Evidence for selective transformation of autoreactive immature plasma cells in mice deficient in Fasl.

Document Type

Article

Publication Date

2004

Keywords

Antibody-Specificity, Autoimmunity, B-Lymphocytes, Cell-Transformation-Neoplastic, Gene-Expression-Profiling, Immunoglobulin-Heavy-Chains, Immunoglobulin-Variable-Region, Lymphoma-B-Cell, Membrane-Glycoproteins, Mice, Mice-Inbred-BALB-C, Mice-Inbred-C3H, Plasma-Cells

First Page

1467

Last Page

1478

JAX Source

J Exp Med 2004 Dec; 200(11):1467-78.

Abstract

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.

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