Principles of immune defense Toxicology Course Vienna MODULE 12 Immunotoxicology, Allergy July 2, 2008 Prof. Erika Jensen-Jarolim, MD Dept. of Pathophysiology Medical University Vienna Gastrointestinaltrakt: Mukosale Pathophysiologie und Immunologie Jensen-Jarolim, Schöll, Szalai. Springer 2006 Wörterbuch Allergologie und Immunologie, Ferencik, Jensen-Jarolim et al, Springer 2004 Immunologie (Charles A. Janeway and P. Travers) Innate immunity Adaptive Immunity available with delay highly specific antigen recognition huge repertoire improvable memory against extracellular or intracellular pathogens B-lymphocytes: Soluble B-cell receptors are immunoglobulins Recognize antigen directly T-lymphocytes: No solublet-cell receptors Recognize digested and presented antigens Primary immune organs: Building and maturation of immune cells and receptors Bone marrow, thymus Primary immune organ: Bone marrow Secondary immune organs: antigen contact sites Lymph nodes, spleen, peyer s patches, appendix 1
The generation of antigen receptors & repertoire The T-lymphocyte receptor Combinatorial diversity: 5,2 x 10^15 Danger of autoreactivity mimimized: negative selection and deletion in thymus Cortex: positive selection for HLA-reactive T-cells APCs Medulla: negative selection for autoreactivity medulla thymus epithelial cells (mtec): AIRE gene expressed Primary immune organs: Building and maturation of immune cells and receptors Bone marrow, thymus Secondary immune organs: antigen contact sites Lymph nodes, spleen, peyer s patches, appendix Negative selection clearing out the bad apples from the T-cell repertoire. Ed Palmer Nature Reviews Immunology 3, 383-391 (May 2003) Cooperation with APCs: antigen focussing and transport Dendritic cells, macrophages, Langerhans cells present intact antigen on surface for B-cells digested antigen with HLA II. for T-cells no costimulation Within 2 days all naive lymphocytes of a certain specificity trapped in secondary lymph organs. Emigration of effector cells within 5 days Clonal expansion Develop into dendritic cells - costimulation 2
Proliferation in germinal centers and expansion of specific effector B- and T-lymphocytes The clonal selection theory by McBurney. SLAM receptors and SAP influence lymphocyte interactions, development and function Pamela L. Schwartzberg, Kristen L. Mueller, Hai Qi & Jennifer L. Cannons Nature Reviews Immunology 9, 39-46 (January 2009) From the following article: The double helix and immunology Gustav J. V. Nossal Nature 421, 440-444(23 January 2003) The building of an immunoglobuline Idiotype Secondary immune organs: antigen contact sites: Expansion Adaption Improvement Isotype: receptor binding The functions of immunoglobulins How can a B-cell switch immunoglobulin isotype? Membrane bound: BCR Secreted: B-cell IgD IgM: neutralization, complement activ. IgA: neutralization, binds FcaR IgG: neutralization, complement act., binds FcgR IgE: cytophilic through FceR, needs crosslink IgM IgE IgG IgA Linking class-switch recombination with somatic hypermutation Kazuo Kinoshita & Tasuku Honjo Nature Reviews Molecular Cell Biology 2, 493-503 (July 2001) 3
Specific in fluid phase: IgG, IgM, IgA In tissues: IgG, IgE IgG: predominant isotype in serum, IgA: in mucosa Most produced Ig-class siga, main source bone marrow Specific Defense in serum: IgG and IgM Aggregation, Agglutination Production (mg/day) IgA IgG Opsonisation Circulation 2100 2100 Saliva Tears 200 5 2? Neutralization Bile 400 160 Small intestines 5200 600 Large intestines 1200 140 Nasopharynx 45 15 Urine 3 Total 9200 Mestecky 1986; Clin Immunol Immunopathol. 3 3000 MDCK cells (no CPE) H5N1 virus infection after 72h (CPE) protected from H5N1 by anti-h5n1 F(ab')2. Somatic hypermutation: Improvement of antigen binding Secondary immune organs: antigen contact sites: Expansion Adaption Improvement Affinity: Binding strength to a single antigenic determinant Avidity: Sum of binding strengths to antigenic determinants Nature Medicine 9, 164-166 (2003) B cell memory: Sapping the T cell Raymond M. Welsh, Susan E. Stepp & Eva Szomolanyi-Tsuda Boost injections in vaccination induce and improve immunity and memory against extracellular or intracellular pathogens B-lymphocytes: Soluble B-cell receptors are immunoglobulins Recognize antigen directly T-lymphocytes: No solublet-cell receptors Recognize digested and presented antigens 4
Helper & regulatory T-cells Proper stimulation of T-lymphocytes involves cell-cell interactions HLA II. HLA I. Cytotoxic T-lymphocytes Cytotoxic Helper & regulatory The many important facets of T-cell repertoire diversity Janko Nikolich- ugich, Mark K. Slifka and Ilhem Messaoudi Nature Reviews Immunology 4, 123-132 (February 2004) The many important facets of T-cell repertoire diversity Janko Nikolich- ugich, Mark K. Slifka and Ilhem Messaoudi Nature Reviews Immunology 4, 123-132 (February 2004) Antigen digestion by antigen present.cells & HLA HLA typing: Forensic medicine and transplantation All APCs All cells with nuclei Polymorphism HLA = MHC Cytotoxic T-lymphocytes: CD8+ need HLA I. presentation Viral infections, aberrant cells, high HLA I. NK Helper T-lymphocytes: CD4+ need HLA II. presentation IL-12 Th1 Inflammation, IgG1, 2, 3 Tu IL-4 Th2 Target cell recognition: specific HLA I expression and viral peptides Tu IL-23 IgG4, IgE Lysis program and target cell death NK Th17 Inflammation NK cell lyses tumor cell Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells Chen Dong, Nature Reviews Immunology 6, 329-334 (April 2006) 5
Regulatory T-cells modulate immune responses Activation of Tregs Th-cells help B-cells for isotype switch Th17 IgA Clark & Cupper, JID 2005: Immature dendritic cells are polarized by the binding of type 1, type 2, or regulatory PAMP and differentiate DCs decide into mature on dendritic type cells of immune that induce the response formation of Th1, Th2, or T regulatory T cells, respectively. In general, viral-associated PAMP give rise to Th1 responses, and PAMP from parasitic organisms favor Th2 responses. Synthesized cytokines induce isotype switch Costimulation decides T-cell activation How to activate a T-cell? Signal 1: Specific interaction MHC/TCR Signal 2: DANGER! costimulation B7/CD28 Costimulation by professional APC Immunity without costimulation Tolerance via Anergy Then proliferation, and cytokine synthesis occur Toxicology Course Vienna MODULE 12 Immunotoxicology, Allergy July 2, 2008 Prof. Erika Jensen-Jarolim, MD Dept. of Pathophysiology Medical University Vienna 6