ACCELERATION OF LPR LYMPHOPROLIFERATIVE AND AUTOIMMUNE-DISEASE BY TRANSGENIC PROTEIN-KINASE CK2-ALPHA

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalit ies of apoptosis, lymphoproliferation, and a lupus-like autoimmune dis ease associated with the production of autoantibodies, Other than Fas pathway defects, little is known about molecular abnormalities that pr edispose to autoimmunity. Protein kinase CK2 (also termed casein kinas e II), a serine-threonine protein kinase whose targets include many cr itical regulators of cellular growth, is highly expressed in a lymphop roliferative disease of cattle and in many human cancers. Overexpressi on of the CK2 alpha catalytic subunit in lymphocytes of transgenic mic e leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Pas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2 alph a transgene, the lymphoproliferative process is dramatically exacerbat ed, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the un usual B220(+)CD4(-)CD8(-) T cells typically seen in MRL-lpr/lpr mice, not the B220(-)CD4(+)CD8(+) or B220(-)CD4(-)CD8(+) T cells typically s een in CK2 alpha transgenic lymphomas, The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplant able or immortal in cell culture. Thus, although the lpr lymphoprolife rative and autoimmune syndrome is potentiated by the presence of the C K2 alpha transgene, this combination of apoptotic and proliferative ab normalities appears to be insufficient to transform lymphoid cells.