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1
Departments of
*
Medicine,
Microbiology, and
Pathology, Boston University Medical Center, Boston, MA 02118; and
§
Department of Mathematics, Sonoma State University, Rohnert Park, CA 94928
MRL-lpr/lpr mice have a Fas receptor mutation that
leads to abnormalities of apoptosis, lymphoproliferation, and a
lupus-like autoimmune disease associated with the production of
autoantibodies. Other than Fas pathway defects, little is known about
molecular abnormalities that predispose to autoimmunity. Protein kinase
CK2 (also termed casein kinase II), a serine-threonine protein kinase
whose targets include many critical regulators of cellular growth, is
highly expressed in a lymphoproliferative disease of cattle and in many
human cancers. Overexpression of the CK2
catalytic subunit in
lymphocytes of transgenic mice leads to T cell lymphoma. We
hypothesized that CK2 dysregulation and Fas mutation might
cooperatively augment lymphocyte proliferation and transformation. We
find that in MRL-lpr/lpr mice bearing the CK2 transgene,
the lymphoproliferative process is dramatically exacerbated, 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 unusual
B220+CD4-CD8- T cells typically
seen in MRL-lpr/lpr mice, not the
B220-CD4+CD8+ or
B220-CD4-CD8+ T cells typically
seen in CK2 transgenic lymphomas. The T cells do not fulfill the
criteria for transformation, as they are polyclonal and not
transplantable or immortal in cell culture. Thus, although the
lpr lymphoproliferative and autoimmune syndrome is
potentiated by the presence of the CK2 transgene, this combination
of apoptotic and proliferative abnormalities appears to be insufficient
to transform lymphoid cells.
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