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Charles A. Janeway, Paul Travers, Mark Walport, Mark Shlomchik Immunobiology: The Immune System in Health & Disease Sixth Edition Chapter 1 Basic Concepts in Immunology Copyright © 2005 by Garland Science Publishing Edward Jenner 1796 •Observation that milk maids infected with cowpox were resistant to smallpox (already folklore) •Innoculated a poor farm boy with fluid from a blister/pox of an cow pox infected milk maid. •Weeks later he challenged the boy with an injection of a lethal dose of smallpox. •The boy was protected from smallpox. The eradication of smallpox by vaccination . QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Two defining characteristics of adaptive immunity. • Specificity – Response is directed against specific antigenic determinants of a pathogen • Memory – The memory of having been exposed to the same pathogen previously – Both implicate receptor diversity Gowens 1962, Nature • Identificationof lymphocytes as the cellular units of clonal selection in adaptive immunity. – B cells • Humoral immunity – T cells • Cellular immunity Innate Immunity • Eli Metchnikoff (1893; nobel prize 1908 with P Erlich in recognition of their work on immunity) – Innate immune response of starfish (phagocytosis) • Mediated by – Cells; phagocytes and NK cells – Proteins (complement) – Anti-microbial peptides (defensins) Use germline encoded “pattern recognition receptors” to recognize molecular structures (patterns) on microbes (LPS) Two roles – Front line defenses – Stimulation for adaptive immunity • Activation of the innate response cues the adaptive response to the presence of “danger” All the cellular elements of blood, including the lymphocytes of the adaptive immune system, arise from hematopoietic stem cells in the bone marrow. Figure 1-3 Myeloid cells in innate and adaptive immunity Myeloid cells in innate and adaptive immunity Lymphocytes are mostly small and inactive cells prior to infection. Natural killer (NK) cells. These are large granular lymphocyte-like cells with important functions in innate immunity. Although lacking antigen-specific receptors, they can detect and attack certain virus-infected cells Figure 1-7 Most Infectious agents induce inflamatory response by activating innate immunity The course of a typical antibody response. Serum therapy anti-toxin against diptheria Emil von Behring1901 nobel prize • O-4 hours Innate immunity – Recognition by preformed non specific effectors; removal of infectious agent • 4-96 hrs – Recruitment and activation of innate effector cells • 96 + hrs Adaptive Immunity – Transport of antigens lymphoid organs T and B cell recognition Clonal expansion and recognition Molecular basis of diversity • Tonegawa in 1970’s (nobel prize;1987) • Antigen receptors of B and T lymphocytes are encoded by genes that result from somatic recombination segments at at defined stages of maturation • Recombination requires RAG recombinase • Presence of RAG genes during phylogeny identifies the evolutionary time of acquisition of adaptive immunity – just past the the appearance of vertebrates – jawless fish lack RAG and lymphoid organs whereas the cartilagenous fish have a RAG genes and a well developed adaptive immune response Recombination of antigen receptors • Allows a vast number of receptors to be generated from a small amount of genes • Maximizes diversity by introducing sequence variation at sites of recombination • Regulates the development of individual lymphocytes – Signal expansion and development of only cells with specificities • reactivity with antigens challenging the individual • Not reactive with self antigens The structure of the antibody molecule demonstrates how diversity in ligand recognition is coupled to a common effector mechanism (Edelman and Porter Nobel Prize 1972 for their discoveries concerning the chemical structure of antibodies 1959) Diversity yes, but how do we every get enough to be effective? Clonal Selection Hypothesis (Burnet 1959) (Jerne,Kohler and Milstein Nobel prize 1984) T cells see antigen in a different way Transplantation studies revealed that tissue rejection map to MHC region Immune responsiveness also mapped hereVirus specific killer T cells generated in one inbred strain only kill virus infected target cells if they share the same MHC (Zinkernagel and Doherty, 1974, nobel prize) T cells have a dual specificity for antigen and MHC TCRs bind to a composite ligand composed of antigenic bound to a MHC molecule There are two types of MHC which patrol for different types of antigens Studies on Tumor Transplantation, identification of the MHC • Inbred mice created by Japanese mouse fanciers for centuries (early 1900s Loeb and Tyzer) • Jw carcinoma transplant would grow in Jw mice but not in common mice • Thought they were studying immune response to tumors • Actually studying immune response to transplant • Generation of congenic mice genetically identical at all loci except for one thought to be important in transplantation (Snell, Amos 1950s) • Major histocompatibility complex MHC (H-2 in mice HLA in humans a locus of tightly linked genes (Benacerraf; Dausset;Snell Nobel Prize 1980) MHC class II molecules present antigen originating in intracellular vesicles CD4+ TH1 and helper T cells (TH2) recognize antigen presented by MHC class II molecules. Figure 1-26 Figure 1-24 part 1 of 3 MHC class I molecules present antigen derived from proteins in the cytosol CD8+ Cytotoxic T cells recognize antigen presented by MHC class I molecules and kill the cell. Figure 1-25 Two signals are required for lymphocyte activation The second signal is the innate immune response alerting adaptive immune response to “danger”/infection Adaptive immune response • Selection (purge the repertoire of self reactivity; ensure coopertivity) • Expansion (clonal selection; receptor engagement promotes proliferation) • Peripheral tolerance mechanisms ensure no autoreactivity (active processes for antigen specific activation and antigen specific tolerance induction) • Differentiation into effectors suited for response • Contraction (induce apoptosis, self limitation) • Development into memory response • Maintenance of memory without cross reactivity to self Figure 1-33