casein-kinase-ii and Autoimmune-Diseases

Autoimmunity directed against antigens of immune privileged sites, which are hidden from the immune system by blood-organ-barriers, is difficult to explain: it would require already activated cells to enter the tissue where the respective autoantigens are sequestered. Autoimmune uveitis, a sight-threatening inflammatory disease of the eye, is such an example. To induce disease autoreactive T cells must have been activated outside the eye to pass the blood-retina-barrier and then crossreact with retinal autoantigen. We have described two environmental peptides mimicking a highly pathogenic epitope from retinal S-antigen. One mimicry antigen is from rotavirus, a common pathogen causing gastroenteritis, the other from bovine milk alpha s2casein, a frequent nutritional protein ought to induce oral tolerance. Lewis rats develop uveitis after immunization with both mimicry peptides and casein protein. However, these mimicry antigens failed to induce oral tolerance for protection from uveitis, suspecting that they rather induce immunity than tolerance. Humoral and cellular immune responses to these antigens are enhanced and more frequent in patients with uveitis compared to healthy individuals. Our findings suggest that multiple environmental antigens mimic autoantigens and might cause autoimmune diseases by eliciting defensive immune responses, however, they are not necessarily useful for therapeutic tolerance induction.

Topics: Animals; Antigens, Viral; Autoantigens; Autoimmune Diseases; Casein Kinase II; Environmental Exposure; Humans; Immune Tolerance; Molecular Mimicry; Rotavirus; Uveitis

Although it has historically been studied in the context of cancer, recent literature has highlighted the importance of the highly conserved serine/threonine kinase casein kinase II (CK2) in inflammatory disorders. Most strikingly, CK2 is a major regulator of the Th17-Treg axis relevant to many T cell-driven autoimmune disorders including multiple sclerosis (MS).

Topics: Animals; Autoimmune Diseases; Casein Kinase II; Clinical Trials as Topic; Emodin; Humans; Immunity; Immunomodulation; Inflammation; Mice; Molecular Targeted Therapy; Multiple Sclerosis; Naphthyridines; Neoplasms; Phenazines; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells

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.

Topics: Animals; Autoimmune Diseases; Casein Kinase II; CD4 Antigens; CD8 Antigens; Gene Expression Regulation; Heterozygote; Homozygote; Leukocyte Common Antigens; Lymphatic Diseases; Lymphoproliferative Disorders; Mice; Mice, Inbred MRL lpr; Mice, Knockout; Mice, Transgenic; Protein Serine-Threonine Kinases; Splenomegaly; T-Lymphocyte Subsets; Transgenes