CMB2004

Structure of an antibody (immunoglobulin)
2 heavy and 2 light chains. 2 types of L chain. Each chain has a variable (V) region and a constant (C) region. Variable region Vh and Vl are the antigen-binding site. Ch regions (Fc region) interact with effector cells and complement
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5 antibody classes
IgM, IgA, IgD, IgG, IgE Constant region genes, will bind to different Fc receptors, class is determined by heavy chain (c region)
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Homology regions of H and L chains
L chain - 2 domains. H chain - 4 or 5 domains. Each domain around 110aa, comprises 2 B sheets, linked by a disulphide bridge. Domains are paired into folded units within the protein
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TCR (T-Cell receptor)
Unlike antibody it does not bind free antigen. Interacts with processed antigen (peptide) bound to MHC. Smaller than antibody and remains membrane bound. Expressed on T-cell plasma membrane.
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TCR structure
4 lg-like domains. Heterodimer of a and b chain, each chain has a V and C region.
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MHC class 1
Expressed on all nucleated cells, tissue typing. HLA-A, HLA-B, HLA-C. Heterodimer of a chain and b-microglobulin a1 and a2 domains form peptide binding site. a3 domain and b2-microglobulin are lg-like. Polymorphic aa in a1 and a2
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MHC class 2
Expressed only on APC and cytokine activated cells. HLA-DP, HLA-DQ, HLA-DR. Heterodimer, a and b chains, both transmembrane and both encoded by separate genes encoded within MHC. a2 and b2 domains lg-like. Polymorphic a2 and b2 domains form pbs
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Peptide binding groove of MHC class 1 and 2
MHC class 1 - small binding site, can only bind short peptides. MHC class 2 - more open and can bind bigger, longer peptides which hang outside
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V and C regions of antibody and TCR polypeptide chains are encoded by separate gene segments that rearrange during lymphocyte differentiation
H chain and TCR-B: V region encoded by 3 gene segments: V, D, and J (V is the biggest). L chain and TCR-a: V region encoded by 2 gene segments: V and J
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Heirachy of rearrangements
H chain genes: D-J then V-D, then Light chain genes: K: V-J, if K rearrangement unsuccessful then lambda genes rearrange
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What loci H chain encoded
Chromosome: 14
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What loci K chain encoded
Chromosome: 2
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What loci lambda chain encoded
Chromosome: 22
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Recombination activating gene
RAG-1 and RAG-2 genes encode lymphoid specific components of the recombinase. Mutations in RAG genes results in immunodeficiency
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mechanisms to ensure individual B cells produce only one specificity of antibody
Allelic exclusion: in a single B cell only one allele of H chain expressed, similarly for L chain,. L chain: isotype exclusion: a single B cell expresses EITHER K or lambda
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Mechanisms for generation of antibody diversity
1) multiple germline genes 2) Combinatorial diversity 3) Junctional diversity 4) Combinations of heavy and light chains 5) somatic hypermutation
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Multiple germline genes
mltiple Vh, Vk and Vlambda. Also multiple D and J (no D for K and lambda)
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Combinatorial diversity
Different V, D and J segments recombine to produce different sequences.
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Junctional diversity
Imprecise joining (small differences in position of V-D and D-J join). N regions (random addition of nucleotides at junctions of V-D and D-J by terminal transferase)
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Somatic hypermutation
mutation frequency in antibody Vh genes orders of magnitude higher than normal spontaneous mutation rate. Occurs in germinal centres after antigenic activation of B cells. Involves the enzyme, activation-induced deaminase (AID).
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Somatic hypermutation Cont
AID acts on DNA to deaminate cytosine to uracil. Uracil recognised by error-prone DNA repair pathways leading to mutations
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Membrane (BCR) Vs Secreted antibody
as B cells differentiate the start to secrete BCR as antibody. Secreted form has an alternative hydrophilic C-terminus but same specificity as membran Ig (BCR. Membrane and secreted forms produced by alternative RNA processing
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Generation of diversity of TCR
Similar mechanisms to Ig. Multiple V, (D) & J gene segments, Combinatorial diversity: between V, (D) & J, and Junctional diversity. But NO somatic hypermutation
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Gene structure of human MHC is on which chromosome?
6
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Effects of high levels of polymorphism
Good: Allows the binding of a vast range of peptides that can be presented to T cells. Bad: Cause of graft rejection, influence susceptibility to various diseases eg autoimmune diseases
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How peptides end up in MHC molecules
Protein antigens must be processed to peptides in order to bind MHC molecules. Endogenous antigens (made in cytoplasm) are presented by class 1. Exogenous antigens (from outside the cell) are presented by class II
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Antigen processing and presentation by MHC class 1 molecules
1.Antigen synthesised in cytoplasm 2.Protein cleaved to peptides by proteasome 3.Peptides transported to endoplasmic reticulum by TAP transporter 4.Peptides bind to MHC class 1 molecules. 5.MHC-peptide complex transported to cell surface
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TAP
a component of a multi-protein assembly, the peptide loading complex. Includes tapasin and calreticulin
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Antigen processing and presentation by MHC class II molecules
1.Antigen endocytosed into intracellular vesicles 2.Protein cleaved to peptides by acid proteases 3.Vesicles fuse with vesicles containing class II 4.Peptides bind class II molecules 5.MHC-peptide complex transported to cell surface
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Antigen processing and presentation by MHC class II molecules after
6.MHC class II molecules bind to invariant chain in the ER, preventing peptides from binding in the groove. 7.in endocytic (acidified endosome) pathway lysosomal enzymes degrade this leaving CLIP peptide associated with the binding groove.
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Antigen processing and presentation by MHC class II molecules after cont
8.Peptides from antigen displace CLIP when the bind. 9.HLA-DM, a class II-like molecule, is required for loading peptides into the groove
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MHC class 1 trigger:
cytotoxic T cells
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MHC class II trigger:
T helper cells eg macrophages, dendritic cells, B cells
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Other cards in this set

Card 2

Front

5 antibody classes

Back

IgM, IgA, IgD, IgG, IgE Constant region genes, will bind to different Fc receptors, class is determined by heavy chain (c region)

Card 3

Front

Homology regions of H and L chains

Back

Preview of the front of card 3

Card 4

Front

TCR (T-Cell receptor)

Back

Preview of the front of card 4

Card 5

Front

TCR structure

Back

Preview of the front of card 5
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