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B Cell Proliferation, Somatic Hypermutation, Class Switch Recombination, and Autoantibody Production in Ectopic Lymphoid Tissue in Murine Lupus¹

Dina C. Nacionales^2,*, Jason S. Weinstein^2,*, Xiao-Jie Yan, Emilia Albesiano, Pui Y. Lee^*, Kindra M. Kelly-Scumpia^*, Robert Lyons^*, Minoru Satoh^*, Nicholas Chiorazzi and Westley H. Reeves^3,*

^* Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease, University of Florida, Gainesville, FL 32610; and The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030

Intraperitoneal exposure of nonautoimmune mice to 2,6,10,14-tetramethylpentadecane (TMPD) causes lupus and the formation of ectopic lymphoid tissue. Although associated with humoral autoimmunity, it is not known whether Ab responses develop within ectopic lymphoid tissue or if B cells only secondarily migrate there. We show that ectopic lymphoid tissue induced by TMPD not only resembles secondary lymphoid tissue morphologically, but it also displays characteristics of germinal center reactions. Proliferating T and B lymphocytes were found within ectopic lymphoid tissue, activation-induced cytidine deaminase was expressed, and class-switched B cells were present. The presence of circular DNA intermediates, a hallmark of active class switch recombination, suggested that class switching occurs within the ectopic lymphoid tissue. Individual collections of ectopic lymphoid tissue ("lipogranulomas") from the same mouse contained different B cell repertoires, consistent with local germinal center-like reactions. Class-switched anti-RNP autoantibody-producing cells were also found in the lipogranulomas. Somatic hypermutation in the lipogranulomas was T cell-dependent, as was the production of isotype-switched anti-Sm/RNP autoantibodies. Thus, ectopic lymphoid tissue induced by TMPD recapitulates many of the functional characteristics of secondary lymphoid tissue and contains autoantibody-secreting cells, which may escape from normal censoring mechanisms in this location.

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 Research Grants R01-AR44731 and T32-007603 from the U.S. Public Health Service and by generous gifts from Lupus Link, Inc. and Mr. Lewis M. Schott to the University of Florida Center for Autoimmune Disease. D.C.N. is the recipient of an Arthritis Foundation Postdoctoral Fellowship. The work was supported with resources and the use of facilities at the Malcolm Randall Veterans Affairs Medical Center (Gainesville, FL).

² D.C.N. and J.S.W. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Westley H. Reeves, Division of Rheumatology and Clinical Immunology, University of Florida, P.O. Box 100221, Gainesville, FL 32610. E-mail address: whreeves{at}ufl.edu

⁴ Abbreviations used in this paper: SHM, somatic hypermutation; AID, activation-induced cytidine deaminase; CDR, complementarity determining region; CSR, class switch recombination; FDC, follicular dendritic cell; TMPD, 2,6,10,14-tetramethylpentadecane.