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Transcript
Immunology for Surgeons: The Basics 101 Principles of Surgery Jeff Warren, MD, FRCSC October 19, 2010 Objectives The Players -- T-cells and B-cells Immunoglobulins Antigen Recognition Phagocytosis Mediators and Complement Immunization Hypersensitivity Reactions Transplant Immunology Basics Immunology Conceptually challenging Complex series of reactions triggered by immunogens Compartmentalize to simplify, but actual events at molecular and cellular level are “boundary-less” and only partially understood More we learn the less we know Introduction Innate vs Adaptive immunity Self vs non-self vs altered self Three phases of immune response: Cognitive phase Activation phase Effector phase Primary and Secondary responses Lymphoid organs: primary/secondary Humoral and Cell-mediated responses Lymphocytes T-cells Thymus CD3+ CD4+ -- Helper and DTH CD8+ -- cytotoxic and suppressor NK Cells Non B-cell, non T-cell lymphocytes +IL-2 --> LAK cells B-cells Bursa fasicularis (birds) Fetal liver and bone marrow CD19+/CD20+ --> plasma cells --> Ab production APCs B-cell-->Plasma cell--> Ig production IgA: secretory, dimer IgG: most abundant, 2o response, opsonin, C’ binding IgM: 1o repsonse, C’binding, pentamer IgE: mast cells and basophils, Type I hypersensitivity IgD: small quantities, ?? Immunoglobulin Immunoglobulin -- Fab and Fc Antigen Recognition Immunogen: can stimulate immune response Antigen: recognized by immune system Immunogenicity: Complexity: proteins > CHO > nucleic acids > lipids Size: usually > 5000 Da Foreigness: xenogeneic > allogeneic > syngeneic > autologous MHC HLA in humans on chromosome 6 With Ag --> Self vs non-self vs altered self Class I: A and B regions, on all nucleated cells and platelets, recognized CD8+ T-cells --> lysis Class II: D region, on APCs, recognized CD4+ helper T-cells --> activation and proliferation of helper T-cells (-> cytokines), cytotoxic T-cells (--> lysis), and B-cells (-> plasma cells --> Ab) Class III: Complement MHC Class I and Class II Antigen Presenting Cells (APC) Capable of activating CD4+ T-cells Recognition usually occurs in 2o lymphoid organs: spleen, lymph nodes, GALT, Peyer’s patches… Monocyte and macrophage lineage: Dendritic cells (skin) Kupfer cells (liver) Glial cells (CNS) B-cell subset Any nucleated cell APC Ag Recognition …but not enough… need Co-Stimulatory Signal 2 T-cell receptor Phagocytosis Mononuclear (monocytes) vs polymorphonuclear (neutrophils) Engulfed foreign particle --> phagosome + lysosome --> phagolysosome Oxygen-dependent mechanisms: Myeloperoxidase, superoxide anion, H2O2, singlet O2, OH- radicals Oxygen-independent mechanisms: Cationic proteins, lysozymes, proteinases Phases of Phagocytosis Complement Component proteins mediators of inflammation and cell lysis Numbered according to chronological discovery, not necessarily order of activity in cascade reactions Traditionally divided into Classic, Alternative, and Lectin pathways Small stimulus --> amplified effect Initiated by Ag-Ab immune complexes and microbial products C3a and C5a are chemotactic Some components are anaphylatoxins --> mast cell degranulation, smooth muscle contraction, increased vascular permeability End-product is C5b-8 MAC Complicated!… …simplified. Cytokines Greek -cyto, cell; and -kinos, movement Large group of cell-signaling molecules: proteins, glycoproteins, peptides Grossly include interleukins, lymphokines, and chemokines; redundancy and pleitropism make this classification obsolete today. Interleukins IL-1: pro-inflammatory and wound healing; macrophages, neutrophils, fibroblasts, NK cells, endothelial cells, vascular smooth muscle; fever, vasodilation, hypotension, collagen deposition, T-and B-cell proliferation, IL-2 and IL-2R upregulation IL-2: “T-cell growth factor” in response to IL-1; NK cells and activated T-cells (auto- and para-crine); up regulates many other cytokines, namely TNF and CSF; deficiency --> SCID IL-3: hematopoetic growth factor IL-4: inhibits macrophages IL-6: inhibits TNF IL-8: neutrophil chemokine IL-10: inhibits monocytes/macrophages and antiinflammatory IL-4, 6, and 10 are “inhibitory” cytokines IL-2 Tumor necrosis factor (TNF) Hemmorhagic necrosis in methycholanthrine -induced sarcomas in mice TNF-alpha: 1o monocytes/macrophages, but NK cells and neutrophils also Stimulates neutrophils Endothelial cells --> IL-1 Procoagulant, increased vascular permeability Catabolism and cachexia in malignant disease Apoptotic mediator Gram negative shock --> endotoxin --> TNF-alpha --> hypotension + DIC TNF-ß: T- and B-cells Wound healing, PG and collagen deposition Cytolytic and cytostatic for many tumor cell lines Interferons Glycoproteins Inhibit viral proliferation via signaling pathways and translation machinery inhibition INF-alpha -- macrophages INF-beta -- epithelial cells, fibroblasts, macrophages INF-gamma -- T-cells and NK cells Antiproliferative Can induce differentiation Stimulate or inhibit a variety of cells to release other cytokines Chemokines Low molecular weight cytokines that serve as chemoattractants 4 cysteine molecules linke by disulfide bonds C-C or C-X-C and their receptors IL-8 is actually a chemokine that binds CXCR1 or CXCR2 on neutrophils 100s of chemokines identified and the catalogue continues to grow! Immunization Active: injection of intact attenuated organism or component. Recipient mounts an immune response with the goal being memory DPT, MMR, pneumovax, HepB, vaccine, polio vaccines Passive: exogenous active component is given to recipient; immediate but temporary immunity Antitoxins: C.tetani antitoxin Immunoglobulin: IgG to immundeficient recipient Specific immune globulin: RhoGAM (prevent sensitization to Rh Abs crossing placenta from Rh+ infant at delivery) Who were these guys?… Dr. Albert Sabin Dr. Jonas Salk Hypersensitivity Reactions Type I: immediate hypersensitivity Type II: cytotoxic reactions IgG and/or IgM mediated; preformed Abs ABO and Rh incompatibility, myasthenia gravis, Graves disease, ITP Type III: immune complex mediated IgE mediated --> mast cells and basophils Anaphylaxis, hay fever, food allergy Deposition of Ab-Ag complexes PSGN, serum sickness, SLE, rheumatoid arthritis Type IV: DTH Previously sensitized CD4+ T-helper cells Tuberculin skin test, contact dermatitis Transplant Rejection Hyperacute Acute Preformed Ab; immediate: “in the OR” ABO incompatible or high titre donor specific HLA Class I Ab T-cell mediated; days to weeks Treatment and prevention via T-cell depletion: ATG or IL-2R blocker Chronic (CAN) Kidneys IF/TA Immune and non-immune mechanisms Difficult to predict, prevent, or belay Alternative: ANTIBODY vs CELLULAR rejection THE END Thank you and Good Luck!