Isotype commitment in the in vivo immune responses. I. Antigen-dependent specific and polyclonal plaque-forming cell responses by B lymphocytes induced to extensive proliferation.

Abstract

The control of immunoglobulin (Ig) isotype production has a wide range of implications, ranging from the regulation of gene expression in eucaryotic cells to clinical applications such as allergy and "facilitation." In spite of the rapidly accumulated knowledge (1-3) on the structure and organization of Ig C-genes and flanking "switch regions," there is at present no general agreement on the rules determining the selective expression of one or another isotype in specific antibody responses. A model based on the order of structural C-genes along the direction of transcription (4) and on the repeated finding that all C-genes 5' to those being transcribed in secretory cells are deleted from the expressed chromosome (5-8) has recently received much attention. This model (9, 10) assumes no specific control of switch recombination, rather, it postulates randomness in these genetic events and, consequently, dictates, that cells in a clonal progeny will successively delete C-genes and express those located most 3' in the chromosome. Because, in accordance with current molecular models (1) and as shown by direct evidence (11), switch recombination requires DNA replication, it follows that such a model predicts a direct correlation between the number of mitoses undergone by a competent cell and the number of switch recombination events that have taken place in its DNA. This model explains, for example, the high frequency of IgA-secreting cells in some anatomic sites or biological situations by postulating a long process of replication in these cells before being induced to terminal maturation (10).We have now directly tested these assumptions by making use of a serial transfer system, originally described by M611er (12) and later used to analyze clonal stability of V-gene expression (13). It is particularly important to point out that, in this transfer system, the progenies of immunocompetent B cells are analyzed for their whole life span because the experiment is continued until clonal senescence limits further proliferation. It appeared that the analysis of the isotypes produced by antibodysecreting cells along their whole life-span would provide direct indications as to the validity of that random recombination hypothesis. The results obtained do not support that model.

A “Trans” Perspective on the Control of Immunoglobulin C Gene Expression

“…accumulate with maintained proliferation. Rather, a loss of both IgM-and IgAsecreting PFC took place, resulting in consequent accumulation of antibodies in the various IgG isotypes (Bjorklund & Coutinho 1982a.…”

Ontogenic development of “natural” and induced plaque‐forming cell isotypes in normal mice

“…This notion is also compatible with the late appearance of IgG3 PFC at the time of weaning. The late appearance of IgA PFC, a strongly T cell-dependent and strictly regulated isotype [27], could reflect the requirements for external stimulation 1191 and Th cell maturity. Alternatively, T cells ensuring the early appearance of IgG2, and IgGl PFC could be "class restricted" and unable to bring about IgA production.…”

Effect of anti‐γ3 antibodies on immunoglobulin isotype expression in lipopolysaccharide‐stimulated cultures of mouse spleen cells

“…Although the use of helper T cells rather than mitogens and a longer study interval may more nearly approximate normal switching conditions, recent in vivo experiments also provide support for a direct rather than sequential switching mechanism. In these studies, clones allowed to develop to senescence by continued passage through murine spleens, did not exhibit increased frequencies of cells expressing y and a isotypes, as would be expected if switching occurred sequentially [38].…”