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 constitutive anti- DNA Ab secretion in nonautoimmune mice, two anti-dsDNA H/L chain transgene combinations were constructed using an IgG2b C region with secretory but no transmembrane domain exons. One H/L combination, consisting of the V(H)3H9 H and V(K)4 L chain transgenes, was chosen to recreate 3H9, an autoantibody that originally arose in an autoimmune MRL/lpr mouse; the other paired a higher affinity variant of V(H)3H9, 56R, with the same V(K)4 L chain. Elevated titers of IgG2b along with normal levels of other isotypes were observed in transgene-positive mice, indicating that constitutive transgene- directed Ab secretion was achieved. Sera and hybridoma supernatants from V(H)3H9γ transgene-positive animals exhibited binding to dsDNA, ssDNA, and cardiolipin. Mice expressing the 56Rγ H chain and the V(K)4 L chain showed enhanced binding. Expression of the transgenes correlated with signs of autoimmune disease, including prolonged plasma clotting in vitro, and reduced litter size. The results suggest that even a single autoreactive H chain that escapes tolerance may suffice to induce features of autoimmune disease.