THE EXAMINATION OF VITAMIN D IN UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE By Eva Zold Supervisor: Edit Bodolay M.D., Ph.D., D.Sc. UNIVERSITY OF DEBRECEN GYULA PETRANYI DOCTORAL SCHOOL OF CLINICAL IMMUNOLOGY AND ALLERGOLOGY, 2010

Summary

The undifferentiated connective tissue disease is a chronic inflammatory autoimmune disease, involving a disorder of the body's connective tissues. Data showed that 30-40 % of patients with UCTD at the onset will develop a defined CTD. The presence of autoantibodies to nuclear or cytoplasmic components and more organ involvement reflects that the patients with UCTD have complex immunoregulatory abnormalities. Environmental factors play an pivotal role in the development and progression of systemic autoimmune diseases, along with susceptible genetic and hormonal background. Vitamin D deficiency may have a role in the pathogenesis of systemic autoimmune diseases. The aims of our study were to measure the vitamin D levels, the IL-17 producing capacity of TH17 cells, the rate of nTreg cells and TH17 cells, and functional activity of nTreg cell in patients with UCTD. We examined, whether 0.5 mg daily dose of vitamin D analogue, alfacalcidol treatment during 5 weeks can modify the number and function of nTreg cells and the IL-17 production. In addition, we assessed the plasma concentrations of proinflammatory Th1 cytokines, IL-12, IFN-g, as well as IL-23, IL-6, IL-17 also the key regulatory cytokine IL-10 before and after vitamin D supplementation. According to our studies in UCTD patients vitamin D levels significantly lower than the control group both the summer and winter periods. Circulating levels of vitamin D fluctuate seasonally in UCTD patients. In our result, the presence of dermatological symptoms (photosensitivity, vasculitis, and erythema), oesophagus dysmotility and pleuritis correlated with vitamin D insufficiency (<30 ng/ml). The presence of anti-U1-RNP, anti-SSA, and anti-CCP occurred more frequently in these particular patients. The lowest levels of vitamin D (<30 ng/mL) were measured in UCTD patients who subsequently evolved to defined CTDs. In UCTD patients the regulation of immune responses is defected and the suppressor activity towards autoimmune processes is diminished. The IL-17 expression of CD4+T lymphocytes was high in UCTD patients. We found significant elevation of the proinflammatory cytokines IL-12, IFN-g, as well as the TH17 cell associated cytokines, namely IL-23, IL-17 and IL-6 in UCTD patients. Alfacalcidol treatment has an affect on CD4+CD25+ Treg cells, and the vitamin analogue can increase the suppressive effect of Tregs on the proliferation of autologous CD4+CD25- T cells. Alfacalcidol inhibits both Th1 and TH17 cells, while shifting the response towards the regulatory cytokine, IL-10. The supplementation of vitamin D can restore the immune-homeostatic disturbance and it may influence Th17/nTreg imbalance, therefore could be beneficial in the management of autoimmune diseases.

Keywords: vitamin D, UCTD, regulative T cells