Regulation of RLR-Mediated Antiviral Responses of Human Dendritic Cells by mTOR

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Új terápiás módszerek kifejlesztése és hatásmechanizmusuk tanulmányozása poliszisztémás autoimmun kórképekben = Development of new therapeutic methods and the analysis of the ways of their action in patients with polysystemic autoimmune diseases

1.Az autoimmun betegeknél végzett autolog haematopetikus őssejt transzplantációk után a CD8+ citotoxikus T sejtek számának követése a legalkalmasabb laboratóriumi módszer a perifériás limfociták regenerációjának monitorozására. Ennek van prognosztikus értéke. A CD8+ sejtszám és szérum IL-6 emelkedése párhuzamos. 2.A Bortezomib új, kiegészítő terápiás szerként történő alkalmazása az SLE-s betegekben korlátozottnak látszik a protein kináz C (PKC) izoenzim szint emelő hatás elmaradása miatt, ugyanakkor az apotózis indukció hasznos lehet az autoreaktív sejtklónok eliminációjában. 3.Az SLE-s betegek D3 vitamin kezelésében a kisebb értékekkel való kezdés és az egyéni adagolás ajánlott, mivel az alacsony, 1 nM (80 NE/nap) vitaminnak is már lehet gátló hatása a T sejtek IL-2 termelésre, ami egyébként is kórosan csökkent. A magas (100 nM, 8000 NE/nap) vitamin kezelés nem befolyásolja a PKC enzim szinteket sem egészséges, sem SLE-s személyek T sejtjeiben, de egészségesekben szignifikánsan emeli az IL-10, míg gátolja az IL-2, IL-6, IFN? és TNF? termelést. 4.Sjögren szindrómás betegek mononukleáris sejtjeiben fokozott mikroRNS-146/a/b, TRAF6 gén és csökkent IRAK1 gén expressziót találtunk az egészséges személyek sejtjeihez képest. A miRNS-146a és TRAF6 gének fokozott párhuzamos expresszióját betegség specifikus jelenségnek tartjuk a Sjögren szindrómában. 5.Modellt hoztunk létre a monociták arachidonsav termelésének különbségeinek megvilágítására az egészséges személyekben és SLE-ben. | 1.The best laboratory method for the monitoring of the regeneration of peripheral lymphocytes after the autologuos haematopetic stem cell transplantations is the measurement of the increase in number of CD8+ cytotoxic T cells for the patients with therapy resistant autoimmune diseases. It has also some prognostic value. The change in serum IL-6 is in parallel with CD8+ cell count. 2.The use of Bortezomib as a new complementary therapeutic agent in SLE seems to be limited because of the lack of the elevating effect on the expression of PKC isoenzymes in the T lymphocytes.But its apoptosis inducing effect may have some advantage in the elimination of autoreactive cell clones. 3.In the treatment of SLE patients with vitamin D3, to start with lower doses, and to find the optimal individual dose is recommended, as already 1 nM (80 IU/day) of vitamin can inhibit the production of IL-2 what is otherwise low. The high dose of vitamin D3 (100 nM, 8000 IU/day) inhibits the production of IL-2, IL-6, IFN?, TNF?, increases the production of IL-10 in healthy persons. Even this dose of vitamin D3 is ineffective on the expression of PKC isoenzymes in the T cells of both groups. 4.We suppose that the parallel increase in the expressions of miR-146a and TRAF6 genes can be a disease specific marker in the mononuclear cells of Sjögren’s syndrome. 5.We created a model for the explanation of difference between the production of arachidonic acid in the monocytes of healthy persons and SLE patients

MicroRNA expression profiles identify disease-specific alterations in systemic lupus erythematosus and primary Sjögren's syndrome

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Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R

Systemic lupus erythematosus (SLE) is characterized by the breakdown of self-tolerance, the production of high-affinity pathogenic autoantibodies and derailed B cell responses, which indicates the importance of central players, such as follicular T helper (TFH) subsets and follicular T regulatory (TFR) cells, in the pathomechanism of the disease. In this study, we aimed to analyze the distribution of the circulating counterparts of these cells and their association with disease characteristics and B cell disproportions in SLE. We found that the increased percentage of activated circulating TFH (cTFH) and cTFR cells was more pronounced in cutaneous lupus; however, among cTFH subsets, the frequency of cTFH17 cells was decreased in patients with lupus nephritis. Furthermore, the decreased proportion of cTFH17 cells was associated with low complement C4 levels and high disease activity scores. We also investigated whether the blocking of the IL-21 receptor (IL-21R) with an anti-IL-21R monoclonal antibody inhibits the B cell response, since IL-21 primarily produced by TFH cells potentially promotes humoral immunity. We observed that anti-IL-21R inhibited plasmablast generation and immunoglobulin production. Our study demonstrated that, besides cTFR/cTFH imbalance, cTFH17 cells play a crucial role in SLE pathogenesis, and modulating cTFH-B cell interaction through the IL-21/IL-21R pathway may be a promising therapeutic strategy to suppress the pathological B cell response

Fatal CMV-Infection after Autologous Stem Cell Transplantation in Refractory Systemic Lupus Erythematosus

High-dose chemotherapy followed by autologous stem cell transplantation can be a rescue for patients with severe refractory systemic lupus erythematosus (SLE). However, the procedure might have fatal complications including infections and bleeding. We report on a young female patient with SLE whose disease started in her early childhood. After many years, severe renal, neurological, and bone marrow involvement developed that did not respond to conventional therapy. She was selected for autologous stem cell transplantation. A successful peripheral stem cell apheresis was performed in March 2006. The nonselected graft was reinfused in August 2006 after a conditioning chemotherapy containing high-dose cyclophosphamide and antithymocyte globulin. Engraftment was detected within 11 days. On the 38th posttransplant day, severe cytomegalovirus (CMV) infection developed that included pneumonitis, hepatitis, and pancytopenia. The patient died in a week due to multiorgan failure. With her case, we want to call the attention to this rare, but lethal complication of the autologous transplantation