Lymphocyte-specific TRAF transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer

摘要

Tumor necrosis factor (TNF) receptor-associated factor (TRAF) regulates both innate and adaptive immunity by modulating signaling by Toll-like receptors (TLR) and TNF receptors. TRAF was recently identified as a tumor suppressor in human multiple myeloma, suggesting a prominent role in plasma cell homeosta-sis. We have generated transgenic mice expressing human TRAF in lymphocytes. These mice are normal at birth, but they develop over time plasmacytosisand hypergammaglobulinemia, as well as systemic inflammation and tertiary lym-phoid organ formation. The analysis of the humoral responses of the TRAF mice demonstrated increased responses to T-dependent and T-independent antigens with increased production of antigen-specific immunoglobulin Gs (IgGs) compared with wild-type mice. Furthermore, TLR-mediated IgG production is also increased in TRAF B cells. In addition, TRAF mice develop autoimmunity andare predisposed to cancer, particularly squamous cell carcinomas of the tongue (50% incidence) and salivary gland tumors. In summary, TRAF renders B cells hyperreactive to antigens and TLR agonists, promoting autoimmunity, inflammation, and cancer, hereby providing a new model for studying de novo carcinogen-esis promoted by B cell-initiated chronic inflammation.