OF the various classes of antibodies that B lymphocytes can produce, class M (IgM) is the first to be expressed on the membrane of the developing cells. Pre-B cells, the precursors of B-lymphocytes, produce the heavy chain of IgM (μ chain), but not light chains1. Recent data suggest that pre-B cells express μ chains on the membrane together with the 'surrogate' light chains λ5 and VpreB (refs 2–7). This complex could control pre-B-cell differentiation, in particular the rearrangement of the light-chain genes8. We have now assessed the importance of the membrane form of the μ chain in B-cell development by generating mice lacking this chain. We disrupted one of the membrane exons of the gene encoding the μ-chain constant region by gene targeting9 in mouse embryonic stem cells10. From these cells we derived mice heterozygous or homozygous for the mutation. B-cell development in the heterozygous mice seemed to be normal, but in homozygous animals B cells were absent, their development already being arrested at the stage of pre-B-cell maturation.

A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene

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.

A critical role of λ5 protein in B cell development

Recent studies on the structure of the B cell antigen receptor demonstrate that the membrane-bound and antigen-binding immunoglobulin molecules are noncovalently associated with a heterodimer of two novel transmembrane proteins. The B cell antigen receptor is thus a multicomponent receptor complex whose structural features are similar to those of the T cell antigen receptor complex. Cross-linking of the B cell antigen receptor results in rapid tyrosine phosphorylation of substrate proteins. This suggests that the B cell receptor belongs to a subgroup of the tyrosine kinase receptor family with a noncovalently associated src-like tyrosine kinase.

Antigen Receptors on B Lymphocytes

During B cell development V kappa gene rearrangement seems to occur only in mu-positive pre-B cells. To study the role of the mu chain in the activation of the Ig kappa locus, we introduced expression vectors carrying different forms of the mu gene into null pre-B cells. The activation of the Ig kappa locus followed the expression of the membrane form (micron) of the mu chain. The expression of the secreted form (microS) did not result in the activation of the Ig kappa locus. We further show that both forms of the mu chain differ in their intracellular transport in pre-B cells.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1987.tb02649.x

Activation of V kappa gene rearrangement in pre-B cells follows the expression of membrane-bound immunoglobulin heavy chains.

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Activation of V kappa gene rearrangement in pre-B cells follows the expression of membrane-bound immunoglobulin heavy chains.