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Tolerance to DNA in (NZB x NZW)F₁ Mice That Inherit an Anti-DNA V_H as a Conventional µ H Chain Transgene but Not as a V_H Knock-in Transgene¹

Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163

Lupus-prone (NZB x NZW)F₁ (BWF₁) mice were made transgenic (Tg) for an anti-DNA Ab inherited either as a conventional V_H3H9-µ H chain Tg (3H9-µ) with or without a conventional V8- Tg, or a V_H3H9 V_H knock-in Tg allele (3H9R) with or without a V4 V knock-in Tg allele (V4R). V_H3H9 yields an anti-DNA Ab with most L chains including an anti-ssDNA with the V8 Tg and an anti-dsDNA with the V4 Tg. BWF₁ mice that inherited the conventional 3H9-µ had normal serum IgM, little to none of which was encoded by 3H9-µ, and only a small percentage of those mice had serum anti-DNA, none of which was transgene encoded. B cells expressing the conventional 3H9-µ Tg were anergic. BWF₁ mice that inherited the knock-in 3H9R Tg allele also had normal serum IgM, one-half of which was encoded by 3H9R, and produced anti-DNA encoded by the Tg allele. Most B cells expressing the knock-in 3H9R Tg also had an anergic phenotype. The results indicate that autoimmune-prone BWF₁ mice initially develop effective B cell tolerance to DNA through anergy, and anergy was sustained in 3H9-µ Tg peripheral B cells but not in 3H9R Tg B cells. B cells expressing the 3H9R knock-in Tg allele were able to achieve an activation threshold that B cells expressing the 3H9-µ conventional Tg could not. The maintenance of B cell tolerance to DNA in autoimmune-prone BWF₁ mice appears to differ from both normal mice and autoimmune-prone MRL^lpr/lpr mice.