The actual existence of IgM‐induced antibody‐dependent cell‐mediated cytolysis (ADCC) is still a matter of debate. In the preseni study four IgM anti‐sheep erythrocyte (SRBC) and one IgM anti‐trinitrophenyl (TNP) monoclonal hybridomas have been studied for their ability to produce antibodies with ADCC‐inducing capacity. All five hybridomas were shown to release into the culture supernatant antibodies with specific ADCC‐inducing capacity. Compared with IgG‐induced ADCC, however, much higher concentrations of IgM antibodies were necessary. To exclude the possibility that low numbers of IgG antibodies could be present in the culture supernatams, derived from hypothetical switching of hybridoma cells from IgM to IgG, several sets of controls were performed. Positioning of the inducing antibody with regard to size agreed with it being of IgM nature. Passage through protein A (PA)‐Sepharose columns removed no ADCC activity from the IgM hybridoma supernatants while completely retaining the activity from IgG hybridoma supernatant. In contrast, after passage over a concanavalin A (Con A)‐Sepharose column, ADCC activity from IgM hybridoma supernatants was recovered in the bound and eluted fraction. Addition of aggregated human gammaglobulin (aggHGG) caused a complete inhibition of IgG‐induced ADCC but did not significantly inhibit IgM‐induced ADCC. Finally, trypsin treatment of the effector cells removed their ability to function in IgM ADCC, but IgG ADCC was left largely intact. We conclude from the above findings that IgM antibodies can function in ADCC in the absence of IgG antibodies, although their efficiency on a molar basis is significantly inferior to that of IgG antibodies.
Transgenic mouse models have demonstrated clonal deletion as well as clonal anergy of monospecific, high-avidity autoreactive B cell. The function and fate of naturally activated B cells, many of them displaying degenerate specificity including autoreactivity, are still a matter of debate. The question was pursued in Sp6-transgenic mice. Sp6, a monoclonal anti-2,4,6-trinitrophenyl (TNP) IgM has been shown to react with a variety of self antigens. Responsiveness of antibody-secreting B cells was followed throughout postnatal development of Sp6-transgenic mice and was related to the availability of antigen- and idiotype-specific help. Thymus as well as spleen cells of transgenic mice contained a significantly higher number of TNP-specific B cell than non-transgenic controls. In contrast to control mice, the number of TNP-specific B cells remained unchanged or decreased in thymus and spleen of transgenic mice after antigenic stimulation with TNP in T-dependent (TD) and T-independent (TI) form. Since the relative frequency of transgenic B cells was in particular diminished after repeated stimulation with TD antigen, it was examined whether limited responsiveness was linked to the available repertoire of helper T cells. Early after birth of transgenic individuals, thymic as well as splenic T cells which proliferated in response to TNP and Sp6 and provided help for B cells were found to be significantly augmented. Their number decreased rapidly during postnatal maturation and Th cells did not expand after antigenic stimulation. There was no indication that in the naive host transgenic B cells would suppress proliferation of TNP- and Sp6-specific T cells, but they did so after antigenic stimulation. Furthermore, and in contrast to B cells of non-transgenic mice, transgenic B cells were unable to present nominal antigen in a stimulatory way. The decrease in the number of B cells after antigenic stimulation indicated that autoreactive transgenic B cells may be subject to (functional) deletion under selected circumstances. In addition, idiotype- and antigen-specific help was impaired in Sp6-transgenic mice and this clearly was due to interactions with B cells expressing the immunoglobulin transgene.
Splice variants of the glycoprotein CD44 (CD44v) that confer metastatic behavior to noninvasively growing rat tumor cells are transiently expressed on lymphocytes during activation. A mAb directed against an epitope encoded by CD44 exon v6 blocks both metastasis formations and lymphocyte activation, implicating CD44v in normal immune function. To explore the nature of this function of CD44v, transgenic mice were generated that constitutively express rat CD44v4-v7 on thymocytes and peripheral T cells. The number of lymphocytes as well as the distribution of lymphocyte subpopulations were similar in nontransgenic and rat CD44v4-v7 transgenic mice. T cells of the transgenic mice, however, responded faster to activating stimuli, particularly during primary stimulations with T cell mitogens and T-dependent Ags in vivo and in vitro. This accelerated response depended on the expression of the transgene product, since a rat CD44v6-specific Ab reverted the response profiles of the transgenic mice to those of nontransgenic mice. Since the transgene gained in vivo and in vitro functional activity only upon antigenic stimulation, it is likely that CD44 variant isoforms are involved in the process of signal transduction during lymphocyte activation.
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