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105 Cards in this Set
- Front
- Back
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What is humoral immunity?
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B cell-mediated immunity. Depends on Ig.
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T/F Ig by itself is not destructive
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T
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What causes initial B Cell Activation?
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BCR Crosslinking.
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Do all isotypes of Ig initiate the same signal transduction cascade?
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Yes
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What other proteins are required to transduce signal in the BCR?
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Igα and Igβ
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What allows the receptor-associated kinases to phosphorylate the Immunoreceptor tyrosine-based activation motif(ITAMs)?
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Antigen-induced clustering of B cell receptors
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Which proteins have ITAMS?
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Igα and Igβ
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What phosphorylates the ITAMs? What activates them?
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Tyrosine kinases; The TKs are activated when BCRs cluster when they bind antigen
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What protein docks on Igβ to set off the cascade after ITAMs are phosphorylated?
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Syk
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What comprises the BCR Co-receptor? (3)
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CD19, CD21 (CR2 - receptor for complement), CD81
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What is used as a marker for BCR Co-receptor?
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CD19
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What are the 2 complement receptors on B cells?
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These receptors recognize two different things.
CR1: interacts with C3b --> cleavage to iC3b + C3d CR2: binds C3d |
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What does CR1 do?
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Interacts with C3b --> iC3b + C3d
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What does CR2 do? What are the implications?
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Binds C3d.
The CR2: C3d binding causes the BCR and Co-BCR to juxtapose. This allows Igα activated tyrosine kinase to phosphorylate CD19. CD19 then amplifies BCR signaling >100x |
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What series of events leads to the activation of CD19?
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CR2 binds to C3d, causing the BCR and co-BCR to come into juxtaposition. When this happens, Igα activated tyrosine kinase to phosphorylate CD19. CD19 then amplifies BCR signaling >100x.
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T/F T cell and B cell recognize the same parts of the same antigen.
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False. The recognize the same antigen but different parts
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What are the two signals B cells require for activation?
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T Indpt (there would have to be 2: TI-1 and TI-2) and T dept (There is only one T-dept, the other is T-indept)
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How is signal transduction of T and B cell receptors similar?
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1) Both require cytoplasmic protein kinases that are activated by receptor clustering
2) Both use similar intracellular signaling paths |
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Why is CR1 considered a "cofactor" role with regard to CR2?
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CR1 does the initial cleavage of C3b --> C3d. C3d is what CR2 binds to.
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Can a B cell be activated without T Cell help? If so, how?
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Yes. Additional signals are required. There are two types of thymus-indpt. antigens: TI-1 and TI-2.
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How are B cells activated by TI-1 antigens?
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TI-1 antigens, in addition to the BCR, also use receptors associated with <b>innate immune system</b>, for example, Toll like receptors (TLRs). The combination of all these signals is sufficient to activate the B cell in the absence of antigen-specific helper T cells.
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What does TLR4 recognize?
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LPS
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What type of antibodies do B cells activated by TI-1 antigens produce? Why?
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ONLY IgM. This is because cytokines secreted by T helper cell are required for isotype switching.
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How does TLR9 (most common TLR in humans) get activated?
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Bacteria cell binds mIg. BCR internalizes and degrades bacterium releasing its DNA into an endocytic vesicle, where it's detected by TLR9.
During this process activating signals will be generated by all three receptors and the B cell will be activated to make antibodies against the cell-surface component of the bacterium recognized by BCR. |
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How are B cells activated by TI-2 antigens?
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TI-2 antigens possess repetitive epitopes generate a strong signal via high level of crosslinking. It's believed the cross-linking of BCRs and CoRs are so extensive there is no need for additional signal.
They're usually repetitive - eg., polysaccharides |
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T/F TI-1 and TI-2 Antigen cause polyclonal B-cell activation
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False. Only TI-1
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Which Thymus-indept antigen requires repeating epitopes?
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TI-2
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Where does Thymus-dept activation occur?
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Secondary lymphoid tissue via helper T cells
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How do B cells get into the lymph node?
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Like T cells, they express integrins and other CAMs that direct them through lymphoid tissue.
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T cells that enter a lymph node thru a HEV, encounter a specific antigen on a ________ cell, proliferate and differentiate to become ____________ cells.
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Dendritic; T<sub>H</sub>2 helper cells
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What happens if a B cell encounters its antigen when it circulates thru the lymph node?
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1) Cross-linking of the BCR and CoR induces signals --> Change in B cell expression of adhesion molecules/chemokine-receptors.
2) B cells are now trapped in the T cell zone. (Stay at the "bar") 3) BCR binds antigen and internalizes it for processing. Then it presents it with MHC Class II. 4) The TCRs sample the antigen-stimulated B cells trapped in the T cell zone. If they find their antigen they form a <b>conjugate pair</b> where both B and T cell recognize same antigen, different epitope. |
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When a B cell is activated the previous way, what is the 1st and 2nd signal?
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1st: Antigen binding to BCR
2nd: T helper cell delivers 2nd signal via CD40 ligand |
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What does the cognate interaction between the B and T cell induce the T cell to do?
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The T cell faces the B cell; the contact prevents IL-4 from assisting irrelevant B cells. T cell reorients entire machinery to B cell.
IL-4 going only to the correct B cell |
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What's the role of IL-4?
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It's the characteristic cytokine for the T<sub>H</sub>2 response. It's essential for B cell proliferation and differentiation. It comes from the Helper T cell
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T/F Thymus indpt B cell activation proceeds thru somatic hypermutation/isotype switching.
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False. The response to antigen does not get any better.
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What is the <b>primary focus?</b>
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The conjugate T-B cell pair move out of the lymph node cortex and into the medullary cords. They begin to divide, forming the primary focus of clonal expansion. This period lasts for several days, producing dividing B lymphoblasts that start to secrete IgM.
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What are the fates of the B cells in the primary focus? (2)
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1) B cell becomes plasma cell which exits and goes to bone marrow
2) B cell enters a follicle along with T cells to form a secondary focus (germinal center) |
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What drives the secondary focus/germinal center?
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Follicular dendritic cells (FDCs). They bind antigen in the form of complexes and retain them at the cell surface for long time.
The antigen on the FDCs as well as the T<sub>H</sub> cells stimulate the germinal center reaction |
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What isotype are the plasma cells in the medullary cords expressing?
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IgM
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What does the primary follicle (B cell zone) become when stimulated with antigen?
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The secondary focus/germinal center.
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What are centroblasts?
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Closely packed rapidly proliferating B cells forming the dark zone of germinal center. They're undergoing somatic hypermutation. They differentiate into non-dividing centrocytes and move to light zone.
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What is the cause of the swollen lymph node?
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The germinal center reaction
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What are the centrocytes?
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Formerly centroblasts, but have stopped dividing, moved to the light zone, and express different isotypes. They also have undergone somatic hypermutation.
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Centroblasts are in the ________ zone while centrocytes are in the _______ zone of germinal center
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Dark; Light
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After somatic hypermutation, how does affinity maturation occur?
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The centrocytes are fragile cells and will die unless they receive signal.
The germinal center centrocytes that have high affinity for limited antigen on FDCs get survival signal. It's a competitive process. Low affinity receptors don't get the survival signal and die. |
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Where does isotype switching occur primarily?
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Germinal center
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What directs isotype switching?
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Cytokines secreted by T cells.
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What happens if patients lack CD40 ligand? What does this demonstrate?
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Hyper-IgM syndrome.
This shows that CD40-CD40L interaction is NECESSARY to induce isotype switching. |
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What isotype does TGFβ induce cells to switch to? What does it inhibit?
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IgA. It inhibits switching to IgM and IgG3 (inhibitory effects are largely due to the positive effects of the cytokine on switching to another isotype)
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What isotype does IL-4 induce cells to switch to?
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IgG1 and IgG4, IgE
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What isotype does IL-5 induce cells to become?
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IgM (causes them to remain), and augments production of IgA
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What isotype does IFN-γ induce cells to switch to? And what isotype does it inhibit?
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IgG3 and IgG2a. ALSO inhibits IgM and IgG4 (know what it inhibits)
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If a patient has chronic infections, but no swollen lymph nodes, what should be suspected?
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An immune deficiency. Possibly that there is no CD40 interaction that is causing the lack of formation of germinal centers
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What directs choice
between memory or plasma cell development? |
Cytokines: memory (IL4) and plasma cell (IL10)
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If centrocyte matures under the influence of an IL-10-secreting helper T cell, what does it differentiate into? When is this more likely to occur?
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Plasma cell.
More likely to occur at the height of the adaptive immune response when the primary need is for large quantities of antibodies to fight infection. |
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If centrocyte matures under the influence of an IL-4-secreting helper T cell, what does it differentiate into? When is this more likely to occur?
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Memory B cells - the investment that prevents future infections from causing disease
More likely to occur towards the end of the successful immune response, as infection subsides |
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T/F Response to TI antigens induce neither immunological memory nor long-lasting immunity
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True
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What is changed in isotype switching?
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H chain constant region
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How is IgM secreted? (What form/shape)
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As a pentamer
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When do infants make Ig? What protects them before then?
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about 6 months; in utero and breast milk protects them before then
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What determins the anatomic allocation and function of isotypes?
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The Fc region (constant domains of H chains)
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Which Igs predominate in plasma?
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IgG and IgM
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Which Ig is found in GI tract and secretions (breast milk) of mucosal epithelia?
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Dimeric IgA
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What Ig is found in skin and epithelium?
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IgE
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What is the Brambell receptor/FcRn?
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IgG is actively transported from blood into extracellular spaces. Endothelial cells of blood vessels take up proteins via vesicles. <b>Brambell receptor/FcRnA is a membrane receptor in the endocytic vesicles that binds IgG and prevents it from being degraded by lysosomes</b>. It takes it to basolateral surface of cell where receptor releases IgG.
Protects IgG from proteolysis while its carried in the vesicle from the apical to basolateral surface. Structurally reminiscent of MHC Class I. |
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What molecule is the Brambell receptor/FcRn structurally reminiscent of?
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MHC Class I.
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Transcytosis: defn
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Unilateral transfer of macromolecules thru a cell
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How does dimeric IgA get to the mucosal surfaces to protect them?
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1) IgA is made in MALT in lamina propria.
2) Dimeric (NOT MONOMERIC) IgA binds to the poly-Ig receptor and is transcytosed thru the cell. 3) When receptor-bound IgA appears on apical surface, protease cleaves the poly-Ig receptor, resulting in release of dimeric IgA that's still bound to a small piece of receptor. 4) IgA is bound to receptor surface by interaction with glycoproteins in mucus. 5) IgA molecules bind to microorganisms to prevent their attachment and facilitate expulsion of pathogens thru bodily fluids. |
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What are neutralizing antibodies? How do they work?
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High-affinity antibodies that bind to the microbial ligand prevent attachment to human epithelium to stop infection before it starts. The bacteria/virus must adhere to epithelium in order to colonize cells and cause infection.
Often dimeric IgA. |
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Ig isotypes differ in their ability to activate complement via the classical pathway. Which activates/fixes complement the BEST?
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IgM and IgG3
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T/F Most antibodies have a direct inhibitory effect on a pathogen's ability to live and replicate in human body.
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F. Most of the time it's thru recruit of other molecules or cells of immune system
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What activates the Classical C3 Convertase?
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Pentameric IgM adopts a conformation so it can activate complement via binding of C1.
(IgG3 can also do it, but it takes 2 molecules as compared to one IgM) |
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C1 can bind either to ____ or _____ to get activated via the Classical pathway
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C-reactive protein (acute phase protein released during innate immune response) or IgM.
the shape is similar |
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What shape of proteins does C1 bind?
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Pentamers
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What proteins of complement are involved in the classical pathway and what is the convertase?
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C1, C2, and C4
C3 convertase = C4bC2a |
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After Classical C3 convertase (C4bC2a) deposits C3b on pathogen surface, how can the alternative pathway come into play?
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Deposition of C3b activates the alternative C3 convertase (C3bBb) and enhances complement deposition on cell surface.
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How is complement activated by IgG?
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It requires participation of 2+ IgG molecules. Each IgG molecule has a single binding site, so you need 2 molecules of IgG to activate C' (ie., bind the C1q component of C1)
IgG can activate C' better is antigen is soluble. IgG binds in solution, if 2 IgGs are close enough, they can bind C1 |
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What is the main cell type that removes complexes with complement?
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erythrocytes/RBCs
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What part of the RBCs bind the complex and lead to their destruction by macrophages in liver or spleen?
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RBCs have CR1, a C3b receptor, that binds complexes
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What are advantages of IgG flexibility?
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Allows simultaneous binding of two epitopes, allows simultaneous binding of antigen and effector molecules
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What are disadvantages of IgG flexibility?
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The non globular hinge region confers flexibility but also leaves it susceptible to protease degradation
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What are the IgG subclasses? What do they differ in?
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IgG1-4. They differ in the constant region of the heavy chain, especially thru the hinge region that's susceptible to proteolytic cleavage
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Which IgG is most susceptible to proteolytic cleavage but also best able to fix complement? Why?
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IgG3; it has the longest hinge region.
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What is another IgG that is very good (not as good as IgG3) at fixing complement?
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IgG1
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What is special about IgG4?
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In circulation IgG4 molecules become functionally monovalent.
In serum, H/L chain exchange occurs making it monovalent and can only neutralize pathogens (not fix complement). Because of this it is not inflammatory. It can actually reduce severity of allergic reactions, by blocking binding of IgE |
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What does IL-4 induce switching to?
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IL4 induces switching to both IgE and IgG4
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What are Fc receptors? What is their function?
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Receptors on certain cells that recognize Fc portion of Ig. They're specific for certain isotypes.
They interact with (mostly) IgG coated pathogens and increase efficiency of phagocytosis (ie., they're opsonants). Some, however, are inhibitory (ITIMs) |
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What is FcγRI? How does it bind? What does it do?
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A high affinity receptor for <b>IgG1and IgG3</b>, constitutively expressed on monocytes, macrophages, and DCs.
Binds with a high affinity via α chain. It activates a signaling cascade via γ chain, thereby facilitating pathogen clearance. |
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How can FcγRs inhibit as well as activate cells?
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Instead of the usual ITAM domain, inhibitory FcγRs have an ITIM domain - immonoreceptor tyrosine based inhibitory motifs - that associated with intracellular proteins that develop inhibitory signals.
The activating signal is thru a common gamma chain containing and ITAM. |
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What is antibody-dependent cell-mediated toxicity? (ADCC)?
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1) Antibody (IgG1) binds antigen on surface of target cell
2) Fc receptors on NK cell recognize bound antibody. This juxtaposes target and NK. 3) Cross-linking of Fc receptors signals the NK cell to kill the target cell 4) Target cell dies via apoptosis. |
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What happens when IgE BINDS FcεR ON MAST CELLS and basophils?
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Crosslinking FcεR results in release of inflammatory mediators --> allergic reaction
(IgG4 may attenuate this) |
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Most types of FcR are on ________ and________. Mast cells ONLY have __________
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macrophages and neutrophils; Fcε
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What is radioimmunoassay and ELISA used for? How does it work?
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Use it to figure out how much of something is in serum (drugs, hormones, proteins).
General principle: Plate bound antibodies capture molecules which are themselves detected by labeled antibodies recognizing a different epitope. Values compared to standard curve. 1) Add anti-A antibodies covalently linked to enzyme to the sample you wish to analyze. 2) Wash away unbound antibodies. 3) The enzyme will make a colored product from the added colorless substrate. This can be measured via light absorption. |
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What is Agglutination/Hemagglutination? What is it used for?
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It's the process of using antibody to cause clumping when it binds to antigen on the surface of a large particle.
Dilution of serium required to induce clumping is TITRE. |
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What is Titre?
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The titer corresponds to the highest dilution factor that still yields a positive reading. The higher the titre, the higher the concentration of antibody in serum.
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What is the Coombs test?
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A method of determining the Rh factor of the mother. Works by hemagglutination
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How are monoclonal antibodies produced?
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1) Immunize animal with an antigen.
2) Immortalize the B cells producing antibody against that antigen in the animal by hybridizing them with myeloma cells. 3) Select the hybridoma that makes the antibody specific for the antigen you want (the one you initially immunized the animal with). 4) Clone selected hybridoma. |
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What is immunoflourescence microscopy?
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Antibodies labeled with fluorochrome are used to detect antigens in situ. When they are looked at under a flourescent microscope, the bound antibodies glow.
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What is flow cytometry/FACS?
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Fluourochrome labeled antibodies are used to detect antigens in/on individual cells in a mixture. Cells expressing the antigens are detected by their ability to emit a specific wavelength in response to laser stimulation. Detectors also measure "scatter" of the laser which indicates other characteristics of the cell (size, granularity). Charged plates can be used to separate labeled cell.
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Why might a person with Hyper IgM syndrome not have difficulty switching to IgD?
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Because IgM and IgD are on the same RNA transcript.
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Why can someone with no germinal centers make antibodies to blood antigens but not toxoids/other antigens?
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The blood group antigen that gets recognized is a carbohydrate, which unlike most proteins, can be recognized without T cell help (thymus-indepdent mechanism, TI-2)
Blood group antigens are T-cell indept because they're carbohydrates. |
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What possible B cell intrinsic difficulties could lead to an inability to isotype switch?
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A defect either in CD40 (T cells) or CD40 ligand (B cells)
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For a person with SLE, why might C3 levels decrease during active disease?
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The antibodies are self-reactive, and there is a lot of "self" in the body. You're using up complement in self-reaction by forming IgG complexes
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How does production of anti-nuclear antibodies create inflammation?
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Antinuclear antibodies are directed against body's own cells' nuclei.
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What would a lymph node biopsy of a person with SLE reveal?
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LOTS of germinal centers.
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