Antigen receptor on lymphocytes Flashcards
What is the composition of the BCR?
our polypeptides, two identical light chains and 2 identical heavy chains, connected by disulphide bonds
What are the two types of light chains?
Lambda and Kappa
What is the valency of the BCR?
2
What is the composition of the TCR?
two polypeptides, also disulphide linked and spanning the membrane.
What is the valency of the TCR?
1
What are the two types of TCR?
alpha/beta or gamma/delta heterodimers
What are the 2 fundamental differences between the TCR and the BCR?
- T cells do not secrete TCR while B cells secrete immunoglobulin molecules by deleting the
transmembrane-spanning exon during alternative splicing of the primary RNA transcript - The BCR is specific for native or intact antigen, but the TCR is not. Instead, antigen must be presented by self MHC molecules to the TCR
What are 2 other differences between the BCR and the TCR
- The BCR variable region undergoes hypermutation during affinity maturation while the TCR variable regions do not hypermutate
- The constant regions of the BCR heavy chain can be replaced during class switching while the equivalent does not occur with the TCR
What is a similarity between the TCR and the BCR
both receptors associate with additional polypeptides that don’t bind antigen but transmit a signal
- Ig alpha and beta for the BCR
- CD3 for the TCR
What are the 2 theories explaining the variable amino terminus on the light chain but the constant carboxy terminus
- Germ line theory
2. Somatic variation theory
What does germ line theory propose?
Different genes for each immunoglobulin
-this would take up a huge portion (15%) of our genome
What does somatic variation theory propose?
The genome contains a relatively small number of Ig genes from which a larger repertoire arises by recombination or mutation events
What did Dreyer and Bennet propose in 1965?
wo genes encode a single immunoglobulin light or heavy chain, and that a recombination event explained their contributing to a single polypeptide
Also that there were a larger number of variable genes than constant region genes
What did Tonegawa and Hozumi prove in 1976
Showed direct evidence that seperate genes encode the V and C regions of immunoglobulins
What are the 3 types of gene segment regions?
(V)ariable, (D)iversity, (J)oining
Where is the D region present?
Only in the heavy chain DNA and only in one of the heavy chains
What is the order of recombination events?
D to J rearrangement followed by a V to D rearrangement
What is the splice site it in each segment called?
The coding joint
What is the RSS
recombination specific sequence
What are the two forms of RSS and what is the general composition?
The two forms are based on the size of the variable spacer
-one is 12 bp the other is 23 bp
both forms contain conserved PALINDROMIC heptamer and nonamer sequences separated
by variable sequences
What is the relevance of the variable spacer lengths?
may related to the number of bases in a turn of supercoiled DNA, where 12 bp is a single turn while 23 bases encompass two turns
What multiprotein complex is responsible for recombinations?
the V(D)J recombinase
What are the two lymphoid cell specific molecules in the V(D)J recombinase?
RAG1 and RAG2
how do the RSS elements impact the order and process of recombination?
A 12 bp RSS matches with a 23 bp RSS to identify a site suitable for recombination
What are the 5 steps of Variable region recombination?
- RAGs bind to the RSS and catalyze synapse formation - forms a hairpin coding end and blunt signal end
- Opening of hairpin loop by Artemis yields 3 possible options
- P nucleotide additions results in a short palindrome - ** in heavy chain VD and DJ joint only there is exonuclease trimming at either side of the joint
- N nucleotide additions by terminal deoxynucleotide transferase (TdT)
- Ligation of free ends to seal coding joint by DNA ligase IV and NHEJ proteins
What are 5 mechanisms that contribute to antibody diversity?
- Multiple gene segments
- permutations of V to D to J - P nucleotide addition
- Exonuclease trimming (at 3’ end)
- Non templated N nucleotide additions
- Combinatorial diversity
- 2 chains combining into one antigen binding site
How does polyadenylation allow for simultaneous expression of IgM and IgD?
polyadenylation signals flag splicing points in the mRNA product of the mu and delta heavy chains
What is somatic hypermutation? when does it occur? Where does it occur?
Somatic hypermutation occurs in the complementarity determining regions (CDR) of the variable region DNA.
After the BCRs bind antigen, slight alterations are made in the V region to improve affinity of the immunoglobulin for the antigen
What is affinity maturation?
the net increase in Ig affinity within a B cell population
What enzyme is responsible for somatic hypermutation?
AID (activation induced cytosine deaminase)
Class switch recombination is also known as?
Isotype class switching
What are switch regions?
Highly repetitive DNA stretches
What enzyme is used for class switch recombination?
AID (activation induced cytosine deaminase)
Describe the process of class switch recombination
- AID makes double stranded break in S regions upstream and downstream of segment to be removed
- Switch regions are joined and intervening DNA removed
Where is there NOT a switch region present?
between the mu and delta regions
What class switch does IL-4 induce?
to IgG1 and IgE
-has to go through IgG1 to get to IgE
What class switch does IL-5 induce?
to IgA
What class switch does TGFß induce?
to IgA and IgG2
What class switch does INF gamma induce?
to IgG3 and IgG2a
What are 6 similarities between TCR and BCR gene rearrangement
- Multiple gene segments for each of V, (D), and J
- ß and ∂ have D regions like the heavy chains of BCR
- Like IgH, ß and ∂ chains pair with chains without D regions (alpha and gamma)
- Order of recombination is D to J and then V to D
- N and P nucleotide additions occur in the coding joint
- 2 polypeptides combine their V regions to form the antigen binding site
What is a fundamental difference between TCR and BCR gene rearrangement
TCR gene segments have RSSs but alternate arrangement of the 12 bp and 23 bp variable sequences allows for recombination between D regions
How does alternate joining of D region segments affect the coding joint of delta chains?
Allows multiple D regions to be included in the coding joint
Do TCR segments undergo somatic hypermutation?
nope
Name the 5 somatic immunoglobulin deficiencies
- X-linked agammaglobunlinemia
(Bruton’s hypogammaglobulinemia) - Hyper IgM syndrome
- Common variable immunodeficiency (CVIDs)
- Hyper IgE
- Selective IgA deficiency
X-linked agammaglobunlinemia
(Bruton’s hypogammaglobulinemia) causes:
No peripheral B cells
- B cells arrested at pro-B stage
Extremely low IgG
No other classes of Ig
Hyper IgM syndrome causes:
Deficiency in IgG, IgA, and IgE
Increased IgM
What is hyper IgM caused by?
T cell defect which prevents B cells from receiving a class switch signal
What causes X-linked agammaglobunlinemia
Bruton’s hypogammaglobulinemia
Defect in Bruton’s TK = B cells arrested at pro-B stage
Common variable immunodeficiency (CVIDs) cause:
low # of antibody producing cells and antibody
B cells fail to mature into plasma cells
What causes hyper IgE and what is the result?
Multisystem disorder with high IgE due to mutates STAT3 resulting from abnormal Th activity
What is selective IgA deficiency ?
IgA+ cells cannot differentiate into plasma cells
