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Objective To characterize the systemic phenotype of primary Sjögren’s syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores. Methods The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in clinical research in Sjögren’s syndrome from the five continents. Results The cohort included 10 007 patients (9352 female, mean 53 years) with recorded ESSDAI scores available. At diagnosis, the mean total ESSDAI score was 6.1; 81.8% of patients had systemic activity (ESSDAI score ≥1). Males had a higher mean ESSDAI (8.1 vs 6.0, P 65 years, P Conclusion The systemic phenotype of primary Sjögren’s syndrome is strongly influenced by personal determinants such as age, gender, ethnicity and place of residence, which are key geoepidemiological players in driving the expression of systemic disease at diagnosis.

Abstract: MicroRNAs (miRNAs) are 18–25 nucleotide long, single stranded, endogenous, non-coding small RNAs playing an important role in regulating gene expression at posttranscriptional level. miRNAs control approximately 90% of protein-coding genes, and play a central role in various biological processes including immune cell lineage commitment, differentiation, proliferation, apoptosis and maintenance of immune homeostasis. Changes in the expression of certain miRNAs may lead to the development of many diseases, including systemic autoimmune diseases. In this study, we summarize the biogenesis of miRNAs, their role in regulation of the immune system, and review the latest research findings in systemic lupus erythematosus, primary Sjögren’s syndrome, rheumatoid arthritis and systemic sclerosis. In the future, miRNAs may help not only in establishing diagnosis and prognosis but potentially serve as targets for modern therapeutic approaches in autoimmune diseases. Orv Hetil. 2019; 160(15): 563–572.

Autoimmune diseases are characterized by the development of autoreactive T- and B-cells targeting self-antigens, which eventually can result in chronic and persistent organ damage. The autologous hematopoietic stem cell transplantation (AHSCT) opened new avenues in the treatment of patients with severe, treatment-resistant autoimmune diseases. This paper reviews the immune-regulatory mechanisms behind AHSCT, and also summarizes the experiences of clinical practice related to the therapy in organ-specific and systemic autoimmune diseases. It seems that the intricate interplay of various immune competent cells with regulatory capacity control in a synergistic manner the repopulated immune system after AHSCT, which potentially leads to a significant clinical improvement in certain autoimmune diseases. However, the widespread use of AHSCT was intrinsically limited, due to the serious side-effects of conditioning treatment and relatively high treatment-related mortality; moreover, the development of new effective and safe therapeutic approaches and the dawn of biological agents further limited its indications in the last decade. Nevertheless, with an appropriate patient selection and increased experience of transplant centres, the risks can be minimized, and AHSCT remained still a reasonable choice in multiple sclerosis and systemic sclerosis when the conventional therapy failed and further progression of disease is inevitable.

MicroRNAs (miRNAs) are single-stranded, endogenous non-coding small RNAs, ranging from 18 to 25 nucleotides in length. Growing evidence suggests that miRNAs are essential in regulating gene expression, cell development, differentiation and function. Autoimmune diseases are a family of chronic systemic inflammatory diseases. Recent findings on miRNA expression profiles have been suggesting their role as biomarkers in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. In this review, we summarize the characteristics of miRNAs and their functional role in the immune system and autoimmune diseases including systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis, systemic sclerosis, multiple sclerosis and psoriasis; moreover, we depict the advantages of miRNAs in modern diagnostics.

MicroRNAs (miRNAs) are 18-25 nucleotide long, single stranded, endogenous, non-coding small RNAs playing an important role in regulating gene expression at posttranscriptional level. miRNAs control approximately 90% of protein-coding genes, and play a central role in various biological processes including immune cell lineage commitment, differentiation, proliferation, apoptosis and maintenance of immune homeostasis. Changes in the expression of certain miRNAs may lead to the development of many diseases, including systemic autoimmune diseases. In this study, we summarize the biogenesis of miRNAs, their role in regulation of the immune system, and review the latest research findings in systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis and systemic sclerosis. In the future, miRNAs may help not only in establishing diagnosis and prognosis but potentially serve as targets for modern therapeutic approaches in autoimmune diseases. Orv Hetil. 2019; 160(15): 563-572.Absztrakt: A mikro-RNS-ek (miRNS) 18–25 nukleotid hosszúságú, egyszálú, endogén, nem kódoló kis RNS-ek, melyek fontos szerepet játszanak a génexpresszió poszttranszkripcionális szinten történő finomhangolásában. A fehérjét kódoló gének körülbelül 90%-a áll a miRNS-ek regulációs hatása alatt, melyek így kulcsszerepet játszanak különböző biológiai folyamatokban, többek között a sejtfejlődés, -proliferáció, -differenciálódás, -apoptózis és az immunhomeosztázis szabályozása során. Egyes miRNS-ek expressziójában bekövetkező változások hozzájárulhatnak számos kórkép, köztük szisztémás autoimmun betegségek kialakulásához is. A jelen tanulmányban összefoglaljuk a miRNS-ek biogenezisét, az immunrendszer szabályozásában betöltött szerepüket, illetve áttekintjük a legújabb kutatási eredményeket szisztémás lupus erythematosusban, primer Sjögren-szindrómában, rheumatoid arthritisben és szisztémás sclerosisban. A jövőben a miRNS-ek nemcsak mint biomarkerek segíthetnek majd a diagnózis és prognózis meghatározásában, hanem potenciális terápiás célpontokként is alkalmazhatók lehetnek az autoimmun betegségek modern terápiájában. Orv Hetil. 2019; 160(15): 563–572.

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.

Myeloid-derived suppressor cells are a heterogeneous group of immature myeloid cells with immunoregulatory function. When activated and expanded, these cells can suppress T cell functions via cell-to cell interactions as well as soluble mediators. Recent studies investigated the involvement of MDSC in autoimmune diseases. Some papers have described beneficial effect of MDSC during the course of autoimmune diseases, and suggest a potential role as a treatment option, while others failed to detect these effects. Their contributions to autoimmune diseases are not fully understood, and many questions and some controversies remain as to the expansion, activation, and inhibitory functions of MDSC. This review aims to summarize current knowledge of MDSC in autoimmune disorders.

Differential diagnosis of patients with Sjögren's syndrome (SS), IgG4-related disease (IgG4-RD) and SS patients having high risk for lymphoma (LHR) can be challenging. Some patients with IgG4-RD might be misdiagnosed as having SS. There are special symptoms of SS that raise the possibility of IgG4-RD whereas other symptoms identify patients as having LHR. The purpose of this study was to characterize and compare patients with SS, possible IgG4-RD and SS patients with LHR. Sixty-five SS patients were divided into 4 subgroups according to having possible IgG4-RD (n = 15), LHR (n = 16), eligible for both aforementioned groups (n = 20) and not eligible for either group (n = 14), respectively. Four patients fulfilled the diagnostic criteria for IgG4-RD. The serum levels of IgG4 were significantly higher in patients suspicious for IgG4-RD compared to that of LHR patients (0.46 g/l vs. 0.12 g/l, p = 0.032). Shared features of the patient groups (salivary gland swelling (SGS) and lymphadenopathy), were separately analysed: SGS patients had higher IgG4/IgG ratio (p = 0.036), lymphadenopathic patients had higher IgG4 levels (p = 0.042). Some patients may be "hidden" under the diagnosis of SS. Although patients with LHR and patients with possible IgG4-RD share some symptoms, they differ significantly regarding IgG4 levels and IgG4/IgG ratio.

Influence of epidemiology and ethnicity on systemic expression of primary Sjogren syndrome in 9974 patients

Background Primary Sjogren’s syndrome (pSS) is a systemic and progressive autoimmune disease characterised by lymphoid infiltration and progressive alteration of exocrine glands secretory function. Ectopic germinal center-like structures harbour plasma cells that generate autoantibodies leading to immune complex formation. Leniolisib (CDZ173) is an oral low molecular weight compound that selectively inhibits the lipid kinase PI3Kδ. In animals, leniolisib blocks PI3Kδ-dependent B cell functions, disrupts germinal centre formation and immune cell trafficking, supporting the rationale for a PI3Kδ–targeted therapy in pSS Objectives To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical efficacy of multiple oral doses of leniolisib, after 12 weeks of treatment, in pSS patients Methods Double-blind, randomised, placebo-controlled, parallel-design study recruited 30 seropositive pSS patients with moderate to severe disease activity as determined by EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI)≥6, EULAR Sjogren‘s Syndrome Patient Reported Index (ESSPRI)≥5 and stimulated whole salivary flow rate >0 mL/min. Patients were randomised in a 2:1 ratio to receive leniolisib (70 mg b.i.d) or placebo. The primary outcome was change in ESSPRI at week 12. Secondary outcomes included PK, changes in ESSDAI, the Short Form-36 (SF-36), Multidimensional Fatigue Inventory (MFI) and global Visual Analogue Scales (VAS) completed by patients and physicians. Additional assessments included lacrimal gland function and biomarkers relevant to pathway and disease Results Overall safety and tolerability profile of leniolisib was acceptable, but appeared less favourable than placebo. In particular, rash occurred more frequently in the leniolisib group (11/20 patients) compared to placebo (1/10 patients). There was a slight improvement (not statistically significant) in ESSPRI scores (dryness, pain and fatigue) favouring leniolisib. Similar trends were observed in secondary endpoints (SF-36/mental and physical, MFI, VAS completed by patients and physicians). After 12 weeks of treatment, there was a slight improvement (not statistically significant) in the lacrimal gland function in the leniolisib group compared to placebo. The observed PK profile was as expected based on healthy volunteer data. Biomarker results suggest a strong and sustained target and pathway engagement, as evidenced by inhibition of phosphorylated Akt in ex-vivo stimulated B cells, significant decrease in serum CXCL13 and reduced frequency of circulating Follicular T helper-like cells. There was a trend of decreasing autoantibody levels in leniolisib-treated patients Conclusions Leniolisib had an acceptable safety and tolerability profile, but caused rashes a known class effect of PI3K inhibitors. Target and pathway engagement were confirmed, however no clear efficacy signal for leniolisib was seen based on ESSPRI and ESSDAI in this Proof-of-Concept study at the studied dose. Disclosure of Interest T. Dorner: None declared, M. Zeher: None declared, U. Laessing: None declared, F. Chaperon: None declared, S. De Buck: None declared, A. Hasselberg: None declared, M.-A. Valentin Shareholder of: Novartis stock option, Employee of: Novartis, S. Ma: None declared, M. Cabanski: None declared, C. Kalis: None declared, C. Burkhart: None declared, P. Gergely: None declared

Objectives To take a “high-definition” picture of the main features of primary Sjogren syndrome (SjS) following a worldwide data-sharing cooperative merging of international clinical SjS databases. Methods The Big Data Sjogren Project Consortium is an international, multicentre registry created in 2014 including leading clinical centres in SjS of the 5 continents that shared a harmonised data architecture and conducted cooperative online efforts to refine collected data of primary SjS patients fulfilling the 2002 classification criteria. Results By January 2018, the participant centres had included 10 475 patients from 22 countries, including 7637 (73%) patients from Europe, 1420 (14%) from America, 1186 (11%) from Asia, 167 (1.4%) from Australia and 65 (0.6%) from Africa. The cohort included 9781 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years. The frequencies of fulfilment of the 2002 criteria were 92% for dry eye, 94% for dry mouth, 83% for abnormal ocular tests, 82% for positive minor salivary gland biopsy, 78% for abnormal oral diagnostic tests and 76% for positive anti-Ro/La antibodies. The frequency of positive immunological markers at diagnosis was 79% for ANA, 73% for anti-Ro, 49% for RF, 45% for anti-La, 13% for low C3 levels, 14% for low C4 levels and 7% for cryoglobulins. Conclusions International data sharing-based projects merging disperse clinical registries may be essential tools to increase current knowledge and to improve patient care in specific systemic autoimmune diseases. Disclosure of Interest None declared

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.

Objectives To analyse the influence of geolocation on the clinical systemic presentation of primary Sjogren syndrome (SjS) at diagnosis. Methods The Big Data Sjogren Project Consortium is an international, multicentre registry created in 2014. Centres were classified by continent, with an additional north-south sub-classification according to latitude (>or or or Results The highest baseline ESSDAI scores were reported from Southern vs Northern countries in Europe (7.2 vs 4.6, p Conclusions This study provides the first evidence for a strong influence of geolocation on the systemic phenotype of primary SjS at diagnosis. Geographical determinants should be considered as key variables when systemic disease is scored. Disclosure of Interest None declared

Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis.

Baseline Essdai/ Das Scores In 8061 Patients With Primary Sjogren Syndrome : Characterization Of Systemic Disease

Objectives Baseline characterization of European patients diagnosed with primary Sjogren syndrome (SS) according to the 2002 AE criteria. Methods The Big Data Sjogren Project was formed in 2014 to take a “high-definition” picture of the main features of primary SS by merging international SS databases. International experts of the EULAR-SS Task Force were invited to participate. By January 2017, the database included 9302 consecutive patients recruited from 21 countries of the 5 continents. Results A total of 6586 (71%) patients were included from European countries. In comparison with non-European countries, European patients had a higher mean age (54 v 51yrs, p Conclusions European patients are diagnosed at older age, are more frequently men, and presented a lower frequency of anti-Ro/La antibodies and a higher frequency of immunological markers related to mixed cryoglobulinemia. Disclosure of Interest None declared

Aim We described earlier a simultaneously increased that the increased expression of miRNA-146a/b was accompanied by an increase in the expression of and TRAF6 and a decrease in the expression of IRAK1 genes in the peripheral mononuclear cells (PBMCs) of patients with primary Sjogren's syndrome (pSS) patients. Recently, the expression of EBV encoded. RNA (EBER) was published in the B cells of salivary glands of in pSS. In the present study, we applied an EBV-EBER1 specific synthetic single stranded complementary DNA molecule (EBV-EBER1-cDNA) to test whether any EBER1 related effect exists also in PBMCs of pSS patients. Methods In the PBMCs of pSS patients and healthy controls, we investigated in vitro the effects of a synthetic single stranded EBV-EBER1-cDNA molecule, synthetic double-stranded (ds)RNA polyinosinic-polycytidylic acid [poly (I:C)] and polyadenylic acid potassium salt poly-adenylic acid [poly-(A)] on the expression of TRAF6 gene tested by qRTPCR. The release of interferon -α was detected by ELISA. Results EBV-EBER1-cDNA resulted in a significant reduction in the expression of TRAF6 in the cells of patients, but in the healthy controls not, whereas the treatments with poly (I:C) and poly-(A) could not reduce the TRAF6 over-expression. No release of EBER1 could be observed in the culture supernatants of patients with pSS. Only the treatment with poly (I:C) resulted in a significant increase of interferon -α release, and only in the heathy controls. No release of EBER1 molecules took place during the culturing of cells. EBV-EBER- cDNA acted functionally on the cells of patients only. Conclusion These findings give a further evidence of the linkage between EBV and pSS, furthermore, they show the possible role of EBV-EBER1 in the induction of increased TRAF6 expression in the peripheral B cells of Sjogren's patients.

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.

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies.

ObjectivesTo analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.MethodsThe Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed.ResultsWe included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69).ConclusionsThis study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

Follicular helper T (TFH) cells play crucial role in B-cell differentiation and antibody production. Although, atopic dermatitis (AD) is often associated with increased serum IgE levels, B-cell mediated responses have not been studied thoroughly. The aim of our study was to investigate the proportion of TFH-like cells in the disease. Twelve children and 17 adults with AD as well as 14 healthy controls were enrolled in the study. The frequency of CD4+CXCR5+ICOS+PD-1+ TFH-like cells and their IL-21 cytokine production were determined by flow cytometry. Immunohistochemical analysis was performed on skin biopsy specimens from AD patients for the detection of TFH markers. The percentages and absolute numbers of circulating TFH-like cells were significantly increased in children with AD compared to adult patients and healthy controls. IL-21 cytokine production of TFH-like cells was also elevated and showed a strong positive correlation with paediatric patients' SCORAD index. The expression of TFH-specific markers showed only a non-specific scattered pattern in skin biopsy specimens. This is the first study to demonstrate that TFH-like cells expanded in the peripheral blood of children with AD compared to adults. These results reinforce the importance of further investigations on TFH-like cells in different phenotypes and endotypes of AD.

Objective: The objective was to investigate the early (20 minutes) effects of 21 L-amino acids on the activation of human neutrophils and to determine in healthy individuals the effects of a meal on the 1) number and relative luminescence unit (RLU) of peripheral neutrophils, 2) serum glutamate and glucose levels and 3) mTOR signaling network. Methods: The RLU of neutrophils stimulated by Ca2+ ionophor (CaI) and phorbol myristate acetate (PMA) following amino acid supplementation (3 x 10-4 M) or after consuming a meal was determined. L-glutamate was measured by HPLC. Results: All amino acids resulted in significant inhibitions of neutrophil RLU, except for arginine, which stimulated neutrophils. The ratios of amino acid induced inhibition were significantly higher in the cells stimulated by PMA than by CaI. The consumption of a meal resulted in a significant serum glutamate elevation compared to baseline (2.3 versus 0.9 x10-4 M) 90 minutes after ingestion of the meal. It was independent of the body mass index and returned near fasting levels after 150 minutes. The number of neutrophils was significantly elevated 90 minutes after the meal but the PMA induced RLU was significantly decreased. Conclusion: Our ex vivoand in vivoresults suggest that the L-amino acids, independent of their metabolic significance, may continuosly and quickly modify the activity of human peripheral neutrophils, and also the outcome of various immunologic reactions. The activation of the mTORC1 complex likely involves a transient impairment in the function of mTORC2 complex in these processes.

Several autoimmune rheumatic diseases have been associated with accelerated atherosclerosis or other different types of vasculopathy depending on the underlying disease, leading to increased cardio- and cerebrovascular disease risk. Polymyositis (PM) and dermatomyositis (DM), members of idiopathic inflammatory myopathies (IIMs), a group of systemic autoimmune diseases are also associated with elevated risk of cardiovascular diseases (CVD). Up until now, no specific data is known on the mechanisms, risk factors, or possible vasculopathy leading to increased CVD risk. The aims of the present study were to assess the flow-mediated dilatation of the brachial artery by a TensioClinic arteriograph and to measure the thickness of carotid artery intima-media, the augmentation index, and the pulse wave velocity using high-resolution ultrasonography in a cohort of PM and DM patients. We also investigated the correlation of these parameters with the traditional risk factors of atherosclerosis and overall cardiovascular status within PM and DM patients. Twenty-seven patients (21 females, six males) with IIMs were enrolled in this study, and 38 healthy individuals matched for sex and age served as controls. We found a decreased flow-mediated dilatation in the brachial artery (6.36 vs. 8.39 %) with increased arterial stiffness and carotid artery thickness in our patients compared to healthy controls. We found significantly decreased flow-mediated dilatation of the brachial artery (5.57 vs. 8.39 %) in DM patients. We also detected a correlation between these parameters and the traditional cardiovascular risk factors, as well as hypertriglyceridemy, hypertension, and peripheral arterial disease. In DM, overall, more vascular abnormalities were found than in PM. Our findings suggest that flow-mediated dilatation of the brachial artery, arterial stiffness, and carotid artery thickness measurements could be beneficial for predicting the CVD risk in myositis patients. Further investigations need to find the potential differences and role of inflammation and immune mechanisms in atherosclerotic processes in DM and PM.

The changes in the number of CD8⁺ T lymphocytes were studied before (0 day) and then 30 days after the autologous hematopoietic stem cell transplantations (AHSCT) in 14 therapy refractory patients with autoimmune diseases. The years of survival and the clinical states were also evaluated. The number of CD8⁺ T cells was determined by an hematologic automat and by flow cytometry. Longer than 5-year survival times were found in 6 cases, whereas there was no progression (improvement) in 2 cases, and 4 patients were lost. The increase in the number of CD8⁺ cytotoxic T cells was gradual in the first 2 months and reached the significantly highest values among all subtypes of lymphocytes. It was of a special interest that in all the 4 patients who died, the numbers of CD8⁺ T cells were less than 150/μl on the 30th day after AHSCT, whereas all the 10 patients with a higher cell number survived. These results suggest that the early monitoring of the number (not only the ratio) of regenerating CD8⁺ T cells in the peripheral blood can be a useful and quantitative laboratory measurement after AHSCT, and it has a significant relation also to the survival times of transplanted patients.

Objective.To study the survival rate and prognostic indicators of mixed connective tissue disease (MCTD) in a Hungarian population.Methods.Two hundred eighty patients with MCTD diagnosed between 1979 and 2011 were followed prospectively. Clinical features, autoantibodies, and mortality data were assessed. Prognostic factors for survival were investigated and survival was calculated from the time of the diagnosis by Kaplan-Meier method.Results.A total of 22 of 280 patients died: the causes of death were pulmonary arterial hypertension (PAH) in 9 patients, thrombotic thrombocytopenic purpura in 3, infections in 3, and cardiovascular events in 7. The 5, 10, and 15-year survival rates after the diagnosis was established were 98%, 96%, and 88%, respectively. The deceased patients were younger at the diagnosis of MCTD compared to patients who survived (35.5 ± 10.4 vs 41.8 ± 10.7 yrs; p < 0.03), while there was no difference in the duration of the disease (p = 0.835). Our cohort study showed that the presence of cardiovascular events (p < 0.0001), esophageal hypomotility (p = 0.04), serositis (p < 0.001), secondary antiphospholipid syndrome (p = 0.039), and malignancy (p < 0.001) was significantly higher in the deceased patients with MCTD. The presence of anticardiolipin (p = 0.019), anti-β2-glycoprotein I (p = 0.002), and antiendothelial cell antibodies (p = 0.002) increased the risk of mortality.Conclusion.Overall, PAH remained the leading cause of death in patients with MCTD. The prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD. The presence of antiphospholipid antibodies raised the risk of mortality.

The therapeutic options in systemic sclerosis (SSc) are limited mainly to the management of complications, and decelerating fibrosis and preventing disease progression are still great challenges. Extracorporeal photopheresis (ECP) is one of the promising therapeutic strategies in SSc; nevertheless, there is no consensus on the ideal timing and frequency of treatment cycles. In the present study, we evaluated the long-term effects of consecutive ECP treatments, and the stability of clinical and laboratory improvements. We enrolled nine patients with diffuse cutaneous SSc and performed 12 ECP cycles (24 ECP treatments) per patient in total. ECP cycles were carried out once in every 6 weeks, and each cycle consisted of two procedures. Sixteen healthy individuals served as controls for laboratory assessment. Following the sixth ECP cycle, we observed further improvement in skin score, which was confirmed by high-resolution ultrasonography as well. After the second ECP cycle, values of Tr1 and CD4+CD25(bright) Treg cells increased; however, Tr1 cells remained under control values until the 10th cycle. Suppressor activity of CD4+CD25+ Treg cells improved, while percentages of Th17 cells decreased. At the end of 12-month follow-up, we did not observe significant deterioration in skin involvement; however, improvement in laboratory parameters diminished after 12 months. If the first six ECP cycles are effective, uninterrupted continuation of treatment should be considered, which may lead to the normalization of Tr1 cell values along with further clinical improvement. Our laboratory observations indicate that immunomodulatory effect of ECP treatments lasts for 1 year only.

Recently, we reported elevated proportions of circulating follicular T helper cells and higher levels of interleukin- (IL-) 21 in primary Sjögren’s syndrome (pSS). Interaction of invariant natural killer T (iNKT) cells with B cells and granzyme B (GrB) production may be also important in pSS. Thirty-two pSS patients and 24 healthy controls were enrolled in our study. We investigated the expression of intracellular GrB and IL-21 receptor (IL-21R) of CD19+CD5+and CD19+CD5−B cells; furthermore, we determined the IL-21 expression of iNKT cells as well. We also assessed the proportion of transitional (CD19+CD24highCD38high), mature (CD19+CD24intCD38int) and primarily memory (CD19+CD24highCD38-) B cells. CD5+but not CD5−B cells showed elevated GrB and IL-21R expression in pSS; additionally IL-21 expression of iNKT cells was also elevated. The ratios of transitional and mature B cells were elevated in pSS, while primarily memory B cell percentages were decreased, which correlated with GrB and IL-21R expression of CD19+B cells. Our results suggest that enhanced IL-21R expression of CD19+CD5+B cells and production of IL-21 by iNKT cells may play an important role in the pathogenesis of pSS by regulating CD19+CD5+B cell functions and increasing GrB production, presumably leading to a counter-regulatory effect in the disease.

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.

Background There are conflicting data on the occurrence of subclinical myocardial dysfunction in psoriatic patients and on the impact of long-term tumour necrosis factor-alpha (TNF-α) inhibitor therapy on cardiac function. Objective In this study, we explored whether there are any signs of subclinical cardiovascular disease (echocardiographic abnormalities) in severe psoriatic patients without clinically overt heart disease. As a second objective, the influence of long-term treatment with TNF-α inhibitors on the ventricular functions of psoriatic patients was also investigated. Methods Clinical and echocardiographic data from 44 psoriatic patients and 45 age- and sex-matched controls were processed. As a first step, the echocardiographic parameters of psoriatic patients obtained before anti-TNF-α treatment were compared with controls. As a second step, to detect the effect of long-term anti-TNF-α treatment on echocardiographic parameters, data of patients before and after therapy were analysed. Results The right ventricular Tei index was higher (P

The aim of the present study was to assess the autoantibody profile, dominant clinical symptoms and cluster characteristics of different Mixed connective tissue disease (MCTD phenotypes. Two-hundred-and-one patients with MCTD were followed-up longitudinally. Five clinical parameters, Raynaud’s phenomenon, pulmonary artery hypertension (PAH), myositis, interstitial lung disease (ILD), erosive arthritis and five auto-antibodies besides anti-U1RNP, antiendothelial cell antibodies (AECA), anti-CCP, anti-cardiolipin (anti-CL), anti-SSA/SSB and IgM rheumatoid factor (RF) were selected for cluster analysis. The mean age of patients was 52.9 ± 12.4 years and the mean follow-up of the disease was 12.5 ± 7.2 years. Patients were classified into three cluster groups. Cluster 1 with 77 patients, cluster 2 with 79 patients and cluster 3 with 45 patients. In cluster 1 the prevalence of PAH (55.8%; p

Atherosclerosis is a systemic disease affecting the coronary, carotid, intracerebral, renal and peripherial arteries. The early morphological and functional impairments could be detected in the second or third decades of life and their progression depend on the number and severity of risk factors and individual susceptility. Although the vascular risk factors (smoking, overweight, age, unhealthy diet, lack of physical exercise, hypertension, diabetes mellitus, chronic kidney disease and dyslipidemia) are the same and common in the different vascular diseases, the present clinical routine artificially classifies the diagnosis and therapy of different vascular diseases into different subfields of medicine with the negative impact of possible polypragmasia. Recently, worldwide health surveys (e.g. REACH registry) have proven the usefulness of a holistic approach in the diagnosis and therapy of multiorgan-affected vascular patients. This review summarizes the multidisciplinary advances and future perspective of vascular diseases. Orv. Hetil., 2012, 153, 483–498.

The aim of this study was to evaluate the clinical and immunomodulatory effects of extracorporeal photochemotherapy (ECP) in systemic sclerosis (SSc). We enrolled 16 patients with diffuse cutaneous SSc, who received 12 ECP treatments in total. After ECP treatments, the dermal thickness reduced and the mobility of joints improved. Internal organ involvement did not deteriorate. The percentages and numbers of peripheral Th17 cells decreased, the values of Tr1 and Treg cells increased, and the suppressor capacity of Treg cells improved. Interestingly, we found a positive correlation between the reduction of IL-17 levels and skin thickness measured by ultrasound. Moreover, levels of CCL2 and TGF-beta decreased, while the concentration of IL-1Ra, IL-10 and HGF elevated during the therapy. ECP treatments contribute to the restoration of disproportional autoimmune responses and attenuate fibrotic processes, thus decelerate the disease progression. Accordingly, ECP can be a useful element of novel treatment modalities proposed for SSc.

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.

Aim The microRNA-155 (miR-155) is regarded as a central modulator of T-cell responses and could be a potential therapeutic target for certain inflammatory diseases. In our present study we analyzed the expression rate of miR-155 and its functionally linked gene, the suppressor gene of cytokine signaling 1 (SOCS1) in primary Sjogren's syndrome (pSS). Method We enrolled 23 pSS patients and 10 healthy individuals in the study. The expression of miR-155 and SOCS1 gene were measured by real-time polymerase chain reaction. Results We observed the over-expression of miR-155 in the peripheral mononuclear cells of patients with pSS. Surprisingly, SOCS1 gene was also over-expressed in pSS patients. Conclusion This unanticipated phenomenon might be a laboratory characteristic of Sjogren's syndrome, and presumably a consequence of the noteworthy difference in the pSS immune system reacting with Epstein–Barr virus.

Abbreviations ABVD Doxorubicin 25mg/m2, bleomycin 10mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2 Anti-SSA Anti-Sjogren’s syndrome A (SSA) Anti-SSB Anti-Sjogren’s syndrome B (SSB) ASCT Autologous stem cell transplantation Bwkg Body weight kilogramm CA 19–9 Carbohydrate antigen 19–9 CD Cluster of differentiation EBV Epstein-Barr virus HL Hodgkin’s lymphoma NHL Non-Hodgkin lymphoma PET-CT Positron emission tomography—computed tomography PTLD Posttransplant lymphoproliferative disorder SCT Stem cell transplantation VAD Vincristine 2 mg i.v., doxorubicin 9 mg/m2 i.v. es dexamethasone 40 mg WHO World health organisation Background

Mycophenolic acid, in combination with glucocorticoids, has been shown in a series of trials to be safe and effective for treatment of lupus nephritis. Regimens that permit glucocorticoid dose reduction without loss of efficacy would be advantageous. MyLupus was a 24-week, multicentre, open-label, study in patients with active proliferative lupus nephritis treated with enteric-coated mycophenolate sodium (EC-MPS), randomized to standard-dose ( n = 42) or reduced-dose ( n = 39) glucocorticoids. Complete response at week 24, the primary endpoint, was achieved in 19.8% (16/81) of patients (19.0% standard-dose, 20.5% reduced-dose; lower limit of 97.5% CI for the difference −15.9%, p = 0.098, i.e. non-inferiority was not shown). Partial response occurred in 42.0% of patients (34/81). From baseline to week 24, the mean global British Isles Lupus Assessment Group (BILAG) score decreased from 14.0 ± 5.4 to 5.0 ± 3.8 ( p

Conflicting data exist on the number of invariant NKT (iNKT) cells in atopic dermatitis (AD); furthermore, no data have been published on their functional capacity.The frequency and number of circulating CD3+6B11+ iNKT cells and their CD4+ and CD4- subpopulations were evaluated in peripheral blood obtained from 41 patients with AD by four-color flow cytometry. Likewise, functional properties of iNKT cells were measured by five-color intracellular cytokine staining.The number and percentage of total iNKT cells and their CD4/CD8 subpopulations were significantly lower than the controls. Of further importance, the CD4-CD8- (double negative, DN) iNKT subgroup showed the strongest positive correlation with total iNKT cells. In addition, the DN subgroup exhibited the most pronounced functional alteration with significantly decreased levels of intracellular IFNγ and significantly increased levels of intracellular IL-4 in AD patients compared with the controls.The significantly altered number and cytokine production of iNKT cells from AD patients suggests that these cells may play an important role in the pathogenesis of AD.

Autoimmune diseases are signified by complex errors of immune-regulation, and the development of autoreactive T and B cells targeting self-antigens, which eventually can lead to permanent organ damage. Despite novel therapeutic protocols, the disease course is chronic, debilitating and in some instances the outcome is lethal. Previously, stem cell transplantation has been reported to be beneficial in autoimmune animal models, as well as in autoimmune diseases related to hematological abnormalities, which opened potential new avenues in the treatment of human autoimmune diseases.In this review, the authors describe the compound cellular regulatory effects of autologous hemopoietic stem cell transplantation (ASCT) and also clinical observations, related to the therapy in a variety of organ-specific and systemic autoimmune diseases.ASCT has a broad effect on the re-populated immune system, complex regulatory potentials and long term beneficial effect via down-regulating immune-reactivity, yet its widespread use in autoimmune diseases is limited, mostly due to the serious side-effects of the conditioning treatments. However, in certain autoimmune diseases with severe debilitating, or even life-threatening course, including systemic lupus erythematosus, systemic sclerosis or multiple sclerosis, ASCT can be a reasonable choice when conventional therapy has failed.

The aim of this study was to evaluate a wide spectrum of peripheral immune-competent cell types, reflecting overall disturbances in immune homeostasis, characteristic of systemic sclerosis (SSc). We also assessed visceral organ involvement and evaluated the relationship between cell proportions and clinical symptoms of the disease.Twenty-one patients with diffuse cutaneous SSc (dcSSc) and 15 healthy individuals participated in the study. Peripheral blood lymphocyte subgroups were quantified by flow cytometry, soluble cytokines were assessed by enzyme-linked immunosorbent assay (ELISA), serum complement levels were measured by nephelometry, and autoantibodies were determined by indirect immunofluorescence staining and ELISA technique. Functional tests of regulatory T (Treg) cells were also carried out.Patients with SSc had higher percentages of activated CD3+/HLA-DR+ T cells. Comparing naive vs. memory subsets of CD4+ and CD8+ T cells, a shift towards central memory phenotype was observed in SSc. Natural killer (NK) and T-helper (Th)17 cell percentages were increased, while NKT, Th1, Treg type 1 (Tr1), and CD4+CD25+ Treg cell percentages were decreased in patients. Moreover, the suppressor activity of CD4+CD25+ Treg cells was lower in SSc. Negative correlations occurred between modified Rodnan skin score (MRSS) and Tr1 cell percentages and between complement levels and CD4+CD25+ Treg cells. We also found decreased interleukin (IL)-10 levels in SSc.Our data suggest that the increased Th17/CD4+CD25+ Treg ratio and the altered regulatory function of CD4+CD25+ Treg cells play an important role in the development of SSc. Moreover, our study reveals the potential role of the decreased profile of IL-10-producing Tr1 cells in the progression of disproportionate immune responses in SSc.

Interleukin-1 receptor antagonist (IL-1Ra) is a good indicator of disease activity in patients with systemic lupus erythematosus (SLE). Glucocorticosteroids are the most frequently used drugs in SLE. Our goal was to compare IL-1Ra activity in SLE patients with and without renal involvement and to determine the effect of different dosage of glucocorticosteroids used in 17 patients with active SLE without nephritis, 7 patients with inactive lupus nephritis (LN), and 8 patients with active LN, along with 10 healthy controls. IL-1Ra levels were measured in the serum of SLE patients by Human Luminex [100] analyzer. Both in patients with active SLE without nephritis and in patients with LN, serum levels of IL-1Ra (p

A szisztémás lupus erythematosus poliszisztémás autoimmun betegség, egyik legjelentősebb szervi szövődménye a lupus nephritis. A lupus nephritis időbeni, a krónikus szervi érintettség kialakulását megelőző felismerése, a shubok előrejelzése, a korai agresszív kezelés elkezdése és a terápia sikerességének lemérése kívánatos lenne. Ezért a kutatások egy része intenzíven a legmegfelelőbb, aktivitást előre jelző biomarker megtalálására irányul. Jelen összefoglaló célja a hagyományos szerológiai markerek megbeszélésén túl a legújabb, részben még kísérletes, a klinikai gyakorlatban nem használt, de az SLE, illetve lupus nephritis aktivitását jellemző specifikus biomarkerek bemutatása.

Objective Autoimmune polyendocrine syndrome type I (APS I) is a rare primary immunodeficiency disorder characterized by chronic mucocutaneous candidiasis, multi-organ autoimmunity and ectodermal dysplasia. Autoantibodies to parathyroid and adrenal glands and type I interferons (IFN) are hallmarks of APS I, which results from mutations in the autoimmune regulator (AIRE) gene. We wished to study clinical, immunological and genetic features of APS I in Hungarian patients, and to correlate anti-IFN-omega serum concentration with APS I and other multi-organ autoimmune diseases. Design Detailed analysis of patients with APS I and multi-organ autoimmune diseases. Patients Seven patients with APS I and 11 patients with multi-organ autoimmune diseases were studied. Measurements Mutational analysis was performed by bidirectional sequencing of AIRE. Antibodies against IFN-omega and endocrine organ-specific autoantigens were studied with radioimmunoassay. RFLP was performed by digestion of DNA with Hin6I restriction enzyme. Results AIRE sequence analysis revealed homozygous c.769C>T mutations in three patients and compound heterozygous sequence variants (c.769C>T/c.44_66dup26bp; c.769C>T/c.965_977del13bp; c.769C>T/c.1344delC) in four patients with APS I. All the six live patients tested had markedly elevated IFN-omega antibodies, which were not found in heterozygous siblings or parents. One of the identified patients was negative for antibodies against IFN-omega at 6 weeks of age, but became positive at 7 months. At age 1, he is still without symptoms of the disease. In contrast to patients with APS I, no AIRE mutation or elevation of IFN-omega antibodies were detected in patients with multi-organ autoimmune diseases. Conclusion This is the first overview of patients diagnosed with APS I in Hungary. A novel c.1344delC mutation in AIRE was detected. Anti-IFN-omega antibodies seem to appear very early in life and are helpful to differentiate APS I from other multi-organ autoimmune diseases.