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* Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease,
Department of Surgery, and
Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610; and
Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030
Chronic inflammation promotes the formation of ectopic lymphoid tissue morphologically resembling secondary lymphoid tissues, though it is unclear whether this is a location where Ag-specific immune responses develop or merely a site of lymphocyte accumulation. Ectopic lymphoid tissue formation is associated with many humoral autoimmune diseases, including lupus induced by tetramethylpecadentane in mice. We examined whether an immune response to 4-hydroxy-3-nitrophenyl acetyl-keyhole limpet hemocyanin (NP-KLH) and NP-OVA develops within ectopic lymphoid tissue ("lipogranulomas") induced by tetramethylpecadentane in C57BL/6 mice. Following primary immunization, NP-specific B cells bearing V186.2 and related heavy chains as well as 
-light chains accumulated within ectopic lymphoid tissue. The number of anti-NP-secreting B cells in the ectopic lymphoid tissue was greatly enhanced by immunization with NP-KLH. Remarkably, the H chain sequences isolated from individual lipogranulomas from these mice were diverse before immunization, whereas individual lipogranulomas from single immunized mice had unique oligo- or monoclonal populations of presumptive NP-specific B cells. H chain CDR sequences bore numerous replacement mutations, consistent with an Ag-driven and T cell-mediated response. In mice adoptively transferred with OT-II or DO11 T cells, there was a striking accumulation of OVA-specific T cells in lipogranulomas after s.c. immunization with NP-OVA. The selective colocalization of proliferating, Ag-specific T and B lymphocytes in lipogranulomas from tetramethylpecadentane-treated mice undergoing primary immunization implicates ectopic lymphoid tissue as a site where Ag-specific humoral immune responses can develop. This has implications for understanding the strong association of humoral autoimmunity with lymphoid neogenesis, which may be associated with deficient censoring of autoreactive cells.
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1 This work was supported by Research Grants R01-AR44731 and T32-AR007603 from the U.S. Public Health Service and by generous gifts from Lupus Link, Inc. (Daytona Beach, FL) and Lewis M. Schott to the University of Florida Center for Autoimmune Disease. D.C.N. is the recipient of an Arthritis Foundation Postdoctoral Fellowship. This work was supported with resources and the use of facilities at the Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL.
2 Address correspondence and reprint requests to Dr. Westley H. Reeves, Division of Rheumatology and Clinical Immunology, University of Florida, PO Box 100221, Gainesville, FL 32610. E-mail address: whreeves{at}ufl.edu
3 Abbreviations used in this paper: TMPD, tetramethylpentadecane; DC, dendritic cell; NP-KLH, 4-hydroxy-3-nitrophenyl acetyl-keyhole limpet hemocyanin.
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  D. C. Nacionales, J. S. Weinstein, X.-J. Yan, E. Albesiano, P. Y. Lee, K. M. Kelly-Scumpia, R. Lyons, M. Satoh, N. Chiorazzi, and W. H. Reeves B Cell Proliferation, Somatic Hypermutation, Class Switch Recombination, and Autoantibody Production in Ectopic Lymphoid Tissue in Murine Lupus J. Immunol., April 1, 2009; 182(7): 4226 - 4236. [Abstract] [Full Text] [PDF]
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