CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Vol. 81, No. 2, November, pp. 145–152, 1996 Article No. 0170 Hyperproliferation of BXSB B Cells Is Linked to the Yaa Allele 1 LUCY E. DESJARDIN,EDWARD J. BUTFILOSKI,ERIC S. SOBEL, AND JOEL SCHIFFENBAUER 2 Department of Medicine, University of Florida College of Medicine, P.O. Box 100221, Gainesville, Florida 32610 ment of C57BL/6-lpr mice with anti-IgM antibody to Systemic lupus erythematosus is characterized by deplete B cells reduced lymphoproliferation and vascu- polyclonal B cell activation, the production of autoan- litis (10). In another murine lupus model, transfer of tibodies, and often by renal disease. Previous studies pre-B cells from (NZB/W)F 1 mice into SCID recipients demonstrated that unfractionated B cells from sev- led to hypergammaglobulinemia, autoantibody produc- eral strains of mice with lupus hyperproliferate in tion, and proteinuria secondary to glomerular deposits culture when stimulated with lipopolysaccharide of IgG (11). Recent studies have shown that in the case (LPS) or anti-IgM. We wished to further examine pro- of the MRL/lpr mouse, CD4 positive cells are responsi- liferation of resting B cells from the BXSB mouse ble for B cell activation, whereas, in the (NZB/W)F 1 , model of lupus and mice with the Yaa allele, when polyclonal B cell activation appears to be the result of activated with a number of stimuli. Our work demon- an intrinsic B cell defect (12). strates that: (1) resting B cells from mice containing The BXSB strain is a murine model that develops a the Yaa allele hyperproliferated compared to that lupus-like disease similar to that seen in humans. This seen with B cells from mice lacking the Yaa allele, (2) model is characterized by polyclonal B cell activation, this hyperproliferation occurred whether cells were stimulated with phorbol myristate acetate/iono- autoantibody production leading to glomerulonephritis, mycin, LPS, anti-IgM, or CD40L cross-linking, (3) this and mild lymphadenopathy. The male BXSB is the most hyperproliferation is specific to B and not T cells. severely affected individual in this strain, developing a Taken together these data suggest that one mecha- more rapid, severe disease and a shortened life span than nism by which the Yaa allele contributes to the accel- the female. Males develop 50% mortality by about 6 – 8 erated onset of lupus in BXSB male mice is through months as compared to females who develop 50% mortal- its influence on B cell activation.  1996 Academic Press, Inc. ity by about 20 months of age. This rapid onset of disease has been linked to a gene located on the Y chromosome called the Y-accelerating autoimmune gene (Yaa). The INTRODUCTION gene product and function are currently unknown. How- ever, it has been shown that the presence of Yaa on a Systemic lupus erythematosus (SLE) is an autoim- normal genetic background will not lead to disease, mune disorder characterized by the development of whereas this gene on the BXSB background will acceler- anti-nuclear antibodies followed by end organ damage ate the disease process (13, 14). Several lines of evidence (1, 2). In murine models of SLE, the earliest immuno- point to the B cell as the critical cell type in the develop- logic abnormality, occurring even before the onset of ment of disease in this strain. Smith et al. (15) demon- clinical symptoms, is polyclonal B cell activation (3, strated that neonatal thymectomy of BXSB led to an in- 4). The mechanisms for this activation are not well crease in autoantibody production, an increase in lymph- understood; however, there is information to suggest adenopathy (predominately B cell), and a worsening of that both T and B cell abnormalities contribute to poly- renal disease. This suggested that the thymus actually clonal B cell activation (5, 6). An intrinsic B cell defect acts to modulate or suppress the disease in this strain. has been demonstrated in the MRL/lpr murine lupus Recently, Merino et al. (16), using chimeric mice demon- model, such that B cells from the lpr mouse are neces- strated autoantibody production by Yaa positive B cells sary for autoantibody production (7 – 9). Also, treat- and suggested that the Yaa gene contributes to an intrin- sic abnormality in these B cells. 1 This work was supported by National Institute of Health grant Previous work has demonstrated that B cells from R01 AI-27324 to Joel Schiffenbauer, the Florida chapter of the Ar- thritis Foundation, and in part through funding by the Marcia Whit- BXSB male mice hyperresponded to stimulation with ney Schott Endowment to the University of Florida in support of anti-IgM or lipopolysaccharide (LPS) (17). However, research in rheumatic disease. these studies used unfractionated B cells, suggesting 2 To whom correspondence should be addressed at Department of that hyperproliferation may have been due to a higher Medicine, University of Florida College of Medicine, P.O. Box 100221, Gainesville, FL 32610. Fax: (352) 392-8483. percentage of in vivo activated B cells in the lupus 145 0090-1229/96 $18.00 Copyright  1996 by Academic Press, Inc. 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