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202 Cards in this Set
- Front
- Back
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immunological lab applications
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diagnose HIV, hepatitis, herpes -- elisa, western blot, immuno-fluorescense
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US life expectancy doubled since 1850
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76.7 in 2000
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immune system function
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distinguish self from non-self, protection from invading organisms (parasites, bacteria, fungi, virus)
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two arms of immune system
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innate immune system, adaptive immune system
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innate immunity
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first line of defense; preformed, lacks immunological memory, does not improve over time, non-specific; often unable to control infection -> adaptive immunity
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components of innate immunity
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barriers (skin and mucous memb., acidic pH in stomach); cells of innate defense; antimicrobial peptides, complement, c-reactive proteins
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cells of innate defense
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phagocytic: neutrophils, monocytes, macrophages, dendritic cells; non-phagocytic: natural killer cells
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neutrophils
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aka polymorphonuclear leukocytes (PMN); have multilobed nuclei, phagocytose organism and kill it intercellularly, have short life (one day in circulation), replaced by new cells from bone marrow, only participate in innate defense, do not express MHC, have acidic and basic granules, multilobed nucleus, differentiation takes two weeks from megamyeloblast (nucleus undergoes major changes(concave to multilobed), develop primary granules(azurophilic granules contain lysozyme, myeloperoxidase(green, commonly seen in pus, indicates ongoing host-inflammatory response), and beta-defensin) and secondary granules(lactoferrin, DNAase, RNAase, and proteasees), 60-70% of WBC, excessive neutrophils in circ. Suggests chronic infection (exception S. typhi), can leave circulation to mediate inflammation(called diapedesis), induce pyogenic response and provide protection against staphylococcus auerus and streptococcus pneumonia
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monocytes
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phagocytic, kidney shaped nucleus, lack granules, more efficient in controlling intracellular pathogens, leave circulatory system and differentiate into macrophages, 5-10% of WBC population, live for 2 days in circulation, lack myeloperoxidase
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macrophage
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phagocytic, found in tissues, longer life span (months to years), larger than monocytes (have numerous intracellular organelles), can present antigens to T-lymphocytes (activating adaptive immune response), CD14 on surface, play major role in innate defense by controlling intracellular infections, called: alveolar macrophage in lungs, kupfer cells in liver, mesangial cells in kidney, microglial cells in brain, play important role in granulomatous response, lack myeloperoxidase but can generate: superoxide, H_2O_2, nitric oxide and reactive nitrogen intermediates, and has lysozyme, express (iNOS/NOS2)
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monocytes and macrophages
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efficient phagocytic cells, clear dead cells and debris
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dendritic cells
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aka DC cells, derived from monocytes, phagocytic, found in tissues(skin), have long memb. Extensions, capable of phagocytosis and pinocytosis, can present antigens to T-lymphocytes (activating adaptive immune response), CD14 on surface, most efficient antigen presenting cells, present with MHC I and II to T cells, CD4 and CD8 proccessing in different cellular compartments.
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phagocytosis
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take microorganisms inside (at special cell surface locations -- clatherin-coated pits, plasma membrane invaginates and ends of memb. fuse to form a vacuole called phagosome), kill with reactive oxygen species, reactive nitrogen species, antimicrobial peptides, fusion of phagosome (containing microbes) with lysosomes,
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oxygen dependent killing by neutrophils
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perturbation of plasma membrane results in activation of NADPH oxidase which reduces oxygen to superoxide radical, which then forms H_2O_2 (can control growth of some intracellular pathogens), some pathogens have superoxide dismutase and catalse which degrade superoxide and H_2O_2, H_2O_2 can combine with Cl- in the prescense of myeloperoxidase to form hypochlorous acid(potent antimicrobial angent that can inhibit growth of intracellular pathogens), singlet oxygen is derived from recation between hypochlorous acid and H_2O_2
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oxygen independent pathogen control
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lysosomal enzymes and other antimicrobial peptides
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natural killer cells (NK)
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Lymphocytes that don't express CD3, CD4 or CD8,large granular lymphocytes, usually not phagocytic, usually lyse abnormal cells (cancer cells or microbe infected cells); recognized due to down regulation of MHC I in abnormal/infected cells, lysis induced via perforin (creates pores in cell memb for entry of granulysin) and granulysin (kills target cells and intracellular microbe), activated by KAR (killer activating receptor), inhibited by KIR (killer inhibitory receptors)
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adaptive immunity
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not preformed, onset is slow, highly effective once active, highly specific, improves over time, has immunological memory; phases: recognition, activation, response
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components of adaptive immunity
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T-lymphocytes(undergo differentiation in thymus), B-lymphocytes(undergo differntiation in bone marrow)
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B cell overview
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produce antibodies(immunoglobulins) which bind antigens and neutralize the antigens, antibodies also opsonize the bac. for phagocytosis
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antibodies
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protein molecules that bind and neutralize microbe derived antigens
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T cells
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produce proteins: cytokines or interleukins (IL), activate macrophages, induction and suppression of immune system, express cluster of differentiation antigens (CD), all T cells express CD3, those that express CD4 are also called helper T cells, those that express CD8 are also called cytotoxic T cells
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cytokines
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activate cells of innate and adaptive immunity
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lactoferrin
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macrophages and neutrophils(in secondary granules); sequesters iron, inhibiting microbe growth, pathogen death due to iron starvation
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defensins
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positively charged proteins bind to negatively charged bacterial surface and induce lysis
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alpha-defensin
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neutrophils and panneth cells; prevent HIV from binding to CCR4 receptors on macrophages (thus preventing HIV invading macrophages)
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beta-defensin
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epithelial cells of lungs
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CCR4
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cemokine receptors on macrophages
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HIV
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enters macrophages by binding CCR4, after binding HIV is taken in
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apolipoprotein RNA editing enzyme
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aka APO3CEG; produced by cells can inactivate HIV by deaminating the cytosine residue in both RNA an DNA (virus inactivation); HIV has countered with host defense (viral inhibitory factor that inactivates APO3CEG
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complement
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group of serum proteins (30 complement factors) whose activation leads to cascade of events leading to bacterial lysis, activation: during antigent-antibody reaction, upon infection with gram – bac. (LPS), mannose (mannan polymer) either from fungal infection or from some gram + bac., three mechanisms by which complement can lead to microbe distruction: inflammation (granule released from mast cells), opsonization(stimulate phagocytosis), and lysis
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memb. attack complex
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C5b, C6, C7, C8, C9
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classic pathway
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Antigen-antibody(IgM/IgG) reactions C1 -> C4 -> C2, C142 -> C3 -> C5 -> C6 -> C7 -> C8 -> C9, complex binds bac. cell surface and causes lysis
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alternate pathway
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LPS activates C3 -> C5 splits into C5a & C5b, C5b part of attack comples with C6, C7, C8, C9, complex binds bac. cell surface and causes lysis
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mannose lectin pathway
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mannose binds host protein lectin, mannose-lectin complex activates C4 binds C2, C42 -> C3 -> C5 -> C6 -> C7 -> C8 -> C9, complex binds cell surface and causes lysis
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C5a
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functions as an anaphylotoxin inducing mast cells and basophils to release histamine
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opsonisation
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neutrophil and and moncyte ability enhanced by complement and antibodies; these phagocytes have cell surface receptors that bind antibodies and complement; phagocytic activity is enhanced when bac. Is coated with antibodies or complement, aglutination (cells), precipitation (soluble) of Ag
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opsonins
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antibodies or complement when used to enhance phagocytic activity
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C-reactive proteins
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produced by liver cells, can bind staphylococcus cell surface and inactive, can activate complement
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HLA
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human leukocyte antigen, MHCs, 3 copies from mother, 3 from father
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MHC
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major histocompatability complex, similar to blood group antigens, expressed on surface of nucleated human cells
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MHC I
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down regulated in abnormal cells (mutated/infected), such cells subject to lysis by NK cells
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ADCC
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Antibody-dependent cellular cytotoxicity, death by NK cells, neutrophils, eosionophils
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FcRs
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Fc receptors expressed on NK cells, neutrophils, and eosinophils, bind epitope enganged Ab
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PAMP
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pathogen associated molecular pattern
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pattern recognition receptors (PRRs)
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allows innate immunity to distinguish between self/not self; pattern recognition receptors include (toll like receptor(TLR-2 and TLR-4), and lectin (binds mannose))
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TLR-4
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recongizes gram neg. bac.; LPS released from gram neg. bac., LPS binds LPS-binding protein in serum, LPS-binding protein transfers LPS to CD14, CD14 coexpressed with TLR-4 on macrophage, TLR-4 and CD14 complex connected to cytoplasmic MD2 adaptor which activates TLR4, host cell signalling and expression of transcription factor NFkappaB, NFkappaB binds neucleus and induces TNF-alpha synth., pro inflammatory cytokines produced (IL-1, IL-6), pro inflammatory cytokines can act on liver cells to make c-reactive protein
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TNF-alpha
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tumor necrosis factor-alpha, excess TNF-alpha: can lead to cachexia(muscle wasting), anorexia(lack of appetite) and inflamation; excess TNF-alpha along with IL-1 and IL-6 can induce inflammation and septic shock, at optimal levels TNF-alpha protects host by activating immune system, TNF-alpha and IL-1 cause hyperpyrexia (elevation in body temperature), can enhance nitric oxide producation, activates eNOS and iNOS/NOS2 (leading to vasorelaxion and hypotension, induce bradykinins (induce hypotension by enhancing nitric oxide production), plays important roll in inducing desseminated intravascular coagulation, enhances expression of TF on monocytes and neutrophils, induces the expression of P-selectin, E-selectin, and ICAM on endothelial cell surface
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nitric oxide
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can cause hypotension
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nitric oxide synthase
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exists in three isoforms endotheial (eNOS), neuronal (nNOS) and inducible (iNOS or NOS2)
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tissue factor
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TF, triggers clotting by extrinsic pathway
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epitope
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Actual part of the antigen that interacts with the antigen-specific molecule (Ab or TCR), typically ~8-22 a.a. for B(sequential or non-sequential) interact with Ab, ~8-10 a.a. for CD8+ and ~13-18 a.a for CD4+, T cells must be sequential and Ag must interact with TCR and MHC(fit in binding groove), an antigen can have multiple epitopes, B and T cells can respond to single epitope of the antigen, epitopes that stimulate an immune response are called immunodominant epitopes, mutations in the immunodominant epitopes can have deleterious effects on the immune response to a given microbe (single a.a. Mutation in epitope can prevent immune recognition (e.g. seasonal flu, and annual flu vaccines), B and T generally don't share same immunodominant epitopes, T generaly only responds to peptides, B can respond to peptides, carbohydrates, lipids, and nucleic acids
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polysaccharides
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immunogenic: highly complex, glycoproteins, glycolipids, when assocaited with cells (ABO blood groups)
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lipids
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poor immunogens, act as haptens when protein bound
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nucleic acids
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poor immunogens, immunogenic if conjugated to protein, anti-DNA antibodies can be made (e.g. SLE)
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immunoglobulin (ig)
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is Ab is gamma globulin, Ig general, Ab specific
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Antibody (Ab)
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bind to epitopes to identify them or tag them for destruction, produced by B cells or plasma cells (secretion), secreted antibodies contains two(serum IgD, IgG, IgE, IgA), four(secreted IgA) or ten(secreted igM) binding sites, antigen binding protein of b cells, made from four polypeptide chains connected by disulfide bonds, two heavy chains (bound together by pair of disulfide bonds in hinge region) each connected to a light chain by single disulfide bond in the C_L region, antigen binding domain located in F(ab)'_2 region, Fc region (fraction that is crystallizable) has the effector functional region, hinge (inbetween F(ab)'_2 and Fc regions) allows for flexibility of antibody molecule, tips of F(ab)'_2 region has the variable domains, rest of Ig is fairly constant, n-terminus is where the Ag binds, c-terminus is membrane bound if it's a membrane bound antibody
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gamma globulin
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antibodies are present in gamma peak of electrophoresis gel of serum proteins
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multiple myelomas
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cancer of b cell producing a monoclonal Ig (normally gamma peak is broad, with myeloma narrow tall peak on gel electrophoresis
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interchanin disulfide bonds
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connect heavy chains together and heavy chain to light chain
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intrachain disulfide bonds
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cause immuoglobuil fold in heavy and light chains
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CDR
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Aka hypervariabile regions, complementarity determining regions, parts of V_H and V_L where variability is concentrated (in the folded protein it's at the tip with
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effector function
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(e.g. activate compliemnt or opsonize) determined by glycosylations in the constant region and a.a. sequence of the constant region
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affinity
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strength of Ab/Ag binding
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avidity
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highest strength Ab (takes into account # of binding locations)
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Antigens (Ag)
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high molecular weight proteins derived from microbes (bac. Fungus, virus, parasites) that stimulate Ab production, mostly proteins but carbohydrates and lipids can also elicit an immune response,
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antigen specific receptor
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interact with their cognate antigen in specific and often strong interaction, strength of binding is called affinity, generally antibodies have much strong affinity for their antigens than TCRs
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autoantigens
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antigens that recognize “self” molecules (autoimmune disease)
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alloantigens
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slight differences between members of same species (e.g. MHC different between people in the classroom(alloantigenic differences))
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xenoantigens
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most common types of antigens recognized by the immune system, immune response typically concerns xenoantigens
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immunogenic
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molecules that activate an immune response, typically proteins, based on 1) how different the molecule is than those in our bodies, 2) relative size of molecule, 3) complexity of compound and 4) whether the compound can be presented to T cells and is therefore subject to antigen processing/presentation, t cells only can only recognize molecules presented with self MHC molecules, those that cannot be presented with self-MHC can't stimulate t cells, t cells activation needed for strong immune response, t cell processing/presentation very important for normal immune activation
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immune response
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generally shows exquisite specificity, cross reactions can occur
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Cross-reaction
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foreign antigen shares an epitope with a self protien, immune response to microbe can also damage self tissue, (e.g. rheumatic fever)
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steptococcus pyogenes
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group A steptococci, cause of streptococcal pharyngitis (strep throat), immune response can cross react with epitope of cardiac tissues (and other tissues), heart tissue damage causes rheumatic fever (prophylactic antibiotics maybe used prior to oral surgery to kill any Group A streptococci)
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haptens
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low molecular weight proteins that bind antibodies, but cannot induce an immune response unless bound to protein carrier, important to our understanding of immune system(immune system is so specific that the addition of a single carboxy-group to amino benzene, or change in location of carboxy group will not produce a response from an antibody that will react to unchanged molecule), penicillin can function as a hapten, when penicillin associates with a carrier protein it can stimulate an immune response resulting in an allergic reaction in some individuals (life threatening)
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adjuvant
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compounds that when mixed with immunogens makes them more immunogenic, stronger response, not chemically bound to the immunogen (e.g. alum, alum w/ muramyl dipeptide), mech: increase half-life of immunogens(slow release of immunogen), increase production of infammatory cytokines (e.g. stimulate TLRs on APCs), improve presentation and co-stimulation of APCs to T cells
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recognition
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macrophage presents antigen (fragmented peptide) via MHC I or II for possible recognition by T-cells,
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CD4+T cells
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aka helper T cells, two thirds of T cell population, activate other cells of immune respons, express CD3 and CD4 antigens, recognize antigens displayed by MHCII on dendritic cells, produce interferon-gamma(activates macrophages and neutrophils),IL-2(T cell growth factor), IL-4(B cell growth factor) and IL-5(B cell differentiation factor), IFN-gamma (enhance macrophage function to control intracellular pathogens)
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Th1 (CD4+T)
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stimulate cell mediated immunity (CMI) in response to intracellular microbes, inflammatory/cytotoxic, aid in cellular immunity, characterized by secreation of IL-2 and IFN-gamma
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Th2 (CD4+T)
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initiate humoral response in cases of extracellular microbes, aid b cells to produce certain classes of antibodies, characterized by expression of IL-4, IL-5, and IL-10
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CD8+T cells
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Aka cytotoxic T cells, CTLs (cytotoxic T lymphocytes), one third of T cell population, destroy virus invected cells, express CD3 and CD8 antigens, recognize antigens displayed by MHC I on dendritic cells, these cells recognize virus glycoprotein on the surface of infected cells and produce perforin and granulysin to lyse the cell and kill the virus
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perforins
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preformed perforins are released at the target cell surface generating transmembrane pores
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granzymes
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introduced to target cell cytosol through perforin pores and induce apoptotic events
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mycobacterium leprae
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intracellular acid-fast + bac., leprosy, some mount CMI response - less severe disease, some mount humoral response - causes systemic disease often much more severe
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T-independent Ags (TI)
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does not require t cells, b cell response, no memory cells, not presented with MHC b/c they are not proteins, no class switching (IgM only)
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TI-1
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mitogenic effects on B cells - polyclonal b cell activators (e.g. LPS, brucella abortus)
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TI-2
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Ag specifically recognized by Ab on Ag-specific b cell, without t help memory response is not seen repetitious cell wall components, flagelin, (e.g salmonella, and sugars associated with steptococcus pneumoniae (used for vaccination against 23 serotypes of this bac.))
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T-dependent Ags (TD)
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response requires t cell help (cytokines), generates immunological memory, (e.g. Diptheria toxin, viral hemagglutinin, PPD( purified protein derivative ofmycobacterium tuberculosis))
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mitogens
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not antigen specific, cause cell proliferation, LPS is B cell mitogen, ConA (concanavalin A) is T cell mitogen
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clonal selection
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only b cells that recognize its Ag will poliferate (allows for expansion of b cells specific for one antigen)
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B cells
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produce antibodies (IgG, IgM, IgA, IgD, IgE) in response to antigenic stimulus, respond to either: t cell indepenent (LPS or lipids) or T cell dependent (protein), express IgM on cell surface as monomer, a given b cell produces Abs with one antigenic specificity
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IgM
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cell surface monomer (2 mu, 2 kappa or 2 lambda or secreted pentamer (5 monomers plus J), 4 constant region domains, appears first in primary response, best at Complement activation, best agglutination Ab (pentamer)
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Poly-Ig receptor (on m cells)
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grabs IgA from basal surface, internalizes it in vesicle and moves it to apical surface (gi/lungs/reproductive)
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IgA
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tears and colostrum, 3 constant region domains, monomer on surface of b cell, dimer (or tetramer) when secreted (J chain), SC (secretory component, extra polypeptide helps protect IgA, mucophilic,
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igG
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can cross placenta, 3 constant region domains, made in early secondary response and late primary response, predominant in blood and lymph, t_1/2 = 23 days, can activate compliment, some subclasses can cross placenta, opsonization, and mediates ADCC
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igE
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alergic rxns, 4 constant region domains, helped against parasitic worms, cause mast cells to release histamines, leukotrienes (strong vigors inflammatory rxn)
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igD
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monomeric(2 delta, 2 kappa or 2 lambda), displayed on surface, not well characterized, 3 constant region domains, second receptor on cell with IgM
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b cell binding LPS or lipid
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binds to IgM on cell surface, directly activates B cell to produce IgM, only IgM will be produced
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b cell binding protein
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antigen internalized, processed, presented to T cells, T helper cells will produce IL-4(b cell growth factor) and IL-5(b cell stimulating factor), b cells will then produce IgG, IgE and IgA (class switching)
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tolerance
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anergy/toleragenic/toleragen, high dose (could be self) or low dose (not worth the effort), IV and SC routes of vaccination generally less effective than IM, oral antigens can tolerize
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passive antibody
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individual given antibody, protection is immediate, but since it's exogenous, the protection will fade
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Active-passive
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treated both with antibody and given vaccination, provides short term and long term protection
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newborn immunity
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derived from maternal IgA and igG (disappear after three months), polysaccharide vaccines given bound to protein, as newborns respond well to protein antigens
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elderly immunity
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weakens with age, looses tolerance to self antigens (autoimmune diseases)
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hematocrit
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pct RBC out of total blood volume
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blood plasma
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90 pct water, many disolved substances(nutrients, salts(metal ions), respiratory gases, hormones, proteins, waste products
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plasma proteins
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albumin (regulates osmotic pressure), clotting proteins (help stem blood loss when vessel injured), antibodies (help protect the body from antigens)
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formed elements
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erythrocytes (lack nuclei or organelles), leukocytes and platelets(cell fragments); most formed elements only survive in blood for a few days, most blood cells renewed from cells in bone marrow
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hematopoiesis
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first in yolk sack, then in liver & spleen (3-7mo), then on bone marror (7mo. And on)
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granulocytes
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have cytoplasmic granules, neutrophils, basophils and eosinophils
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agranulocytes
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do not have granules, lymphocytes and monocytes
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hemocytoblasts
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pluripotent stem cells -- source of all blood cells, present in bone marrow with other differentiated blood cells (ratio of differentiated cells to stem cells in bone marrow is 10^5:1
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lymphoid/lympoblast
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give rise to b, t and NK cells (via pro-B cells and thymocytes which lack antigen receptors), no changes in nuclear morphology, epitope specific receptors on cell surface (identical twins will have different T and B cell receptors)
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myloid
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give rise to erythrocytes, neutrophils, baseophils, esinophils, monocytes and platelets
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proerythroblast
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gives early and then late erythroblasts (differentiate to erythrocytes), between early and late the nucleus and ER are lost and hemoglobin is acqired
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mature erythrocyte
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biconcave, lacks nucelus and organelles, contains abundant hemoglobin, primary function transport O_2, 120 day life span, makes ATP anerobically
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erythropointin
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cytokine that stimulates stem cells into erythropoiesis, secreted by kidney when oxygen levels are low
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erythropoiesis
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requires vitB12, iron and colony stimulating factors
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myeloblast
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gives rise to promyelocyte
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promyelocyte
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gives rise to eosinophil myelocyte, neutrophil myelocyte, and basophil myelocyte, which then differentiate into eosinophils, neutrophils and basophils
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monoblast
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gives rise to promonocytes, which then differentiate monocytes
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myeloperoxidase
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catalyzes rxn leading to hypochlorous acid, and oxygen radicals, both potent antimicrobials
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lysozyme
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degrades peptidoglycan on cell surface of gram + bac., present in macrophages and primary granules of neutrophils
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increased neutrophils in circulation
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suggests infection
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eosinophils
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Bilobed nucleus, basic granuals(major basic protein(MBP), eosinophil cationic protein(ECP), eosinophilic derived neurotoxin(EDN), eosinophil peoxidase(EPO) in cytoplasm, stained by acidic dye, 1-4% of WBC, increased during parasitic infections
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basophils
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u or s shaped nucleus contain acidic granules that secrete histamine(contract blood vessels and smooth mm), 1% of WBC, can leave circulation to form mast cells, high affinity Fc receptors on surface that bind IgE and lead to release of heparin and histamine
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mast cells
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have longer life, release histamine during alergic reactions to contract smooth mm and increase vascular permeability
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eosin
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red, acidic
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haematoxylin
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blue, basic
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granulocyte formation induced by
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Granulocyte-macrophage colony stimulating factor (GM-CSF)
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monocyte formation induced by
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macrophage colony stimulating factor (M-CSF)
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leukopoiesis
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stimulated by Ils and CSFs
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thymocytes
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go to thymus to be educated, screened, and acquire t cell receptor, CD3 and either CD4 or CD8
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Pro-b cells
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undergo differentiation in bone marrow where they acquire b cell receptor or IgM, those that react to self are eliminated (apoptosis), survivors go to secondary lymphoid organs for development
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secondary lymphoid organs
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spleen, lymph nodes, and payers patches, tonsils, where T and B cells go for further differentiation (T cells acquire CD28 and LFA(leuokocyte function associated antigen)) and (B cells acquire CD40)
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spleen
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secondary lymphoid organ, red(arterioles) and white pulp(lymphocyte accumulation), blood and lymphatic supply, traversed by endothelial reticluar venules that facilitate the migration of cells from circulation to the organ, antigenic materials are trapped by spleen and provided to B and T cells for recognition (B and T cells interact in spleen)
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lymph nodes
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circular or ovoid, has cortex and medulla, outer superficial cortex made of clusters of B cells forming follicles (predominately B cells -- called t cell independent area), center of folicle contain b cells that proliferate in response to the antigenic stimulus (called germinal center), T cells present in deep cortex, after undergoing further development T and B cells exit through medulla, mesh like structure formed by dendritic cells and macrophages that aid in filtering antigens from lymph
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payers patches
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present in submucosal region of alimentary canal, have cortex and medula, cells enter through cortex and leave through medulla, protects digestive system from intestinal flora
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memory T or B cells
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can live for more than a decade
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lymphocyte formation induced by
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IL-7
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apoptotic markers
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p53(initiates),FasL(initiates), bcl-2(prevents apoptosis) Bax(opposes bcl-2), Bcl X_L(inhibits apoptosis), BcL_S(opposes Bcl X_L), and intracellular enzymes (e.g. caspases(promote))
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apoptotic signalling
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Fas on target cell surface, from Fas ligand on CTL surface
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hematopoietic hormones
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used clinically to stimulate bone marrow
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plasma cells
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final descendant of B cells, produce antibodies, live for only 30 days, don't express B cell receptor on surface, stellar or star shaped nucleus
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S. typhi
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invades macrophages (ciprofloxacin)
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CD MHC II CD4 processing
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extracellular proteins phagocytosed by DC, processed in endosome, and then antigen is associated with MHC II and transported to memb. For CD4 recognition
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CD MHC I CD8 processing
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viral proteins degraded in proteasomes of Dcs, transported to rough ER by TAP protein, associated with MHC I in rough ER, complex is transported to memb for CD8 recognition
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thymus
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cortex and medulla, prothymocytes in cortical thymus acquire CD3, CD4, and CD8 (double positive cells), those that survive positive screening and negative screening go to secondary lyphoid organs for cellular interactions and exposure to antigens
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positive selection
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promotes thymocytes that interact with MHC I and II molecules (retain either CD4 or CD8), eliminates those that cannot (apoptosis)
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negative selection
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Single positive cells migrate to medulla, thymocytes eliminated that react against self epitopes
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immunologic synapse (DC to CD4+T cell)
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MHC class II on DC presents antigen to CD4 TCR on T cell, to induce T cell activation, DC CD80 or CD86 should bind T cell CD28, and DC ICAM-1 should bind LFA-1
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ICAM
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intracellular adhesion molecule, enhanced expression of ICAM on endothelial cells cause increased binding of neutrophils/monocytes and endothelial cells through LFA
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LFA
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leukocyte function associated antigen
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diapedesis
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binding of monocytes to endothelial cells and increased vascular permability result in cells leaving circulatory system and going to site of infection
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CD40
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B cell antigen acquired in secondary lyphoid organs, binds CD40 ligand
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skin
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skin is composed of several layers of stratum corneum secreted by keratinocytes, highly impermeable and prevents organisms from having access to internal organs, outer layer of dead skin is sloughed off eliminating organisms that are bound to the skin, skin contains sebaceous glands which scerete sebum and maintains a pH of 5.5 which prevents bacterial colonization
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lysozyme
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contained in secretions of skin and eyes, degrades peptidoglycan on surface of gram + bac.
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lactobacillus
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symbiotic present in vagina of matrue women that secretes lactic acid leading to a low pH of 4.5 (preventing infections) antibiotics can kill off lactobacillus leading to increased risk for candida and other fungal infection
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stomach
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secretes HCl maintains pH of 2.2
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panneth cells of stomach
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secrete alpha defensin, which has antimicrobial effects on pathogens (defensins ability to distringuish from body cells is not well understood)
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lungs
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coordinated beating of cilia in epithelial cells drives mucosa bound organisms out of respiratory tract
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respiratory cells
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secrete beta-defensin (similar to alpha defensin)
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lipases and DNAases
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Lysosomal enzymes that can damage bac. By acting on cells or DNA
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phagocytic cells
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can release intercellular contents when the organism is extracellular, or bigger in size
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antimicrobials
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release will inhibit microbe growth
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interferons
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activate macrophages and Nks
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IFN type I
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interferon is released during cell infection (major cytokine), virus infected cells release type I (including IFN-alpha(WBCs) and IFN-beta(fibroblasts) which induce resistance in neighboring cells, uninfected cells produce protein kinase R (PKR), PKR blocks viral reproduction in neighboring cells, PKR digests RNA and DNA in infected cells, kills both infected cells and the virus), alpha-IFN is FDA approved for HepC and genital warts(herpes virus)
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IFN type II
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Produced by CD4+T cells, IFN-gamma effects on macrophages: activates them, increased levels of ROI and promote fusion of phgosome containing microbes with lysosomes, expression of inducible nitric oxide synthase
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inflammatory response
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tissue response to injury, prevents spread of damaging agents to nearby tissues, disposes of cell debris and pathogens, sets the stage for repair processes
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acute inflammation
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redness, heat, swelling and pain
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chemokines and cell migration
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neutrophils migrate in response to IL-8, monocytes and macrophages migrate in response to CCL5 aka(MCP (monocyte chemotactic protein)), MIP (monocyte inflammatory protein), and CCL5 (aka RANTES – Regulated upon Activation Normal T-cell Expressed and Secreted)
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endothelial cell surface
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THF-alpha induces expression of P-selectin, E-Selectin and ICAM on endotheial cell surface, enhanced expression of P-selectin and E-selectin on endotheial cell surface facilitates binding of leukocytes (and gentle rolling while being attached, enhanced expression of ICAM on endothelial cells cause increased binding of neutorphils/monocytes to endothelial cells through LFA, binding of monocytes to endothelial cells and increased vascular permeability result in cells leaving the circulatory system and going to the site of infection (called diapedesis), cells migrat to the site of infection to induce inflammation
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HDN
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Hemolytic disease of the newborn(erythroblastosis fetalis), Rh neg. mother, Rh pos father, Rh pos 1st baby, 1st baby sensitizes mother to Rh, subsequent Rh pos. babies at great risk.
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ABO
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A N-acetyl galactosamine, B galactose, O unchanged
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gene rearrangement
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b cell randomly selects different gene segments to be joined together to form the functional antibody molecule (DNA is cut out in B cells to produce an antibody), heavy VDJC, light VJ, variable diversity, joining, constant, ~200 V, 20 D, 6 J genes, during devel. of b cell Ig genes rearrange randomly, mature b cell can class switch based on T cell cytokines, b cells show allelic exclusion and only express one allele
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b cell development
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rearrange H chain genes (VDJ), rearrange L chains (VJ), express IgM, and soon after IgD, enters periphery if it doesn't encounter its antigen it dies, if it encounters its cognate antigen it will proliferate and produce two populations (memory or plasma), plasma makes antigen, memory cells wait and class switch,
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RSS
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recombination signal sequences, control the recombination, made up of 1) heptamer, 2) a 12 or 23 bp spacer followed by 3) a nonamer, during rearrangement a 12spacer can join a 23 spacer or a 23 spacer can join a 12spacer (not usually 12 and 12)
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12/23 bp rule
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12 and 23 bp go together?
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RAG1 and RAG2
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recombination activating genes, recognize RSS and bring the appropriate ones together,
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Tdt
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terminal deoxynucleotidyl transferase, can add in DNA between joints of rearranging DNA (extra bases called N nucleotides)
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allelic exclusion
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only one heavy and one light chain expressed (one at a time) so you can use both from mom, both from dad or one of each
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factors in antibody diversity
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V(D)J, Tdt, heavy and light chains, slop in rearrangement at D-J junction (extra Tdts, P-nucleotides) – CDR3 region of heavy chain (most important in determining epitope specificity)
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affiniity maturation
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further changes after mature b cell interacts with its antigen, hypermutation can take place in CDR3 on heavy and CDR1 on light
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differential RNA processing
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only for heavy chain, determines the switch from membrane bound to secreted Igs, also determines if IgM or IgD is produced in b cells that haven't yet encountered their Ag, secrete signal cut out of transcript (mRNA) if it is going to produce memb. bound, or hydrophobic memb. spanning region cut out if it's going to secrete. M or D is determined because primary transcript has both, prior to translation on of the isotypes is removed from the transcript
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class switching
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after antigen recognition and with help of T cell via cytokines b cell can switch isotype, cytokines in area will help determine which isotype will be produced (e.g. near mucous membranes often switch to IgA, class switching is a loss of information so once IgD or IgM is cut out they can't switch back
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secreted Ig
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rER(protein assembly), ER( H / L chains assembled), golgi( glycosylation of H chain, vesicle leaves golgi, fuse w/ memb. secreted
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proliferation cytokines
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Il-2, IL-4, IL-5
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differentiation cytokines
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Il-2, IL-4, IL-5,IFN-gamma, TGF-beta
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igM
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2-4 then 2-4
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IgE or IgG1
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2-4 then 4
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IgA or IgG2b
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2-4 then TGF-beta
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Ig2a or IgG3
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2-4 then IFN-gamma
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b cell antigen binding rate
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90 percent don't find their antigen and die within 1-2 weeks
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Ag independent B cell devel.
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takes place in bone marrow, Ig gene rearrangement, H-chain first, D with J then V with DJ, b cell expresses CD45R surface marker and rearrangement genes RAG and Tdt, once H chain is complete it can be transported to cell surface with surogate L chain (SLC)(V-preB and gamma5) this antibody then interacts with bone marrow stromal proteins, cytokines along with cytokines (IL-7) are sent to B cell that it can begin to rearrange the light chains, the cell tries the kappa chains and then the lambda chains(stopping if successful), RAG genes are expressed during light chain rearrangement (begin to express Ig-alpha and Ig-Beta, Ig-alpha/Ig-beta heterodimer being an important signaling molecule), once heavy and light chains are successful they can travel to cell surface, cell will express IgM and then later IgM and IgD, once complete moves to periphery, during development b cells are screened for ability to bind self-antigens if so they get the apoptosis signal, other self reactive cells can try again with the light chain, if self-reactive cells leave the bone marrow they can cause autoimmune symptoms, most self receptive b cells become anergic
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Ag dependent B cell devel.
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often in secondary lymphoid tissues(lymph nodes, payers patches, waits for antigen, once it binds along with T cell help it proliferates can produce memory and plasma cells (class switching can take place at this point, if binding is TI it can still become active but probably wont make memory cells nor class switch (TI is associated with IgM), (or TD example) interacting with an antigen (must cross link, must interact with multiple copies to cross link, signal is sent into cell via Ig-alpha/Ig-beta molecules, usually not enough to complete process, second signal can be interaction with T cell CD40L(aka CD154) to the B cell CD40 or T cell cytokines, cell can make plasma and memory cells and class switch, after interacting with the antigen the first molecules are phosphorylated and the signaling cascade begins, other molecules can effect the process, CD21(aka complement receptor #2) interacts with C3b/C3d(product of complement casecade) then associated CD19 molecule can send the b cell a signal, or CD22 can interact with its ligand and a negaitve/inhibitory signal can be sent to the b cell
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Constitutive expression in b cells
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Ig enhancers/promoters constitutively expressed, so if oncogene is translocated next to Ig promoter/enhancer in b cell then it will also be constitutively expressed, Burkitt's lymphoma (c-myc is translocated next to the Ig enhancer
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B cell T cell itneraction
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B cell activation depends on t cells with depend on APC (which b cells can do), there are also signaling molecules and adhesion molecules to insure proper b cell activation, b cell can help activate t cells (two way street) tcells and their cytokines are also important in determining the effector functions of b cell, which class switching will occur, (IL-4 and IL-5 work together to produce IgE (including other factors)
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B1
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not all b cells follow the above rules, CD5+B cells (B1 B cells) express CD5 on cell surface (usually T cell marker) these have limited use of V region genes so not as diverse as normal or (B2 B cells), also less affinity than (B2) and a higher rate of cross-reactivity, CD5+ b cells seem to have a role in reacting to polysaccharide antigens from bac. In pleural and peritoneal cavities, these are also said to produce 'natural' antibodies (e.g. anti-AB antibodies)
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B cell response
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primary response 7-10 days before IgM is secreted, class switch after/during; secondary response(memory response) 1-3 days, better, IgG or other, needs T cell help
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lymph tissue and B cells
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typically Ag-dependent phase occurs in lymph tissue (usually the lymph node) B cells in cortex T cells in paracortex, activated b cell can produce millions of clones in relatively short amount of time (happens in germinal center) those b cells going ot become plasma cells can then move to the inner medulla to secrete
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FDC
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follicular dendritic cell, can phagocytose but not a good APC (exception)
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ITAM
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immunoreceptor tyrosine based activation motif (e.g. Ig-alpha/Ig-beta)
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ITIM
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immunoreceptor tyrosine phosphate inhibitory motif (e.g. CD22)
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