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54 Cards in this Set
- Front
- Back
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Describe the humoral response.
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B cells recognize antigen via their surface immunoglobulin molecules. When a B cell becomes activated and becomes an Ab-secreting cell, the surface Ig has the same specificity as the secreted Ab. Ab recognizes an intact Ag. It recognizes a fully folded, intact protein from a bacterium.
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Describe the cell mediated response.
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Cytotoxic T cells and helped T cells recognize Ag in a completely different form. The T cell receptor on the helper T cell and the cytotoxic T cells engage the MHC molecule, whether its class I or II. If its a low affinity interaction that means its a self molecule. If its a high affinity interaction, it is interpreted as foreign
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MHC receptors recognize what type of biomolecule?
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peptides
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What is the main difference between B cells and T cells and how they recognize antigens?
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B cells - recognize folded and intact proteins
T cells - recognize peptide fragments |
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What are the two types of T cells and what are their fxns?
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1. Cytotoxic T cells - kill virally infected cells, kill cells containing cytosolic bacteria, and kill tumor cells.
2. Helper T cells -- TH1 - activates macrophages to kill intracellular bacteria -- TH2 - activate B cells to make Abs ** T helper cells provide help by secreting cytokines |
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When T cells are surveying MHC II molecules and looking for something foreign, what do these cells secrete?
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IL-2
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Describe the structure of MHC I.
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heterodimer with an alpha chain and a beta-2 microglobulin.
Within alpha chain, have an alpha1 and alpha2 domain which forms the Ag binding site Ag can only be 8-9 residues long to fit in Ag binding site Recognizes endogenous antigens |
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Describe the structure of MHC II.
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heterodimer with alpha and beta chains - the 2 different chains form the antigen binding site; the peptides for class II can be much larger; antigens are derived from exogenous antigens
peptides are 12 to 20 AA. |
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What are the 3 HLA molecules you have as part of MHC Class I?
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HLA-A, HLA-B, and HLA-C
We have 2 copies of each - one from each parent |
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What are the 3 HLA molecules you have as part of MHC Class II?
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HLA-DP, HLA-DQ, HLA-DR
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What does HLA stand for?
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human leukocyte antigen
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Where is the binding sites on MHC I and MHC II receptors?
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MHC I - between the alpha 1 and 2 domains
MHC II - between the alpha and beta chains |
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Describe the anchor residue in antigens that will bind to MHC I.
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The last position for any peptide biding to a MHC I is almost always a larger, hydrophobic or basic AA. It is usually leucine or isoleucine. This last AA is known as the anchor residue and is critical for the binding of Ag.
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Describe the type of AA needed for a peptide to bind to a MHC Class II.
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4th position shows aspartic acid and glutamic acid. Acidic AA residue requirement in binding platform.
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What is the purpose of having MHC molecules?
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to be able to differentiate between self and non-self.
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What gives you a pre-disposition to rheumatoid arthritis?
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have a class 2 molecule called DR4. Not everyone with arthritis will have HLA-DR4 but if you do have it you are 10 times more likely to develop it
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What is a target cell?
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anything that is expressing the MHC 1 molecule on it
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What is MHC Restriction?
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Take a mouse and inject a virus. The mouse will develop T cells to virus.
Then take the cells from the mouse that hasnt been infected. Take cells from same mouse that has been infected. Then take cells from another mouse that has been infected. The first mouse with non-affected cells will not show cell lysis. The second set of cells that were infected will lyse. However, the 3rd set of cells which were from another mouse will not show cell lysis. This shows that there are differences in MHC I molecules from one person to another. |
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For helper T cell activation, you can either monitor _______ or __________?
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T cell proliferation or release of IL-2
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What is the role of APCs? Which cells are APCs and which MHC class do they express?
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APC degrades the antigen that comes in from the outside into peptide fragments
dendritic cells, macrophages, and B cells MHC II |
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Describe the cytosolic pathway.
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endogenous antigens become ubiquinated. Ubiquitin is a red flag that indicates that the cell needs to degrade a protein. The proteosome clips the endogenous Ag into peptides. The AA are either reutilized by cell but some peptides are transported into lumen of the ER and they become a part of MHC I complex.
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Describe the endocytic pathway.
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Antigen has come from the outside either by endocytosis or through phagocytosis. The antigen then gets into endocytic compartments like lysosomes. The lysosomes have proteases that chew up the proteins. Some of the constituents become associated with MHC-2 complex
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What is ubiquitin?
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60 AA protein that signals the proteasome. The ubiquitin is not degraded but the protein gets degraded into peptides
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How do proteins that are synthesized in the cytosol and the proteosome that is also in the cytosol become associated with MHC I molecules that are synthesized in the lumen of the ER?
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Transported called TAP (Transporter associated with Ag processing)
It is a 2 subunit ATPase that uses ATP hydrolysis to pump those peptides into the lumen of the ER |
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What is the role of chaperones in the cytosolic pathway?
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They are there to make sure the alpha chain and beta 2 microglobulin and the peptide become associated. They bind the alpha and beta chains until they become loaded with peptide. If they are released prior to peptide loading, they wouldnt have anything to present to the T cell receptor
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Describe the sequence of events that occur to get a peptide onto a MHC I complex.
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1. MHC alpha chain is synthesized - it is polymorphic and has the peptide binding site
2. Calnexin interacts withs the alpha chain until the beta-2 microglobulin comes along. 3. When calnexin comes off, Tapasin and Calrectulin become associated with the complex. 4. Once the peptide gets loaded onto the complex, we now have what looks like a properly-folded protein. 5. Tapasin and Calrectulin fall off. 6. The complex then exits the ER and goes to the cell surface. At the surface it performs its biological function to present the peptide to surveying CTLs. |
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What is the function of Tapasin?
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gets the alpha chain and beta-2 microglobulin close to the transporter
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What is the function of Calrectulin?
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keeps the MHC I complex in the ER until peptide loaded onto MHC
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What is the invariant chain?
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chaperone who sequence is not polymorphic. Everyone's invariant chain is the same. It sits in the peptide binding site of the alpha and beta subunits and blocks it. It also provides targeting information to get the newly synthesized alpha and beta chains to the lysosomal compartment where it meets Ag.
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Describe the sequence of events for loading a peptide into the MHC 2 molecule.
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1. MHC complex 2 leaves the ER, where it is synthesized
2. It is delivered to the lysosomal compartment 3. Exogenous antigens are coming in from the outside, either through endocytosis or phagocytosis. 4. They get chewed up by the proteases that are in the lysosomal compartment. 5. Once the invariant chain gets to the lysosomal compartment, it has performed its biological function and it gets chewed up by the same proteases that degrade Ag. 6. In the lysosomal compartment, peptide Ag becomes associated with MHC 2 and then it goes to the cell surface where it performs its biological function. |
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What is CLIP?
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When the MHC 2 complex gets delivered the lysosomal compartment, the invariant chain gets chewed up. However a fragment of the invariant chain remains associated with MHC 2 in the peptide binding site. It's known as CHIP.
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What is the fxn of HLA-DM?
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It facilitates the exhange of CLIP for peptide Ag. If you don't have HLA-DM, you will have MHC 2 molecules with CLIP fragments still attached.
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What are the basic components in the lymphcyte activation response?
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1. Antigen-receptor interaction
2. Protein synthesis 3. Entry into cell cycle to have proliferation (clonal expansion) |
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T and B cells are circulating in what state?
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quiescent state (G0)
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Approximately how many lymphocytes are circulating in your blood?
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10^11
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In addition to the Ag-receptor interaction, what other signal do you need to undergo proliferation?
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co-stimulatory signal -- need signals from cytokines which are important in stimulating proliferation and inducing differentiation.
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What is somatic hypermutation?
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The genes that encode the Ag-receptor on the B-cell are mutated randomly and are introduced into the gene that make up the receptor site. Specifically the mutations occur in the part of the gene that encodes the part of the receptor that recognizes the Ag.
As the response ramps down, your system begins to select for clones with teh higher affinity according to the classical Darwinian mechanism. Clones with lower affinity are selected against, so that over time you have more and more cells that can bind to a specific Ag with very high affinity. T CELLS DO NOT UNDGERGO HYPERMUTATION!!! |
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What immunoglobulin is expressed on mature naieve B cells?
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IgM or IgD
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What does it mean to have class switching?
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B cells can have class switching during the proliferative phase of an immune response where it can switch its receptor to like IgE or IgG
A class switched receptor will still respond to the exact same epitope but the heavy chain constant regions will be different (of a different isotype) |
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What is antigen recognition site formed from?
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Receptor site is bivalent and is formed by hyper-variable domains
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What are complimentary determining regions (CDR)?
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aka hypervariable regions
These variable domains in the heavy or light chain are some 100 AA spans that determine what Ag it responds to |
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What is the framework domain?
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domains outside the CDRs that are less variable. These provide Ig domain structure for each domain
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How many CDRs does each heavy and light chain have?
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Each has 3 CDRs
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Describe IgM.
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It spans the membrane and has 3 AA tail in the cytoplasm. The receptor is associated non-covalently with a heterodimer (IgAlpha/IgBeta or CD79a/CD79b). This is the signal transducing subunit of the antigen-receptor complex on the surface of the B cell.
This actuall drives the signal to protein synthesis and entry into the cell cycle/proliferation. |
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What are Immunoreceptor Tyrosine Activation Motifs?
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ITAMs - Tyrosine-X-X-Leu-IsoLeu
drives signal transduction in immune cells. the tyrosine gets phosphorylated and produces a phosphotyrosine motif. this creates a docking site for other proteins; proteins important in signaling protein synthesis and cell cycle entry |
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What is the sequence of events of when an Ag binds to a receptor on a B cell?
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1. Ag binds to the receptor and the receptor redistributes within the membrane.
2. Receptor complex co-localizes with tyrosine kinases. 3. Tyrosine kinases phosphorylate the ITAMs into signal transducing subunits. 4. Generate a phosphotyrosine motif and recruitment of signaling proteins to the activation complex occurs. 5. The proteins are activated and signal the initiation of protein syntehsis that drives induction of the cell cycle. |
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Describe the antigen receptor on T cells.
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disulfide linked heterodimer
At the amino terminues there are variable domains and within the variable domains are the CDRs of the T cell receptors; the pairing of the CDRs in teh alpha and beta chains forms teh Ag recognition structure The heterodimer spans the membrane and just like in B cells, ends a short cytoplasmic tail |
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What does the Ag-receptor on T cells need to transduce a signal?
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There are CD3 complexes and the zeta chain homodimer do this. Both the CD3 complex and zeta chain contain several ITAM sequences. Ag-binding and receptor distribution leads to the phosphorylation of the ITAM tyrosines to begin the signal transduction similar to that in B cells.
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Where do the CD4 and CD8 molecules bind to MHC molecules?
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When an APC presents an Ag to the T cell, the CD4/CD8 molecule will come in and bind to the non-polymorphic zones of the MHC molecule to stabilize the interaction.
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Do B cells or T cells have a lower affinity for their antigens?
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T cells which is why you need CD4/CD8
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What is LFA1 and LFA2?
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They are integrins that help T cells adhere to APCs
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What is the sequence of events of a T cell binding to a APC to determine if an Ag is foreign or self?
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1. T cell interacts with an APC
2. Have a low affinity interaction between integrin (LFA1) on the surface of the T cell with its counter receptor (ICAM1) on the APC 3. This gives the T cell the time to scan the APC cell surface for the MHC-Ag complex 4. If it sees the complex, the integrin complex is now there to further stabilize the interaction-- in addn to T cell binding to MHC-Ag complex and binding of CD4/CD8 to the MHC molecule 5. This allows a much longer and more stable interaction and therefore easier time activating a strong signal |
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What is the co-stimulatory molecule on T cells and how does it act?
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It is CD28 and it interacts with B7 molecule on APCs. When they bind together, it produces the co-stimulation that pushes the T cells into full blown proliferation
You do still need cytokines, but this interaction of CD28 and B7 is enough to get the machinery started. W/o stimulation, cell would beome inergic and apoptotic |
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What is the co-stimulation needed for B cells?
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CD40 on the B cell binds to the CD40 ligand (CD40-L) or CD154 on activated T helper cells.
T cell has been activated and up-regulated the expression of CD40L/CD154. It goes on to contact a B cell already activated by contact with an Ag. This is the signal needed to promote full proliferation of a B cell that has come into contact with an Ag. |
