The first IgM-expressing cell during B-cell development is called an immature B cell. Immature B cells express the µ protein together with a light chain, κ or λ. DNA recombination in the κ light-chain locus occurs in a similar manner as in the Ig heavy-chain locus (see Fig. 1B). There are no D segments in the light-chain loci, and therefore recombination involves only the joining of one V segment to one J segment, forming a VJ exon. This VJ exon remains separated from the C region by an intron, and this separation is retained in the primary RNA transcript. Splicing of the primary transcript results in the removal of the intron between the VJ and C exons and generates an mRNA that is translated to produce the κ or λ protein. In the λ locus, alternative RNA splicing may lead to the use of any one of the four functional Cλ exons, but there is no known biological difference between the resulting types of λ light chains. Production of a κ protein prevents λ rearrangement, and λ rearrangement occurs only if the κ rearrangements in both the inherited κ chain loci were nonproductive or, more commonly, if the rearranged κ light chain is deleted by receptor editing because it contributes to the formation of a self-reactive BCR, discussed later. As a result, an individual B-cell clone can express only one of the two types of light chains; this phenomenon is called light-chain isotype exclusion. As in the heavy-chain locus, a κ or λ gene is expressed from only one of the two parental chromosomes in any given B cell, and the other inherited locus is excluded. Also, as for heavy chains, if both loci for both κ and λ chains are nonfunctionally rearranged in a developing B cell, that cell fails to receive survival signals that are normally generated by the BCR and dies.
Fig1. Immunoglobulin (Ig) heavy- and light-chain gene recombination and expression. The sequence of DNA recombination and gene expression events is shown for the Ig µ heavy chain (A) and the Ig κ light chain (B). In the example shown in (A), the V region of the µ heavy chain is encoded by the rearranged V1, D2, and J1 gene segments. In the example shown in (B), the V region of the κ chain is encoded by the V2 and J1 gene segments. C, Constant; D, diversity; J, joining; L, leader; mRNA, messenger RNA; V, variable.
The assembled IgM molecules on immature B cells and in all later stages of development are expressed on the cell surface in association with Igα and Igβ, where they function as specific receptors for antigens. The presence of a complete BCR on the cell surface is essential for a developing B cell to survive. Survival signals are provided by the BCR alone in the absence of any triggering antigen and these are called tonic signals. Assembly of the complete BCR suffices to activate signaling molecules, including PI3-kinase, that keep the B cell alive. These signals also suppress RAG gene expression, thus preventing further Ig gene rearrangement. Immature B cells do not proliferate and differentiate in response to antigens. In fact, if they recognize antigens in the bone marrow with high avidity, which may occur if the B cells express receptors for multivalent self antigens that are present in the bone marrow, the B cells may undergo further light-chain gene rearrangements, called receptor editing, or cell death, as described later. These processes are important for the negative selection of strongly self-reactive B cells. Immature B cells that are not strongly self-reactive leave the bone marrow and complete their maturation in the spleen before migrating to other secondary lymphoid organs.
Distinct stages of maturing B cells that have emerged from the bone marrow and are found in the peripheral blood in humans are called transitional B cells. Transitional B cells that are self-reactive are inactivated or eliminated in the spleen and other secondary lymphoid organs. Transitional B cells that mature into follicular B cells express IgM and IgD on the surface and acquire the ability to recirculate and populate all secondary lymphoid organs. These follicular B cells home to lymphoid follicles in secondary lymphoid organs and are able to recognize and respond to foreign antigens. The development of a mature B cell from a lymphoid progenitor is estimated to take 2 to 3 days in humans.
