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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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Submitted May 23, 2005
Accepted July 28, 2005

Lack of IL-12R{beta}2 signalling predisposes to spontaneous autoimmunity and malignancy

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

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

* Corresponding author; email: irmaairoldi{at}ospedale-gaslini.ge.it.

The IL-12 receptor (IL-12R){beta}2 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. Aim of this study was to investigate whether targeted inactivation of the IL-12R{beta}2 gene in mice resulted into increased susceptibility to spontaneous tumor formation and immunopathology. IL-12R{beta}2 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 Sjogren syndrome were detected in association with systemic B and T cell activation. In a half of aged animals, lymph node plasmacytoma or lung carcinoma were 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 to oligoclonal B cell expansion. The emergence of lung tumors may likely be attributed to an IFN-{gamma} deficiency secondary to lack of IL-12 signalling. The development of autoimmunity, lymphoproliferation and B cell tumors in IL-12R{beta}2 KO mice suggests that IL-12 functions physiologically to restrain aberrant B cell activation.


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