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Immune system: how life fight against invaders! 4-18-2016 Multicellular organism: the heaven of bacteria/virus and parasites The three layers of vertebrate immune defenses. 血清療法的發明人! Using horse serum against diphtheria toxin to treat patients. http://nobelprize.org/nobel_prizes/medicine/laureates/1901/ 血清療法帶來的新思維 抗白喉毒素血清中的有效成分是什麼? 怎麼產生的?為什麼可以解毒? 抗毒素(抗体)與毒素(抗原)結合, 帶引出二個重要的概念: 1, 結構的辨識 (specificity); 2, 分子問的親和力(affinity)。 “antitoxines represent nothing more than side-chains reproduced in excess during regeneration, and therefore pushed off from the protoplasm, and so coming to exist in a free state…….” http://nobelprize.org/nobel_prizes/medicine/laureates/1908/ Challenge of acquired immunity 1, how to specifically recognize infinite different foreign molecules; 2, how to distinguish self from non-self! Conceptual framework of acquired immunity • Clonal selection hypothesis – Variation: randomly generated. – Inheritance. – Selection by foreign antigens. Normal median survival time of A strain skin on CBA mice is 11 days. Injected CBA mice in utero with tissues from A strain mice, then grafted with A strain skin at adult. Three of them accepted for more than 2 months (tolerance) Transfer of lymphoid tissue from CBA donors immunized with A strain tissue caused rapid rejection of the previously tolerated grafts. Cooper MD, Raymond DA, Peterson RD, South MA, Good RA. The functions of the thymus system and the bursa system in the chicken. J Exp Med. 1966;123:75–102. Cells of the adapted immune system • Lymphocytes – B cells • Plasma cells (Ab producing) – T cells • Cytotoxic (CTL) • Helper (Th) – – – – Th1 Th2 Th17 T-reg The basic structure of an immunoglobulin molecule. Hybridization of labeled RNA probes, specific for the entire k gene (V +C) and for the 3’ end that encodes the C region, to fraction of digested DNA separated by agarose gel electrophoresis. N. Hozumi and S. Tonegawa, 1976, Proc. Nat’l. Acad. Sci. USA 73:3629. For light chain variable region : 30 V X 5 J = 150. For heavy chain variable region: 45 V X 23 D X 6 J = 6,000. 150 X 6,000 = One million plus 1,000 X from imprecision junction and 1,000 X from hypermutation Total variation is around 100 billion! Organization of the major histocompatibility complex in mice and humans. Snell GD & Higgins GF 1951, "Alleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantation", Genetics 36:306–310 How T cell recognizes specific antigen? Through cell surface receptor namely T cell receptor (TCR) Organization and recombination of TCR loci. Zinkernagel-Doherty experiment demonstrating that MHC restriction is required for activation of a cytotoxic T-cell response. If T cell receptor can recognize antigen directly, what role of MHC played in TCR recognition? T cell TCR Ag Figure 23.22 Peptide binding and MHC restriction. Signals involved in T-cell activation and termination. Perforin- and granzyme-mediated cell killing by cytotoxic T cells. Why T cell need MHC for its antigen recognition? Collaboration between T and B cells is required to initiate the production of antibodies. Collaboration between T and B cells is required to initiate the production of antibodies How memory T cells are generated? Science 315: 1673-4; 2007 How tumor cells suppress cytotoxic T cells? Can w e block such inhibitory pathway to reactivate T cells to kill tumor cell? MHC pathway of antigen processing and presentation. Class II MHC pathway of antigen processing and presentation. Positive and negative selection of the T cell repertoire: To expand T cell population and to eliminate clones recognize self antigen Innate immune system • Pattern recognition receptor – LPS for Toll-like receptor – dsRNA/ DNA for interferons induction • Complement proteins • Phagocytes (cells) (e.g., macrophages) • Natural killer (NK) cells The three pathways of complement activation converge Figure 2-18 Combination of adaptive and innate immune responses Innate immunity Innate immunity Macrophages can engulf and digest bacteria Macrophage about to eat a bacterium http://www.biochemweb.org/neutrophil.shtml Arm race between immunity and pathogens Pathogens have also developed ways to remove some of the cell’s critical proteins, often so that they can escape detection by the immune system. For example, in the adaptive immune system, T lymphocytes (T cells) recognize viral fragments (peptides) bound to MHC proteins. It’s hard for a virus to hide out in a cell if the cell surface MHC proteins contain viral fragments that can be recognized by T cells. What’s a virus to do? Get rid of the host MHC proteins! For every strategy a virus comes up with, the immune system (usually) has an answer… Natural killer cells recognize cells that do not express adequate levels of MHC proteins on their surface. They respond to “missing self”. Natural killer (NK) cells • Identify targets based on “missing self” – Two types of NK receptors: inhibitory and activating – If inhibitory receptor recognizes a self protein (a class I MHC molecule) on a target cell, the NK cell is turned OFF even if activating receptor binds a ligand on the same target cell – If activating receptor binds a ligand, but inhibitory receptor does not (target cell has down-regulated class I MHC proteins), NK cells kill – Many virally-infected cells and tumor cells down-regulate expression of class I MHC molecules (NK cells important for preventing cancers) Molecular mechanisms of natural killer cell activation in response to cellular stress Cell Death and Differentiation (2014) 21, 5–14 How does bacteria fight for viral infection? Does bacteria have immunity against viral infection? , Innate immunity of bacteria: modification and restriction system Acquired immunity of bacteria: CRISPR (clustered regularly interspaced short palindromic repeats) system Science 341: 833-836; 2013 J Bacteriol. 169: 5429–5433; 1987. Identification of genes that are associated with DNA repeats in prokaryotes Molecular Microbiology 43, 1565–1575; 2002 CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. Microbiology. 2005; 151:653–663. CRISPR provides acquired resistance against viruses in prokaryotes. Science. 2007; 315:1709–1712 Bacteria get vaccinated! Nature 513: 175-6; 2014 New Tool for Genome Surgery Science 339: 768-9; 2013 • • • • • 1. Constructionist “ side chain theory “ (Ehrlich) 2. Instructionist “antigen template theory “ (Pauling) 3. Selectionist “natural selection theory “ (Jerne) 4. “Clonal selection theory “ (Burnet, Talmage, Jerne) 5. Seminal confirmatory experiments (Tonegawa, Nossal, Lederberg, many others) Conceptual framework of acquired immunity • Clonal selection hypothesis • Two kinds of recognition • Generation of Diversity (God’s problem) – Allelic exclusion (only one allele of H/L chain is expressed) • Self and non-self discrimination Conceptual framework of acquired immunity • Clonal selection hypothesis • Two kinds of recognition • Generation of Diversity (God’s problem) – Allelic exclusion (only one allele of H/L chain is expressed) • Self and non-self discrimination Conceptual framework of acquired immunity • Clonal selection hypothesis • Two kinds of recognition • Generation of Diversity (God’s problem) – Allelic exclusion (only one allele of H/L chain is expressed) • Self and non-self discrimination Specificity of adaptive immune response • Resides with Ag R on T and B cells • TCR and BCR – both specific for only ONE antigenic determinant • TCR is monovalent • BCR is divalent T cell B cell TCR BCR Major distinguishing markers Marker B cell CTL T-helper Antigen R BCR (surface Ig) TCR TCR CD3 -- + + CD4 -- -- + CD8 -- + -- CD19/ CD20 + -- -- CD40 + -- -- Sequence of Events in B-Cell Activation by a Thymus-Dependent Ag Important B-cell Differentiation Events Take Place in Germinal Centers 1. Affinity maturation 2. Class switch 3. Formation of plasma cells and memory cells Immune cells and other blood cells made in bone marrow -- all are descendents of self-renewing stem cells Make variable antibodies Membrane-bound variable T cell receptors Kill cells that are missing self proteins Phagocyte Phagocyte Note these are adult stem cells, NOT embryonic stem cells. Binding of mannose-binding lectin, a plasma protein, initiates lectin pathway of complement activation. MBL discriminates self carbohydrates from non-self carbohydrates by recognition of a particular pattern of sugar residues Figure 2-11 Figure 2-35 part 3 of 3 One of the end results of complement activation -- the membrane attack complex kills a cell Electron micrographs of ~100 Å diameter membrane attack complex channels How the acquired immunity evolved ? Rag1/2 mediated diversity generation for immunoglobulin and TCR only appear after jawed vertebrate (500 millions years) The sea lamprey is often called “living fossils” because they are thought to have changed little since they arose 450 million to 500 million years ago, as part of a branch of jawless creatures that split off early from the rest of the vertebrate tree