Evidence for selective transformation of autoreactive immature plasma cells in mice deficient in Fasl.
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.
Zhang
Jian Qiao
JQ
Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Okumura
Cheryl
C
McCarty
Thomas
T
Shin
Min Sun
MS
Mukhopadhyay
Partha
P
Hori
Mitsuo
M
Torrey
Ted A
TA
Naghashfar
Zohreh
Z
Zhou
Jeff X
JX
Lee
Chang Hoon
CH
Roopenian
Derry C
DC
Morse
Herbert C
HC
Davidson
Wendy F
WF
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*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins