Adaptive immunity 2 Flashcards
What are ITAM molecules? Why are they important?
Immunoreceptor tyrosine-based activation motif
- Important for signal transduction in imune cells. Tyrosine residue tails become phosphorylated following interaction of receptor and ligand
Which IRREVERSIBLE changes in Ig genes occur during a B cells life?
- V region assembly from gene fragments
- Generation of junctional diversity
- Assembly of transcriptional controlling elements
- Somatic hypermutation
- Isotype switch
Which REVERSIBLE changes in Ig genes occur during a B cells life?
- Transcription activated with coexpression of surface IgM and IgD
- Synthesis changes from membrane Ig to secreted Ab
Which loci are present in B and T cells. How are new gene combinations made from germline sequences?
B cell: delta and kappa light chain loci, heavy chain locus
T cell: alpha and beta chain loci
New . gene sequences are produced through V(D)J recombination
- light chain rearrangement is a single step VJ recombination
- heavy chain rearrangement involves a DJ recombination event followed by a VDJ rearrangement
How is the germline configuration arranged
(V)ariable segments
(D)iversity segments
(J)oining segments
Constant region
State the 4 main stages in VDJ recombination?
What does this produce?
- D to J recombination
- V to DJ recombination
- Transcription and splicing
- Translation and assembly
Many possible combinations from 44 v segments, 27 d segments and 6 j segments
Where and how is rearrangement faciltitated?
- Rearrangement occurs between specific sites on the DNA called recombination signal sequences (RSSs)
- Catalysed by 2x recombination activating genes: RAG1 and RAG2. These genes encode enzymes
Outline in detail the stages of VDJ recombination
- Ig genes are composed of seperated sections of genes that become a single functional gene in somatic recombination
- Heavy chain by VDJ, light chain by VJ
- RSSs are adjacent to segments of genes that can possibly be put together
- RAGs bind to RSS motifs randomly at each gene locus. They cleave the DNA exactly at the junction of the gene segment and its adjoining RSS motif leading to ‘hair pin; of DNA at end of gene segment and ‘double stranded brakes’ at the end of RSSmotifs
- Additionally proteins are incorporated into large complex with RAG proteins
- RSS joined forming signal point creating a closed circuit of DNA that has no further role
- ‘Hair pins’ are cleaved and and Tdt is cruited and addds N-nucleotides to end of the DNA strand. Other enzymes in complex ligate together segments by pairing of strands
How are the ‘hair pins’ made in VDJ recombination?
What happens to them at the end?
By RAG nicking 1 strand of DNA which generates palindromic P nucleotides
- Unpaired nucleotides removed by exonuclease and gaps filled by DNA synthesis
Which process is involved in the following steps:
- Germline DNA –> rearranged DNA
- Rearranged DNA –> Primary RNA transcript
- Primary RNA transcript –> mRNA
- mRNA –> polypeptide chain
- Somatic recombination
- Transcription
- Splicing
- Translation
How does maturity maturation occur
- Germinal centre inside activated b cell: AID induces point mutations at a rate a million> normal (HYPERMUTATION)
- DNA is replicated and B cells divide and produce antibodys with a range of affinities to specific antigen
- Germinal centre also produces dendritic cells with antigens on surface. The ABs with the greatest affinities will bind more and spread across surface of FDC (COMPETITIVE SELECTION)
- Centrocytes contract taking with them the antigens bound, interanlise and present them to t cells which return chemical signals required for survival. Low affinity centrocytes undergo apoptosis.
- Only high affinity centrocytes survive and replicate, with each generation, affinity increases
Where does hypermutation occur the most in maturity maturation?
- Somatic hypermutation targets the rearranged gene segments encoding V region
What is class switch recombination?
Same receptor, different constant region
- allows the cell to perform a range of effector functions
- alternative splicing results in IgM and IgD
- constant regions are spliced out using switch regions located upstream of each constant region with the 1st cut occuring just before Gu region (IgM) and the 2nd cut determined by cytokines secreted by follicular Th cells
Follicular T helper cells cause secretion of cytokines that influence the 2nd cut in class switch recombination.
Which cytokines are released from TH1, TH2 and Treg?
TH1–> IFN-y –> IgG3
TH2–> IL4 –> IgG1, IgG4, IgE
–> IL5
Treg –> IL10, TGF-Beta
Which enzyme is critical to class switch recombination?
AID
- The first targeted switch region is always the Su switch region. The partner switch region determined by cytokines.
