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52 Cards in this Set
- Front
- Back
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Structure of antibodies
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2 heavy chains + 2 light chains, bound by disulfide bonds. Fab = bind antigen; Fc = binds FcR on APC's.
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Structure of chains
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L and H chains have constant and variable domains. Variable domains have hypervariable regions
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antigen-combining sites
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formed from folding of chains that brings together HV regions of H and L. Each antibody has 2 identical sites.
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constant regions
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differ btw AB classes. mediate a variety of functions such as activating complement or binding to the surfaces of phagocytes or mast cells.
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IgM
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1st AB made by B cell; primary AB of primary response; efficiently fixes complement; secreted as pentamer. Mostly intravascular -- too large to diffuse out of circ.
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IgD
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Found, along w/ IgM, on surface of newly matured B cells. (not yet stimulated by antigen)
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IgM and IgD
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Have same variable regions, so same antigen specificity. Differ only in H chain constant region.
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IgG
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primary AB of secondary response; monomer that easily diffuses and can cross placenta (protective for fetus). binds microbes to help w/ phagocytosis and activates complement OK.
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IgA
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Dimer that keeps microbes from adhering to mucosal surfaces; found in sweat/tears/colostrum and lining of tracts; can fix complement.
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IgE
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defends against bacterial organisms that penetrate mucosa. activates mast cells.
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polyclonal antibodies
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During immune response, many classes and subclasses of AB are made, directed at various epitopes of the same antigen.
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monoclonal antibodies
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Made by fusing AB-secreting immune cell w/ neoplastic B cell >> creates an immortal producer of a specific AB. *If murine, must be humanized by grafting human Fc to it.
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Gene rearrangement
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Occurs during B cell dev in bone marrow. VDJ segments (variable region) spliced w/ constant region (M,D,G,A or E) to make heavy chain of AB. After H chain, L chain does VJ recomb.
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diversity
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possible combinations of 3 segments + flexibility of joining sites + nucleotides that are added @ junctions increases the diversity.
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allelic exclusion
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Only 1 H chain is allowed to rearrange. If 1st not productive, 2nd can rearrange. Prevents autoimmunity, ensuring only 1 AB is made by cell.
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Where does rearrangement occur
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in bone marrow (and fetal liver/spleen)
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rearrangement process
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DJ joined >> early Pre-B >> VDJ joined >> large pre-B >> cell division >> small pre-B >> VJ of light chain >> Immature B expressing IgM >> leave marrow for spleen >> T1 >> T2 >> mature B cell w/ IgM and IgD. Accumulate in spleen.
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2 processes that occur in germinal center
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class switch and somatic hypermutation
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H chain class switch
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After antigen stimulation, rearranged Vh can be expressed w/ constant region genes of other class. Requires enzymes to cleave and ligate.
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somatic hypermutation
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After antigen stimulation, high rate of random mutation adds diversity and allows selection for mutants w/ highest affinity for antigens than those initially stimulated. Mutation can be silent/lethal or a substitution that increases or decreases affinity for antigen.
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B cell maturation process
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Immature IgM+ B cells go from marrow >> spleen, become transitional B cells (T1, T2, T3). Become mature IgM+/IgD+ in about 1 week.
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3 types of mature B cells
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Follicular (B2), Marginal and B1
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Follicular B2
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most common type of B cell, naive, respond slowly to antigen. T-dependent responses
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where are B2 found
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live in follicles of lymphoid tissue and in circulation. Half-life = 3 months, not self-renewing.
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differentiation of B2
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differentiate into plasma cells that make AB or long-lived memory cells
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Marginal zone B cells
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Live in marginal zones of follicles, screen blood for antigens.
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B1 cells
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live in peritoneum, screen gut for antigens
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MZ and B1 cells
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Mature B cells, antigen selected, partially activated so can produce plasma cells very quickly (days). 1st line of defense in spleen (MZ) and lining of gut (B1)
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Primary B Cell response
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Naive B2 cells bind antigen and divide/differentiate >> AB detected in 4-5 days >> Only B cells specific to antigen are activated (clonal selection) >> primary plasma cells secrete IgM but some become long-lived memory cells that secrete IgG.
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Secondary B cell response
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Derived from memory B cells. Takes only 2 days to produce AB and reaches 100-1000x magnitude of primary response. Major AB = IgG
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TI-1 antigens
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Nonspecifically activate B cells of any specificity. Not very productive response. Via TLR.
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TI-2 antigens
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Antigens w/ lots of repeating epitopes activate B cells specific to antigen via crosslinking BCR. Mainly activates MZ B cells -short-lived IgM. Can only produce primary response. Does not occur in infants.
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T-dependent antigens
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typically globular proteins that need T cell help to activate B cells. Mainly activates B2 cells - predominantly make IgG; make long-lived plasma cells and memory B cells. Does occur in infants.
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T-dep antigen mechanism
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Antigen binds B cell, is internalized & broken down into epitopes >> complexes w/ MHC II and is expressed on B cell membrane and can bind T cell
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cell adhesion molecules
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LFA on T cell and ICAM on B cell help link cells together
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T cell signals
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Signal 1: TCR/MHCII/peptide complex; Signal 2: B7 on B cell binds CD28 on T cell >> activates T cell so it can help B cell.
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B cell signals
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Signal 1:BCR/antigen; Signal 2: activated T cell expresses CD40L on membrane that interacts w/ CD40 on B cell.
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activation of T cells
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T cells must be activated by antigen from APC in order to induce CD40L expression.
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signal 1 vs signal 2
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only signal 1 is antigen-specific; signal 2 will not occur unless signal 1 already has.
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role of cytokines
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T cells also secrete cytokines that induce and control AB class switch in B cell.
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IL-4
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induces IgE switch
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IFN gamma
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induces IgG switch
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TGF beta and IL5
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induce IgA switch
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germinal centers
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antigen-activated B and T cells interact here, in secondary lymphoid tissue (spleen, nodes, peyer's patch, tonsils)
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What happens in germinal center
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DC's take up antigen in the skin >> express MHCII and migrate to lymph node to activate naive T cells >> T cells express CD40L on their surface and proliferate >> interact with B cells expressing antigen-specific MHCII. >> Activated B and T cells migrate back into the follicle and begin to undergo proliferation and differentiation, ultimately forming a germinal center.
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role of FDC
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live in light zone of germinal center, take up antigens from lymph and release over time to B cells.
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dark zone of germinal center
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Contains densely packed dividing B cells called centroblasts. They do not express a BCR. Site of somatic hypermutation. Migrate from dark to light and become centrocytes.
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light zone of germinal center
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In light zone; stop dividing and express BCR. Can bind antigen. Some that develop greater affinity for antigen may return to dark zone and proliferate.
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central deletion
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Autoreactive B cells are eliminated in the bone marrow as soon as they express a BCR. Limited to self antigens w/ high affinity BCRs reactive to antigens that are present in the bone marrow.
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receptor editing
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occurs in bone marrow as alternative to deletion. Can avoid cell death if they change the specificity of the BCR. This can be done by expression of a different Ig light chain that is not self-reactive.
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peripheral deletion
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transitional B cells programmed to initiate cell death upon encounter w/ antigen in spleen.
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anergy
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Some autoreactive B cells do not receive a deletion signal, possibly because they have low affinity for a self-antigen. Unable to be activated
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