03 - January 23, 2013.docx

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Laboratory Medicine and Pathobiology
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LMP430 – January 23, 2013 Cellular and humoral immune responses B cells How BCR produced, how diversity of receptor generated by rearrangement How isotype switching occurs in B cells B cell receptor somatic hypermutation – increases diversity – important for affinity maturation that occurs in germinal centre of lymph noid and lymphoid tissues Ig gene rearrangements in B cells VDJ segments rearrange at DNA level – joined to various constant regions to RNA splicing, etc. Most B cells are born expressing IgM and IgD – through stimulation with antigen and T cell help, that other isoforms are made, IgA, IgG, etc. TCR gene rearranemgent – similar to B cell NO SOMATIC HYPERMUTATION Once selected for receptor – the only receptor ever expressed Presumably less diversity Ig – various classes and subclasses – different effector functions – KNOW THIS IgE involved in allergic reactions, type 1 IgA for gut immunity IgG key Ig for many things IgM is largest Ig – very active in certain kinds of immune responses especially effective at activating complment All the effector functions of Ig depend on Fc segment – bind to Fc receptors that activate and turn off immune cell depending on which IgG – five units – IgA – dimer All others are monomers Antigen stimulation – thymus dependent and Independent antigens Most antigens, espeiclaly protein, won’t crosslink B cell receptor very much – so weak But endocytosed when binding to BCR – B cell acts as APC interact with Thelper cell, activate Some antigens with multiple repeating units – indepentn antigens – can cross link B cell receptor extensively – activate B cells without T cell help Precursor of B cells in bone marrow – mnmigrate to lymphoid tissues – lymph nodes – Peyer’s patches and so on – in the lymph nodes, there is B cell zone, the cortex, where B cell meets antigen and then migrate to inside follicles where they interact with T cells with different shapes; knockout mice made, if knock out NFkappa B signalling, events in the spleen cannot occur – CD40 knockout, no B cell maturation B cells differentiate into plasma cells – almost all Ig secreted by plasma cells; many of them go back to Bone marrow B cells mostly in the cortical areas; T cells B cells migrate to germinal centre and they interact with T cells – cooperation and interaction with T cells Plasma cells go to lymphatic go all over body CD40 – key molecule for STIMULATING cell BAFF receptor – TNF family member; in some diseases like lupus, a lot of autoantibody production, BAFF over produced, B cells overstimulated, apply drug to block interaction CD40 and BAFF – turn on NF kappa B pathway – critical for B cell activation, survival, proliferation, etc BAFF and APRIL (a proliferation inducing ligand) – members of TNF family – produced by all sorts of cell – produced by macrophages – fibroblasts – many cell types can make them in the tissue – interaction between tissues and immune system Bind to BAFF R TAC BCM HSPG TACI BCMA – stimulatory to B cells Role of cytokines – produced by Th cells mostly Most of them influence the Ig isoform made In IgE mediated disease, IL4 important to stimulate IgE – allergy IFN gamma induce TGF beta – produced by many cell types – all cells in body have receptors; in immune system, inhibitory Increase IgA production Cytokines key to determine type of humoral response Pentameric IgM IgG molecule can also activate complement C1q bind to two IgG molecule – complement cascade to be activated Can bind to receptors – effector mechanism Fc receptors found on macrophages, dendritic cells, polymorphonuclear lymphocotes Two functions Most are activated – activate Fc receptor positive cells, increase function – can activate macrophages so their killer function is improved One receptor which is Fc gamma R two B is inhibitory – ITIM motif in cytoplasmic portion and turns immune cells off B cells only express the inhibitory receptor If knock off inhibitory receptor, get production of autoantibodies – autoimmune disease On the B cells – multiple inhibitory receptors – FcR2B inhibits when it is crosslinked to B cell receptor somehow (perhaps part of immune complex) to turn off B cell; CD72 is inhibitory receptor; PRB also These inhibotyr receptors found on immune cells important to regulate immune response – to keep and dampen – to prevent unwanted immune responses Simplified classification of hypersensitivity reactions Hypersensitivity – any kind of immune reaction with tissue injury Classical IgE mediated hypersensitivity is one type of hypersensitivity called type ONE Antibody can mediate disease – types two and three Type 2 are cytotoxic antibodies – bind to antigens on cell membrane or tissue; could be anywhere; activate effector mechanism like complement system, phagocytes, killer cells Type 3 – antibodies bind soluble molecule – form soluble complex but may then precipitate in tissues and activate complement and other effector mechanism causing inflammation Delayted – type 4 – everything that does not require antibodies Type 2 hypersensitivity – easiest type to understand – antibodies produced against infectious agents Autoantibody reacting to cell – normally if it were a bacteria or something like that, antibodies could activate complement – bind to phagocytes and macrophages Fc receptor Engulfed and killed – phagocytosis B complement F c receptor – polymorphs are highly phagocytic cells with Fc receptors When complement system activated can punch hole in membrane through MAC complex Some split products released attract neutrophils and activate them and get acute inflammation Complement activation usually associated with acute inflammation – can cause tissue injury if in excess Antibodies can cause disease through other means – can bind to receptors and block their action In m gravis, antibodies against ach receptor – block signal, cause weakness; stimulate _________, second way to damage junction Block receptor can be stimulatory so antibodies against Tsh receptor which stimulates tyroid cells – these antibodies can duplicate hormone action and cause hyperthyroidism Stimulatory autoantibodies – cause grave disease, thyroid toxic disease Goodpasture’s syndrome – antibody produced against basement membrane Basement membrane of glomeruli and in the lung IF stain of conjugated antibody – linear stain along the end – if look at this with regular histology – polymorphs present can destroy destroy the glomerulus and cause acute kidney failure Red blood cells – prime targets fo various lymph antibodies Red cells coated with antibody – lysed by Lysed by complement system – hemolytic anemia Type 3 hypersensitivity Soluble antigen If antibody excess, small conmplexes Equivalence – large complexes Serum sickness – example – horse serum injected to treat toxins – at antigen excess, acute lymphomatic reactions in many tissues (ex glomerulus, blood vessels, lungs) – will clear up, but damage to tissues may be permanent Deposition of immune complex – SLE – disease where circulating immune complexes and targets include DNA and other nuclear antigen Immune complexes resembling Glomerlus of SLE patients – activation of complement – acute glomulero One of the most common target is blood vessels, especially small ones Where complex forms - deposit in wall of vessel – activate mechanisms Acute inflammation and acute vasculitis – Cell mediated immunity Autoimmune disease have genetic basis but can be environmental factors that come in and activate the – can have inflammation of these autoantibodies – last form of hypersensitivity is cell-mediated This is not specific because so many different types of cellular immune responses – late type hypersensitivity because of time frame Immediate is IgE type hypersensitivity – reactions depending on cytotoxic complexes take more time to dvelo – hours Cell mediated autoimmunity takes days Three main considerations 1. Infectious agent – some kind of precipitating event known 2. Type of effectors generated – generate cytotoxic T lymphocytes – 3. Regulation – multiple mechanisms – how this happens – involves inhibitory receptors, regulatory T cells, some inhibitory cytokines T cells vs B cells Type 1 diabetes – autoimmunity against islet cells – transfer by T cells to naïve animal – T-cell dependent injury Antibody production is almost always T cell dependent – CD4 T cells orchestrate or regulate most immune responses T cells and immunopathology T cell immunopathology – often times, collateral damage – in order to eliminate infectious agent – immune system must produce effector mechanisms – detrimental factors produced, proteolytic enzymes, etc – normal tissues damaged accidentally because immune response is so srong and destructive Normal T cell response – tuberculosis – immune system reacts by forming granules – activate macrophage – encapsulate the microorganism – tissue lesions associated Immunopathology –c aused by excessive response – in order to eliminate the virus – activate cytotoxic T cells but if the majority of the liver cells infected with virus – immune system wipes out – massive liver necrosis – usually fatal unless do something about that – not normal immune – other people don’t, no massive liver necrosis so chronic hepatitis – so virus is never totally cleared Autoimmune disease Allergic responses – Very important immune responses occurring – autoimmune probably; not yet proven Immune system is not alone Interacts with other cells constantly Under normal circumanstances, immune systems quiescent – inhibitory environment that is turning everything off – may not be true in gut – tissues To distinguish between self and non-self – immune system distinguish pathogenic non-self and innocuous non-self Pattern recognition receptors that distinguish between pathogens and non-pathogens IS interacts with other tissues by detecting danger signals – picked up by the – when cells die, release molecules that interact with receptors and macrophages that stimulate – daed cells removed Damaged cells also release cytokines, etc that initiate immune response in various ways – innate immunity Dendritic cells in tissues quiescent – tend to be inhibitory – not stimulate T cells, tend to tolerize Danger signals – have pathogen pattern recognition receptors – combine bacteria components like LPS – these injury of tissue ____; and micro organisms bind to macrophages, activating them together results in activation of dendritic cells – DC can activate T cell – so antigen specific stimulation of immune response – starts with injury and danger signal – interaction between tissue and immune system many cells in body express ligands of inhibitory receptors – like PD1 ligands expressed by cells binds to PB1 of __ cells – not turned off, unless another signal overcomes this negative regulation macrophages express receptors for many microbial constituents wide variety of receptors that bind multiple agents When activated, multiple lytic mechanisms – can produce nitric oxide, superoxide ion, various proteolytic enzymes so kill phagocytose agents; produce cytokines to boost inflammatory response; unless activated by T cells – mechanism will not be operative or much less TLR – some on membrane of immune cells; some on endosomes – bind bacterial components, LPS, flagellin, - those that are intracellular can bind nucleic acids, ex viral – to recognize infectious agents NOD proteins – families of receptors usually end up activating NF kappa B – important for B cell activation – important for activating other immune cells – extremely important – TLR can be expressed by various immune cells – present on phagocytes, present on dendritic cells, B cells, T cells Macrophages are not the best APC – dendritic cells B cell is APC – can pick up antigens specific for that cell with receptors – can present to T cells Three key types of APCs Macrophages and DC produce many cytokines – influence polarization of immune response IL1, IL6, etc All cytokines have profound influence on immune response APCs deliver three kinds of signals to naïve T cell Interactions between
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