Term
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Definition
| MHC is a genetic locus whose products are MHC molecules, which are proteins |
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Term
| What does MHC restriction mean to a T cell? |
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Definition
| The T cell can only "see" an AG presented with a particular MHC |
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Term
| What is a TCR specific for |
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Definition
| the combination of AG and MHC |
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Term
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Definition
| cells that capture microbial AG and display them to T cells |
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Term
| What are the primary imunologic filters for blood and tissue? |
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Definition
blood - spleen
tissue - lymph nodes |
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Term
| Where do AG go after capture by APC? Where do microbes mainly enter in the body? |
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Definition
| Protein AG of microbes are captured by APCs and concentrated in peripheral lymphoid organs where immune responses are initiated – microbes enter mainly through the skin, GI, and respiratory tract |
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Term
| Why are epithelial dendritic cells considered immature? How are they activated? |
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Definition
Epithelial dendritic cells are called “immature” b/c they are inefficient at stimulating T cells
*They have membrane receptors for things like mannose
*Dendritic cells get activated b/c the microbes also bind to TLRs, which produces inflammatory cytokines like TNF |
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Term
| What happens when dendritic cells are activated? What's induced? |
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Definition
*Inflammatory signals induce maturation and movement of dendritic cells (migration and maturation happen at the same time)
*Expression of costimulatory molecules –
When the dendritic cells are activated they lose their adhesiveness and express surface receptors specific for chemokines made in the T cell zones of lymph nodes (attracts them to LN |
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Term
| What does the maturation of dendritic cells include? |
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Definition
| Maturation includes expression of Co-stimulatory molecules and increased synthesis and stable expression of MHC |
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Term
| Where are the 2 sources of AG? |
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Definition
| They can be taken from the outside or can come from internally produced proteins |
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Term
| What is MHC? When was it first discovered? WHo has the same MHC? What is the MHC locus in humans? In mice? |
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Definition
*Membrane proteins – locus was 1st discovered as the main determinant in graft rejection – inbred animals and identical twins have the same MHC, everyone else is slightly different
*HLA = Human Leukocyte Antigen (humans)
*H-2 = Histocompatibility 2 (in mice) |
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Term
| Who expresses MHC class I? |
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Definition
Class I – Tc cells
All nucleated cells and platelets, RBCs (mouse, but not humans) – it’s a good thing we don’t have MHC on our RBCs, otherwise blood transfusions would be just about impossible – as hard as transplanting a kidney |
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Term
| Who expresses MHC class II? |
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Definition
Class II –
*APCs to Th cells:
*B lymphocytes
*Macrophages / monocytes
*Dendritic cells |
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Term
| where does peptide bind in the MHC complex? is it stable without a peptide |
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Definition
*binds at the amino end
*not stable without a peptide |
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Term
| Describe the structure in general of MHC molecules. Describe the class I and class 2 specifically - what do they look like? |
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Definition
| Heterodimers
*Two different chains
-Transmembrane protein
*Part goes through the cell membrane
-Two types of domains
*Ig domain
*Alpha helix
[image] |
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Term
| Describe in detail MHC class I molecules - their heavy and light chains, what binding sites they have, what this means to imposing restriction. |
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Definition
Class I
*heterodimer (2 different chains)
--chains not covalently linked
Heavy Chain = alpha-chain
Each alpha chain is covalently attached to a β chain
*alpha 1 and alpha 2 (amino terminals) form the peptide binding cleft, a3 is invariant and has the binding site for CD8 - this is the reason CD8 cells are MHC I restricted-these are the only cells with CD8 receptors on them and you have to bind both to be active
*different AAs are in the a1 and a2’s depending on the individual – some of the variations between these aa’s can change the floor of the pocket slightly, which is why different MHCs bind different peptides – others vary in the top of the cleft, which influences recognition by T cells
*Light chain = Beta2 microglobulin – encoded by genes outside MHC
96 amino acids |
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Term
| The MHC I alpha chain - what are its parts, describe the parts. How many domains? |
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Definition
*Cytoplasmic - Charged- anchors structure
*Transmembrane - hydrophobic - goes across membrane
*Extracellular - largest contains CHO – glycoprotein, which makes it more water soluble and harder to be degraded by proteolysis
*a 1, a 2, a 3
*a 2 and a 3 disulfide bond 60 aa apart.
Carbohydrate on a2 |
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Term
| Beta2microglobulin - describe its variability, what does it resemble, how is it linked? Where is it located? |
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Definition
*Constant, highly conserved
*Good homology with C4 of Ig and alpha 3 of MHC I
*Single disulfide bridge approximately 60 aa apart.
*Associated noncovalently with a 3 under a 1 +2
*Does not extend into membrane |
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Term
| Describe the structure of class II MHC. What is it made of? What forms the binding cleft? Where is the CD4 binding site? What regions does it have and how many external domains? |
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Definition
Heterodimer
*Alpha -chain 230 A.A.
*Beta-chain ~ 220 A.A.
not covalently linked
*The amino ends (extracellular) a1 and b1 have polymorphic residues and form the peptide binding cleft
*b2 has the binding site for CD4
both chains have 3 regions.
*cytoplasmic, transmembrane, and extracellular
2 external domains 1 and 2 |
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Term
| What do alpha 1 and 2 look like in an MHC class II molecule? |
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Definition
Each domain ~ 90 A.A. and have carbohydrate
Alpha-1 domain -
No S-S,
Structurally resembles alpha 1 of MHC class I
*Alpha 2 domain -
disulfide bridge,
Very similar in structure to alpha 3 of MHC Class I, beta2 microglobulin, and Immunoglobulin constant domain |
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Term
| Describe the beta chains in MHC class II - where is the most variable region, which section has carbohydrate, bonds, etc. |
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Definition
Both domains have S-S
*Beta 1 domain -
Structurally similar to alpha2 of MHC Class I
*most variable allotypic variation
*carbohydrate
*Beta 2 domain -
Very similar in structure to alpha3 of MHC Class I, beta 2microglobulin, and Immunoglobulin constant domain |
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Term
| In MHC molecules, what forms the peptide binding groove? What influences recognition by T cells? |
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Definition
*Peptide binding groove-
Formed by the “floor” – polymorphic residues in this region are the reason we can bind different peptides (AGs)
*Polymorphic residues in the top of the cleft influences recognition by T cells |
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Term
| Does the binding pocket of an MHC ever change shape? |
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Definition
*Different peptides in same MHC give different shapes
*The interaction of the peptide with the pocket changes the shape of the pocket |
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Term
| What is the most common source of peptide for an MHC molecule? |
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Definition
| self – this is why it’s so important to have co-stimulators so you don’t react with yourself – all the cells that can’t recognize self from non-self were killed during the “education” phase |
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Term
| Summarize peptide-MHC interactions - how many peptides are displayed at a time? What are the sources of peptide for the 2 classes? Are the interactions specific or broad? Off-rate? What they respond to. |
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Definition
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Term
| Describe the class I pathway to AG presentation. |
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Definition
| *Internal proteins-proteins (AGs) are produced in the cytoplasm by the virus that infected the cell
*Cut at proteasome – bad protein is unfolded and targeted by ubiquitin and threaded into the proteosome (organelle where degradation takes place)
*Transported by TAP – transporter associated with AG processing – special molecule that brings peptide frags from the cytoplasm to the ER
*Fragments associate with alpha chain – in ER
*Will not associate with beta chain unless peptide is present
*Only complete molecules are transported to surface – if a class I molecule doesn’t find a peptide in the ER it becomes unstable and is degraded by proteases
[image] |
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Term
| Describe the path of AG presentation in a class II MHC molecule. |
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Definition
*Initial assembly with CLIP portion of invariant chain in groove – for every new MHC II molecule – binds to the peptide-binding cleft – molecule goes to a phagolysosome
*In phagolysosome CLIP is removed by DM (protein) via a change in pH and groove is available to peptides
*Transport – if the MHC II finds a peptide, it’s stabilized and gets transported to the cell surface – if not it’s unstable and gets degraded by proteases |
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Term
| Summarize the MHC class I and class II pathways- composition of the complex, types of APCs, T cell responders, source of AG, enzymes, accessory proteins,site of peptide loading. |
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Definition
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Term
| What happens when a microbe meets a) a macrophage b) a B cell c)an MHC I molecule |
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Definition
a) macrophage presents to Th cells, which release cytokines activating the macrophage and the microbe is destroyed
b)binds to a Th cell, secretes cytokines, causes activation of B cell which makes AB
c) presents to a Tc cell - cell gets killed |
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Term
| What are the various genes and gene products on the MHC class I, II, and III loci in humans and mice? |
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Definition
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Term
| How are MHC genes expressed? Why? |
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Definition
| Codominant expression - good b/c it means you have twice the chance that you'll put out a molecule that will interact with an AG |
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Term
| How many MHC molecules are expressed? Are people homozygous or heterozygous? What about inbred mice? |
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Definition
| 8 - people are hetero, inbreds are homozygous |
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Term
| What is the significance of polymorphic genes? |
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Definition
| it ensures that different people will be able to respond to different microbial peptides |
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