Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy.
The interleukin-12 receptor beta2 (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.
Airoldi
Irma
I
Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16148 Genova, Italy. laboncologia@ospedale-gaslini.ge.it
Di Carlo
Emma
E
Cocco
Claudia
C
Sorrentino
Carlo
C
Fais
Franco
F
Cilli
Michele
M
D'Antuono
Tommaso
T
Colombo
Mario Paolo
MP
Colombo
Mario Paulo
MP
Pistoia
Vito
V
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D004198:Disease Susceptibility / Q000276:immunology; D005434:Flow Cytometry; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology / Q000503:physiopathology; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000503:physiopathology; D018123:Receptors, Interleukin / Q000172:deficiency* / Q000235:genetics; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000276:immunology*
C508439:IL12RB2 protein, human; C508443:Il12rb2 protein, mouse; D015850:Interleukin-6; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12