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 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 CK2alpha 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 CK2alpha 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 CK2a 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 CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.
Rifkin
I R
IR
Department of Medicine, Boston University Medical Center, MA 02118, USA.
Channavajhala
P L
PL
Kiefer
H L
HL
Carmack
A J
AJ
Landesman-Bollag
E
E
Beaudette
B C
BC
Jersky
B
B
Salant
D J
DJ
Ju
S T
ST
Marshak-Rothstein
A
A
Seldin
D C
DC
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D047390:Casein Kinase II; D005786:Gene Expression Regulation / Q000276:immunology; D006579:Heterozygote; D006720:Homozygote; D017493:Leukocyte Common Antigens / Q000032:analysis; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology*; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019076:Transgenes / Q000276:immunology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D017493:Leukocyte Common Antigens