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¹ Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855
² Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD 20852
³ University of California, Los Angeles, Los Angeles, CA 90095
⁴ Translational Genomics, Gaithersburg, MD 20878
⁵ Ibaraki Prefectural Central Hospital, Ibaraki 310-0815, Japan
⁶ The Jackson Laboratory, Bar Harbor, ME 04609
⁷ Department of Immunology, Institute for Biological Sciences, George Washington University, Washington, DC 20037

Address correspondence to Wendy F. Davidson, Greenebaum Cancer Center and Dept. of Microbiology and Immunology, University of Maryland School of Medicine, 15601 Crabbs Branch Way, Rockville, MD 20855. Phone: (301) 517-0324; Fax: (301) 517-0344; email: wdavi002{at}umaryland.edu

Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms. B lymphomas occurring in Fasl mutant (gld) mice usually are immunoglobulin (Ig) isotype switched, secrete Ig, and are plasmacytoid in appearance but lack Myc translocations characteristic of other plasma cell (PC) neoplasms. Here, we explore the relationship between B cell autoreactivity and transformation and use gene expression profiling to further classify gld plasmacytoid lymphomas (PLs) and to identify genes of potential importance in transformation. We found that the majority of PLs derive from antigen-experienced autoreactive B cells producing antinuclear antibody or rheumatoid factor and exhibit the skewed Ig V gene repertoire and Ig gene rearrangement patterns associated with these specificities. Gene expression profiling revealed that both primary and transplanted PLs share a transcriptional profile that places them at an early stage in PC differentiation and distinguishes them from other B cell neoplasms. In addition, genes were identified whose altered expression might be relevant in lymphomagenesis. Our findings provide a strong case for targeted transformation of autoreactive B cells in gld mice and establish a valuable model for understanding the relationship between systemic autoimmunity and B cell neoplasia.

Key Words: autoimmunity • B cell lymphoma

Abbreviations used in this paper: ANA, antinuclear antibody; BCR, B cell receptor; BL, Burkitt lymphoma; BLL, Burkitt-like lymphoma; CBL, centroblastic; CDR, complementarity-determining region; CL, cardiolipin; dsDNA, double-stranded DNA; FBL, follicular B cell lymphoma; FWR, framework region; GC, germinal center; GL, germline; IBL, immunoblastic; MALT, mucosal-associated lymphoid tissue; MZL, splenic marginal zone lymphoma; PC, plasma cell; PCA, principal component analysis; PCT, plasmacytoma; PL, plasmacytoid lymphoma; PPC, phosphorylcholine; R mutation, replacement mutation; RF, rheumatoid factor; S mutation, silent mutation; SBL, small B cell lymphoma; SJL, SJL-ß2M^–/– lymphoma; ssDNA, single-stranded DNA.

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