CONSTITUTIVE SECRETION OF TRANSGENE-ENCODED IGG2B AUTOANTIBODIES LEADS TO SYMPTOMS OF AUTOIMMUNE-DISEASE

Anti-DNA Ab are strictly regulated, except in autoimmunity, where they are expressed and may contribute to pathogenicity. To study constitut ive anti-DNA Ab secretion in nonautoimmune mice, two anti-dsDNA H/L ch ain transgene combinations were constructed using an IgG2b C region wi th secretory but no transmembrane domain exons. One H/L combination, c onsisting of the V(H)3H9 H and V kappa 4 L chain transgenes, was chose n to recreate 3H9, an autoantibody that originally arose in an autoimm une MRL/lpr mouse; the other paired a higher affinity variant of V(H)3 H9, 56R, with the same V kappa 4 L chain. Elevated titers of IgG2b alo ng with normal levels of other isotypes were observed in transgene-pos itive mice, indicating that constitutive transgene-directed Ab secreti on was achieved. Sera and hybridoma supernatants from V(H)3H9 gamma tr ansgene-positive animals exhibited binding to dsDNA, ssDNA, and cardio lipin. Mice expressing the 56R gamma H chain and the V kappa 4 L chain showed enhanced binding. Expression of the transgenes correlated with signs of autoimmune disease, including prolonged plasma clotting in v itro, and reduced litter size. The results suggest that even a single autoreactive H chain that escapes tolerance may suffice to induce feat ures of autoimmune disease.