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Differential Activation of Anti-Erythrocyte and Anti-DNA Autoreactive B Lymphocytes by the Yaa Mutation¹

Thomas Moll^*, Eduardo Martinez-Soria^*, Marie-Laure Santiago-Raber^*, Hirofumi Amano^*, Maria Pihlgren-Bosch^*, Dragan Marinkovic and Shozo Izui^2,*

^* Department of Pathology and Immunology, Centre Médical Universitaire, Geneva, Switzerland; and Department of Physiological Chemistry, Ulm University, Ulm, Germany

An as-yet-unidentified mutation, Y-linked autoimmune acceleration (Yaa), is responsible for the accelerated development of lupus-like autoimmune syndrome in mice. In view of a possible role for Yaa as a positive regulator of BCR signaling, we have explored whether the expression of the Yaa mutation affects the development and activation of transgenic autoreactive B cells expressing either 4C8 IgM anti-RBC or Sp6 IgM anti-DNA. In this study, we show that the expression of the Yaa mutation induced a lethal form of autoimmune hemolytic anemia in 4C8 transgenic C57BL/6 mice, likely as a result of activation of 4C8 anti-RBC autoreactive B cells early in life. This was further supported, although indirectly, by increased T cell-independent IgM production in spleens of nontransgenic C57BL/6 mice bearing the Yaa mutation. In contrast, Yaa failed to induce activation of Sp6 anti-DNA autoreactive B cells, consistent with a lack of increased IgM anti-DNA production in nontransgenic C57BL/6 Yaa mice. Our results suggest that Yaa can activate autoreactive B cells in a BCR-dependent manner, related to differences in the form and nature of autoantigens.

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