L12 and 13 Diversity in the Immune Response Flashcards
Hb
gene switching within a gene cluster during development
Immunoglobulin
rearrangements of contiguous genes/gene segments to create enormous diversity using mechanisms which contravene the “basic dogmas of genetics?
Antibody molecule structure
see onenote
- four polypeptide chains: 2 identical heavy chains and 2 identical light chains
- 2 antigen binding sites are identical: each formed by N-terminal region of light chain and N-terminal region of heavy chain
- hinge region formed by two heavy chains
Ig variable domain
see onenote
variable domain
- can be split into 3 regions of sequence variability - “complementary determining regions (CDRs)”
- 4 regions of relatively constant sequence termed the framework regions (FR)
Ig classess
see onenote
depends on aa sequence of the constant region of the heavy chain
5 classes
Three properties of antibodies
- vast diversity of Ab specificities
- variable region and a constant region in each chain
- existence of isotypes with the same antigenic specificity
Hypothesis regarding antibody variation
see onenote
- germ-line theory
- somatic-variation theory
- two gene model proposed by Dreyer and Bennett
Main stages in B-cell development
Development in bone marrow:
- stem cell
- pre-B cell
- immature naive B cell
circulation through peripheral lymphoid organs:
1. mature naive B cell
all stages occur independently of antigen
when activated by specific foreign antigen and helper T-cells in peripheral lymphoid organs, mature naive B cells proliferate and differentiate into effector or memory cells
Once B cells are activated
see onenote
effector cells produce and secrete antibodies with unique antigen-binding site, same as that of original membrane bound antibodies that served as antigen receptors
Clonal anergy
antigen may also silence lymphocyte either through apoptotic cell death or induction of refractory state known as clonal anergy
Clonal ignorance
if antigen conc. is very low or if affinity of receptor for antigen is low, lymphocyte mat remain unaffected by antigenic encounter
Chromosomal locations of Ig genes in human and mouse
see onenote
Organisation of Ig germ-line segments in mouse
see onenote
heavy chain families contain additional D for diversity
DNA is rearranged during B-cell development
see onenote
Mechanism of variable-region DNA rearrangement
see onenote
allelic exclusion, ensure that B cell possesses a single antigenic specificity
the allele is chosen randomly
Selection process
see onenote
evolution may tolerate a certain frequency of allelically included dual receptor cells, balancing autoimmune outcome with that of counteracting infection
Allelic exclusion
Allelic exclusion is a process by which only one allele of a gene is expressed while the other allele is silenced. For autosomal genes, diploid organisms inherit one copy from each parent.
In B lymphocytes, successful heavy chain gene rearrangement of the genetic material from one chromosome results in the shutting down of rearrangement of genetic material from the second chromosome. If no successful rearrangement occurs, rearrangement of genetic material on the second chromosome takes place. If no successful rearrangement occurs on either chromosome, the cell dies.
Gene rearrangement
see onenote slides
Junctional flexibilities
see onenote
gives additional variation
Hinge region
The hinge region is a flexible amino acid stretch in the central part of the heavy chains of the IgG and IgA immunoglobulin classes, which links these 2 chains by disulfide bonds. It is rich in cysteine and proline amino acids, extremely variable in amino acid sequence, and has no resemblance to any other immunoglobulin region
Putative recognition sequence for rearrangement of Ig and T-cell receptor genes
see onenote slides
12-23 rule
DNA cleavage by RAG protein
see onenote slides
VJD Recombination
see onenote slides
SCID
see onenote
Somatic hypermutation (SHM)
see onenote
SHM induces point mutations into V region antigen-binding pocket, creating Ig variants with enhanced affinity for particular Ag
Activation induced cytidine deaminase (AID) converts cytidine to uridine to initiate hypermutation process
Genetic processes used in generation of antibody diversity
see onenote
Four main mechanisms of antibody diversification
- combinatorial joining of gene segments
- junctional diversification during gene segment joining
- combinatorial joining of L and H chains
- somatic hypermutation
Genetic basis of sever combined immune deficiency (SCID)
see onenote
Most commonly due to adenosine deaminase (ADA) deficiency and purine nucleotide phosphorylase (PNP) deficiency - result in accumulation of nucleotide metabolites that are toxic to developing T cells, B cells also somewhat compromised in patients
