TY - JOUR
T1 - Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy
AU - Airoldi, Irma
AU - Di Carlo, Emma
AU - Cocco, Claudia
AU - Sorrentino, Carlo
AU - Fais, Franco
AU - Cilli, Michele
AU - D'Antuono, Tommaso
AU - Colombo, Mario Paulo
AU - Pistoia, Vito
PY - 2005/12/1
Y1 - 2005/12/1
N2 - The interleukin-12 receptor β2 (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-γ (IFN-γ) 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.
AB - The interleukin-12 receptor β2 (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-γ (IFN-γ) 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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U2 - 10.1182/blood-2005-05-2034
DO - 10.1182/blood-2005-05-2034
M3 - Article
C2 - 16081683
AN - SCOPUS:28444443017
VL - 106
SP - 3846
EP - 3853
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -