Term
| Differences between B lymphocytes (Igs) and T lymphocytes (TCRs) |
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Definition
-Variable binding sites: Igs=wide range of Ags; TCRs=on type of Ag)
-Function: Igs=sole fxn is to secrete antibdies; TCRs=multiple diverse roles with other cells
-Binding: Igs=Bind to epitopes on intact molecules (proteins, carbs, and lipids on surface of bacteria, viruses, and parasites - soluble toxins); TCRs=bind to one type of antigen, requires presentation by another human cell (antigen-presenting glycoproteins: MHC molecules plus a peptide) |
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Term
| Similarities between B lymphocytes (Igs) and T lymphocytes (TCRs) |
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Definition
-Stucture is the reslut of gene rearrangment
-They have variable and diverse antigen specificity
-Clones (made from proliferation) express a single species of antigen receptor
-Clonal distribution of diversity in receptors is produced by genetic mechanisms |
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Term
| Major histocompatibility complex (MHC) |
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Definition
-Ag presenting molecules (glycoproteins)
-Expressed on almost all cells
-Large number of genetically determined variants in the human population |
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Term
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Definition
-Membrane-bound glycoprotein (no secreted form)
-Resembles a FAB of an Ig (single antien-binding arm)
-Consisits of 2 polypeptides (alpha and beta chains) with one Ag-binding site |
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Term
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Definition
| Each has a variable region that binds Ag and a constant region |
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Term
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Definition
-Gene rearrangement=sequence variablility in V regions (like B-cells)
-After antigen stimulation- no further mutation in Ag-binding site
-No effector fxn!! (only job is to recognize antigen) |
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Term
| Functions of TCRs and Igs |
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Definition
-TCR: No effector fxn!! (only job is to recognize antigen)
-Ig: Recognition in Fab region(variable)and effector in Fc region (constant) |
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Term
| Genes encoding alpha and beta chains of TCRs: |
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Definition
| consist of segments that must be rearranged to form a functional gene (like Igs) |
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Term
| rearrangment of TCRs occurs: |
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Definition
| during T-cell development; mature T cells have one functional alpha and one functional beta chain which together define the unique TCR |
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Term
| Organization of TCR alpha and beta chains |
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Definition
-has both V and C regions
-folded into discrete protein domains
-Each chain has an amino terminal V domain followed by C domain, then a membrane-anchoring domain |
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Term
| Variability in TCRs is located |
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Definition
| in the amino acid sequence in CDRs (complementarity-determining region)= CDR1, CDR2, and CDR3 |
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Term
| Bcell rearrangement sequence: |
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Definition
b4 antigen encounter:
-gene rearrangement in V region sequence
After antigen encoding:
-mRNA splicing --> secreted Ig
-C-region DNA rearrangments (isotype switching)
-Somatic hyermuation= AB of higher affinity |
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Term
| Tcell rearrangement sequence: |
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Definition
b4 antigen encounter:
-gene rearrangement in V region sequence
After antigen encoding:
-genes encoding TCR remain unchanged |
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Term
| Orginization of TCR C-region is simpler than Ig: |
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Definition
-only one C-alpha gene and two C-Beta genes (no functional distinction known)
-The alpha chain V and J segments (like L-chain in Ig) and the beta chain has V,J, and D segments (like H-chain in Ig) |
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Term
| TCR rearrangement occurs in the thymus during T cell develoment where: |
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Definition
-V domain of alpha is encoded by V and J
-V domain of beta encoded by V,D and J
-TCR gene segments are flanked by recombination signal sequences (RSS)
-RA complex and other DNA-modifying enzymes are involves in the recombination proces
-In addition to V,D, and J recombination, juncional diversity is also attained by insertion of additional, non-templated P and N nucleotides |
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Term
| The opportunity for more diversity within the variable region is greater in |
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Definition
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Term
| SCID- severe combined immunodeficiency disease is caused by: (symptoms can be yeast infection in mouth) |
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Definition
| Non-functional RAG protein causing there to be no functioning B or T cells (requires bone marrow transplant for survival) |
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Term
| Omenn syndrome: (symptoms are red rash on face and shoulders) |
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Definition
| Missense mutations that roduce with partial enzymatic activity (requires bone marrow transplant for survival) |
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Term
| What type of cell can present w/ MHC I? |
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Definition
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Term
| What type of cell can present w/ MHC II? |
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Definition
| denrditic cells, macrophages, and Bcells |
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Term
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Definition
| turns T and B cells to mature cells |
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Term
| Expression of the TCR on the cell surface requires association with additional proteins |
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Definition
TCR = alpha:beta heterodimer
-Alone can not leave ER
alpha:beta heterodimer stable association with 4 “invariant” membrane proteins
-CD3 complex
-zeta chain
-TCR has short cytoplasmic tails |
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Term
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Definition
| 2 epsilon, 1 delta, and one gamma, plus zeta chain for signaling |
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Term
| Lack of functional CD3-delta & CD3-epsilon = ? |
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Definition
| low TCR expression and impaired signal transduction = immunodeficiency |
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Term
| The TCR complex is composed of |
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Definition
-8 polypeptides
-alpha-beta chains form core
-the zeta chains interact with intracellular signaling molecules |
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Term
| 1-5% of Tcells can be processed as: |
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Definition
| gamma:delta chains- which act more like BCRs and dont need MHC plus peptide to recognize (can recognize native tructures) |
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Term
| What are the two types of chains made for TCRs? What is the standard main population of chains made? |
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Definition
-alpha:beta and gamma:delta (can never be anything ese - i.e alpha delta..etc)
-alpha:beta=main chain created |
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Term
| The delta gene segments are situated “within” the alpha-chain locus on chromosome 14 causing: |
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Definition
| deletion and inactivation of the delta-chain because the delta-chain is between the V-alha and J-alpha and when they are brought together, delta is looped out and degraded |
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Term
| during delta-gene rearrangement two D segments can be incorporated into the final gene sequence which results in: |
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Definition
= increased variability of the delta chain
1. Increase in the potential numbers of recombinations.
2. Extra N nucleotides can be added at the junction between the two D segments, as well as at the VD and DJ junctions.
(gives junctional diversity) |
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Term
| How Bcells and Tcells interact with antigen |
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Definition
Bcells: involves bnary complex of membrane Ig and Ag
Tcells: involves ternary complex of TCR, Ag, and MHC plus peptide |
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Term
| What type of cell bind to a soluble antigen (B or T cells)? WHich requires involvement with MHC? |
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Definition
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Term
| TCR recognize Ag as a peptide bound to MHC on human cell surface |
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Definition
| Pathogen-derived protein must first be broken down (Ag processing) and displayed on the surface of cells bound to MHC (Ag presentation) |
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Term
| Microorganisms that infect the human body can be broadly divided into two groups intracellular and extracellular |
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Definition
MHC I recognize intracellular (viruses)
MHC II recognize extracellular |
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Term
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Definition
cytotoxic and kill cells that are infected with a virus or other
intracellular pathogen
(Prevents pathogen replication and further infection of healthy cells) |
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Term
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Definition
| help other immune cells respond to extracellular sources of infection. |
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Term
| CD4 T-cells are helper T-cells with two subclasses: |
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Definition
-TH1 cells activate macrophages
-TH2 cells stimulate B cell |
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Term
| MHC Class I presents intracellular Ags to |
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Definition
| CD8 T-cells (ex. Virus infected cell). |
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Term
| MHC Class II presents extracellular Ags to |
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Definition
| CD4 T-cells (ex. phagocytosed or endocytosed antigens). |
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Term
| MHC Class I = transmembrane heavy chain, or alpha chain noncovalently complexed to beta-microglobulin |
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Definition
-alpha-chain has 3 extracellular domains (alpha1, alpha2 and alpha3) encoded by a gene in the MHC loci.
-beta-microglobulin is not coded by a gene in MHC loci.
-Folding of 1 and 2 = peptide-binding site farthest from the cell membrane, supported by 3 and -microglobulin |
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Term
| MHC Class II consists of two transmembrane chains, alpha and beta chain |
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Definition
-Each contributes one domain to the peptide-binding site and one Ig-like supporting domain.
-Both alpha and beta chains are encoded by genes in the MHC. |
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Term
| The similar 3-D structures of MHC I and MHC II molecules consist of two pairs of extracellular domains |
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Definition
The paired domains farthest from the membrane resemble each other and form the peptide-binding site.
The domains supporting the peptide-binding domains are Ig-like domains: alpha3 and beta-microglobulin in MHC I and alpha2 and beta2 chain in MHC II. |
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Term
| Ig-like domains of MHC class I and II are not just a support for the peptide-binding site. |
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Definition
-They provide binding sites for the CD4 and CD8 co-receptors.
-Allows the simultaneous engagement of both T-cell receptor and co-receptor by an MHC molecules. |
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Term
| MHC molecules have degenerate binding-capable of binding peptides of many different amino acid sequences |
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Definition
| Peptide-binding site = deep groove on the surface of the MHC molecule, a single peptide is tightly noncovalently bound |
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Term
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Definition
8,9, 10a.a. (slight kinking to accommodate)
-Also may have a hydrophobic or basic residue at the carboxyl terminus complementary to pocket present in MHC I binding groove. |
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Term
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Definition
13-25 a.a. in length or longer
-Two ends of the peptide not pinned down into pockets at each end
-Extend out at each end of the groove
-Longer and more variable in length than peptides bound by MHC class I |
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Term
alpha helices on MHC are:
beta sheets on MHC are: |
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Definition
-the shoulders
-the binding groove |
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Term
| Peptides derived from degradation of intracellular proteins or pathogens are: |
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Definition
-Formed in the cytosol
-Delivered to the ER
-Bound by MHC class I |
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Term
| Peptides derived from degradation of extracellular proteins or pathogens are: |
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Definition
-Taken up by cellular phagocytosis and endocytosis.
-Degraded in the lysosomes and other vesicles of the endocytic pathways.
-Bind to MHC class II molecules in these endocytic vesicles. |
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Term
| The processing pathway determines: |
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Definition
| which class of MHC molecule interacts with a peptide that originates from extracellular or intracellular pathogen |
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Term
| Formation and transport of peptides that bind to MHC class I molecules |
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Definition
-Proteins in the cytosol are degraded by the proteasome protein complex
-Ag peptides are then transported into the ER
By TAP-1 and TAP-2 (heterodimer)
-Transport dependent on the binding and hydrolysis of ATP
-TAP transports peptides of eight or more amino acids having hydrophobic or basic residues at the carboxy terminus |
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Term
| Newly synthesized MHC class I H-chains and beta-microglobulin translocate to the ER |
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Definition
-Partially complete folding
-Associate together
-Bind peptide to complete folding |
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Term
| Chaperones = Calnexin and calreticulin |
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Definition
| = proteins that assist in correct folding of proteins and assembly of other proteins, protection until they enter their respective cellular pathways and to carry out their intended functions |
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Term
| When MHC class I heavy chains enter the ER they bind a membrane protein-calnexin |
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Definition
| Calnexin retains the partly folded alpha-chain in the ER |
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Term
| Nonfunctional TAP leads to |
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Definition
| lack of MHC I on surface and CD8 T cells not being activated (Bare lymphocyte syndrome) |
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Term
| MHC class I H-chain binds beta2-microglobulin and calnexin is released from the alpha:beta-microglobulin |
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Definition
-Calreticulin and tapasin bind the TAP-1 subunit of the peptide transporter to position the partly folded alpha:beta-microglobulin heterodimer to wait for a suitable peptide from the cytosol.
-A peptide delivered by TAP binds to class I heavy or alpha-chain, forming mature MHC class I molecule.
-The class I molecule dissociates from calreticulin, tapasin, and TAP and is exported from the ER to cell surface. |
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Term
| Peptides Presented by MHC Class II are Generated in Acidified Vesicles |
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Definition
-Vesicles travel inwards from the plasma membrane, their interiors become acidified by the action of proton pumps in the vesicle membrane.
-Vesicle membranes fuse with other vesicles (lysosomes) to form phagolysosomes that contain proteases and hydrolases that are activated at low pH.
-Enzymes degrade the vesicles contents to produce peptides from proteins and glycoproteins. |
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Term
| MHC Class II Molecules are Prevented from Binding Peptides in the ER by the |
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Definition
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Term
| MHC class II compartments or MIIC (Endocytic vesicles )contain |
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Definition
proteases (cathepsin S) that selectively cleave invariant chain leaving a small fragment of the invariant chain to cover the MHC class II peptide-binding site
Class II-associated invariant-chain peptide (CLIP fragment) |
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Term
| Removal of CLIP and binding of peptide the MHC class II molecule is aided by |
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Definition
interaction HLA-DM glycoprotein.
-HLA-DM catalyzes the release of CLIP and allows MHC class II molecule to sample other peptides until it finds one that binds strongly.
-MHC class II molecule binds appropriate peptide and is transported to cell surface by outward going vesicles. |
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Term
| MHC class II molecules are normally expressed only by |
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Definition
| a subset of hematopoietic cells (antigen presenting cells- dendritic, macrohpages, Bcells) and by stromal cells in the thymus. |
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Term
| MHC class II molecules can be produced by other cell types on exposure to |
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Definition
| to the cytokine interferon-gamma |
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Term
| Differences in MHC molecules responsible for |
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Definition
| graft rejection in organ transplantation. |
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Term
| Diversity of MHC molecules in the human population is due to |
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Definition
1. Multiple similar gene families
-encoding MHC class I heavy or alpha chains and
-encoding MHC class II alpha and beta chains
2. Polymorphism: existence within the population of a great many alternative forms of a MHC class I or class II gene.
Individuals are therefore heterozygous for MHC genes |
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Term
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Definition
alpha and beta chains
procesing protein genes |
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Term
| MHC I isotypes (HLA locus) |
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Definition
| A, B, and C - each have multiple allotypes leading to high polymorphism |
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Term
| MHC II isotypes (HLA locus): |
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Definition
DPA1, DPB1
DP, DQ, and DR are prepresenting molecules |
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Term
| All the diversity of MCH II comes from |
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Definition
| beta, DRB1, DRB3, DRB4, DRB5!! EVeryone had DRB1!! |
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Term
| HLA = human leukocyte antigen complex |
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Definition
Antibodies used to identify human MHC molecules react with white cells (leukocytes) but not with red cells.
The isotypes differ in function and the extent of their polymorphism. |
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Term
Human MHC class I isotypes
HLA-A, HLA-B and HLA-C present peptide Ags to |
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Definition
| CD8 T cells and form ligands for NK-cell receptors |
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Term
Human MHC class II isotypes
HLA-DP, HLA-DQ and HLA-DR present peptide Ags to |
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Definition
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Term
| The number of known functional alleles in the human population for each HLA class I (greater diversity) and class II genes |
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Definition
-Class II, diversity contributed by alpha and beta chains
-Class I, H-chain = polymorphism |
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Term
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Definition
| invariant (everyone has them) diversity is in DRB (Beta) |
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Term
| Class II region of the MHC is almost entirely dedicated to genes involved in |
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Definition
| processing and presenting Ag to T cells |
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Term
| Variation between MHC allotypes is concentrated in the sites that bind peptide and TCR. |
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Definition
T cells that responds to peptide presented by one MHC allotype will not respond to that peptide bound to another MHC allotype –
(MHC restriction ) |
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Term
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Definition
With respect of a linked cluster of polymorphic genes, the “set of alleles” carried on a single chromosome
Every person inherits 2 haplotypes, one from each parent |
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