J. Exp. Med., Volume 186, Number 12, December 15, 1997 2005-2012

Self-reactive B Cells Are Not Eliminated or Inactivated by Autoantigen Expressed on Thyroid Epithelial Cells

By Srinivas Akkaraju, Karen Canaan, and Christopher C. Goodnow

From the Program in Immunology, Department of Microbiology and Immunology, and The Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305-5428

Graves' Disease results from the production of autoantibodies against receptors for thyroid stimulating hormone (TSH) on thyroid epithelial cells, and represents the prototype for numerous autoimmune diseases caused by autoantibodies that bind to organ-specific cell membrane antigens. To study how humoral tolerance is normally maintained to organ-specific membrane antigens, transgenic mice were generated selectively expressing membrane-bound hen egg lysozyme (mHEL) on the thyroid epithelium. In contrast to the deletion of autoreactive B cells triggered by systemic mHEL (Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow. 1991. Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells. These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms. The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.

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