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71 Cards in this Set
- Front
- Back
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How many complement activation pathways are there and what are they?
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1. Classical pathway. Antibody dependent. Starts at C1 binding to membrane bound antigen-antibody complex
2. Alternative pathway (most important). Antibody independent. Starts with C3b binding to surface of microbe 3. MBL (mannose binding lectin) pathway. Antibody independent. Bypasses C1 and starts with C4 binding to pathogen surface |
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What are the results of complement activation?
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1. Membrane attack complex, puts holes in pathogen and causes osmotic lysis
2. anaphylotoxins (C3a, C4a, C5a) stimulate mast cells and granulocytes to release chemical mediators of inflammation that enhance blood vessel permeability 3. chemoattractants (C5a) promote the migration of neutrophils and other leukocytes to sites of foreign antigen 4. opsonization of pathogen (C3b) leading to phagocytosis |
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How do we regulate complement activity
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1. C1INH--inhibits C1 activation and therefore classical (and MBL??) path
2. DAF (decay accelerating factor)--inhibits the convertases (promotes decay) 3. CD59/S protein--inhibits the MAC, most important one |
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Important pathogen-associated molecular pattern (PAMP) receptors and what they bind
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1. MBL (mannose binding lectin)--binds to carbohydrates found only on microbes,not displayed on cells, activates complement pathway
2. CD14--toll-like receptor that is displayed on macrophages and dendritic cells, binds to LPS, activates cel l3. Toll-like receptors - are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. mainly on macrophages/dendritic cells cause inflammatory/immune response bind dsRNA, LPS, flagellin, CpG DNA |
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How do NK cells kill virus infected cells?
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Release perforin and granzyme into area around cells
perforin puts pores in the infected cell granzyme enters cells through pores cell killed by apoptosis or osmotic lysis |
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Killer inhibitory receptors
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found on NK cells
recognize MHC I displayed on cell surface When NK cell encounters a normal cell, the MHC I binds to the KIR and keeps the NK cell from killing it When there is a lack of MHC I (in a virus infected cell) the NK cell does not get the inhibition and kills the cell |
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TNF alpha and IL-1
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Tumor necrosis factor alpha.
Cytokine released by macrophages when they encounter a pathogen Causes inflammation and fever increases adhesion molecules in blood vessels close to infection to attract monocytes and neutrophils to infection site increases adhesion molecules in blood vessels close to infection to attract monocytes and neutrophils to infection site |
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IL-12
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secreted by macrophages
encourages NK cells and TH1 cells to secrete more IFN gamma |
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IFN-gamma
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secreted by NK cells and TH1 cells
activates macrophages to kill phagocytosed microbes |
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IFN-alpha and beta
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secreted by lymphocytes, macrophages, etc.
stimulate macrophages and NK cells to elicit anti-viral response and are active against tumors Increases NK lytic properties increase expression of MHC I on virus infected cells |
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Anti-microbial defenses
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defensins--host defense peptides that are produced in epithelia and neutrophil granules. form pores.
lysozyme--secreted in tears and saliva mucus low pH histamine ROS produced by phagocytic cells |
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Immunoglobulin (antibody)
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proteins produced by B cells that bind antigen
come in two types-- the secreted form is produced by plasma cells and the membrane bound form is expressed on B cell surface after the pre-B cell stage |
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How many chains does an antibody have?
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two heavy chains and two light chains
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Heavy chain types
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IgM--Naive B cell antigen receptor, primary response, low affinity but hight avidity, complement activation, pentamer
IgG--secondary response (after somatic mutation), high affinity, opsonization, complement activation, antibody-dependent cell-mediated cytotoxicity, crosses placenta, monomer IgA--mucosal immunity (binds to bacteria, keeps it from invading), dimer IgD--naive B cell antigen receptor, sometimes coexpressed with IgM, no soluble form IgE--defense against helminthic parasites, found in skin, monomer |
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Light chain types
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kappa and lambda
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Fab
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Fragment antigen binding
portion of antibody that binds the antigen, contains the V region |
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Fc
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"Fragment crystalizable"
portion of the antibody that interacts with cells of the immune system contains most of the heavy chain C regions |
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allelic exclusion
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B cells only express one type of antibody
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what type of epitopes can antibodies recongnize?
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linear and conformational
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How do BCRs signal to the inside of cells?
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through help of Ig alpha and Ig beta molecules
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T cell receptor (TCR)
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protein that is expressed on T cells at and beyond the double positive stage
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What are the T-cell receptor types and what is the most common?
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and ; is most common
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What is the role of the TCR?
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binds to and recognizes specific peptide-MHC complexes
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What are CD4 and CD8?
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co-receptors that increase the avidity of the TCR for the MHC
mature T cells only express one or the other |
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Which T cells are CD4+?
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helper T cells, bind to MHC II
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Which T cells are CD8+?
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cytotoxic T cells (CTLs), bind to MHC I
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What are maturing T cells called, and what stages do they go through in the thymus?
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Thymocyte
1. Double negative stage (CD4- and CD8-) 2. Double positive stage (CD4+ and CD8+) 3. Single positive stage (CD4+ or CD8+) |
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Which T cells express CD3?
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All of them
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How many types of TCR do T cells express?
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Just one due to allelic exclusion
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CD3 complex
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Helps TCRs signal to the inside of the T cell
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MHC I molecule
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expressed by all nucleated cells
present peptides that are derived from the inside of the cell to CD8+ T cells composed of polymorphic a chain and beta 2 microglobulin (invariant) |
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MHC II molecule
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expressed by APCs (dendritic cells, macrophages, monocytes, thymic epithelial cells, B cells)
present preptides that are derived from outside of the cell to CD4+ T cells consists of a polymorphic a and polymorphic b chain |
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MHC and transplants
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MHC molecules are important in the field of organ transplantation because they are targeted in alloimmune responses
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How are MHC molecules inherited?
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as linked sets of alleles on chromosomes (haplotypes)
MHC alleles of an individual are co-dominantly expressed MHC alleles are highly polymorphic in the population |
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Innate immunity
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can occur anywhere
response occurs rapidly (PAMPs are pre-formed and ready to go) use phagocytic cells, granulocytes, NK cells features of the response include inflammation (a call to arms for the adaptive immune system, display of the pathogen to the adaptive immune system, no memory). |
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Adaptive immunity
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is more targeted to sites of infection, regional (draining) lymph nodes and spleen (in the case of pathogens in the blood)
primary response takes time (usually ~10-14 days) memory response is faster responding cells include B cells, T cells, APCs, plasma cells etc. cardinal features of adaptive immunity: specific, inducible, appropriate effector function, memory and tolerance to self. |
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V(D)J recombination
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mediated by RAG 1, RAG 2, and NHEJs
contributes to generation of the diverse variable regions of BCRs (antibodies) and TCRs |
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junctional diversity
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N-addition--Hairpin cuts
P-addition--adding on extra bp's, happens after N-addition exonucleolytic nibbling altered D reading frames) |
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Ways of generating diversity in variable regions of BCRs and TCRs
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V(D)J recombination
junctional diversity pairing of H chains and L chains |
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somatic hypermutation
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B cells undergo this after being activated
DNA point hypermutation mediated by the enzyme AID (activation induced cytidine deaminase) occurs in T cell dependent immune responses in the germinal center results in increasing affinity of the antibody for the antigen. |
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Type 1 hypersensitivity
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immediate type
IgE mediated degranulation of mast cells and basophils can produce reactions to bee venom and some allergens found in food (peanuts) or in the air (pollen, ragweed, dust mites etc.) Reactions can range in severity from anaphylaxis to asthma, hives, hayfever etc. |
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Type 2 hypersensitivity
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antibody mediated
B cell autoimmune conditions in which antibodies to self-antigens (or modified self antigens) result in disease pathology |
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autoimmune hemolytic anemia (AIHA)
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antibodies bind to red blood cells, promoting their opsonization and clearance
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immune thrombocytopenic purpura
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antibodies binding to platelets
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myasthenia gravis
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antibodies to acetylcholine receptor
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Type 3 hypersensitivity
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immune complex mediated
generation and failure to clear immune complexes that deposit in the joints and kidneys, leading to secondary damage for example, activation of complement and recruitment of inflammatory cells causing glomerulonephritis in systemic lupus Also, erythematosus and serum sickness |
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Type 4 hypersensitivity
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T cell mediated
sometimes called delayed type hypersensitivity foreign substance (such as the oil in a poison ivy plant) enter the skin and haptenates self proteins such that the peptides presented in MHC now appear to be foreign to CD4+ T cells T cells responding to the antigen promote a cell-mediated immune reaction, resulting in a rash within a day or more after exposure Examples: poison ivy (in individuals who are susceptible), TB testing, skin allergies to nickel, gold etc. |
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Ways antibody can cause type 2 hypersensitivity problems
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1. self-antibodies can induce complement activation, causing inflammation and tissue injury
2. self-antibodies can opsonize tissues, causing them to be phagocytosed 3. self-antibodies can bind to cell receptors, inappropriately stimulating a response (graves disease) 4. self-antibodies can bind to cell receptors, blocking normal signaling pathways |
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cytokines that cause Isotype switching
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INF-gamma: IgG
IL-4: IgE TGF-beta: IgA |
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Cytotoxic T cells
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CD8+
Fas ligand Effector molecules: perforin and granzymes, cytokines excreted: IFN |
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TH1
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CD4+
produced in presence of INF-gamma (and IL-12?) characterized by transcription factor T-bet macrophage activating cytokines (IFN, GM-CSF, TNF, CD40L), produce IFN-gamma, stimulate phagocytic cells |
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TH2
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CD4+
produced in presence of IL-4 characterized by transcription factor Gata-3 B cell activation and development (expresses CD40L) secrete IL-4 and IL-5 and IL-13 stimulate class switching IL-10 (inhibits TH1) |
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TH17
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CD4+
produced in presence of TGF-beta and IL-6 characterized by transcription factor RORgammat extracellular bacteria proinflammatory, important in autoimmunity chronic inflammation (recruitment of neutrophils and macrophages) IL-6, IL-17 Produces IL-23 |
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Treg
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CD4+
regulatory T cells made in presence of TGF-beta but without IL-6 characterized by transcription factor Fox3P secrete cytokines that suppress other TH subsets: IL-10, TGF |
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peripheral tolerance
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If a CTL sees its antigen for the first time on a dendritic cell and gets activated, it becomes an activated cell
if it sees its antigen for the first time on a cell without co-stimulation, it becomes anergized |
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Clonal deletion
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elimination of cells that are strongly reactive to self
often Fas mediated for T cells this occurs at the single positive stage in the medulla of the thymus for B cells this occurs in newly formed B cells (IgM+) in the bone marrow; deletion can also occur outside the primary lymphoid organs. |
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Receptor editing
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the process of altering the specificity of an antibody by undergoing further rounds of gene rearrangement, usually at the light chain loci
occurs in the bone marrow for B cells. |
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Anergy
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lymphocytes that receive signal 1 (via either BCR or TCR) without co-stimulation (B7-CD28 for T cells; CD40L-CD40 for B cells) are rendered non-responsive and eventually die unless they receive co-stimulation in time
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Suppression
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inhibition of an immune response by regulatory T cells
regulatory T cells secrete suppressive cytokines and can block T cell activation/proliferation |
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Sequestration
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keeping self-reactive lymphocytes away from their targets
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Activation induced cell death
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most cells that participate in an immune response die
Fas mediated (T cells upregulate expression of Fas when they are activated) T cells have inhibitory signaling via CTLA4 (start expressing this instead of CD28, this binds better to B7 and is a negative signal) |
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signal 1 for T cells
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TCR crosslinking and signaling to the inside of the cell via CD3
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signal 2 for T cells
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B7 on APC binds to CD28 on the T cell
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signal 1 for B cells
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BCR crosslinking
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signal 2 for B cells
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CD40L on T cell binds to CD40 on B cell
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linked recognition
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B cell internalizes an antigen and can present it to the T cell as a series of peptides bound to MHC class II. As such, the epitope bound by the B cell does not have to be the same as the epitope bound by the T cell, but in order for the B cell to help the T cell, the epitopes have to be linked. This results from the fact that B cells don’t internalize antigens efficiently unless they are bound to their BCRs
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recognition phase
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mast cells recognize antigens, release histamine and leukotrienes, increase vascular permeability, recruit macrophages, complement and neutrophils
macrophages release TNF and IL-1, pro-inflammatory cytokines, acute inflammation meanwhile dendritic cells undergo maturation when they are stimulated via their TLRs and other PAMP receptors (for example TLR4 binding to LPS), up-regulate MHC class II, B7 and migrate via the lymphatics to the regional lymph nodes |
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activation phase
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in lymph nodes (or spleen) dendritic cell presents antigens to T cells, indicates to T cell what type of bug it is via its cytokine profile
primed TH cells up-regulate CD40L and go talk to the B cells, which encounter antigen via the lymphatics and/or trapped on the surface of follicular dendritic cells primed CD8+ CTL cells (who received signals from the DCs) increase expression of IFN and perforin Fully activated B cells undergo proliferation, isotype switching, somatic mutation and differentiation into plasma cells and memory cells |
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effector phase
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primed CD8+ cells go back to the site of infection and release perforin from their granules and kill infected cells
secretion of IFN by effector T cells (TH1) promotes further macrophage recruitment to the site of infection direct interaction of TH1 cells with macrophages (via CD40L-CD40 interaction) can activate macrophages further secreted antibody and complement facilitate opsonization and clearance |
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contraction phase
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activated T cells switch over from CD28 to CTLA4 expression, resulting in their inhibition instead of activation
up-regulation of Fas along with dwindling IL-2 levels promotes their cell death as antigen levels decrease, B cells capable of receiving signal 1 in the germinal center decrease, resulting in attrition of antigen-specific cells (only the cells with the highest affinity BCRs survive, some differentiate into memory cells or long-lived plasma cells.) The long-lived plasma cells enter the circulation and take up residence in the bone marrow |
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memory
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lymphocytes bearing receptors that are specific for the pathogen are increased in frequency; long-lived plasma cells may secrete antibodies that are capable of neutralizing toxins or preventing viral entry, memory responses are more rapid and can protect the immune individual from future disease due to the same pathogen.
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