title: Evidence for selective transformation of autoreactive immature plasma cells in mice deficient in Fasl.
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.
authors.affiliation: Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
authors.forename: Jian Qiao
authors.initials: JQ
authors.lastname: Zhang
authors.forename: Cheryl
authors.initials: C
authors.lastname: Okumura
authors.forename: Thomas
authors.initials: T
authors.lastname: McCarty
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Shin
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Hori
authors.forename: Ted A
authors.initials: TA
authors.lastname: Torrey
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Naghashfar
authors.forename: Jeff X
authors.initials: JX
authors.lastname: Zhou
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Wendy F
authors.initials: WF
authors.lastname: Davidson
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D002471:Cell Transformation, Neoplastic; D053222:Fas Ligand Protein; D020869:Gene Expression Profiling; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010950:Plasma Cells / Q000473:pathology*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins