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Lecture 3

MICB 202 Lecture 3 Continued

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Department
Microbiology
Course
MICB 202
Professor
All Professors
Semester
Winter

Description
Micb 202 lecture 3 cont. • Inflammatory Response o Damaged mast cells and epithelial cells release chemicals for pain o Mast cells release histamine to dilate BV (pain, swelling, redness, warmth) o Resident Macrophage release  IL1: fever, sticky and leaky BV. Cytokine.  IL6: fever, sticky and leaky BV. Cytokine.  IL8: chemokine for chemotaxis  TNF-a: sticky, leaky BV. Is a cytokine o Sticky + leaky recruit plasma which has complements, neutrophils, monocytes, and dendritic cells  Monocytes mature  All cells move with IL8 gradient. Squeezed through tight junctions of endothelium  *fastest responders are neutrophils, then macrophage, then dendritic o Phagocytosis occurs, and activated dendritic cells move to lymph nodes to present on MHCII to T cells • Activation of Complement System o Is a cascade. o Result is pore formation in pathogen by MAC o Classic Pathway: C3 cleaved into C3a, C3b by antibody o Alternate Pathway: C3 spontaneously cleaves into C3a, C3b *C3b is an opsonin, it also forms part of C3 convertase. Likewise, C5b forms part of MAC • Other functions of complements o C3a: inflammation. Increase permeability by stimulating macrophage to produce more TNF o C3b: opsonin. Phagocytic cells have receptors for opsonins, therefore increase contact points. Not just PRR receptors. o C5a: inflammation. Induce mast cells to make more histamine Major Histocompatibility Complex • MHC: o Polygenic: more than 1 gene codes for similar MHC proteins, probably due to gene duplication then divergence o MHC 1: HLAA, HLAB, HLAC o MHC II: HLADP, DR, DQ o Are also polymorphic: different alleles  And are codominantly expressed so you have 6 o Since they are proteins, has high level of turn over. • MHC 1 VS MHC II MHC 1 MHC II Alpha chain, B chain not covalently Alpha, beta chains bonded to it. With B-microglobulin. Peptide binding groove in alpha . present tPeptide binding groove between the 2. CTL Present to TH 8-10aa, fits in groove a.a. 13 , drapes over groove In most nucleated cells Only inAPCs: macrophage, dendritic, B cell, thyroid epithelial cells Peptides derived from cytosolic proteins: Peptides are derived from Extracellular. self, virus. Peptide loading in ER Peptide loading btwn ER/membrane in vesicle. Lecture 4 • MHC 1 loading: endogenous o Cytosolic proteins degraded into peptides by proteosome, transported to lumen of ER by TAP o Newly made MHC associate with B2-microglobulin--------unique to mhci o Peptides bind to MHC in ER lumen o Leave ER-->Golgi o Displayed for 24h, then internalized and replaced • MHC II loading: exogeneous o Protein/pathogen internalized byAPC o Phagosome or endosome fuse with lysosome o Proteases break down proteins to produce peptides o Newly made MHCII associate with invariant chains which block peptide binding site. Leave ER in vesiclegolgi o Invariant chain digested in golgi to leave a small CLIP in binding site o Peptide vesicle fuse with MHC vesicle, CLIP removed, peptide loaded o Displayed at cell surface for 48h • T cell development o Precursor T cells derived from lymphoid stem cells in bone marrow do not yet express TCR. Migrate to thymus o Begin to express TCR that’s generated randomly thru splicing of gene segments (each cell has 30,000identical copies)  Will eventually become • CD4 aka TH aka recognize MHC II • CD8 aka CTL aka recognize MHC I • More on T cell dvlpment o Undergo positive, negative selection o At a point, thymocyte express both CD4, CD8, but if its TCR binds better with MHC 1, will stop expressing CD4, and vice versa • T cell activation o Must have 2 signals fromAPC (dendritic cell is best) o 1: TCR binds to MHC-peptide complex,( then binding of CD4 or CD8 to MHC just not at binding cleft. CD3 signalling complex activated to deliver SIGNAL 1 to nucleus ) o 2: CD28 protein of T cell binds B7 of apc—only professionalAPCs can deliver o If only signal 1, cell becomes anergic • After activation, T cell requires IL2 to proliferate. Made by TH (a lot), CTL also make some, but need more to proliferate o Cells make and secrete, with IL-2 receptors on cell surface (autocrine loop)  Binding cause prolif, and differentiation  T cell can become effector cells (kill viral infected cells, and memory cells that will reactivate if same virus comes back) • Comparing the 6 MHC I proteins I have o The B2-microglobulin is same for all, region of protein near membrane, region associating with B2, region important to overall 3D shape o This is important to make sure it can still present peptides to T cell (right shape for interactions) o Variable regions=peptide binding site. o Slightly variable regions=region interacting with TCR Lecture 5: • Positive and negative se4lection for T cells o Positive selection: identify developing T cells that can bind to MHC for activation  Need low affinity interaction btwn T cell and MHC+self peptide  After expressing both CD4, CD8, TCR screened against MHC+self peptide by thymic cortical epithelial cells • If bind to MHC I, given signal to express CD8 • If bind MHC II, given signal to express CD4 • If no binding, get no signal, apoptosis o Negative selection: identify developing T cells that bind MHC too tightly —induce self-tolerance and prevent autoimmune disease  Can occur at any immature or mature stage  APCs derived from bone marrow facilitate in thymus  If bind too strongly, apoptosis o Only about 5% of cells entering thymus mature into T cells, of these, only a few will ever be activated in the body to fight infections o But thymus epithelial cells and the bone marrow derivedAPCs have certain genes shut off and doesn’t present some peptides found in other tissues. What to do?AIRE!  AIRE-autoimmune regulator gene expressed in thymic medullary cells (includes epithelial, dendritic, macrophages) • Is a transcription factor that allows thymic cells to express other tissue-specific antigens • If AIRE mutation, getAPECED. Symptoms are chronic candidiasis, hypoparathyroidism, and others. • In vitro different from in vivo o In vitro macrophages can activate naïve T cells. In vivo, activate previously activated T cells, present antigen to activate self o Dendritic cells always bestAPC due to huge SA o B cells in body present antigen to TH to become activated themselves. In vitro, can activate naïve T cells o We will assume in vivo only dendritic cells can activate naïve T cells • Roles of TH o Cytokine support for both humoral, cell mediated responses o Help macrophages kill intracellular bacteria o Help CTLs kill viral infected cells o Help B cells proliferate into plasma • Treg o Express high levels of CD25, part of IL2 receptor o Also have CD4 o TCR, when recognize MHC-peptide complex, gets signal 2, begins to secrete IL-10 o 2 functions  Resets anergic cells  Shuts down self-reactive cells in periphery Lecture 6 • B cell development o As immature B cell, begin to express IgM, as mature B cell but naïve, express IgM and IgD o Each B cell has 10,000 identical copies of BCR and 40% of cells that commit to B cell development end up as a B cell—this is 35% more than for T cells • B cells make a secreted form of BCR=Ab/Ig/sIg—by plasma cells o Vs. membrane bound form of BCR=mIg/BCR (just memory and naïve cells) • 5 classes of Ig: M, D,A, G, E o E lots in ppl with allergies o Have different functions in immune system o All can be either sIg or mIg, except for IgD which is only on membrane of NAÏVE B cells o Functions determined by type of H chain it has N terminus *dark dashes show disulfide bonds. Can be broken if reduced • BCRs have 4° structure: 4 polypeptides o 2 heavy, 2 light chains that are identical. Each have variable and constant regions o Each BCR can bind 2 antigens due to the 2 pockets created by the Vh and Vl regions • Like TCR, BCR associated with signalling complex=Igà, Igb • 3 areas within variable regions are hypervariable regions=parts that contact antigen (just like TCR) o Differences in mIg and sIg is in C terminus of heavy chain  sIg doesn’t have the signalling complex • variable/constant regions refer to primary structure of protein • B cells only undergo negative selection: BCRs cant bind too strongly to own body antigens in bone marrow=clonally deleted o Don’t need positive selection because don’t bind to MHC • B cell activation: o Signal 1: BCR binds to intact antigen, crosslinking of 2 adjacent BCRs  Signal relayed by alpha, beta to nucleus o Signal 2: BCR with antigen internalized, processed, and peptide displayed on MHC II, present to TH  The TH has previously been activated by a dendritic cell  Activated TH is found by B cell in spleen/lymph node, CD40 on B cell binds to CD40L on T cell after the MHC engages with TCR + CD4 and strengthened by CD28 with B7. • TH secrete cytokines to help support B cell proliferation/differentiation itno plasma and memory • Antibodies last few months in body, plasma cells live a few months. Memory cells live years. • Ab bind to epitopes o 3d shapes about size of 4-5a.a o Can be proteins, lipids, carbs, synthetics, vs. TCRs which only recognize peptides complexed with MHC o Side chains of a.a. in pocket ofAb play important role in antigen binding (size and charge of R groups) • Immunoglobulin Class switching o During immune response, B cell may switch to make a different class of antibody  V regions stay same, C regions change • Only heavy chain involved. Involves DNAsplicing  Important since dif Ig work in dif parts of body o Switch is UNIDIRECTIONAL. Can’t switch back. o The gene if PERMANENTLY excised, so theres no way you can make it again. o Induced by TH with cytokines Lecture 7 (see mind map that I wrote down.) Lecture 8: • Antibody functions o Neutralization: only variable region involved o Opsonisation: Fc region ofAb has receptors for macrophage (Fc recepeptors) C3b also has receptors on phagocytic cells. o Complement mediated killing: classical complement cascadeMAC formed Immune Response to INTRACELLULAR Bacteria infection • If cell is infected but no MHCII, can’t activate TH, so bacteria keeps growing until cell dies and bacteria released. Or if MHCI presents a bacteria peptide, activated CTL kills the cell and release bacteria. So hopefully the extracellular bacteria will be picked off by other immune cells or antibodies. (can involve cross-presentation by dendritic) • • • How to superactivate the macrophage: o 1. IFN-γ by TH o 2. CD40L on T cell binds to CD40 on macrophage o These signals cause macrophage to transcribe new set of genes: NO, O radicals, proteases.  Like suicide bomber. Kills cell, bacteria, and surrounding tissue  Eg. Leprosy. Immune response leads to loss of facial structure, fingers.  *this is primary response. If same pathogen encountered, there will be memory T cells so response only 2-3days Lecture 9 VIRAL INFECTIONS! **the problem is, if a cell only has MHCI and display viral peptide, CTL can’t be activated since there’s no signal 2 (B7 mediated), thus, the CTL would become anergic Dendritic cells to the rescue! They can cross-present! -activated CTL look around for cells that have MHC-1-Peptide complexes that bind to its TCR, if bind. Release perforin + granzyme so cell undergoes apoptosis. -takes 45-60mins for target to die. -CTL requires survivial signals to live MICB 202 LEC 10 • Cytokine release during infection can lead to recruitment and activation of more immune cells—this usually produces symptoms eg. Nausea, headache, muscle ache, fever • SEPSIS o When bacteria grows in BV and systemic inflammation response occursseptic shocklow BP, organ failure • Sometimes immune system mounts response against non-harmful substance o Allergies o Tuberculin o Transplant rejections o Autoimmune disease o Results from HYPERSENSITIVY=unreasonable and exaggerated immune response to something that’s not dangerous • Immediate hypersensitivity: (involve TH, dendritic, macrophage, B, mast) o Mediated by IgE that are bound to Fc receptors on mast cells(remember, Fc is region ofAb on bottom) o Person has already had 1° response toAg (class switched to IgE, secreted inblood but high affinity for mast cells in tissues) o IgE cross-linked (2 IgE bind to sameAg) after bindingAg, stimulates cell to release histamineallergic symtpoms whithin mins  Sneeze, cough due to excess mucus secretion, hives, rash, diarrhea, vomiting o Allergies can be localized(if allergen trapped at mucus surfaces) or if travels systemically (peanuts, bee venom, penicillin)anaphylactic shock  BV dilate, and airways constrict to compensate for low blood flow • Why do we
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