01 - January 9, 2013.docx

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Laboratory Medicine and Pathobiology
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LMP403 – January 9, 2013 Two major effective arms of immune system = T cells, B cells Thymus made up of seven pairs of thymic lobes in avian, where T cells would mature and differentiate In mammalian system, in pair of lobes in thymus For B cells, in avians bursa fabricious – but no equivalent invagination in intestines in mammalian cells – bone marrow Side chain theory Antigen sensitive cells have cell surface side chains (now called receptors) When stimulated, produces more similar chains Error: B cells express receptors of ONE specificity – other antigens cannot stimulate the cell to produce more antibodies B-cell Ig receptor – green antigen interacting with B cell Cell cell interactions – hen cells collide, through receptors, recognize the type of cells interacting with Surface associated immunoglobulins Carboxyl terminal anchoring the Ig molecule on the cell surface In circulating Ig, there are intrachain disulfide bonds linking the two heavy chains, so they do not come apart – but in cell-surface Ig receptor, they are already anchored, so do not need intrachain disulfide bonds T cell system T cell receptor – Tak Mak, Davis Major histocompatibility complex MHC governs recognition of T cells in interacting with other cells MHC made up of two classes of molecules – class one molecule has three loci ABC, class two three loci DP DQ DR. Under each locus, there are many alleles – each locus is multiple-alleic – so people in room likely have different combination of alleles Under each locus, hundreds of alleles Perfect match is statistically impossible unless identical twins Histocompatibility complex so called because when this genetic site determined, it was thought that the products were associated with graft rejection MHC governs immune recognition *** MHC in all mammalian species – called Human lymphocyte antigen in humans Class I – ABC antigen made up of a single alpha chain with three extracellular domains; alpha chain cannot be expressed unless in non-covalent association with beta two microglubulin Each antigen made up of about fifty-seven thousand molecular sites – class 1 antigens expressed on all nucleated cells – recognized by suppressor T cells that bear CD8 Class 2 – two chains – does not need beta two macroglobulin; restricted to B cells and macrophages, not universal; recognized by helper T cells bearing CD4 antigen MHC - Structure – alpha one and alpha two chains folded in alpha helices – come together to form a receptor that will interact with antigen - More variable where hypervariable regions are - N intermal of alpha one and two are less variable and the beta two microglubin and alpha three form the support for the two outermore domains for antigen recognition T cell system T cell receptor system is made up of seven chains – CD3 form a pedestal for holding the alpha and beta chains into proper confirguration and conformation for antigen recognition – gamma, delta, epsilon in association with zeta dimer to allow T cell receptor to be phosphorylated Made up of at least seven chains – but this is not sufficient for T cell receptor to recognize an antigen Antigen recognition requires CD4 and CD8 ?? DOUBLE CHECK THIS B cells can freely associate with antigen, but T cells cannot see antigen unless it is presented in MHC So antigen must be associated with MHC – only way T cell receptor will recognize antigen The recognition of antigen would essentially create a signal for the T cell to be ready to be triggered CD4/8 recognizes non variant portion of _____ - they are not variable, so can only recognize specific structure on MHC CD4 or 8 is associated with an intracytoplasmic tyrosine protein kinase – when T cell receptor recognizes antigen in context of MHC – CD4 or 8 recognize MHC as well – under this combined recognition, triggers or activates p56 tyrosine kinase to phosphorylate zeta chains – once phosphorylated, zeta chains send signals to T cell CD4 =/= CD8 CD8 is dimer; CD4 is dimer, three imunobulugin domains, and a less im unoglubulin like domain (triangle) - After destroying tumour cell, can engage another target Two other cytotoxic cell types = NK cells have NK receptor; killer cells recognition depends on antibody sitting on Fc receptor of K cells Antimicrobial immune mechanisms - Complement is innate but can be adaptive (if activated by classical pathway, involving antibody binding antigen) - Macrophages phagocytosis is also innate - Inflammation – when complement system is activated, triggers release of ___, release of histamine, ergo inflammatory response Adaptive response – ex. Immune complex promotes an innate response in complement activation to really manage the microbial infection How the immune system deals with extracellular bacteria through adaptive immune response – extracellular bacteria are circulating bacteria that are not hiding in cells, fully exposed and therefore the most effective mechanism is antibody neutralization C3b or C3b equivalent – complement activation Inflammation – products associated with complement activation that trigger inflammation – C3a, c4a, c5a are hemotactic, are cleavage products from complement that draw neutrophils, monocytes to site of infection – promote extravascularization of circulating cells – anaphilatoxin, so also trigger mast cells release histamine Third biological effect of complement is bacterial lysis – membrane attack complex made up of C5 and C9 – constitute a transmembrane channel allowing water soluble substance to enter cell to burst the cell B cells cannot make antibodies – need T helper cells IL2 secretion promote B cell function Cytokines are mediators – IFN gamma makes macrophages supermacrophages for phagocytosis TNF alpha for promoting the transmigration of cells from vascular system to site of injury Intracellular bacteria – differs from extracellular bacteria are NOT EXPOSED – antibodies are made impotent Innate immunityI L12 is potent stimulat for NK cells – destroys target, then releases IFN gamma – reciprocating stimulation – More powerful than NK cells releasing same mediators____ CHECK Intacellular microbes inside cell – cells destroy bacteria how? Cell engaging intracellular bacteria – release IL12 that trigger CD4 positive cells to release more cytokines – cytokines create delayed hypersensitivity – forming granuloma – blocking/suroudning intracellular bacteria and ending up as caseous necrosis, bacteira is killed Granuloma – includes TNFalpha, TNF promotes transmigration of cells (monocytes, etc.) to site of injury Cytokines include IFN gamma, that promote macrophage function – circulating monocytes into macrophages – macrophages begin to be transformed – epithelial cells are transformed macrophages Collection of multiple cell types in granuloma that blockage and digest the infected cell – lead to permanent scar for people positive for TB TB test – if swollen, positive for tuberculosis; if nothing, negative TB scar tissue always there – Innate and adaptive responses to viruses Infected cell produce type I interferon – coats the infected or non-infected cell, which becomes resistant to any further infection = antiviral state NK cells nondiscriminately kill infected cells Adaptive immunity – ant
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