HIGH COPY NUMBER I-AB TRANSGENES INDUCE PRODUCTION OF IGE THROUGH AN INTERLEUKIN 4-DEPENDENT MECHANISM

To better understand the role of class II major histocompatibility com plex molecules in both normal and autoimmune responses, we have produc ed a series of I-Ab transgenic mice, One of these transgenic construct s, designated NOD,PD, has the sequence of the NOD beta chain (A beta(g 7)) except at positions 56 and 57, where Pro-Asp replaces His-Ser. Sev eral NOD,PD transgenic lines have been produced. One line of these mic e carried a very high number of copies (>50) of the NOD,PD transgene, As has been described in other mice carrying high copy numbers of I-Ab transgenes, B-cell development was abnormal, The steady state numbers of mature B, cells (IgM(+)/IgD(hi)) in the periphery were greatly red uced in transgenic mice compared to nontransgenic littermates. Surpris ingly, rather than being accompanied by a generalized hypogammaglobuli nemia, this B-cell deficiency was accompanied by elevated concentratio ns of IgG1 and IgE in the serum, Conversely, the levels of IgG2a were reduced in transgenic mice compared to nontransgenic littermates. Beca use this isotype pattern was characteristic of interleukin (IL)-4-indu ced class-switching, we then investigated the role of IL-4 in causing the observed phenotype, We crossed the high copy number transgenic mic e with an IL-4-deficient strain of mice, As expected, the elevated lev els of IgE in high copy number transgenic mice were eliminated when th e IL-4 gene was inactivated, However, the reduction in the number of B cells was not ameliorated, These data indicate that the primary defec t caused by the transgene was to reduce the number of B cells in these mice, This reduction was accompanied by a secondary increase in IL-4 production, which drove the remaining B cells toward the production of IgG1 and IgE.