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 VH3H9 H and V kappa 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 VH3H9, 56R, with the same V kappa 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 VH3H9 gamma transgene-positive animals exhibited binding to dsDNA, ssDNA, and cardiolipin. 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 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.
Radic
M Z
MZ
Department of Microbiology and Immunology, Medical College of Pennsylvania, Philadelphia 19129, USA.
Ibrahim
S M
SM
Rauch
J
J
Camper
S A
SA
Weigert
M
M
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D006825:Hybridomas; D007074:Immunoglobulin G / Q000097:blood* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G