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by: Dr. Reina Thompson
Dr. Reina Thompson
GPA 3.52

Gary Splitter

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Gary Splitter
Class Notes
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This 15 page Class Notes was uploaded by Dr. Reina Thompson on Thursday September 17, 2015. The Class Notes belongs to M M & I 528 at University of Wisconsin - Madison taught by Gary Splitter in Fall. Since its upload, it has received 26 views. For similar materials see /class/205261/m-m-i-528-university-of-wisconsin-madison in Microbiology (MICROM) at University of Wisconsin - Madison.


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Date Created: 09/17/15
Immunology Exam 2 Lecture 9 Ag Ab Reactions In Vitro Why do in vitro assays To determine host response to foreign substances measure quantity and class of ab produced To determine health or disease status of animalhuman cause of disease or immune status Categories of interaction Primary ab and ag directly interact all that is needed is one of each Require puri ed ag or ab sensitive quantitative assay method to separate agab complexes and free ag amp ab Uses identify pathogens host proteins Abs in tissues Secondary ab binds ag something else must happen Tertiary occurs within an individual must occur in vivo Assays determine the presence and amount of a substance potentially tells potency of drug Necesssary components ab ag enzymes substrates etc Equipment radioisotope detection ow cytometer ELISA plate reader Forces that hold AgAb together Noncovalent reaction held together by Hbonding ionic Van der Waals and hydrophobic interactions they are very close together short distance between pH is critical as is temperature ph7 and 37 degrees ideal can break by raising or lowering pH or temperature Fluorescent Ab FITC anti 1 so sticks to lambda B cells in lymph node Rhodamine anti It so sticks to kappa B cells in lymph node Theory uorochromes stick to B cells by attatching to antibodies then exposed to light source absorb energy and emit light very quickly lOA9 dyes have different wavelengths so show different colors Staining Direct Fluorochromelabeled antibodies directly attatch to mAg membrane antigen the showing antibody on surface of B cell Indirect Fluorochromes attatched to secondary antiisotype antibody attatch to primary antibody that attatches to mAg most cost effective only one secondary reagent needed to amplify the system Indirect Fluorochrome attatched to protein that attatches primary antibody Flow Cytometry Cells are stained with antiA and antiB antibodies if they have A or B mAg they will have one or both of the abs attatch if they have neither they will remain unstained they are then passed through detection plates with a laser and uorescence passing through and a graph of the amount of each can be created What kind of cells express CD4 Helper T all T cells show CD2 CD8 is for cytotoxic T cells Example CD8 T cells from tumor patient recognize tumor Ag and synthesize Th1 cytokines in a human melanoma model Hu CD8 T cell s TCR demonstrates Ag specify with dendritic cell and peptide of melanoma tumor get CD8 to produce cytokines CD8 and tumor peptide in tetramer gt ow cytometry data analysis Tetramers MHC class I and antigen form a tetramer Tetramer analysis can detect T lymphocytes that have speci c Tcell receptors on their cell surface CD8 tetramer lower left quadrant didn t bind CD8 or Tetramer tumor specific antigen and tumor specific CD8 will be upper right quadrant CD8 T cells specific for tumor melanoma MARTl if we find 7 from peripheral blood we can culture to expand the number of antigen representing cells could put these CD8 cells back into cancer patient Prove that the ab isn t merely nonspecifically sticking use isotype control cell of interest So use isotype antibody IgG antiz when our cell is igG antiA7 see that igG antiZ doesn t bind same degree isotype control eliminates the question of nonspecific binding Radioimmunoassay detection of minute am ts of material excellent sensitivity and specificity RIA screening for Hep B use radiolabeled Hep B surface antigen Put in infected serum and in uninfected serum labeled antigen HBsAg inside is antibody antiHBsAg Increase the amount of unlabeled see decreased amount of labeled virus we know that it is infected and we are outcompeting for Ab Morningafter pill RU486 ends pregnancies by blocking progesterone receptors progesterone production in uenced by human chorionic gonadotropin production by the corpus luteum of the ovary Ovary gt HCG gt progesterone gt uterus allows implantation Phasel clinical trial WHO birth control vaccine worked for 6 months use to immunize human beings Hapten coupled to carrier diphtheria toxoid more antigens gt more antibodies made Smaller response to hapten than to the carrier however because carrier is bigger and more foreign and these patients were already vaccinated for diphtheria ELISA Enzymelinked immunosorbent assay Uses similar to RIA sensitivity but less expensive nonradioactive but carcinogenic reagents more stable a Indirect ELISA antigencoated well wash gt add specific antibody to be measured gt add enzymeconjugated secondary antibody gt add substrate measure color Compound is activated by the enzyme So if enzymeconjugated secondary antibody attaches color b Sandwich ELISA antibodycoated well wash and add antigen to be measured then add enzymeconjugated secondary antibody add substrate and measure color antigen sandwiched between to antibodies the substrate recognized epitope not bound to idiotype of blue original antibody Example CD8 t cells from tumor patient recognize tumor Ag and synthesize Th1 cytokines in the human melanoma model b4 you can use sandwich ELISA to nd interferon gamma release to peptide concentrations of MARTl tumor antigen instead of the ow cytometry c Competitive ELISA incubate antibody with antigen to be measured gt add the Ag Ab mixture to Agcoated well gt add enzyme conjugated secondary antibody won t stick if a lot of original antigen gt measure color Will turn yellow if positive control negative control is clear Abbot ELISA for HIV 1 Beads coated with killed virus 2 Patient s serum Abs likely to many different HIV proteins and epitopes on proteins 3 Wash gt goat antihuman igG 4 Wash gt OPD 5 Yelloworange proportional to am t of HIV ab HIV1 and 2 1985 second type ofHIV discovered in W African prostitutes HIV2 1987 confirmed in US 2000 88 confirmed cases in US Synthetic peptide immunoassay can distinguish HIV types 1 and l indirect ELISA can how HIV 1 or 2 specific abs Potent HIV abs spark vaccine hopes Isolated 2 mAbs that prevented infection in gt70 of 162 viral strains Equilibrium dialysis Control Without antibody present the antigen will be on both sides of the glass with barrier in middle that antibody cannot pass through in equal amounts Experimental Antibody in A out of side A and B More antigenligand in A in equilibrium due to Ab binding Affinity strength which Ab binds Ag thermodynamic measurement Affinity and Avidity Because most Ags have many different epitopes impossible to define intrinsic assoc constant K for a given Ab K affinity Avidity not a thermodynamic measurement a semi quantitative determination of an antiserum T cells to exert certain biologic functions that relate to AbT cell interaction with Ag Avidity depends on Affinity of all the various AbsT cells in sample Ab valence eg IgM v IgG The assay system used eg ELISA CF Varying specificity antisera contains differing proportions of Abs against various functional gps on Ag Not primary binding in avidity bP N Titer Denotes relative strength of an antiserum Is the reciprocal of the last dilution of an antiserum capable of mediating some measurable effect eg ppt or agglutination Western Blot Immune cells gt isolate protein Ags gt add size markers and protein to SDS polyacrlamide gel gt electrophoresis gt migration gt expose xray lm after using radiolabeled antibody speci c for antigen of interest All the above methods are for PRIMARY AgAb interactions Secondary AgAb Interactions utility study heterogeneous Ab populations pitfalls secondary tests negative yet antibody is present IgM easily detected by agglutination reactions but agglutinations is 50500 times less sensitive for IgG to same Ag CF and hemolysis require Clq binding to Ab require C xing Abs Agglutination Reactions Conditions of reactivity Particulate Ag pH optimum at 7276 Ionic strength 15M NaCl optimal Theory Primary step binding 0 Ag binding region of Ab for epitope Secondary step crosslinking of Ags by Ab takes time Coombs test erythrobloastosis fetalis isoimmune hemolytic anemia hemoglobimbilirubin accumulate in brain damage First birth th fetus th mother RhD cells hang out in mom postpartum mum makes anti RhD antibodies Subsequent pregnancies antiRh attacks the RhD blood cells in fetus brain Mother must be treated with Rhogam prevents B cell activation and memory cell formation if given within 72 hours of delivery of RhD baby the rst one Precipitation Reactions Soluble Macromolecules Put Ovalbumin in Oscar the rabbit How many Abs made 9 tubes with decreasing ag amounts and with Ab and PBs look for AgAb complexes What happens in supemate Excess of Ab initial middle is the optimal equivalence point too much ovalbumin and no antibody precipitates too much antibody and not very much antibody precipitates need a balance for precipitation to occur Too much antigen serum sickness too much abs arthus reaction but in equivalence zone we will have neither free antibody nor free antigen and the immune complex will precipitate Precipitation Reaction in Gels 3 wells 2 with antigen inside 1 with antibody inside 1 Identity reaction same antigen Picture 2 Nonidentity reaction two different antigens one per well Picture 3 Partial identity multiple components Picture Will probably be exam questions from an example probably complicated with 3 antigen wells around the antibody well practice it Complement Fixation assay Used for number of viruses protozoan parasites syphilis fungi Ag is usuall a crude extract of organism is popular because of this cheap and sensitive Put antigen in test antiserum with immune complexes and in a tube with no immune complexes add complement to both will x with immune complexes remain free with no immune complexes then add Indicator cells and hemolysin indicator cell lysis without immune complexes no cell lysis with immune complexes Microarray Assays Probes spotted oligonucleotides 70 mers of the entire genom Target mRNA gt cDNA Cy3 activated T cells and cDNA Cy5 resting T cells Hybridized Scan for color signal Tertiary AgAb reactions Passive cutaneous anaphylaxis Toxin neutralization Anaphylaxis Allergy skin testing Clearance of ag from circulation Protection against disease Lecture 10 Complement Something in normal sera complements antibody allows for lyses bc if sera is heated agglutination only occurs not lyses Biological Events Associated with C Lysis Opsonization coating Activation of in ammatory response Clearance of immune complexes Increase vasodilatation Assists in degranulation Aid phagocytosis by opsonization Contribute to chemotaxis direct to site of injury 2 Complement Pathways First The Classical Complement Pathway Activated by immune complexes of lgG and IgM noneimmunological activation can happen by Creactive protein plasmin Exe Pentameric IgM changes con rmation when sees bacterial agella allows complement components to combine Theoretically 1 pentameric IgM or 2 IgG for conformational change the first component Clq binds to an exposed Fc region CH2 domain of lgG or CH3 of IgM these sites CH2 and CH3 are exposed after binding of antigen 1 ClQ binds site on immunoglobin molecules 2 ClR and 2 C18 are activated and attatch to make the C1qr2s2 complex the ClQ first activates ClR then together activate CIS 2 Cls cleaves C4 and C2 cleaving C4 exposes the binding site for C2 C4 binds the surface near C1 and C2 binds C4 forming C3 convertase C4b2a 3 C3 convertase hydrolyzes many C3 molecules some combine with C3 convertase to form C5 convertase 4 The C3b component of C5 convertase binds C5 permitting C4b2a to cleave C5 5 C5b binds C6 initiating the formation of the membraneattack complex C5b678 on poly C9 called poly C9 Complex 6 Causes pores cell swells and lyses Functions of C3a Increases vascular permeability by releasing serotonin and histamine from mast cells degranulation Endothelial cell contraction smooth muscle contraction caused by degranulation helps uid leak out as well as cells in ammation in tissue space Functions of C3b Major coating on target cells receptors CRl present on neutrophils eosinophils monocytesmacrophages and b cells B cells also possess a receptor for the inactive form of C3b or C3d C3b aids phagocytosis of coated organisms and particles IMPORTANT effector macrophages neutrophils cells lack receptors for IgM so c3b xation to target cells and particles is a critical opsonizing event during early igM phase allow ingestion by effector cells C5a 100 more active than c3a Major chemotactic factor for neutrophils margination in vessels Activates neutrophils by triggering bactericidal oxidative burst Causes neutrophils to produce keukotrienes chemotactic for neutrophils and macs and prolongs vascular permeability Increases vascular permeability Causes mast cell degranulation Causes smooth muscle contraction Same as C3a but STRONGER The Alternate Complement Pathway Immunological activation aggregated IgG4 IgA IgE NonImmunological activation Tryipsinlike enzymes plasmin LPS bacterial endotoxins repetitive sugars on bacterial surfaces G bacteria cell wall components Yeast cell wall polysaccharides Cobra venom factor Why host cells more resistant to C killing C3b is inactivated by sialic acid while bacteria and yeast have low sialic acid and mammals have high so a few bystanders may be killed but not many Alternate Pathway 1 C3 hydrolyzes spontaneously C3b fragment attaches to foreign surface 2 Factor B binds C3a exposes site acted on by factor D Cleavage generates C3bBb which has C3 convertase activity 3 Binding of properdin stabilizes convertase 4 Convertase generates C3b some binds to C3 convertase activating C5 convertase C5b binds to antigenic surface Control Mechanisms for Complement System There are many ways to prevent the complement system to go through with killing the cell c4BP stops activity of C4 Factor H breaks down C3b Decayaccelerating factor blocks C3 convertase prevents the enzyme from being created Lecture 11 The Major Histocompatibility Complex MHC The MHC presents portions of Ags that are noncovalently bound to MHC gene products called MHC class I and II molecules to Agspeciflc T cells Any given T cell recognizes foreign Ag bound to only one speci c MHC class I or II molecule MHC A complex of linked multiallelic genes located on one chromosome that code for molecules that restrict speci city of Ag recognition by T cells Most polymorphic of genes 100 s of different alleles for MHC to specialize Two MHC classes I Expressed on virtually all nucleated cells that is everything but red blood cells therefore and restricts Ag recognition by CD8 Tc cells 11 Expressed on APCs and restricts Ag recognition by CD4 Th cells APC s are B cells macrophages and dendrites MHC restriction of cytolytic T cells In spleen cells Cytotoxic T cells learn who self is Each T cell 1 antigenMHC association In humans MHC is codominantly represented in macrophages Major histocompatability complex Histocompatability recognition of class I or II molecules by T cell receptors determines tissue compatibility or incompatability MHC general term referring to this group of loci in any species that are inherited as a haplotype Principal Physiologic Role of t cells for self MHC and Ag T cells interact most efficiently with other cells that bear MHC associated Ag and not soluble Ag present Ag Patterns of Ag associated with Class I or II determines the kinds of T cells stimulated by different forms of Ags peptides from extracellular proteins bind class II endogenously synthesized proteins bind Class I therefore and J proteins 39 J by functionally distinct T cell populations Immune response to foreign protein is determined by the presence or absence of MHC molecules that bind and present protein fragments peptides MHC genes control immune response to protein Ags Mature T cells in an individual recognize foreign Ags but not self proteins therefore MHC molecules shape the repertoire of mature T cells MHC can produce self proteins or present foreign Ags if respond to self autoimmune No good Class 1 CD8 Class 11 CD4 Inheritance of MHC in humans MHC all genes from are on the same chromosome Mice Chromosome 17 I region K IIIII I region D Humans II III I Three regions of II are DP DQ and DR Three regions ofI are B C A III codes for c proteins MHC class I has to associate with a beta2 microglobulin to express on surface MHC class II is two nonidentical glycoprotein chains beta and alpha membrane bound Identi cation of class Ipeptide interaction Peptide binding cleft of MHC does not have ne speci city does not need many peptideMHC complexes as few as 100 to activate T cell Bound peptides to MHC I are 9 AAs with the cleft closed at both ends Contain speci c AA residues essential for binding peptide to a particular MHC molecule anchor residues but many have same or similar aa residues here so it can match a diverse set of peptides MHC class II interaction MHC class II contains 1388 AA residues Cleft is open at both ends Peptides that bind have internal conserved motifs but lack anchor residues at ends Humans 2 K 2D 2L class I 41E rIA class II Codominant expression T cells must recognize MHC Ag to avoid autoimmunity and need neighboring target cell to kill helps direct T cell towards infected viral cell or show which APC is presenting Why enormous allotypic diversityvariation of MHC molecules Abc and TCR diversity generated by random gene rearrangements MHC diversity from polymorphism multiple alleles doesn t change over time within an individual 10A12 possible MHCs in mice even MORE in humans Wh 7 y So perfect pathogen can not kill all humans immune system of each individual unique Less likely for microbe to imitate recognition molecules Lecture 12 How does our Immune System recognize intracellular and extracellular antigens Intracellular viruses revealed by antigen presenting cells to cytotoxic t lymphocytes extracellular bacteria and proteins are recognized by antibodies Antigen presenting cell required for production of IgG Types of Endocytosis used for Antigen accumulation in Macrophages Phagocytoses Macropinocytosis cdc42 RAC actin Clathrinmediated endocytosis clathrin adaptors ap2 dynamin Nonclathrinvaceolae endocytosis dynamin caveolin Organelles used clathrincoated vesicles and caveole endosomes lysosomes nucleus and endoplasmic reticulum Two sources of antigens for MHC molecules Cystolic and Endocytic pathway Cystolic Pathway Intracellular antigen most effectively eliminated by CTL Endogenous antigens gt Ubiquitin and uniquinating enzyme complex ATP Cystoplasmic proteasome complex gt peptides TAP Endoplasmic reticulum gt Peptidesclassl MHC complex Peptides can also go into endycytic compartments in the endocytic pathway or become w help from exopeptidases amino acids Endocytic Pathway Extracellular antigen most effectively eliminated by antibody Exogenous antigens gt endocytosis or phagotycosis Endocytic compartments gt peptides can be used by exopeptidases to become amino acids at this time gt Peptide MHC class II complexes AntigenPresenting Cells Professionals Dendritic cells constitutively high MHC II and costimulatory action Macrophages can be activated to express high MHC II and costimulatory molecules B cells constitutively MHC II but activated for costimulatory molecules Nearly all nucleated cells express MHC I Nonprofessional antigenpresenters Fibroblast skin Glial cells brain Pancreatic beta cells Thymic epithelial cells Thyroid epithelial cells Vascular endothelial cells Antigen Processing and Presentation How important is temperature Very needs to be at 37C or near nothing at cold temps How long does it take 60 minutes necessary Importance of acidic environment Necessary for processing Ag to peptides for MHC class II Is a living APC required to degrade a protein into an immunogenic peptide Fixed APCs can not persent native OVA Ag must be processed most T cells could respond to degraded Ag whether APCs were fixed or not previous Ag degradation bypassed required active processing but in nature Ag processing is required How B cells present Antigenic Peptides Recycling receptors taken in acidic environment removes antigen from receptors golgi complex helps endosome move to lysosome attatch to new BCR and exposed on surface Determinant Selection Model Assumes structure of a given MHC allelic molecule determines strength of its association with any given antigenic peptide animals that respond to antigen peptide A must express at least one class II MHC whose structure facilitates interaction with Ag peptide A whereas animals that do not respond must express class II that do not interact effectively with Ag peptide A MHC polymorphism in a species generates different patterns of responsiveness and nonresponsiveness to different Ag peptides If model correct then MHC II molecules from different mouse strains should show differential binding of an Ag when comparing mouse strains that do or do not respond to the given Ag Ability of individual to mount a high immune response depends on peptide binding to a given MHC II allele to respond to peptide bound MHC II must have T cells specific for a given peptide bound to MHC II allele T cells bearing receptors that recognize foreign Ags closely resembling selfAgs are eliminated during selection Processing and presentation by MHC class I Protein gets uniquitin attached via uniquinating enzyme complex and ATP then a proteasome with proteolytic subunit breaks into peptides which are then placed into TAPlATP complex in RER membrane and is then ready to be loaded onto class I MHC molecule Ag Cross Presentation Possible routes for exogenous Ag to gain access to MHC Imolecules following endocytosis Characteristics of peptide binding by MHC molecules allows effective Ag presentation MHC molecules bind a wide range of different peptides PeptideMHC complex is stable at cell surface Stability of peptide MHC allows even rare peptides to be efficiently transported to cell surface by MHC allowing longterm display lst requirement Second requirement dissociation of peptide from MHC should not allow new peptides to bind empty peptidebinding grooves Class I without peptide are unstable and denaturechange conformation B2M dissociates and chain is intemalized degraded Class II are more stable in the absence of peptide at neutral pH But peptide is lost when class II are recycled through acidified intracellular vesicles class II not associated with peptides aggregate at acidic pH and rapidly degraded Thus loss of peptide again leads to rapid loss of empty MHC molecules Different Antigen processing pathways have importance in vaccine design Lecture 13 cellular and Molecular basis of T Cell Receptor for Antigen Lecture 14 Cellular and Molecular basis of T cell Activation Lecture 15 T Cell Cytokines Lecture 16 Human Genome Contains 3 billion pairs of NTs coding for 30000 genes on 23 pairs of chromosome every cell in your body contains the same DNA except germ cells lt3 DNA instructions for building cells DNA isolated from one cell end to end top of Shaq s head coding DNA would stop b4 his ankle Non Coding DNA origin Blissful coexistence of bacteria viruses and humans Mitochondria alpha proteobacteria mtDNA Pieces of bacteria amp retroviruses Mutually bene cial relationship General features of immunity to microbes l Mediated by innate and acquired immunity 2 Different types of microbes elicit different effector mechanisms 3 Microbe survivalpathogenicity in uenced by evasionresistance to immunity 4 Disease may result from IR to microbe Direct Mechanisms of Tissue Damage by Pathogens Exotoxin production strep or staph cause tonsillitis sores Endotoxin not released until death of bacteria E Coli cause sepsis Cytopathic affect Cold sores Small pox Herpes Indirect Mechanisms We make antibody response the antigenantibody complex circulate blood vascular system and can be filtered out in kidneys Immune Complexes Antihost antibody antihost antibody response antibodies cross react to host Cellmediated immunity tuberculosis herpes lyme arthritis Thl V 1112 Lymphocytes Thl makes IFN gamma and TNF beta which makes macrophages for cell mediated immunity and in ammation ThZ will make 114 and ilS and i113 make B cells for antibodymediated immunity 114 will block thl production so they block each other based on the location Provide a balance for each other preferential bias based on tissue site Extracellular Bacteria Replicate outside host cells in circulation connective tissues airways intestinal lumen urogenitial system Strep E Coli Clostridium Attachment to host cells Host defense Block attachment of bacteria in GI tract by secretory IgA antibodies Bacterial Evolution mechanism Secretion of proteases that break down IgA variation in attachment structures pilli Proliferation Host defense Phagocytosis Ab and C3b mediated osonization Complementmediated lysis and localized in ammatory response Bacterial Evolution mechanism Production of surface structures that inhibit phagocytotic cells ability to survive within phagocytic cells induction of apoptosis in macrophages Generalized resistance of gram bacteria to complement mediated lysis insertion of MAC by long side chain in cell wall LPS Invasion of host tissues Host defense Abmediated agglutination Bacterial Evolution Mechanism Secretion of elastase that inactivates C3a and C5a Toxininduced damage to host cells Host defense Neutralization of toxin by antibody Bacterial Evolution Mechanism Secretion of hyalurindase which enhances bacterial invasiveness Immunity to extracellular Bacteria Cause disease by 1 In ammation gt tissue destruction 2 Many bacteria produce toxins Exotoxin found outside bacteria heatlabile Enterotoxin an exotoxin produced by staphylococcus in intenstines Endotoxin in bacteria cell wall heat stable 3 types of Exotoxins based on Mode of Action Cytotoxins kills or alters cell function NT block nerve impulse transmission Enterotoxins affects cells lining the GI tract water loss Extracellular bacteria 1 Toxin neutralization 2 Complement Mediated Lysis 3 Opsonization and Phagocytosis 4 Anaphylatoxins mediate mast cell degranulation Speci c IR to extracellular Bacteria Humoral IR protective Cell walls and capsules are polysaccharides gt T1 Ags gt IgM Bacteria proteins gt CD4 cells gtBcells gt Abs SuperAgs toxins clinical abnormalities Staph Aureus Disease caused by the staphylococcal entertoxinlike toxins hallmark is shock T cell and T cell receptor The Vbetachain aspect of the T cell DNA is associated with staph toxin effects Mouse has 22 functional Vbeta elements no produces all 22 because of deletions and mutations Holes in T cell repertoire bc can t produce all 22 Look at one toxin and one Vbeta DNA element will stimulate the T cell Pathology Associated with Toxin vomit diarrhea rash SHOCK Mechanism of Superantigen Activation Toxin does not bind in groove binds to the VBeta and a portion of the MHC class II molecule so it functions outside of the Receptor mediated area totally excludes alpha chain of TCR All different entertoxins have different VBeta specificity a huge variety so in a population that has TCR coded by different VBetas and Alphas might have specificity for herpessimplex antigen but because it expresses the VBeta that the superantigen can also bind to it will outside of the MHC and outside of the groove and will stimulate the T cell to divide so you are activating many clones of the T cell making massive amounts of T cell that are responding to the enterrotoxin wrong antigen not the peptide in the groove Massive production of TNFalpha cytokine massive weight loss VBeta Expression in Wild Mice Wild mice also have deleted elements don t have all 22 VBetas therefore must be Disadvantage for expressing too many VBeta elements in an individual Effect of SEB staph superantigen on Nude mice and neonatal mice What is the effect of a toxin on somebody without any T cells Resistant VBeta Activation Depending on strain of mouse of 3040 of T cells might respond TSST in humans engages only VBeta2 stimulates 10 of alphabeta T cells stimulates more cells than a conventional Ag gt proliferation can constitute 50 of peripheral T cells Creates a Cytokine Storm gt TNF causes tremendous in ammatory response Summary of exotoxin effect on Vbeta elements of TCR Mice like us have a diverse TCR alphabeta repertoire do not eliminate a particular TCR polymorphic gene element All elements of Vbeta are available to a species but individuals express only a subset of the total so there must be some selective disadvantage for too many Vbeta elements expressed in one individual Disadvantage of excessive Vbeta expression is susceptibility of mice to microbial toxins that rely on massive stimulation of T cells bearing particular VBeta elements for their toxicity Vbeta T cell stimulation mode of action of exotoxins in animals How to treat Recombinant VBeta of TCR of 12kD long with 3 million fold affinity for SEB compared to wild time VbetaTCR so can out compete toxin binding compared to native TCR Very effective at neutralizing good 2 hours post toxin but then it is too late when most people notice that they are ill Endotoxins Gm bacteria potent stimulator of cytokine production Adjuvant Polyclonal B activator stimulate B cells directly Hallmark of these endotoxins also shock gt death


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