IMMUNOBIOLOGY Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy

gene is silenced in tumor cells from differ-ent human B-cell malignancies as op-posed to their normal counterparts. It was hypothesized that this silencing allows neoplastic B cells to escape the control exerted by IL-12 on their growth. The aim of this study was to investigate whether targeted inactivation of the Il12rb2 gene in mice resulted into increased suscepti-bility to spontaneous tumor formation and immunopathology. Il12rb2 gene– deficient animals developed in the first year of life immune-complex mesangial glomerulonephritis with serum anti-nuclear antibodies. In older animals, mul-tiorgan lymphoid infiltrates with features of vasculitis and Sjögren syndrome were detected in association with systemic B-and T-cell activation. In half of aged ani-mals, lymph node plasmacytoma or lung carcinoma was observed. A mechanism for spontaneous development of autoim-mune pathology and B-cell tumors is sug-gested by a strong IL-6 up-regulation detected in splenocytes and lymphoid infiltrates associated with oligoclonal B-cell expansion. The emergence of lung tumors may likely be attributed to an interferon- (IFN-) deficiency secondary to lack of IL-12 signaling. The develop-ment of autoimmunity, lymphoprolifera-tion, and B-cell tumors in Il12rb2 knock-out (KO) mice suggests that IL-12 functions physiologically to restrain aber-rant B-cell activation. (Blood. 2005;106