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Genetic Studies in NZB Mice

III. Induced anti-Nucleic Acid Antibody Production

From the Laboratory of Experimental Pathology, Section on Cytogenetics and Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014

Abstract

These studies were performed to test the previously advanced hypothesis that the antibody response to ssDNA is controlled by an X-linked immune response gene. The antibody response to single-stranded DNA (ssDNA) complexed to MBSA was studied in NZB, DBA/2, F₁ reciprocal hybrids, and backcross mice. We found that the anti-ssDNA response was not linked to genes located on the X chromosome, but rather that anti-ssDNA production was regulated by sex hormones. Reciprocal F₁ hybrid males with either an NZB or a DBA/2 X chromosome were low responders; however, either castration or castration plus estrogen implants significantly increased the amount of antibody produced. Testosterone implants were immunosuppressive in both females and males. Backcross studies suggested that the ability to respond to ssDNA is inherited as an autosomal dominant trait that is further regulated by sex hormones.

Control studies were performed in hybrids of the CBA/N strain, which has a well established X-linked defect in the ability to respond to a variety of thymic independent antigens including polyriboinosinic·polyribocytidylic acid (rI·rC). F₁ hybrid males that received the CBA/N X chromosome were low-responders to rI·rC despite the hormonal status of the animal. On the other hand, females were high responders to rI·rC but testosterone implants in females decreased the amount of antibody produced.

These studies indicate that it is possible to separate sex hormone effects from X-linked genetic effects on immune responses. We found that the response to ssDNA is controlled by sex hormones but not an X-linked immune response gene.