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Growing evidence indicates the pronounced effects of physical activity on immune functions, which may largely depend on the type of exercise, intensity, and duration. However, limited information is available regarding the effects of low-impact exercises, especially on the level of adaptive immune system. Our study aimed to investigate and compare the changes in a broad spectrum of lymphocyte subtypes after 14 weeks of aerobic-type total-body-shaping workouts (TBSW) and Pilates workouts (PW) among healthy individuals. We determined the percentages of peripheral natural killer cells and different T and B lymphocyte subtypes with flow cytometry. At the end of the exercise program, significant changes in naïve and memory lymphocyte ratios were observed in TBSW group. Percentages of naïve cytotoxic T (Tc) cells elevated, frequencies of memory Tc and T-helper cell subsets decreased, and distribution of naïve and memory B cells rearranged. Proportions of activated T cells also showed significant changes. Nonetheless, percentages of anti-inflammatory interleukin (IL)-10-producing regulatory type 1 cells and immunosuppressive CD4

Generally, a reciprocal antagonistic interaction exists between the antiviral type I interferon (IFN) and the antibacterial nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)-dependent IL-1β pathways that can significantly shape immune responses. Plasmacytoid dendritic cells (pDCs), as professional type I IFN-producing cells, are the major coordinators of antiviral immunity; however, their NLRP3-dependent IL-1β secretory pathway is poorly studied. Our aim was to determine the functional activity of the IL-1β pathway and its possible interaction with the type I IFN pathway in pDCs. We found that potent nuclear factor-kappa B (NF-κB) inducers promote higher levels of pro-IL-1β during priming compared to those activation signals, which mainly trigger interferon regulatory factor (IRF)-mediated type I IFN production. The generation of cleaved IL-1β requires certain secondary signals in pDCs and IFN-α or type I IFN-inducing viruses inhibit IL-1β production of pDCs, presumably by promoting the expression of various NLRP3 pathway inhibitors. In line with that, we detected significantly lower IL-1β production in pDCs of psoriasis patients with elevated IFN-α levels. Collectively, our results show that the NLRP3-dependent IL-1β secretory pathway is inducible in pDCs; however, it may only prevail under inflammatory conditions, in which the type I IFN pathway is not dominant.

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 (T

Maternal B cells play a crucial role in the development and maintenance of pregnancy, due to their humoral activities and regulatory functions. In the study, we investigated the alterations in the distributions of naïve and memory B cell subsets, as well as regulatory B (Breg) cells, in the third trimester of pregnancy. Peripheral blood from 14 healthy pregnant women in the third trimester and 7 healthy non-pregnant women was collected and examined for the frequencies of B cell subsets, including IgD+CD27− naïve, IgD+CD27+ un-switched memory, IgD−CD27+ switched memory, CD38intCD24int mature–naïve, CD38−CD24hi primarily memory and CD38hiCD24hi transitional B cells by flow cytometry. Breg cell subsets were also characterized based on the expression of CD5, CD1d and IL-10. In pregnant women, the proportions of un-switched memory and transitional B cells were significantly decreased. Additionally, the frequencies of both CD5+CD1d+ Breg and IL-10-producing B10 cells were decreased in pregnancy. Changes in the distribution of transitional B cells as well as Breg cells may be crucial contributors for the development of altered maternal immune responses and tolerance needed for the maintenance of normal pregnancy in the third trimester.

Maternal B cells play a crucial role in the development and maintenance of pregnancy, due to their humoral activities and regulatory functions. In the study, we investigated the alterations in the distributions of naïve and memory B cell subsets, as well as regulatory B (Breg) cells, in the third trimester of pregnancy. Peripheral blood from 14 healthy pregnant women in the third trimester and 7 healthy non-pregnant women was collected and examined for the frequencies of B cell subsets, including IgD

Antiphospholipid syndrome (APS) encompasses a wide spectrum of disease manifestations that may prevail in the form of venous or arterial thrombosis or lead to pregnancy complications in the presence of persisting antiphospholipid antibodies (aPL). Unlike in the case of congenital thrombophilias, in which venous thromboses are more likely to occur as compared with arterial events, aPL may cause thrombosis in both types of vascular systems. Arterial thrombosis in APS is fairly common and often involve coronary or cerebral arteries leading to myocardial infarction (MI) or stroke. In this review, we summarize the complex pathomechanisms leading to aPL‑associated thrombosis and list challenges during the laboratory detection of these antibodies. Specific features of MI in patients with APS are summarized based on a comprehensive literature search of available case reports. Preventive and treatment strategies are discussed based on the current recommendations and most recent evidence. We conclude that the risk of MI in patients with APS is considerable and MI may be the first manifestation of the disease. MI in APS shows specific clinical features including relatively young age at presentation, no sex dominance, often normal coronaries without the sign of atherosclerosis, high risk of recurrent thrombotic events. Treatment of acute MI in patients with APS is often challenging and adverse events, including stent thrombosis, are more frequent as compared with patients without APS. Preventive strategies in APS should be personalized and include strict management of additional cardiovascular risk factors and long‑term anticoagulation with vitamin K antagonists. Current evidence does not support the use of direct oral anticoagulants in the management of patients with APS with arterial thrombosis due to the high risk of recurrent events.

Generally, a reciprocal antagonistic interaction exists between the antiviral type I interferon (IFN) and the antibacterial nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)-dependent IL-1β pathways that can significantly shape immune responses. Plasmacytoid dendritic cells (pDCs), as professional type I IFN-producing cells, are the major coordinators of antiviral immunity; however, their NLRP3-dependent IL-1β secretory pathway is poorly studied. Our aim was to determine the functional activity of the IL-1β pathway and its possible interaction with the type I IFN pathway in pDCs. We found that potent nuclear factor-kappa B (NF-κB) inducers promote higher levels of pro-IL-1β during priming compared to those activation signals, which mainly trigger interferon regulatory factor (IRF)-mediated type I IFN production. The generation of cleaved IL-1β requires certain secondary signals in pDCs and IFN-α or type I IFN-inducing viruses inhibit IL-1β production of pDCs, presumably by promoting the expression of various NLRP3 pathway inhibitors. In line with that, we detected significantly lower IL-1β production in pDCs of psoriasis patients with elevated IFN-α levels. Collectively, our results show that the NLRP3-dependent IL-1β secretory pathway is inducible in pDCs; however, it may only prevail under inflammatory conditions, in which the type I IFN pathway is not dominant.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by recurrent thrombotic events, pregnancy loss and thrombocytopenia and the presence of antiphospholipid antibodies (APL). The exact pathomechanism of APS is still unknown, thus we investigated the effect of anti-βFor the separation of anti-βIn normal pooled plasma, the anti-βThe anti-β

One of the most abundant coagulation proteins is β

Background Detection of anti-neutrophil cytoplasmic antibodies (ANCA) by indirect immunofluorescence assays (IFA) is of diagnostic importance in vasculitides and some other inflammatory diseases. Automation of IFA may be beneficial in high-throughput clinical laboratories. An analytical appraisal of the EUROPattern (EPa) automated microscope and image analysis system has not been reported in a routine clinical laboratory setting testing samples from both vasculitis and non-vasculitis patients. Methods Results of EPa and on-screen ANCA pattern recognition of 568 consecutive routine serum samples were compared to those of conventional visual evaluation. Results Agreement of discrimination between negative and non-negative samples was 86.1% comparing EPa and conventional reading, and it increased to 96.7% after on-screen user validation. Importantly, from the 334 samples classified as negative by EPa 328 (98.2%) were also negative by conventional evaluation. Pattern recognition showed ‘moderate’ agreement between classical microscopic and EPa analysis (κ = 0.446) and ‘very good’ agreement after user validation (κ = 0.900). Misclassification by EPa was dominantly due to the presence of anti-nuclear/cytoplasmic antibodies (incorrect pattern, 80/568) and the lower fluorescence cut-off of the automated microscope (false positives, 73/568). Conclusions Automated ANCA testing by EPa is a reliable alternative of classical microscopic evaluation, though classification of sera needs correction by trained personnel during on-screen validation.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. Introduction Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by recurrent thrombotic events, pregnancy loss and thrombocytopenia and the presence of antiphospholipid antibodies (APL). The exact pathomechanism of APS is still unknown, thus we investigated the effect of anti-β2-glycoprotein I (anti-β2GPI) on thrombin generation in different plasma samples. Methods - For the separation of anti-β2GPI IgG, overall 12 APS patients were selected. The criteria were the existence of lupus anticoagulant, and the presence of anti-CL and anti-β2GPI, the latter exceeding at least 25 times the upper reference limit. We purified anti-β2GPI IgG antibodies from APS patients by affinity chromatography and added the antibodies to normal pooled, and heterozygous forms of inherited thrombophilia plasma samples (prothrombin G20210A, factor V Leiden). To further specify the mechanism of the effect, we also used factor deficient plasmas in the thrombin generation assay. Results - In normal pooled plasma, the anti-β2GPI significantly prolonged Lag Time according to the lupus anticoagulant effect, in contrast, it also elevated Peak Thrombin significantly, which suggests a procoagulant effect. The antibody was also able to exert this multi-faceted effect both in FVLeiden heterozygous plasma and prothrombin G20210A heterozygous polymorphism, however, the prolonging effect was more remarkable in the latter. By using factor deficient plasmas, it was found that FVII is required for the prolongation, while intrinsic factors are needed for the elevation of the Peak Thrombin. Conclusion - The anti-β>2GPI autoantibodies exert their effect in both normal and thrombophilic plasmas via various mechanisms.

One of the most abundant coagulation proteins is β2-glycoprotein I (β2GPI) that is present in humans at a concentration of around 200 mg/L. Its physiological role is only partially understood, but it adopts several different structural forms the majority of which are the open and closed forms. We isolated native (circular) β2GPI and converted it into an open conformation. The effectiveness of these procedures was assessed by Western blot and negative-staining electron microscopy. We found that in coagulation assays the open form of β2GPI had a significant prolonging effect on fibrin formation in a dilute prothrombin time test (p

Long-term survival of patients with systemic lupus erythematosus (SLE) improved worldwide; thus, prevention of cumulative organ damage became a major goal in disease management. The aim of our study was to investigate the chronic organ damages and their influence on disease outcome in SLE. We evaluated clinical conditions, laboratory findings and medications of 357 consecutive SLE patients and assessed their impact on Systemic Lupus Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and disease outcome. We detected one or more SDI scores in 77.87% of patients. Patients with disease duration of more than 10 years and subjects diagnosed at age above 40 had significantly higher SDI values. The most frequent damages were valvulopathies, cognitive dysfunction, angina pectoris and venous thrombosis. Higher cumulative glucocorticoid dose increased SDI, while chloroquin treatment was favourable for patients. Male gender, elevated SDI scores and higher cumulative doses of glucocorticoids increased mortality risk. Our data confirmed that disease duration, age at diagnosis and chronic high-dose glucocorticoid therapy have significant effects on the development of chronic organ damage. Higher SDI score is characterized with worse survival ratios. The most common chronic organ damages affected the cardiovascular or neuropsychiatric system. As long-term survival in SLE improves, it becomes increasingly important to identify the determinants of chronic organ damage. Most of the chronic organ damage occurs in the cardiovascular and the neuropsychiatric systems; thus, regular follow-up, screening and adequate therapy are essential for the best clinical outcome.

Antiphospholipid syndrome is characterized by multiple arterial and/or venous thrombotic events, recurrent fetal losses in the presence of antiphospholipid antibodies (aPL). Catastrophic antiphospholipid syndrome is a life-threatening, rare subset of antiphospholipid syndrome when the thrombotic events affect at least three organs, and clinical manifestations develop simultaneously or within a week. Diagnostically, small vessel occlusions can be detected by histopathology in the presence of aPL. Our case report describes an 18-year-old man who has been treated for antiphospholipid syndrome associated with systemic lupus erythematosus (SLE) since 2011. The clinical findings were dominated by recurrent deep vein thrombosis, and severe proteinuria caused by lupus nephritis, accompanied by mild serological and laboratory findings. The patient was hospitalized in March 2014 because of severe thrombocytopenia and infective diarrhoea. At this time the renal functions deteriorated rapidly. Simultaneously, left upper extremity paresis was observed; computed tomography showed ischaemic lesions in the territory of the middle cerebral artery. Abdominal discomfort and pain occurred. On computed tomography scan ischaemic lesions were seen in the spleen, the right kidney and the coeliac trunk. Laboratory and serological findings verified the presence of aPL and anti-DNA antibodies, anaemia and thrombocytopenia. Based on the above-mentioned clinical and laboratory findings, the diagnosis of catastrophic antiphospholipid syndrome was established. Anticoagulation, corticosteroids and plasma exchange treatment, as well as haemodiafiltration were initiated. Although the thrombotic cascade decelerated following these interventions, we could not see an improvement in the renal function. Rituximab treatment was started, leading to a significant improvement in renal function. After 5 weeks of treatment the patient was discharged from hospital.

Introduction/objectives Long-term survival of patients with systemic lupus erythematosus (SLE) improved worldwide, thus prevention of cumulative organ damage became a major goal in disease management. The aim of our study was to investigate the chronic organ damages and their influence on disease outcome in SLE. Method We evaluated clinical conditions, laboratory findings and medications of 357 consecutive SLE patients, and assessed their impact on SLICC/ACR damage index (SDI) and disease outcome. Results We detected one or more SDI scores in 77.87% of patients. Patients with disease duration of more than 10 years and subjects diagnosed at age above 40 had significantly higher SDI values. The most frequent damages were valvulopathies, cognitive dysfunction, angina pectoris and venous thrombosis. Higher cumulative glucocorticoid dose increased SDI, while chloroquin treatment was favourable for patients. Male gender, elevated SDI scores and higher cumulative doses of glucocorticoids increased mortality risk. Our data confirmed that disease duration, age at diagnosis, chronic high-dose glucocorticoid therapy have significant effects on the development of chronic organ damage. Higher SDI score is characterised with worse survival ratios. The most common chronic organ damages affected the cardiovascular or neuro-psychiatric system. Conclusions As long-term survival in SLE improves, it becomes increasingly important to identify the determinants of chronic organ damage. Most of the chronic organ damage occurs in the cardiovascular and the neuropsychiatric systems, thus regular follow-up, screening and adequate therapy are essential for the best clinical outcome.

Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are systemic autoimmune diseases with complex symptoms and pathogenesis that are still not completely understood. Several studies showed that the trace element homeostasis and also the levels of antioxidant plasma proteins are changed in autoimmune disorders; however, these results are controversial. In this study, the potassium (K), calcium (Ca), magnesium (Mg), copper (Cu), zinc (Zn), and iron (Fe) concentrations of the serum and proteins-immunoglobulin G (IgG), transferrin (Trf), albumin (Alb), and ceruloplasmin (Cp)-separated from serum samples by affinity chromatography were determined in patients with SLE and SS. Ca and K levels were found to be decreased in the case of both disorders compared to the control group, and the competitive antagonism of Cu and Zn was also observed: elevated Cu concentration together with a lower Zn concentration was measured in the sera of patients with autoimmune diseases. After fractionation, the trace element concentration of protein containing fractions altered to that of the control group. In case of the autoimmune disorders, the highest Cu concentration was determined in the Alb-containing protein fractions while the Zn level decreased in the Alb and increased in the Cp as well as in the IgG- and Trf-containing fractions compared to the healthy samples. Changes have also been found in the level and distribution of K and Ca.

The clearance of apoptotic cells has an important role in the maintenance of tissue homeostasis and in the protection of tissues from the inflammatory and immunogenic contents of dying cells. A defect in the recognition and phagocytosis of apoptotic cells contributes to the development of chronic inflammation and autoimmune disorders. We have observed that compared with healthy donors, differentiated macrophages from patients with untreated systemic lupus erythematosus (SLE) showed decreased phagocytosis of apoptotic neutrophils. A TaqMan Low Density Array was designed to determine the mRNA expression levels of 95 apopto-phagocytic genes in differentiated non-phagocytosing and phagocytosing macrophages. In the macrophages of clinically and immunoserologically active SLE patients, 39 genes were expressed at lower levels than in the control macrophages. When inactive patients were compared with those with minor immunoserological abnormalities or patients in an immunoserologically active state, a relationship was observed between the altered gene expression profile and the disease state. In the macrophages of patients with engulfing apoptotic cells, an upregulation of genes involved in inflammation, autophagy, and signaling was observed. These results indicate that novel immune-pathological pathways are involved in SLE and suggest targets for potential therapeutic modulation.

Background The causes of increased cardiovascular risk in systemic lupus erythematosus (SLE) are not understood thoroughly, although presence of traditional cardiovascular risk factors and disease-specific agents were also proposed. In this study, we investigated the quantitative changes in the lipid profile, as well as qualitative characteristics of high-density lipoprotein (HDL) and markers of inflammation and disease activity in SLE patients. Methods Lipoprotein levels were determined in 51 SLE patients and 49 healthy controls, matched in age and gender. HDL antioxidant capacity was determined spectrophotometrically with a cell-free method of hemin-induced low-density lipoprotein (LDL) oxidation. Polyacrylamide gel-electrophoresis was used for HDL subfraction analysis. Human paraoxonase-1 (PON1) activity, apolipoprotein A1 (ApoA1) and oxidized LDL concentrations, as well as interleukin-6, high-sensitivity C-reactive protein, serum amyloid A and monocyte chemotactic protein-1 levels were determined. Results HDL-cholesterol and ApoA1 concentrations decreased significantly in SLE subjects. Also, PON1 arylesterase activity (125.65 ± 26.87 vs. 148.35 ± 39.34 U/L, p = 0.001) and total HDL antioxidant capacity (165.82 ± 58.28 % vs. 217.71 ± 54.36 %, p

Summary Follicular T helper (Tfh) cells have a crucial role in regulating immune responses within secondary lymphoid follicles by directing B cell differentiation towards memory B cells and plasma cells. Because abnormal humoral responses are key features in both primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE), the aim of this study was to profile the pathological connection between peripheral Tfh cells and B cells in the two diseases. Twenty-five pSS patients, 25 SLE patients and 21 healthy controls were enrolled into the study. We determined the ratio of circulating Tfh-like cells, their interleukin (IL)-21 production and different B cell subsets by flow cytometry. We observed higher percentages of naive B cells in both diseases, while non-switched and switched memory B cells showed decreased frequencies. The proportions of double-negative B cells and plasmablasts were elevated in SLE and decreased in pSS. The percentages of transitional B cells and mature-naive B cells were higher in SLE. Patients with more severe disease course had an elevated ratio of TFH-like cells and increased IL-21 production. Moreover, expansion of Tfh-like cells correlated positively with parameters related to antibody secretion, including serum immunoglobulin (Ig)G, immune complexes (ICs) and autoantibodies. Correlation analysis between Tfh-like cells and certain B cell subsets revealed possible defects during B cell selection. In conclusion, our observations on the profound expansion of circulating Tfh-like cells and their IL-21 production, along with the characteristic aberrant peripheral B cell distribution in both pSS and SLE, indicate the prominent role of Tfh cell in the regulation of B cell selection.

The effects of proteosome inhibitor Bortezomib (BZ) were studied in vitro for 24 h on the protein kinase C (PKC) profiles, rates of proliferation and apoptosis in Jurkat cells and lymphocytes of 10 patients with systemic lupus erythematosus (SLE) and nine healthy subjects. The expressions of PKC proteins, the rates of proliferation and apoptosis were determined. The effects of BZ were different in the Jurkat and lupus T cells. Whereas BZ elevated the expression of PKC θ, δ and ξ isoenzymes in the Jurkat cells, it was unable to do that in the lupus T cells. BZ induced a dose-dependent increase in the apoptosis of Jurkat cells, while decreased the proliferation. The same effect of BZ was observed on the apoptosis of lymphocytes both in SLE and healthy subjects at concentrations higher than the therapeutic dose. We conclude that BZ treatment in vitro was not able to restore the SLE-specific defect (decrease) in the expression of PKC isoenzymes in the T cells as it was expected. This can be a limiting factor in the positive clinical effects of BZ in lupus.

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.

Disproportionate vitamin D levels may play an important role in the development of certain systemic autoimmune and rheumatic diseases. The aim of the present study was to investigate the prevalence of vitamin D insufficiency in patients with systemic lupus erythematosus (SLE) and to compare serological and clinical parameters in patients with different vitamin D levels from a single centre registry in Central-Eastern Europe.A total of 177 patients with SLE were enrolled in the study. 25-Hydroxyvitamin D [25(OH)D] levels were measured by chemiluminescent immunoassay (CLIA). Autoantibody profiles, complement 3 (C3) and C4, clinical symptoms, and disease activity (using the SLE disease activity index, SLEDAI) of the patients were assessed.Vitamin D concentration in the total SLE group investigated was 26.88 ± 13.25 ng/mL. Vitamin D levels were normal (≥ 30 ng/mL) in 18.1% of patients, insufficient (15-30 ng/mL) in 44.6%, and deficient (15 ng/mL) in 37.3%. The vitamin levels were significantly reduced in postmenopausal compared to premenopausal patients (p = 0.02). Patients with pericarditis (p = 0.013), neuropsychiatric diseases (p = 0.01), and deep vein thrombosis (p = 0.014) had reduced vitamin D levels. SLEDAI score was significantly increased in patients with reduced vitamin D levels (p = 0.038). Anti-double-stranded (ds)DNA autoantibody concentrations increased from normal to insufficient and further increased from insufficient to deficient patient subsets (p = 0.021). Anti-Smith antigen (anti-Sm) concentrations increased (p0.001), C4 levels decreased (p = 0.027), and immunoglobulin (Ig)G concentration increased (p = 0.034) in patients with reduced vitamin D levels.Our data suggest that vitamin D deficiency in SLE may play a role in perpetuation of the disease.

To analyze the association of antiphospholipid antibodies (aPL) with the development of clinical thrombotic manifestations and to characterize the efficacy of anti-thrombotic therapies used.272 systemic lupus erythematosus (SLE) patients participated in the study. Patient files and a cumulative database were used to collect patients' medical histories. Anti-cardiolipin (aCL), anti-beta2-glycoprotein I (abeta2GPI) antibodies, and lupus anticoagulant (LAC) were measured according to international recommendations. New thrombotic events were registered during follow-up.The patients were prospectively studied for 5 years, of whom 107 were aPL negative (aPL- group). Criteria for antiphospholipid syndrome (APS) were fulfilled by 84 of 165 aPL-positive patients (APS+ group) indicating that SLE patients with aPL have around 50% risk to develop thrombotic complications. The aPL+ group (n = 81) consisted of aPL+ but APS- patients. LAC was the most common aPL (n = 27, 32.1%) in patients with APS. The cumulative presence of aPL further increased the prevalence of thrombotic events. During the follow-up period, aPL developed in 8 of 107 patients (7.5%) from the aPL- group, of whom 3 (2.8%) presented with thrombotic complications. Other types of aPL developed in 7 of 165 (4.2%) aPL+ patients within 5 years. New thrombotic events occurred in 3.7% of aPL+ (n = 3) and 8.3% (n = 7) of the APS group. During follow-up, 52 of 81 aPL+ patients received primary prophylaxis, and 1 (1.9%) had transient ischemic attack (TIA). In the non-treatment group, 2 (6.9%) had stroke. Seventy-nine of 84 of the APS patients received secondary prophylaxis, and myocardial infarction occurred in 2 patients (on cumarine therapy maintaining an international normalized ratio around 2.5-3.0), and 5 suffered a stroke/TIA (1 on aspirin and 4 on aspirin + cumarine).The findings emphasize the importance of determining both aCL and abeta2GPI antibodies and LAC in SLE patients and the need for adequate anticoagulant therapy.

As a result of increasing life expectancy of lupus patients, malignant disorders have become major determinants of morbidity and mortality. The objectives of this study were to analyze cancer-associated morbidity and mortality, the type of malignancies in Hungarian lupus patients, and to analyze association with immune-suppressive therapy, disease duration, and age of the patients. Data from 860 systemic lupus erythematosus (SLE) patients were retrospectively analyzed in a study period between 1970 and 2004. Results were compared to data from age- and sex-matched population obtained from the Health for All database, and also to literature data. A total of 37 patients presented with cancer, reflecting 4.3% cancer-associated morbidity. Patients were 47 (20-73) years old at the onset of malignancy, which appeared 13 (1-45) years later than SLE. Cancer prevalence was the highest in the first 5-10 years of lupus. Breast cancer was the most common malignancy (n = 11) followed by gastrointestinal tumors (n = 9), cervix cancer and hematologic malignancies (n = 5 for both), bronchial cancer (n = 4), bladder, skin, and ovarian cancer (n = 1 for each). Standardized incidence ratio was the highest for non-Hodgkin lymphoma (standardized incidence ratio [SIR] 3.5, 95% CI 0.4-12.5) and cervix cancer (SIR 1.7, 95% CI 0.6-4.1). Although 76% of patients with cancer received immune-suppressive therapy besides corticosteroids, no direct correlation could be confirmed between therapy and malignancy. Out of the 164 patients that expired during the study period, 18 were cancer-related. As such the cancer-associated mortality was 11% (18/164). This peaked during the last 4 years of the study period (8/24, 33%). Lupus patients are at high risk for particular types of malignant disorders, highlighting the importance of screening measures and focused patient examination.

The objective of this study was to analyse whether primary antiphospholipid syndrome (PAPS) may precede and modify the characteristics of systemic lupus erythematosus (SLE). Out of the total 362 SLE patients in our service, 223 patients had antiphospholipid antibodies (aPL), of whom 110 met the criteria of antiphospholipid syndrome. In 26 cases (7.2%) PAPS appeared 5.5 years before the onset of lupus (PAPS+SLE Group). Their clinical findings were compared to lupus patients without (SLE only Group, n = 26) and with secondary APS (SLE+SAPS Group, n = 26). The prevalence of deep venous thrombosis, stroke/TIA, recurrent fetal loss, coronary heart disease and myocardial infarction was significantly higher in PAPS+SLE Group as compared to SLE only Group. The difference in prevalence of fetal loss ( P = 0.014) between PAPS+SLE and SLE+SAPS Groups was also recorded. On comparison to PAPS+SLE Group, patients without APS (SLE only Group) were younger at onset of lupus, with more frequent flares and a higher prevalence of WHO type III/IV nephritis ( P = 0.007), requiring higher doses of cyclophosphamide and corticosteroids. Lupus started in the form of PAPS in 7.2% of our SLE patients, who presented with more thrombotic and less inflammatory complications than in SLE patients without a prior or with a following secondary APS. Considering the long latency between the two diseases, PAPS may be a forerunner of lupus, but it may also coexist with SLE as an independent autoimmune disorder. Lupus (2007) 16 , 324—328.

Systemic lupus erythematosus is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Objectives were to determine endothelial dysfunction with a non-invasive method in lupus patients and to analyse correlation with risk factors and atherosclerotic complications. Sixty-one SLE patients and 26 healthy age- and sex-matched control subjects were entered into the study. The diameters of brachial artery at rest, during reactive hyperaemia, and after glyceril trinitrate administration, as well as the intima-media thickness of the common carotid artery were measured using high-resolution B-mode ultrasonography. Demographic characteristics, lipid profile, paraoxonase activity, concentration of anti-phospholipid antibodies and anti-oxLDL were assessed together with atherosclerotic complications. The endothelium dependent vasodilation (FMD) was significantly impaired in SLE patients as compared to controls. The absolute difference of vessel diameter (Δd) was 0.25 ± 0.15 mm vs. 0.38 ± 0.16 mm ( p = 0.001), and Δd as in percent of the rest diameter was 7.31 ± 5.2% vs. 9.86 ± 3.87% ( p = 0.013) in lupus patients and controls, respectively. Nitrate mediated dilation (NMD) did not differ. FMD negatively correlated with age, systolic and diastolic blood pressure in SLE, but did not show significant correlation with the other examined parameters. However, FMD significantly differed between SLE patients with (5.54 ± 4.36%) and without (8.81 ± 5.28%) cardiovascular complications ( p = 0.01). The determination of flow-mediated vasodilation is a useful method to detect endothelial dysfunction in lupus patients, as reduced capacity of brachial artery may distinguish between SLE patients and healthy subjects, as well as lupus patients with and without atherosclerotic vascular complications.

The discovery of microRNAs (miRNAs) and their critical role in genetic control opened new avenues in understanding of various biological processes including immune cell lineage commitment, differentiation, proliferation and apoptosis. However, a given miRNA may have hundreds of different mRNA targets and a target might be regulated by multiple miRNAs, thus the characterisation of dysregulated miRNA expression profiles could give a better insight into the development of immunological disturbances in autoimmune diseases. The aim of our study was to examine the changes in miRNA expression profiles in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). Eight SLE patients, 8 pSS patients and 7 healthy subjects were enrolled in the investigation. MiRNAs were isolated from peripheral blood mononuclear cells, and expression patterns were determined with Illumina next-generation sequencing technology. Since the immunopathogenesis of pSS and SLE encompasses pronounced B cell hyperactivity along with specific autoantibody production, we paid a special attention on the association between miRNA expression levels and altered peripheral B cell distribution. In SLE patients 135, while in pSS patients 26 miRNAs showed altered expression. Interestingly, the 25 miRNAs including miR-146a, miR-16 and miR-21, which were over-expressed in pSS patients, were found to be elevated in SLE group, as well. On the contrary, we observed the down-regulation of miR-150-5p, which is a novel and unique finding in pSS. Levels of several miRNAs over-expressed in SLE, were not changed in pSS, such as miR-148a-3p, miR-152, miR-155, miR-223, miR-224, miR-326 and miR-342. Expression levels of miR-223-5p, miR-150-5p, miR-155-5p and miR-342-3p, which miRNAs are potentially linked to B cell functions, showed associations with the B cell proportions within peripheral blood mononuclear cells. The observed differences in miRNA expression profiles and the better understanding of immune regulatory mechanisms of miRNAs may help to elucidate the pathogenesis of SLE and pSS.

Although most reported patients with immunoglobulin G4-related disease (IgG4-RD) are from the Far East, we aimed to identify patients suffering from IgG4-RD in our University Centre in Debrecen, Hungary.Serum IgG4 levels were measured at 51 of our 800 patients followed up because of Sjögren's syndrome (SS) if one or more clinical signs during the disease course raised the possibility of IgG4-RD (persisting salivary gland swelling, absence of anti-Ro/SSA and anti-La/SSB antibodies in the serum, and positive salivary gland biopsy, coexistence of autoimmune pancreatitis, autoimmune hepatitis, or primary sclerosing cholangitis, persisting lymphadenopathy). Where available, histological samples of small salivary gland biopsies were revised to detect the particular features of IgG4-RD. Pathologists and surgeons were informed about the disease and asked to refer suspicious cases.Based on our survey, eight patients were identified with IgG4-RD. Pancreatic, salivary gland, aortic, and retroperitoneal manifestations were detected. Of the 51 patients with SS, four appeared to have IgG4-RD, but eventually one was excluded.Although IgG4-RD is not yet well known to physicians of Western countries, it occurs in Caucasians and probably in other races as well. Moreover, our eight cases diagnosed with IgG4-RD demonstrate a relatively large European patient population collected in a single centre. European clinicians, and especially rheumatologists, should be informed and at least certain laboratories should be prepared to investigate patient samples if the suspicion of IgG4-RD is raised. The main clinical significance of an accurate diagnosis is the extreme corticosteroid sensitivity of IgG4-RD.

The objective of the study was to investigate the possibility whether the in vitro treatment with vitamin D3 can restore the impaired expression of protein kinase C (PKC) isoenzymes and IL-2 production in the lymphocytes of patients with systemic lupus erythematosus (SLE). Purified T lymphocytes from 14 patients with SLE and 13 healthy controls were cultured for 48 h in the presence and absence of 1 and 100 nM doses of vitamin D3. The expressions of various PKC isoenzymes were tested by Western blot analysis, and the amounts of various cytokines were detected by ELISA in the culture supernatants. Neither the low (1 nM) nor the high (100 nM) doses of vitamin D3 (1α,-25-dihydroxyvitamin) applied in vitro for 48 h were able to restore the decreased expression of PKC isoenzymes in the T cells of SLE patients. However, 100 nM of vitamin D3 significantly increased the release of IL-10, but suppressed the production of IL-2, IL-6, interferon γ and TNF α in the culture supernatants of both groups. As the low production of IL-2 is one of the main pathologic features of SLE, we recommend to avoid the use of high doses of vitamin D3 for treatment of lupus patients with vitamin D3 deficiency.

Background Systemic lupus eyrthematosus can bge associated with antiphospholipid syndrome. Years ago our study team investigated the thrombotic risk factors and complications in 272 lupus patients with and without antiphospholipid antibodies. At baseline, three groups were created, an aPL- group with 107 aPL negative patients, an aPL+ group with 81 aPL positive patients without clinical manifestations and a secondary antiphospholipid syndrome (APS) group with 84 aPL+ patients who met the Sapporo criteria. Objectives The objective of this study was to investigate of new thrombotic events, SLE activity,.co-morbidities, and mortality in total of 272 lupus patients for ten years of follow up. Methods The above mentioned 272 patients with SLE registerered in the Division of Clinical Immunology, University of Debrecen have been followed up prospectively for ten years. Results A total of 28 out of the 272 patients were lost to follow up. A total of 22 new thrombotic complicatons occurred, two in the aPL negative group, three in the aPL+ group. New antiphospholipid antibodies appeared in these patients. 77.3% of the new thrombotic complicatins reoccurred in the APS group despite the adequat anticoagulant and/or anti-platlet therapy. SLE activity was the most common in the APL+ group but the difference was not significant. A total of 27 out of 84 APS (32%), 14 out of 81 aPL positive and 10 out of 107 aPL negative patients died during the follow up. The causes of death were thrombotic events or complications in 40.7% in patients with APS. Conclusions Our data confirm recurring thrombotic events in lupus patients with antiphospholipid syndrome. Antiphospholipid syndrome seems to negatively influence the survival of the patients with systemic lupus erythematosus. Disclosure of Interest None declared

Results Female:Male ratio was 9:1 in both groups. The most common initial manifestations as butterfly rash occured in 60%/62%, cytopenias 60%/57%, kidney involvement 47%/43%, serositis 27%/23%, in the pre/postpubertal group. Arthritis was significantly more common in the older group (57%/77%). General symptomes like fever 47%/57%, weight loss 23%/30%, increased infection rate 20%/13% were also similar in the two age groups, as did ANA, anti-dsDNA, anti-Sm, anti-SSA, anti-SSB positivity and low C3 and C4 levels. Anti-RNP antibody was more common in the younger ages (33%/10%). Mean SLEDAI score was 12 in both groups. Zero SLICC damage index is significantly more common (68%/43%) in the older group after comparable follow-up period.

MicroRNA-146a (miR-146a) is a microRNA supposed to regulate innate immune, inflammatory response and antiviral pathway negatively. Recently, its potential use as a biomarker for disease diagnosis, prevention and treatment has become widely investigated. In the current study, we measured the expression of miR-146a/b, and their target genes, IRAK1, IRAK4, TRAF6 in the peripheral mononuclear cells of patients with Sjogren's syndrome (n=21) and healthy controls (n=10) by quantitative reverse transcription polymerase chain reaction. We found that both miR-146a and miR-146b, furthermore, the gene of TRAF6 were significantly overexpressed in the Sjogren's patients, whereas the expression of IRAK1 gene was significantly decreased. The expression of IRAK4 did not differ significantly. These results suggest that in the peripheral mononuclear cells of Sjogren's patients, the transcriptional repression of IRAK1 is taking place, whereas the other NF-κB pathway regulating gene, TRAF6 is overexpressed. As IRAK1 has been regarded a crucial gene in the pathogenesis of systemic lupus erythematosus, TRAF6 can be a Sjogren's syndrome specific biomarker, confirming and partly explaining the existance of different pathogenic pathways in the two diseases. These observations, however, need still wider confirmations.

We investigated the association between systemic lupus erythematosus (SLE) and polymorphisms of interleukin-23 receptor (IL23R) gene, which was recently found to be associated with autoimmune diseases, including Crohn's disease, rheumatoid arthritis, psoriasis and ankylosing spondylitis.We analysed 383 SLE patients and 253 controls for rs11805303, rs10889677, rs1004819, rs2201841, rs11209032, 11209026, rs10489629, rs7517847 and rs7530511 variants.The analysis was carried out using PCR-RFLP methods. Logistic regression analysis was used to compare the genotype distributions of the polymorphisms and haplotypes between the SLE patients and healthy controls.We observed no significant difference of the examined variants between the patient and control groups.Our results suggest that neither single nucleotide variants nor haplotypes of IL23R indicate susceptibility to developing SLE in the Hungarian population.

We investigated the genetic background regarding major histocompatibility complex (MHC) II alleles in patients with systemic lupus erythematosus (SLE) only, in patients with SLE with secondary antiphospholipid syndrome (SLE+SAPS), and in patients whose clinical course began as primary antiphospholipid syndrome (PAPS) and subsequently progressed to SLE (PAPS+SLE) in order to explain the phenotypical differences found in our previous study. Those with primary or secondary APS present more thrombotic and less inflammatory activity. Fetal wastage was the highest in the PAPS+SLE group. We performed human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 genotyping in 63 patients (26, 22, and 15 in SLE only, SLE+SAPS, and PAPS+SLE groups, respectively) and in 57 healthy controls, using PCR with sequence-specific primers. We found that, as reported in the literature, the occurrence of DRB1*03 and DQB1*0201 alleles was higher in SLE patients than in controls, but these alleles were rare in the PAPS+SLE group (13% in PAPS+SLE vs. 46% in the SLE only group; P = 0.044). HLA-DRB1*04 alleles were expressed frequently in both primary and secondary APS. DRB1*13, DQB1*06, and DQB1*0302 alleles were present more frequently in the PAPS+SLE patients than in the other groups, while the DQB1*0301 allele was rare. In this study we have shown that the SLE-associated DRB1*03/DQB1*02 alleles occurred frequently in our lupus patients as well as in SLE patients with secondary APS. In patients who started as PAPS and later progressed to SLE, the allele frequency was fundamentally different. Taken together, our results confirmed that the HLA-DRB1 and HLA-DQB1 profile of PAPS and SAPS is different. Therefore it is unlikely that these alleles are responsible for the partly similar phenotype of the two groups.