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This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Henry, R. A. Articles by Thomas, J. W. PubMed Articles by Henry, R. A. Articles by Thomas, J. W.

Tolerance induction for immature anti-insulin B cells involves impaired calcium mobilization

¹ Microbiology and Immunology, Vanderbilt University, T-3219 MCN, 1161 21st Ave. South, Nashville, TN, 37232, ² Biology, University of Puerto Rico-Mayagüez, PO Box 9000, Mayagüez, Puerto Rico, ³ Medicine, Division of Rheumatology, Vanderbilt University, MCN T3219, 1161 21st Ave. South, Nashville, TN, 37232

Abstract

B cells that recognize small self proteins are presumed to escape tolerance and reside in a non-tolerant state of "clonal ignorance". In contrast to this assumption, B cells that harbor anti-insulin Ig transgenes (125Tg) are not clonally ignorant; rather they are maintained in a novel anergic state. Anti-insulin B cells do not proliferate to BCR cross-linking and show impaired Ca²⁺ and NFAT responses, but unlike the anti-HEL/HEL model, they are not developmentally arrested and show intact tyrosine phosphorylation. To understand the genesis of this novel form of anergy, IL-7 was used to generate naïve anti-insulin B cells from bone marrow cultures. Naïve anti-insulin B cells mobilize Ca²⁺ upon acute antigen exposure. However, continuous antigen exposure decreased surface IgM expression and lead to impaired Ca²⁺ mobilization following BCR-dependent and BCR-independent stimuli. These data show that anti-insulin B cells are not clonally ignorant; rather, continuous BCR signals initiate tolerance early in development and maintain anergy in the mature repertoire. This highlights the therapeutic potential of targeting developing B cells in the bone marrow for functional silencing.

Support provided by 5T32 HL069765, 5T32 GM08554, AI051448, and JDRF.

This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Henry, R. A. Articles by Thomas, J. W. PubMed Articles by Henry, R. A. Articles by Thomas, J. W.