Lecture 11 Immune System & its Diseases II. Dr. Yasmine Lashine MD, PhD

Transcription

1 Lecture 11 Immune System & its Diseases II Dr. Yasmine Lashine MD, PhD 1

2 ILOs Distinguish between innate and adaptive immunity. Recall the cells involved in the immune response and define their roles. Compare and contrast the origin, maturation process, and general function of B and T lymphocytes. Name several antigen-presenting cells and describe their roles in adaptive defenses. Understand the mechanisms and key players of humoral immunity. Define cellular immunity and describe the process of activation. Describe the roles of different types of T cells and their functions in the body. Discuss the possible mechanisms of graft rejection and the role of MHC molecules. Compare and contrast the types and subtypes of hypersensitivity disorders in terms of examples, pathogenesis, clinical features, key players, antigens Define self-tolerance, and describe its development in B and T lymphocytes. Give examples of immune deficiency diseases and differentiate between primary and secondary immune deficiencies. Understand the pathogenesis of HIV infection and rheumatoid arthritis. Cite examples of autoimmune diseases and understand their mechanisms. 2

3 Outline 1. Types of Hypersensitivity Reactions Type I Hypersensitivity Reactions Type II Hypersensitivity Reactions - Complement-dependent Reactions - Antibody-mediated Cellular Cytotoxicity - Cellular Dysfunction Type III Hypersensitivity Reactions Type IV Hypersensitivity Reactions - Delayed-Type Hypersensitivity - T cell-mediated Cytotoxicity 2. Transplant Rejection 3

4 Type I Hypersensitivity Reactions

5 Type I Hypersensitivity Reactions Activation of Th2 cells Environmental antigens (allergens) Cytokine release Inhalation Ingestion Injection Activation of T H 2 cells and production of IgE antibody Production of IgE antibodies from B cells Attachment of IgE to mast cells Sensitization of mast cells by IgE antibody Re-exposure to the allergen Activation of mast cells and Mediators release Clinical manifestation

6 Inhalation, ingestion, or injection T H 2 subset of CD4+ helper T cells 6

7 Leukocyte activation Amplification of Th2-initiated reaction Stimulation of cell mucus secretion 5-30 min to 1 hour 2-8 hours to several days The dominant inflammatory cells in the latephase reaction are neutrophils, eosinophils, and lymphocytes, especially T H 2 cells 7

8 Type I Hypersensitivity Reactions Mediators of immediate hypersensitivity reaction Vasoactive amines released from granule stores: Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus. Adenosine causes bronchoconstriction and inhibits platelet aggregation. Chemotactic factors for neutrophils and eosinophils. Newly synthesized lipid mediators: Prostaglandin D 2 (PGD 2 ) Causes intense bronchospasm and increased mucus secretion Leukotrienes C 4 and D 4 (LTC 4, LTD 4 ) are the most potent vasoactive and spasmogenic agents. LTB 4 is highly chemotactic for neutrophils, eosinophils, and monocytes Platelet-activating factor (PAF): platelet aggregation, bronchospasm, chemotaxis Cytokines: TNF and chemokines recruit and activate leukocytes. IL-4 and IL-5 amplify the Th2-initiated immune reaction. IL-13 stimulates epithelial cell mucus secretion. 8

9 Type I Hypersensitivity Reactions Local manifestation Skin contact : urticaria Inhalation Ingestion : GIT manifestation as vomiting and diarrhea Seosonal allergy Runny and stuffy nose Sneezing Sore throat Redness in the eyes Asthma Coughing Wheezing Shortness of breath 9

10 Type I Hypersensitivity Reactions systemic manifestation Parenteral administration of Itching, urticarial, skin erythema Drugs as penicillin Antigens as snake venom or bee sting Profound respiratory difficulty ( bronchoconstriction and increased mucous secretion) Laryngeal edema Upper airway obstruction Vomiting, abdominal pain and diarrhea Systemic vasodilatation Anaphylactic shock Circulatory collapse Within minutes Death 10

11 Type I Hypersensitivity Reactions Clinical and pathologic manifestation 2014 Health Care & Alternative Medicine Epinephrine! 11

12 Type I Hypersensitivity Reactions Type I HS in Parasitic Infections 12

13 Case Every springtime, a young healthy man is bothered by episodes of nasal congestion accompanied by sneezing and watery eyes. He has no cough. On physical examination he is afebrile. There is swelling of his nasal passageways, but no other findings. His condition improves with use of loratadine. His problems are most likely produced by release of chemical mediators from which of the following cell types? Neutrophil Mast cell CD4+ cell NK cell 13

14 Type II Hypersensitivity Reactions Antibody-Mediated Diseases This reaction is mediated through Antibodies that are directed against target antigens on the surface of cells or other tissue components Complementdependent reactions Cell-mediated cytotoxicity ADCC Antibody mediated cellular dysfunction Type II hypersensitivity reaction 14

15 Type II Hypersensitivity Reactions Complement-dependent reactions Opsonization and phagocytosis 15

16 Type II Hypersensitivity Reactions Complement-dependent reactions Examples: Transfusion reactions Erythroblastosis fetalis (hemolytic disease of the newborn) Autoimmune hemolytic anemia 16

17 Type II Hypersensitivity Reactions Complement-dependent reactions Transfusion reactions 17

18 Type II Hypersensitivity Reactions Complement-dependent reactions Erythroblastosis fetalis 18

19 Type II Hypersensitivity Reactions Antibody-Dependent Cellular Cytotoxicity (ADCC): Cell-mediated killing of parasites 19

20 Type II Hypersensitivity Reactions Antibody mediated cellular dysfunction Graves Disease Antibodies against the thyroid-stimulating hormone receptor stimulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism Myasthenia Gravis Antibodies against acetylcholine receptors in the motor end plates of skeletal muscles inhibit neuromuscular transmission, with resultant muscle weakness 20

21 Type II Hypersensitivity Reactions Antibody mediated cellular dysfunction Graves Disease 21

22 Type II Hypersensitivity Reactions Disease Target Antigen Mechanisms of Disease Clinico pathologic Manifestations Autoimmune hemolytic anemia Erythrocyte membrane proteins Opsonization and phagocytosis of erythrocytes Hemolysis, anemia Acute rheumatic fever Streptococcal cell wall antigen; antibody crossreacts with myocardial antigen (Molecular mimicry) Inflammation, macrophage activation Myocarditis, arthritis Myasthenia gravis Acetylcholine receptor Antibody inhibits acetylcholine binding, downmodulates receptors Graves disease (hyperthyroidism) TSH receptor Antibody-mediated stimulation of TSH receptors Muscle weakness, paralysis Hyperthyroidism Examples of Antibody-Mediated Diseases (Type II Hypersensitivity) 22

23 Immune Complex Diseases (Type III Hypersensitivity) Endogenous Antigen DNA Exogenous Microbial Antigen Antigenantibody Immune Complex Deposition in blood vessels Complement activation Vasculitis Antigen-antibody complex deposition Can cause Local injury when affecting particular organs as kidney or joints, and can also cause Systemic injury by affecting multiple organs Glomerulonephritis Arthritis 23

24 Systemic Immune-Complex Disease: Serum sickness The use of horse anti-thymocyte globulins for the treatment of severe aplastic anemia 5 days after injection Production of specific antibodies Formation of antigen-antibody complex Deposition of immune complex Inflammatory reaction and clinical manifestation occurs -10 days Fever Urticaria-Arthralgias Lymph node enlargement-proteinuria 24

25 Type III Hypersensitivity Disease Systemic lupus erythematosus Poststreptococcal glomerulonephritis Serum sickness Arthus reaction (experimental) Antigen Involved Nuclear antigens Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane Various proteins, such as foreign serum protein (horse anti-thymocyte globulin) Various foreign proteins Clinicopathologic Manifestations Nephritis, skin lesions, arthritis, others Nephritis Arthritis, vasculitis, nephritis Cutaneous vasculitis 25

26 Case A 9-year-old boy has a sore throat. A throat culture grows group A hemolytic streptococcus. He receives antibiotic therapy. However, 17 days later he develops dark-coloured urine. Laboratory studies show 3+ blood on urinalysis. A renal biopsy is performed. On immunofluorescence staining the biopsy shows granular deposition of IgG and complement around glomerular capillary loops. Which of the following immune hypersensitivity mechanisms is most likely responsible for this pattern of findings? Type I Type II Type III Type IV 26

27 Type IV Hypersensitivity (Cell-Mediated) 27

28 Tuberculin reaction Antigen challenge test in an individual already sensitized to the tubercle bacillus by a previous infection 8-12 hours after injection Intracutaneous injection of tuberculin local area of erythema and induration appears, reaching a peak (typically 1-2 cm in diameter) in 24 to 72 hours HIV? 28

29 Type IV Hypersensitivity Delayed Type hypersensitivity Granulomatous Inflammation The initial CD4+ T-cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These macrophages become large, and flat (epithelioid cells). The epithelioid cells occasionally fuse under the influence of cytokines (e.g., IFN-γ) to form multinucleated giant cells. 29

30 T cell mediated cytotoxicity Type IV Hypersensitivity (Cell-Mediated) CD8+ CTLs is the main key player in this reaction kill antigen-bearing target cells. Class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T lymphocytes, stimulating the differentiation of these T cells into effector cells called CTLs. CTLs play a critical role in resistance to virus infections and some tumors. 30

31 Transplant Rejection Immunologic rejection of transplanted tissue is considered the major barrier to transplantation of organs between individuals of the same species (allografts ). Cell mediated hypersensitivity Directed against donor s MHC molecules Antibody mediated hypersensitivity Tissue rejection Classic acute rejection in a non-immunosuppressed host occurs within 10 to 14 days and includes both DTH and CTL 31

32 Transplant Rejection Direct recognition Indirect recognition Host T cells directly recognize the allogeneic (foreign) MHC molecules that are expressed on graft cells. Host CD4+ T cells recognize donor MHC molecules after these molecules are picked up, processed and presented by the host's own APCs. 32

33 T cell mediated rejection Transplant Rejection CTLs kill cells in the grafted tissue, causing parenchymal and, perhaps more importantly, endothelial cell death (resulting in thrombosis and graft ischemia). Cytokine-secreting CD4+ T cells trigger DTH reactions, with increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages). Antibody mediated rejection Antibodies directed against graft MHC molecules bind to the graft endothelium and cause injury (and secondary thrombosis) via complement activation and recruitment of leukocytes. 33

34 Transplant Rejection T cell mediated rejection Antibody mediated rejection CTLs kill cells in the grafted tissue, causing parenchymal and, perhaps more importantly, endothelial cell death (resulting in thrombosis and graft ischemia). Cytokine-secreting CD4+ T cells trigger DTH reactions, with increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages). Antibodies directed against graft MHC molecules bind to the graft endothelium and cause injury (and secondary thrombosis) via complement activation and recruitment of leukocytes. 34

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36 Hyperacute rejection Transplant Rejection A special form of rejection occurring in the setting where preformed antidonor antibodies are present in the circulation of the host before transplant. Transplantation in this setting results in immediate rejection (within minutes to hours) because the circulating antibodies rapidly bind to the endothelium of the grafted organ, with subsequent complement activation and vascular thrombosis. 36

37 References Basic Pathology 8 th and 9 th Edition, by Kumar, Cotran and Robbins Previous lectures by Dr. Nabila Hamdi 37

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