Regulation of IgA B-cell development in the mucosal immune system

The factors regulating the differentiation of IgA B cells have been of great interest to mucosal immunologists as well as those generally interested in B-cell differentiation. It is now clear that such differentiation involves two major steps: first, isotype switch differentiation of surface IgM-bearing B cells into surface IgA-bearing B cells and, second, terminal differentiation of IgA B cells into IgA-producing plasma cells. Both of these steps are regulated processes that are under the influence of various cytokines and lymphokines. This paper presents data that define the role of cytokines and lymphokines in the regulation of IgA B-cell differentiation. A model of IgA B-cell differentiation is described in which the first step involves activation of the C alpha gene, while the latter is in germline configuration and thus the induction of surface IgM-bearing B cells partially committed to IgA expression. This occurs in Peyer's patches as a result of as yet incompletely defined signals from patch “switch cells.” The second step consists of conversion of the partially committed B cells to fully IgA-committed B cells and thus the completion of isotype switch differentiation. This step may be under the control of interleukin-4 (IL-4). The last step of the model involves the activation of IgA B cells (by antigen or mitogen) followed by the appearance on the cell surface of receptors which allow the cell to interact with cytokines or lymphokines (particularly IL-5). Such interaction results in cells capable of secreting IgA. Evidence is presented that an important adjuvant for mucosal immune responses, cholera toxin, acts to augment IgA production by promoting IgA B-cell differentiation at the isotype switch step.