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 Blood, 1 December 2005, Vol. 106, No. 12, pp. 3846-3853.
Prepublished online as a Blood First Edition Paper on August 4, 2005; DOI 10.1182/blood-2005-05-2034.

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IMMUNOBIOLOGY

Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy

Irma Airoldi, Emma Di Carlo, Claudia Cocco, Carlo Sorrentino, Franco Fais, Michele Cilli, Tommaso D'Antuono, Mario Paolo Colombo, and Vito Pistoia

From the Laboratory of Oncology, G. Gaslini Institute, Genova, Italy; the Department of Oncology and Neurosciences, and Center of Excellence on Aging (CeSI), G. D'Annunzio University, Chieti, Italy; the Human Anatomy Section, Department of Experimental Medicine, University of Genova, Genova, Italy; the Animal Model Facility, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; and the Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto per lo Studio e la Cura dei Tumori, Milan, Italy.

The interleukin-12 receptor {beta}2 (Il12rb2) gene is silenced in tumor cells from different human B-cell malignancies as opposed 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 susceptibility to spontaneous tumor formation and immunopathology. Il12rb2 gene–deficient animals developed in the first year of life immune-complex mesangial glomerulonephritis with serum antinuclear antibodies. In older animals, multiorgan lymphoid infiltrates with features of vasculitis and Sjögren syndrome were detected in association with systemic B- and T-cell activation. In half of aged animals, lymph node plasmacytoma or lung carcinoma was observed. A mechanism for spontaneous development of autoimmune pathology and B-cell tumors is suggested 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-{gamma} (IFN-{gamma}) deficiency secondary to lack of IL-12 signaling. The development of autoimmunity, lymphoproliferation, and B-cell tumors in Il12rb2 knockout (KO) mice suggests that IL-12 functions physiologically to restrain aberrant B-cell activation.


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