Each antibody-producing B cell makes antibodies of unique specificity, reflecting a series of ordered gene rearrangements which must be successfully performed if the cell is to survive. A second selection process occurs during immune responses in which a new antibody repertoire is generated through somatic hypermutation. Here only mutants binding antigen with high affinity survive to become memory cells. Cells expressing autoreactive receptors are counter-selected at both stages. This stringent positive and negative selection allows the generation and diversification of cells while rigorously controlling their specificity.

Clonal selection and learning in the antibody system

Publisher Summary This chapter attempts an interdisciplinary perspective to consider that that both molecular biologists and immunologists have learned about the V (D) J recombination process, as instructed by cross-species (and cross-locus) comparisons. Immune recognition in vertebrates is based on the antigen receptors manufactured by B and T cells. The antigen-binding polypeptides within these multiunit conglomerates are encoded at the immunoglobulin (Ig) and T cell receptor (TCR) loci. Through the process called “V (D) J joining,” antigen receptor genes are constructed from multiply reiterated DNA segments in B and T cells. By this means, an enormous number of binding specificities can be generated in lymphoid cells from a relatively minimal amount of germline information. V (D) J rearrangement can culminate in the production of alternative or “nonstandard” junction products. Demonstrated nonstandard products can account for all theoretically possible signal end-to-coding end assortments. A picture emerges of V (D) J joining as an orderly process that is the sum of disorderly parts. Variability comes into play at a number of levels—namely, variable crossover sites, variable joining signals, variable strand exchange, variable degrees of reciprocity, and so forth. It is argued that the main tactic employed by other site-directed recombination systems is not in evidence for V (D) J joining.

The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses.

The two major classes of antigen receptors on murine B lymphocytes, mIgM and mIgD, are both contained in a complex with two additional molecules, Ig-alpha and Ig-beta, which permit signal transduction Accordingly, early biochemical events after antigen binding to either receptor are similar; biological effects, however, are different Here, we describe three newly discovered intracellular proteins of 32, 37 and 41 kDa molecular mass, that are non-covalently associated with mIgM, but not with mIgD These proteins coprecipitate with mIgM in Triton X-100 and Nonidet P-40, but not in digitonin lysates In addition, mIgM is to some extent associated with 29 and 31 kDa proteins that are predominantly associated with mIgD (see accompanying paper) Amino acid sequencing of p32 and p37 identified p32 as mouse prohibitin; this was corroborated by Western blot analysis with antibodies specific for rat prohibitin p37 is a newly discovered protein cDNA clones for both proteins were isolated and sequenced The deduced amino acid sequence of p32 is identical to that of rat prohibitin p37 is highly homologous to p32 Since prohibitin was identified as an inhibitor of cell proliferation, its association with mIgM, but not mIgD, could explain the different biological events elicited after engagement of each receptor

The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein.

Analysis of the B-cell progenitor compartment at the level of single cells

Developing B cells must pass a series of checkpoints that are regulated by membrane-bound Ig(mu) through the Igalpha-Igbeta signal transducers. To determine how Ig(mu) expression affects B cell development and Ab selection in humans we analyzed Ig gene rearrangements in pro-B cells from two patients who are unable to produce Ig(mu) proteins. We find that Ig(mu) expression does not affect V(H), D, or J(H) segment usage and is not required for human Igkappa and Iglambda recombination or expression. However, the heavy and light chains found in pro-B cells differed from those in peripheral B cells in that they showed unusually long CDR3s. In addition, the Igkappa repertoire in Ig(mu)-deficient pro-B cells was skewed to downstream Jkappas and upstream Vkappas, consistent with persistent secondary V(D)J rearrangements. Thus, Ig(mu) expression is not required for secondary V(D)J recombination in pro-B cells. However, B cell receptor expression shapes the Ab repertoire in humans and is essential for selection against Ab's with long CDR3s.

/pdf/immunoglobulin-heavy-chain-expression-shapes-the-b-cell-4yckuoeqx2.pdf

Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development

During B cell differentiation rearrangement of immunoglobulin (Ig) genes is partially regulated by the Ig proteins. Rearrangement of heavy (H) chain genes is inhibited, whilst that of light (L) chain genes is induced by the membrane form of the mu H chain. In order to analyse additional structural requirements of mu induced L chain gene rearrangement we transfected wild-type mu and mutant mu constructs lacking functional exons encoding the first or second constant domains into Abelson murine leukemia virus (AMuLV) transformed pre-B cells. All mu chains are expressed on the surface of the pre-B cell and all associate with omega and iota, two proteins forming a surrogate light chain, necessary for mu membrane expression. Nevertheless, only wild-type mu and not the mutant mu proteins promote L gene rearrangement. A heterodimer of proteins with Mr of 33 kd and 36 kd was found associated with wild-type but not with the mutant mu proteins. Continuous presence of mu is required for L chain gene recombination since loss of mu stopped and readdition of mu started L gene rearrangement. We propose that the protein complex composed of mu and the 33 kd/36 kd protein heterodimer is responsible for the activation of the L chain gene locus and its rearrangement.

Molecular requirements for the mu-induced light chain gene rearrangement in pre-B cells.

The ordered recombination of the immunoglobulin (Ig) heavy (H) and light (L) chain variable (V) region gene segments facilitates the analysis of early B-cell development. In the bone marrow the Ig VH gene elements are joined in two steps: first a diversity (D) segment recombines to a joining (JH) segment giving rise to a DJH element to which a VH segment is recombined completing the VDJH-V-region gene. Only at this stage the VL-region gene is assembled by joining a VL and JL element. The early B-cell differentiation can therefore be easily followed by monitoring the rearrangement status of the H and L chain genes. Indeed, the analysis of Abelson Murine Leukemia Virus (Abl-MuLV) transformed pre-B-cell lines indicate that rearrangement proceeds step by step through the alleles, thus rarily rearranging two alleles at a time (Alt et al. 1984; Reth et al. 1986). Taking into account only one VH and VL allele at least four stages (Fig. 1, stages 2–5) can be discriminated; considering both alleles, a B-cell can maximally run through seven distinct stages (not shown).

Regulation of Immunoglobulin Gene Rearrangement

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Molecular requirements for the mu-induced light chain gene rearrangement in pre-B cells.

Regulation of Immunoglobulin Gene Rearrangement