Positive skin tests and specific IgE to food or inhalant allergens were related to the clinical expression of different atopic diseases. The combination of AD and food allergy at 12 months reflected the strongest risk factor in this high risk cohort for the development of asthma-like disease at 24 months of age.

van Ommen R. Vredendaal AECM, Savelkoul HFJ. Prolonged In Vivo IL-4 Treatment Inhibits Antigen-Specific IgGi and IgE Formation. Scand J Immunol I994;40:l-9 IL-4 is obligatory for primary IgE responses, whereas primary IgGi and secondary IgE responses are partially IL-4 independent. To investigate the effect of IL-4 on the antigen-specific memory formation for these isotypes, BALB/c mice were treated after primary TNP-K.LH immunization with recombinant IL-4 for a period of 4 months. This prolonged presence of a high IL-4 level resulted in increased serum levels of total IgG, and IgE, whereas total IgG2^ did not change. The expression of CD23, but not I-A*", increased on the splenic B cells. IL-4 treatment did not affect the IL-4 production by Con A stimulated spleen cells, whereas it did decrease the IFN-7 production. In the same mice the TNP-specific IgGi and IgE serum levels, however, were decreased. Similar results were found when the antigen was continuously present during the IL-4 treatment. Furthermore, it was shown that IL-4 decreased the formation of IgGj and IgE memory cells. These results point to different effects of IL-4 in regulating antigen-specific and bystander responses.R. van Ommen.

The crucial role of interleukin (IL)‐4 in the induction of murine IgG1 and IgE responses, which are coupled through the process of sequential isotype switching, has been well documented. Whereas IL‐4 is obligatory for the induction of IgE responses, it enhances IgG1 responses. In this study, using neutralizing antibodies, we provide evidence that, besides IL‐4, also IL‐6 is required for obtaining peak IgG1 responses. The mRNA levels of these two cytokines are coordinately expressed in the spleen of mice immunized with trinitrophenol‐keyhole limpet hemocyanin (TNP‐KLH). No IL‐6 requirement was observed for peak IgE responses. The IL‐6 dependence of IgG1 responses was found for both antigenspecific and polyclonal responses. Moreover, it was noted using TNP‐KLH and goat anti‐mouse (GAM) IgD as antigen that polyclonal IgG1 responses are more dependent on IL‐6 than antigen‐specific responses. In vitro experiments revealed that exogenous IL‐6 neither enhanced nor inhibited the IgG1 and IgE production by naive B cells, suggesting that IL‐6 did not interfere with the IL‐4‐induced isotype switch potential. Primary and memory IgG1 responses were both similarly dependent on IL‐6. These observations point to a role of IL‐6 in the terminal differentation of B cells switched to IgG1. Neutralization of IL‐6 did not inhibit either antigen‐specific or polyclonal IgE responses. Therefore, it was concluded that IL‐6 is not involved in the terminal differentiation of B cells switched to IgE. These findings thus provide a distinct role for IL‐6, besides IL‐4, in regulating murine IgG1 responses. The formation of IgE, however, is completely dependent on IL‐4 alone.

Van Ommen R, Vredendaal AECM, Savelkoul HFJ. Secondary IgE Responses In Vivo are Predominantly Generated Via 7i€-Double Positive B Cells. Scand J Immunol 1993;40:491-50I We have recently developed a model in which mice were treated with IL-4 after primary immunization, resulting in elevated tolal serum IgGi and IgE levels, but decreased antigen-specific levels and memory formation for these isotypes. In this report, we describe that these effects of IL-4 are mediated at the B cell and not the T-cell level. Major changes occurred in the 7iC-double positive B-cell population which is increased as a result of IL-4 treatment. Moreover, it is shown that 7ie-double positive B cells can develop in vitro out of 71-positive primed B cells and that these double positive cells can differentiate into IgGr and IgE-secreting cells. The existence of 7ie-double positive memory B cells can explain the differences in cytokine dependence of TNP-specific memory IgGj and IgE responses found after adoptively transferring primed spleen cells into irradiated naive recipients. Whereas the IL-4 independent TNP-specific memory IgGi responses could be blocked efficiently by neutralizing IL-5 and IL-6, TNP-specific memory IgE responses were virtually not susceptible to such treatment. These IgE responses were also not susceptible to IFN-7, used in doses that could inhibit the primary IgE response. Inhibition of the TNP-specific memory IgG 1 response by neutralizing IL-5 and IL-6 is accompanied by a 10-fold increase of the IL-4 independent TNP-specific IgE memory response. These data indicate that secondary IgE responses primarily result from B cells that are either switched lo IgG|, or are double positive for IgG| and IgE, thereby suggesting a minor role for e-single positive B cells in secondary IgE responses.

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