Altered response to and production of TGF-beta by B cells from autoimmune NZB mice.
New Zealand Black (NZB) mice spontaneously develop immune dysfunction manifested as autoimmune hemolytic anemia and systemic lupus erythematosus. In later life, a subset of these mice develop clonal CD5+ B cell tumors analogous to human chronic lymphocytic leukemia (CLL). NZB disease is marked by B cell hyperactivity characterized by spontaneous immunoglobulin secretion and proliferation. Elimination of autoreactive lymphocytes by apoptosis is a vital mechanism to prevent expansion of self-reactive lymphocyte population. TGF-beta appears to be an important factor in normal and abnormal immune regulation and this cytokine may play a role in the development of chronic human B cell tumors. We asked whether the response to or production of TGF-beta by NZB B cells was aberrant and could contribute to disease development. In this study, we demonstrated that the apoptotic response to TGF-beta was increased in B cells from NZB mice compared to B cells from normal BALB/c mice. The increased apoptosis was related to endogenous activation and was possibly mediated through increased expression of the TGF-beta Type II receptor. Despite functional differences between CD5-negative B cells and CD5-positive B cells, TGF-beta induced apoptosis in both populations to a similar extent. NZB B cells also secrete increased active TGF-beta compared to BALB/c B cells. We suggest that the aberrant secretion of active TGF-beta and the increased response to the apoptotic effects of TGF-beta by NZB B cells may play a role in the disease process of these mice, perhaps attempting to limit the autoimmune phenomena, but possibly also contributing to generalized immunosuppression. We also suggest that the CD5(+) tumors in the NZB mouse may not be a fully appropriate model of human CLL, since CLL B cells are abnormally resistant to the apoptotic effects of TGF-beta.
Douglas
R S
RS
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082, USA.
Woo
E Y
EY
Capocasale
R J
RJ
Tarshis
A D
AD
Nowell
P C
PC
Moore
J S
JS
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D018956:CD5 Antigens / Q000096:biosynthesis / Q000502:physiology; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*
D018956:CD5 Antigens; D008070:Lipopolysaccharides; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II