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Exclusion of Natural Autoantibody-Producing B Cells from IgG Memory B Cell Compartment during T Cell-Dependent Immune Responses¹

Agata Matejuk^*, Michael Beardall, Yang Xu, Qi Tian, Daniel Phillips, Boris Alabyev^*, Kaiissar Mannoor^* and Ching Chen^2,*

^* Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Pathology, Oregon Health & Science University, Portland, OR 97239

In healthy individuals, a substantial proportion of circulating Abs exhibit polyreactivity and self-reactivity. These Abs are referred to as natural autoantibodies (NAAs). As part of the innate immunity, NAAs play an important role in eliminating pathogens. However, inherent to their poly/autoreactivity is the potential for NAAs to differentiate to high-affinity autoantibodies during an immune response. We recently generated site-directed transgenic mice that express a prototypic NAA, ppc1-5, which binds a variety of self- and non-self-Ags including DNA and phosphocholine. We have shown previously that B cells expressing the ppc1-5 NAA are positively selected during their primary development. In this study, we demonstrate that following immunization with the T-dependent Ag, phosphocholine conjugated to keyhole limpet hemocyanin, ppc1-5 NAA B cells mounted a quick IgM Ab response and entered germinal centers, but they failed to differentiate to IgG-producing cells during late primary and memory responses. Hybridomas and cDNA clones derived from the immunized mice included many IgM NAA-producing cells, but IgG NAA clones were extremely rare. Instead, many of the IgG B cells replaced their IgH transgene with an endogenous V_H gene and produced non-autoreactive Abs. These results indicate that although NAA B cells are positively selected in the preimmune repertoire and can participate in early IgM Ab response, they are subjected to regulatory mechanisms that prevent them from developing to high-affinity IgG autoantibody production. This would explain, at least in part, why NAAs do not cause autoimmunity in most individuals.

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 to C.C. from the National Institutes of Health (AI061487), The Pew Charitable Trust, and the Cancer Research Institute.

² Address correspondence and reprint requests to Dr. Ching Chen, Department of Pathology, University of Maryland School of Medicine, MSTF 7-34B, Baltimore, MD 21201. E-mail address: qchen{at}som.umaryland.edu

³ Abbreviations used in this paper: NAA, natural autoantibody; sd-tg, site-directed transgene; PC, phosphocholine; KLH, keyhole limpet hemocyanin; SHM, somatic hypermutation; CSR, class switch recombination; EF, extrafollicular; AFC, Ab-forming cell; LM-PCR, ligation-mediated PCR; TD, T dependent; AP, alkaline phosphatase; GC, germinal center; FWR, framework region.