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G alpha q-containing G proteins regulate B cell selection and survival and are required to prevent B cell-dependent autoimmunity.

Research paper by Ravi S RS Misra, Guixiu G Shi, Miguel E ME Moreno-Garcia, Anil A Thankappan, Michael M Tighe, Betty B Mousseau, Kim K Kusser, Shirly S Becker-Herman, Kelly L KL Hudkins, Robert R Dunn, Marilyn R MR Kehry, Thi-Sau TS Migone, Ann A Marshak-Rothstein, Melvin M Simon, Troy D TD Randall, et al.

Indexed on: 14 Jul '10Published on: 14 Jul '10Published in: The Journal of experimental medicine



Abstract

Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the G(alphaq) subunit of trimeric G proteins (Gnaq(-/-) mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq(-/-) B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq(-/-) chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq(-/-) B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity.