tissue

11. Mediators: Primary: Secondary - Histamine - Phospholipids - Proteases (PGD2, Leukotrienes) - Chemotactic factors - Platelet activating factor - Cytokines

12. ActionMediator Vasodilation, Increased vascular permeability Histamine PAF Leukotrienes C4, D4, E4 Neutral proteases (activate complement) PGD2 Smooth muscle spasm Leukotrienes C4, D4, E4 Histamine Prostaglandins PAF Cellular infiltration Cytokines TNF Leukotriene B4 Eosinophil and Neutrophil chemotactic factors PAF

15. Local hypersensitivity reactions - Immediate phase (initial response): Vasodilation and vascular leakage, smooth muscle contraction Starts 5-30 minutes and subsides in 1 hour Vasoactive amines are responsible - Second phase (Late response): Tissue infiltration by inflammatory cells including eosinophils Starts 2-24 hrs and lasts for many days Other mediators including cytokines Major cause of symptoms in asthma etc. Inflammatory response is sustained without further antigen exposure

16. Type I Hypersensitivity may be genetically determined (ATOPY) Atopic individuals have higher levels of serum IgE Family history of allergy is seen in 50% atopic individuals

17. Antibody mediated (Type II) Hypersensitivity - Antibody directed against antigens present on cells and tissues - Antigen may be self or of external origin (drug metabolite) - Basis for many auto immune diseases

18. Mechanisms 1a) Opsonization and complement and Fc receptor mediated phagocytosis

19. Mechanisms 1a) Opsonization and complement and Fc receptor mediated phagocytosis 1b) Complement mediated lysis of opsonized cells (C5-9) (MAC) 1c) Antibody dependent cellular toxicity (ADCC)

20. Antibody mediated cell destruction and phagocytosis - Blood transfusion reactions - Erythroblastosis fetalis - Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia - Drug induced hemolytic anemia

21. Mechanisms 2) Complement and Fc Mediated inflammation - Antibody deposited in extracellular tissues - Complement activation (C5a) - Inflammatory cells recruited, activated - Enzymes and reactive oxidative metabolites - TISSUE INJURY Causes - Glomerulonephritis - Vascular rejection - Acute rheumatic fever

22. Mechanisms 3) Antibody mediated cellular dysfunction Antibody binds to cell surface receptors and disrupts function Myasthenia gravis, Pemphigus vulgaris Antibody binds to cell surface receptors and stimulates function Graves disease

23. Type III Hypersensitivity (immune complex mediated) - Antigens and antibodies form complexes either in circulation of locally in tissues (Antigen may be exogenous (foreign protein, bacteria, virus) or endogenous (ones own)) - The complexes get deposited in tissues - Inflammatory reaction is initiated resulting in tissue damage - May be generalized (serum sickness) or localized (arthus reaction)

24. Serum sickness - Injection of horse serum into humans (passive immunization) - Antibodies (preformed / new) against horse proteins - Antigen Antibody complexes deposit in tissues - Fever, skin rash, arthritis, nephritis - Resolution following clearing of complexes - Chronic exposure / re-exposure --------------------------

26. Arthus reaction: Local antigen stimulus in a sensitized individual

30. Morphologic consequences: - Fibrinoid necrosis of blood vessels - Proliferative glomerulonephritis - Arthritis Vasodilation and edema Neutrophil and monocyte infiltrate Necrosis