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Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen¹

Department of Microbiology and Immunology and The Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19017

The peripheral B cell compartment contains high levels of "polyreactivity" including autospecificities. We have described a pathway that certain autoreactive B cells may take in gaining stable access to the foreign Ag-responsive peripheral compartment. This pathway was revealed in mice expressing a targeted Ig H chain transgene encoding BCRs with "multireactivity" for the hapten arsonate and DNA-based autoantigens. B cells expressing such BCRs develop to mature follicular phenotype and locale, and are not short-lived. These B cells express very low levels of BCR, indicating that they are not "ignorant" of self Ag, but do not display features of anergy in in vitro assays. Nonetheless, a variety of states of lymphocyte anergy has been described, and some may only be manifested in vivo. As such, we analyzed the ability of these B cells to participate in a T cell-dependent immune response to arsonate in vivo. These B cells mount an early primary response similar to control B cells, including homing to follicles, migration to the T-B interface, and induction of costimulatory molecules, proliferation, differentiation to AFCs, class switching, and entry into GCs and somatic hypermutation. Nonetheless, these B cells display reduced participation in the latter stages of the GC response and in the anamnestic AFC response. In total, these data suggest that while the autoreactivity of this type of B cell does not result in anergy, the ability of such B cells to participate in a cross-reactive immune response to foreign Ag is compromised.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (AI038965) and the Commonwealth of Pennsylvania (ME-03-184) to T.M.

² Address correspondence and reprint requests to Dr. Tim Manser, Department of Microbiology and Immunology and The Kimmel Cancer Center, Jefferson Medical College, Bluemle Life Sciences Building, 708, 233 South 10th Street, Philadelphia, PA 19017-5541. E-mail address: manser{at}mail.jci.tju.edu

³ Abbreviations used in this paper: BM, bone marrow; Ars, arsonate; ANA, anti-nuclear Ag; FO, follicular; AFC, Ab-forming cell; KLH, keyhole limpet hemocyanin; PNA, peanut lectin agglutinin; SA, streptavidin; GC, germinal center; LN, lymph node; FDC, follicular dendritic cell; FR, framework; sIgM, surface IgM; TD, T cell dependent.

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