Genesis of antinuclear antibody in NZB-W mice: role of genetic factors and of viral infections.

Antinuclear antibodies could be induced in young NZB/W mice long before the natural occurrence of such antibodies by immunization with heat denatured DNA coupled to methylated bovine serum albumin (DNA m BSA). While induction of antinuclear antibodies was possible in several strains of mice (NZB/W, A/J, DBA/2, CBA and AKR), NZB/W mice had by far the highest titre of antibody. A genetic determination of this immune hyperreactivity to DNA was suggested by study of the parental strains. The NZW mice which have a low incidence of spontaneously occurring antinuclear antibody made as much antinuclear antibody upon immunization with DNA m BSA as did the NZB/W mice, while NZB mice which develop naturally a moderate incidence of antinuclear antibody responded relatively poorly to immunization. It seemed possible that while the native hyperreactivity of NZB/W mice to DNA might be inherited from the NZW parent, the antigenic stimulus calling forth the anti-DNA response might be transmitted from the NZB parent. A possible source of this stimulus might be a viral infection such as that caused by the leukemia virus found in NZB mice which might liberate unusual amounts or kinds of host nuclear antigens or provide viral nucleic acid antigens. In support of this, induced neonatal infection of NZB/W mice with Polyoma virus markedly enhanced their antinuclear antibody response. Also, neonatal thymectomy of NZW mice which predisposes to reduced resistance to infection also enhanced antinuclear antibody formation. And finally, Statolon treatment designed to increase and maintain interferon levels in both normal and thymectomized NZW mice reduced antinuclear antibody formation.