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5_generation_of_antigen_receptors.md

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The Generation of Lymphocyte Antigen Receptors

TCR genes are organized in a similar pattern and rearranged by the same enzymes as B cells

The variable domain for the alpha chain is formed from V and J regions. The beta chain is formed from V, D and J regions.

Rearrangement occurs in the thymus. The rearrangement process is the same (RSS regions are homologous and the recombinases, including RAGs, are the same). This means that diseases effecting chain diversity are the same for B and T cells.

T cell excision loop is the bit excised

Feature more P / N nucleotides

TCRs concentrate diversity in CDR3

This is because they bind to the MHC (in contrast to antibodies that bind to much broader range of antigens). CDR1/CDR2 are along the edges of contact surface and bind to the less variable MHC while CDR3 binds to the antigen

There are many more J genes than in immunoglobulin light chains, which directly impact diversity of CDR3.

gamma / delta chains admit similar structure

Delta chain genes live entirely between V_alpha and J_alpha locus

Delta chains can have two D domains which obviously increases combinatorial diversity but also increases P-N nucleotide insertion zones from one to three (V-D, D-D, D-J).

Different classes of immunoglobulins are distinguished by heavy chain structure

  • IgM (first to be expressed after B cell activation)
  • A, G, E, D

IgM + IgG activate C1 in the complement cascade

Constant regions have distinct functions

  • Fc receptor binding
    • IgG receptor macrophages / neutrophils
    • IgE receptor on mast cells, eosinophils
  • Complement activation (bind to C1q protein)
  • Active transport by engaging neonatal Fc receptor (FcRn)

IgM / IgD are expressed from the same pre-mRNA transcript

Constant genes lie in 200kb locus

IgM / IgD come from alternatively spliced trnascripts that have not udnergone calss switching.

It has been known for some time that IgM is expressed in immature and IgD in mature.

ZFP318 expression seems to induce the switch from M to M + D, but it is unclear why.

IgD marks B cell maturation

Transmembrane and secreted heavy chains are formed from alternative splicing

There are two polyadenylation site, before and after the hydrophobic transmembrane domains (M1 / M2)

Recall polyadenylation occurs before splicing! If we cleave at the polyadenylation site before M1 / M2, we get a secreted peptide. If we cleave afterwards, we splice out the hydrophillic domain, leaving M1/M2, and we get a membrane bound peptide.

Activated B cell heavy chains are generally modified to produce the secreted form

J chains help IgM and IgA bind to each other

IgM pentamers and IgA dimers are stabilized by an additional 15kD polypeptide chain called a J chain.

Repetitive epitopes are common antigens for multimer antibodies. The individual affinity in these cases is often lower, especially because eg. IgM is produced earlier in the affinity maturation process (?), but the avidity or sum of binding interactions is high because there are 5 or 6 antibodies.

Questions

  • Why do hairpins form with nicks in the RAG recombinase cutting