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IMMUNODEFICIENCIES AND TUMOR IMMUNOLOGY 14th week, 2014 BSc in Public Health IMMUNODEFICIENCIES AGE AND HEALTH DEPENDENT IMMUNOSUPPRESSIVE DRUGS • INHERITED (PRIMARY) • ACQUIRED – Loss of function mutation of genes of the immune system – Enhanced susceptibility to infections – Particular types of pathogens depending on the gene defect – Did not show up until 1950 antibiotics – Due to infectious diseases • AIDS • Other viral infections – Malnutrition – Artificial immunosuppression • Drugs • Radioactive irradiation PRIMARY IMMUNODEFICIENCIES • MOST ARE RECESSIVE MUTATION OF SINGLE GENES – Dominant traits have been eliminated from the population – Autosomal genes or X-linked genes (different inheritance) • DOMINANT: Mutation in the IFNγ receptor results in binding without intracellular signaling DISSEMINATED INFECTION BY THE BCG STRAIN OF Mycobacterium (M. bovis) USED FOR VACCINATION Numerous Immunodeficiency loci reside on the X chromosome CGD: Chronic Granulomatous Disease WAS: Wiscott-Aldrich Syndrome SCID: Severe Combined Immunodeficiency XLA: X-linked Agammaglobulinemia XLP: X-linked Lymphoproliferative Disease XLHM: X-linked Hyper-IgM Syndrome TYPES OF INHERITED IMMUNE DEFICIENCIES B CELL DEFICIENCY recurrent sinopulmonary and GI infections beginning after 3-4 months – B cell development • X-Linked Agammaglobulinaemia – hyper IgM syndrome • CD40L – X-linked • AID – autosomal T CELL DEFICIENCY opportunistic infections beginning early in infancy • SCID – T cell development • • • • IL-7 signaling defect RAG-1/2 def. (Omenn’s sy.) DNA repair enzyme defect Purin catabolism (metabolites toxic to developing B and T cells) – MHC deficiency (Bare Lymphocyte Syndrome) – CVID – selective IgA deficiency • DiGeorge syndrome – lacking thymus epithelial cells (aberrant embrional development) B CELL IMMUNODEFICIENCIES Approx. 70% of all primiary IDs Late Manifestation (3-10 months) Increased sensitivity to epithelial pathogens: • pyogenic bacteria (e.g. streptococci) • GI pathogens (e.g. enteroviruses) Threatment: intravenous human immunoglobulin (hIVIG) every month Flow cytometric measurement of peripheral blood leukocytes CD3 = cell surface marker expressed by T cells CD19 = cell surface marker expressed by B cells DEFECT IN T CELL FUNCTIONS T cells are involved in all aspects of adaptive immunity SEVERE COMBINED IMMUNODEFICIENCY (SCID) (Over 50% of T cell deficiencies) • Neither T cell-dependent antibody response nor cellular immunity are functional • Small body weight, failure to thrive • Persistent and recurrent infections with a broader range of pathogens than in patients with B cell deficiencies • Opportunistic infections (Candida albicans, Pneumocystis carnii) • Treatment: – Bone marrow transplantation, preferably from a histocompatible sibling – (Gene therapy) TYPES OF INHERITED IMMUNODEFICIENCIES 2. • PHAGOCYTIC SYSTEM – CD18 (CR3, CR4, LFA1) deficiency aka Leukocyte Adhesion Deficiency (LAD) • no leukocyte migration to sites of inflammation – NADPH oxidase deficiency aka Chronic Granulomatous Disease (CGD) • granuloma formation in case of several infections by intracellular pathogens – Chédiak-Higashi Syndrome (CHS) • defect of phagolysosome formation • COMPLEMENT SYSTEM – pyogenic infections, primarily with encapsulated microorganisms and Neisseriae TUMOR IMMUNOLOGY GLOBAL MORTALITY RATE What is cancer? Normal tissue Benign tumor Cancer Most frequent sites of tumors Lungs Liver Stomach Colon Pancreas GENERATION OF TUMORS • if mutations accumulate in tissue cells they may become tumorous cells: 1. 2. gain of function mutations of proto-oncogenes that lead to enhanced proliferation signals loss of function mutations of tumor suppressor genes that inactivate regulation of the cell cycle • tumor cells are continuously proliferating cells that have genetic instability mutations and chromosomal aberrations accumulate • invading local tissues – benign: respecting tissue borders (basement membranes) – malignant: spread to all nearby tissues, can even give off metastases (local ones via the lymph, or distant ones via the blood) Tumor cells are generated in our bodies daily but normally they are cleared by the immune surveillance THE IMMUNE RESPONSE TO TUMORS Hidden, changing, proliferating, evolving target TUMOR ANTIGENS Tumor associated antigens – TAA Present also in normal cells Aberrant/dysregulated expression in tumor cells Tumor specific antigens – TSA Unique for individual tumors or tumor types IMMUNE SYSTEM Tumor-specific immune responses can be induced Cytotoxic T lymphocytes can eradicate tumors Activation of tumor-specific T-cells by DC Cross-presentation INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND TLYMPHOCYTES TNF IFN APOPTOTIC TUMOR CELL CD40 CD40L CD40 PS CD4+ TH1 CD40L IL-2 HSP Carbohydrate APC DC MHCII IL-12 IL - 12 Oxidation ICAM-3 M H CI TUMOR CROSS PRIMING IFN Tumor Ag CD8+ Tc B ESCAPE MECHANISMS OF TUMORS production of soluble MIC inhibition of killing by NK cells In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) Tcells, which turn off the inflammatory reaction. BIOLOGIC TUMOR THERAPIES UNCONJUGATED MONOCLONAL ANTIBODIES Antibodies bind to a cell-surface antigen of the tumor cells. The Fc regions of the antibodies engage FcγRIII on an NK cell, which then becomes activated to kill the tumor cell. CONJUGATED MONOCLONALS Treating cancer with immunotherapy immunotherapy (breaking the tolerance!) primary tumor metastases Tumor vaccines tumor antigen DC surgical removal of the primary tumor adjuvant DC therapy CTL DC + tumor Ag DC therapy monoclonal antibodies Tumor specific CTL