A "trans" perspective on the control of immunoglobulin c gene expression.
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Biomedical subjects
Publications and source records attributed to D Holmberg.
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Lectin- and antigen-induced proliferation of murine T cells consists of two major events, namely, a rapid induction of susceptibility to growth factors and a later-occurring, accessory cell-dependent production of T cell growth factors (TCGF). The mechanism by which interferon (IFN) inhibits T cell responses was studied accordingly. A decrease of Con A-induced proliferation was observed in the presence of increasing amounts of IFN. The reduced proliferative response in such cultures was found to be due to an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, the results show that IFN did not inhibit the early events in T cell triggering, because the acquisition of responsiveness of resting T cells to TCGF was unaltered in the presence of IFN, nor did it interfere with production of TCGF. In contrast, IFN was found to interfere with the TCGF-dependent T cell blast growth. Cytofluorometric analysis of the proliferative phase revealed that IFN exerts its effect on T cells, which have entered the proliferative cycle, by a postmitotic accumulation in G0/G1, thus reducing the proliferating population. The results demonstrate that IFN primarily affects the later phase of proliferative activity after T cell triggering, leaving the helper cell functions untouched.
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Hybridoma collections from spleen or peritoneal cells of newborn or adult individuals were screened by RNA hybridization for expression of the VH11-gene family using a V-region probe VCP12, which encodes anti-BrMRBC antibodies. No VH11 expression was observed in hybridomas derived from newborn spleen cells in either BALB/c, NZB or (CBA/N x BALB/c) F1 mice (0/93). Adult NZB and BALB/c spleen cell collections contained only one hybridoma expressing VH11 (1/242). Interestingly, however, the VH11-positive hybridoma showed no anti-BrMRBC reactivity, while one anti-BrMRBC clone in the same collection expressed a Q52 VH gene. In contrast, hybridomas derived from peritoneal cells showed an absolute correlation between expression of VH11 genes and anti-BrMRBC reactivity (15/32). The high expression in the peritoneal cavity of such cells is likely the result of local positive selection.
The principles of lymphocyte activation were summarized for all three sets of immunocompetent cells: B cells, cytotoxic cells and helper T lymphocytes. They were then used to derive the basic mechanisms and specificities which drive internal activity in the normal immune system and which select available antibody repertoires. It was postulated that "natural antibodies" are induced by "natural helper cells" and are selected on the basis of their idiotypic profiles, which are complementary to available T-helper-cell repertoires. "Natural idiotypes" would then carry idiotopes similar to MHC epitopes, the predominant germ-line specificity of T-cell repertoires.
Monoclonal antibodies to Ia.7 were used, in parallel with other antibodies specific for "major" and "private" idiotopes, to define idiotypic profiles in the primary anti-trinitrophenyl plaque forming cell (PFC) response of BALB/c and C57BL/6 mice. A considerable fraction (25%) of BALB/c but not C57BL/6 PFC were inhibited by anti-Ia.7 antibodies, which failed to inhibit PFC with other paratopic specificities. These results suggest idiotypic mimicry between "major" antibody clonotypes and MHC determinants which might play a role in the selection of antibody repertoires.
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Hybridoma collections were produced from lipopolysaccharide-stimulated adult BALB/c spleen cells, small resting spleen B cells and large activated spleen lymphocytes. The hybridomas were examined for production of immunoglobulins and of antibodies directed against a panel of self (actin, myosin, tubulin, DNA) and non-self antigens (myoglobin, spectrin, trinitrobenzene). From the 345 hybridomas secreting immunoglobulin, 68% did not react with any antigen of the panel, 17% reacted with only one, 5.5% with 2 and 7.9% with 3 or more. Apparently, each of the monoclonal multispecific antibodies exhibited a pattern of reactivity which was quite unique. There were no apparent differences in antibody reactivities between self and non-self antigens; moreover, with the exception of DNA, no differences were noted among the 3 different hybridoma collections.