[Show abstract][Hide abstract] ABSTRACT: Although serious ocular manifestations of systemic sclerosis (SSc) have been described, tear analysis of patients with SSc has not been performed in previous studies. Our aim was to measure a wide panel of cytokines and chemokines in tears of patients with SSc and to assess the most significant molecules with a more sensitive and specific method. Unstimulated tear samples were collected from nine patients with SSc and 12 age- and gender-matched healthy controls. The relative levels of 102 different cytokines were determined by a cytokine array, and then absolute levels of four key cytokines were determined by a magnetic bead assay. Array results revealed shifted cytokine profile characterized by predominance of inflammatory mediators. Of the 102 analyzed molecules, nine were significantly increased in tears of patients with SSc. Based on the multiplex bead results, C-reactive protein, interferon-γ-inducible protein-10, and monocyte chemoattractant protein-1 levels were significantly higher in tears of patients with SSc. Our current data depict a group of inflammatory mediators, which play a significant role in ocular pathology of SSc; furthermore, they might function as excellent candidates for future therapeutic targets in SSc patients with ocular manifestations.
Full-text · Article · Dec 2015 · Immunologic Research
[Show abstract][Hide abstract] ABSTRACT: Background. Systemic sclerosis is an autoimmune disease, characterized by widespread small vessel vasculopathy, immune dysregulation with production of autoantibodies, and progressive fibrosis. Changes in levels of proangiogenic cytokines had already been determined largely in serum. Our aim was to assess the levels of VEGF in human tears of patients with SSC. Patients and methods. Forty-three patients (40 female and 3 men, mean (SD) age 61 (48-74) years) with SSc and 27 healthy controls were enrolled in this study. Basal tear sample collection and tear velocity investigations were carried out followed by an ophthalmological examination. Total protein concentrations and VEGF levels were determined in tear samples. Results. The average collected tear fluid volume developed 10.4 μL (1.6-31.2) in patients and 15.63 μL (3.68-34.5) in control subjects. The average total protein level was 6.9 μg/μL (1.8-12.3) in tears of patients and control tears contained an average of 4.132 μg/μL (0.1-14.1) protein. In patients with SSc the average concentration of VEGF was 4.9 pg/μL (3.5-8.1) and 6.15 pg/μL (3.84-12.3) in healthy samples. Conclusions. Total protein production was increased because of the smaller tear volume. Decreased VEGF in tear of SSc patients can be explained also by the decreased tear secretion of patients.
Full-text · Article · Sep 2015 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: Psoriasis is a systemic immune-inflammatory disease characterized by chronic or recurrent skin symptoms, psoriatic arthritis, enthesopathy, and uveitis. Psoriasis has recently been published to appear with various autoimmune disorders, but the coexistence has been systematically reviewed by only few studies until now. In the present study, charts and electronic database of 4344 patients with various systemic autoimmune disorders, under regular medical control at our department, were reviewed retrospectively searching for association with psoriasis. Hereby, we demonstrate 25 psoriatic patients coinciding with various systemic autoimmune diseases. The coexistence of psoriasis and autoimmune diseases resulted in the worsening of the clinical outcome of the autoimmune diseases as indicated by higher frequency and dosages of glucocorticoid use, need for biologicals, and other comorbidities. These results suggest common environmental and genetic background as well as therapeutic possibilities in the future.
Full-text · Article · Sep 2015 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: Autoimmune processes can be found in physiological circumstances. However, they are quenched with properly functioning regulatory mechanisms and do not evolve into full-blown autoimmune diseases. Once developed, autoimmune diseases are characterized by signature clinical features, accompanied by sustained cellular and/or humoral immunological abnormalities. Genetic, environmental, and hormonal defects, as well as a quantitative and qualitative impairment of immunoregulatory functions, have been shown in parallel to the relative dominance of proinflammatory Th17 cells in many of these diseases. In this review we focus on the derailed balance between regulatory and Th17 cells in the pathogenesis of autoimmune diseases. Additionally, we depict a cytokine imbalance, which gives rise to a biased T-cell homeostasis. The assessment of Th17/Treg-cell ratio and the simultaneous quantitation of cytokines, may give a useful diagnostic tool in autoimmune diseases. We also depict the multifaceted role of dendritic cells, serving as antigen presenting cells, contributing to the development of the pathognomonic cytokine signature and promote cellular and humoral autoimmune responses. Finally we describe the function and role of extracellular vesicles in particular autoimmune diseases. Targeting these key players of disease progression in patients with autoimmune diseases by immunomodulating therapy may be beneficial in future therapeutic strategies.
Full-text · Article · Aug 2015 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jul 2015 · Immunologic Research
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Feb 2015 · Clinical Reviews in Allergy & Immunology
[Show abstract][Hide abstract] ABSTRACT: A strong connection between spondylarthropathies and inflammatory bowel diseases (IBD) is well established. About 10-15 % of IBD are associated with different forms of spondylarthritis. Arthritis can be manifested as axial, peripheral form or both. The primary functions of the gastrointestinal tract are digestion and absorption of nutrients, electrocytes and maintenance of water homoeostasis. The anatomic and functional lesions could lead to the development of IBD based on molecular mimicry and bystander effects. The mechanism of the macromolecules is uptaken may affect intestinal and extraintestinal manifestation in genetically susceptible individuals by gut-associated lymphoid tissue, the interplay between innate and adaptive immunity and the neuroendocrine network.
Full-text · Article · Nov 2014 · Immunologic Research
[Show abstract][Hide abstract] ABSTRACT: Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities. In systemic autoimmune conditions, a quantitative and qualitative impairment of regulatory T cells has been shown previously, and in parallel, a relative dominance of pro-inflammatory Th17 cells has been introduced. Moreover, the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD. Additionally, we depict a cytokine imbalance, which give raise to a biased T cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of interleukin (IL)-6, IL-12, IL-17, IL-23, and interferon (IFN)-γ were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression toward serious systemic autoimmune diseases. Moreover, the early targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage.
No preview · Article · Oct 2014 · Clinical Reviews in Allergy & Immunology
[Show abstract][Hide abstract] ABSTRACT: Objective:
In this study the alteration of endothelial function, arterial stiffness and autoantibodies was investigated in patients with UCTD.
Thirty-one patients with UCTD were included in this prospective study. All the patients remained in the UCTD stage during the average 3.8 years follow-up period. The onset of UCTD was denoted as UCTD1, while the end of the follow-up period was called UCTD2. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), autoantibodies [such as anti-SSA, anti-SSB, anti-DNA, anti-RNP, anti-CCP, aCL, anti-oxidized low-density lipoprotein (oxLDL) and AECA], von Willebrand factor antigen, thrombomodulin (TM), endothelin 1 (ET-1) and lipid parameters were measured.
In the UCTD1 stage, high-sensitivity CRP (hsCRP) and endothelial cell activation and/or damage markers such as TM, ET-1 and AECA levels were significantly higher compared with controls (controls vs UCTD1: hsCRP, P < 0.0001; TM, P = 0.001; ET-1, P < 0.0001). In the UCTD2 stage, the carotid IMT increased (UCTD1 vs UCTD2, P = 0.01) and FMD further deteriorated (UCTD1 and UCTD2, P = 0.001). In UCTD2 there was a close correlation between the carotid IMT, and duration of the disease (r = 0.612, P < 0.001), the level of TM (r = 0.673, P < 0.001) and anti-oxLDL (r = 0.800, P < 0.001).
Our data suggest that the presence of inflammation and autoantibodies provoke endothelial cell activation and/or injury in UCTD patients. The persistent endothelial dysfunction may provoke the development of atherosclerosis. FMD was found to be the most sensitive marker for arterial stiffness, and the increase of IMT clearly indicated the existence of preclinical atherosclerosis in UCTD patients.
No preview · Article · Jun 2014 · Rheumatology (Oxford, England)
[Show abstract][Hide abstract] ABSTRACT: Background Heat Shock Proteis (HSP) are intracellular proteins conserved in the course of evolution. Resulting from the antigenic homology of various species, HSP60 and antibodies produced against them can provoke inflammation. Several studies have confirmed that antibodies produced against HSP can facilitate the occurence of atherosclerosis in autoimmune diseases.
Objectives The authors analysed the presence of anti-HSP antibodies and their correlation with cardiovascular diseases (CVD) in 30 MCTD patients.
Methods The serum level of HSP60 antibodies was measured in the serum of thirty MCTD patients at the Division of Clinical Immunology. Fifteen out of the thirty patients had cardiovascular (CVD) disease. The antibodies were detected by ELISA assay. The lipid parameters, beside the paraoxonase activity, also identified the anti-U1RNP antibody, the antibody against endothelial cell (AECA), the anti-cardiolipin (anti-CL), the endothelin-1 (ET-1) levels and the intima-media (IMT) thickness.
Results The level of anti-HSP60 antibodies was higher in the serum of patients with MCTD than in the control group (control and all MCTD: 104.0 (69.0-173.0) OD vs. 173.0 (125.0-265.0) OD, p<0.016). The CVD positive patients had a higher anti-HSP60 level than the CVD negative ones (MCTD CVD positive and CVD negative: 259.0 (176.0-316.0) OD, vs. 137.0 (84.0-157.0) OD, p=0.0013).
The MCTD patients' HDL cholesterol level (p=0.024) and their paraoxonase acitivity were lower than those of the control group. The anti-U1RNP (p<0.0022) serum level and the IMT were also higher in the control group (p=0.002).
The CVD positive patients' serum concentration of anti-HSP60 (p<0.0013), anti-CL IgG (p=0.0005) the ET-1 (p<0.05), and IMT (p<0.001) were significantly higher than that of the CVD negative control group. A close correlation was found between the anti-HSP60 antibody and the AECA (r=0.36, p=0.01) and between the serum levels of anti-HSP60 and ET-1 (r=0.62, p<0.001)
Conclusions The presence of anti-HSP60 antibody showed a strong correlation in MCTD with CVD disease, endothelial injury, IMT value and can be considered an atherosclerotic risk factor in MCTD patiens.
Disclosure of Interest None declared
No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract] ABSTRACT: Heat-shock protein 60 (Hsp60) has been shown to provoke inflammation, and anti-Hsp60 may facilitate the development of atherosclerosis. In this study, we have investigated 30 patients with mixed connective tissue disease (MCTD) and assessed anti-Hsp60 and their relationship to cardiovascular diseases (CVD). Out of 30 patients with MCTD, 15 had CVDs. Anti-Hsp60 antibody was determined by enzyme-linked immunosorbent assay. Since endothelial dysfunction and accelerated atherosclerosis are characteristic to MCTD, a wide array of MCTD-, endothelial dysfunction- and CVD-associated parameters was investigated: serum lipid levels, paraoxonase activity (PON1), rich nuclear ribonucleoprotein U1 (anti-U1RNP), anti-endothelial cell antibodies, anti-cardiolipin and anti-β2-glycoprotein I antibody isotypes (anti-CL and anti-β2GPI), endothelin-1 (ET-1) levels, also intima–media thickness (IMT), a quantitative indicator of atherosclerosis. In MCTD, anti-Hsp60 antibody levels were significantly higher than in healthy individuals (p
No preview · Article · May 2014 · Immunologic Research
[Show abstract][Hide abstract] ABSTRACT: The authors report a rare case of a female patient with mixed connective tissue disease (MCTD) with coexisting antiphospholipid syndrome (APS). Five years after the diagnosis of MCTD high concentrations of anticardiolipin (anti-CL) and anti-β2-glycoprotein (anti-β2GPI) autoantibodies were present in the patient's serum without thrombotic events. Epstein-Barr virus (EBV) reactivation provoked APS, with the clinical manifestations of livedo reticularis, digital gangrene and leg ulcers. Skin biopsy from the necrotic area showed multiple fibrin microthrombi in the superficial vessels. Corticosteroid pulse therapy, and plasma exchange in combination with synchronized cyclophosphamide was administered, which led to improvement of the digital gangrenes, while no new lesions developed. The number of CD27(high) plasma cells decreased, and the previous high levels of autoantibodies also normalized in the peripheral blood. In the case of MCTD with coexisting APS combination therapy, including plasmapheresis has beneficial effects.
[Show abstract][Hide abstract] ABSTRACT: Our aim was to assess whether the presence of highly active effector T-cells in atopic dermatitis (AD) is associated with changes in the number and/or function of regulatory T-cells (Tregs). Flow cytometry was utilised to determine the percentage of CD4+CD25brightCD127-/lowFOXP3+ and skin-homing CLA+CD4+CD25brightFOXP3+ Tregs in healthy controls and AD patients. The correlation between disease severity and Treg percentages was estimated. Treg suppressor activity and cell proliferation were measured after T-cell stimulation. Significantly increased percentages of Tregs were found in AD patients compared to healthy individuals, and significant correlation between the frequency of Tregs and disease severity was also detected. The otherwise normal suppressor activity of Tregs decreased in the presence of Staphylococcus enterotoxin B (SEB). In conclusion, the continuous presence of SEB can trigger an acquired functional impairment of Tregs in AD patients and the correlation between the increased frequency of Tregs and disease severity supports their important role in AD pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is a common autoimmune disease in which a heterogeneous course and different pathogenic mechanisms are implicated in chronic inflammation and joint destruction. Despite the diagnostic contribution of anti-citrullinated protein/peptide antibodies (ACPAs) and rheumatoid factors, about one-third of RA patients remain seronegative. ACPAs belong to a heterogeneous family of autoantibodies targeting citrullinated proteins, including myelin-basic protein, several histone proteins, filaggrin and fibrin, fibrinogen or vimentin. In addition to ACPAs, antibodies directed against other post-translationally modified-carbamylated proteins (anti-CarP) were detected in up to 30% of ACPA-negative patients. Using phage display technology, further autoantibodies were recently discovered as candidate biomarkers for seronegative RA patients. Furthermore, in clinical practice, ultrasound may reveal subclinical synovitis and radiographically undetected bone erosions. To improve diagnostic certainty in undifferentiated arthritis and seronegative patients, ultrasound imaging and several new biomarkers may help to identify at risk patients and those with early disease. In this commentary we summarize recent advances in joint ultrasound and future potential of serological biomarkers to improve diagnosis of RA.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Mar 2014 · Clinical Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Avascular or aseptic necrosis is a well-defined entity leading to the degradation of cellular elements of the bone. The pathogenesis of osteonecrosis (ON) is still unknown. There are two main types of ON: traumatic or non-traumatic. Several clinical entities could associate with ON, systemic diseases, environmental factors, pregnancy, systemic autoimmune or rheumatic diseases, thrombophilia, corticosteroid therapy, cytotoxic dugs, infections, metabolic and hematologic diseases, etc. Corticosteroids (CS) are still the most frequently used therapeutic options in the early phase and during flares of these diseases. Inflammatory cytokines and antibodies have been described to participate in the pathogenesis of ON. The infiltrative disorders of the bone marrow could also contribute to the development of ON. Hereby, we describe a female patient with NHL followed by SLE in whom ON has developed at least in two localisations. Lupus flare, long-term CS therapy, lymphoma relapse or the presence of antiphospholipid antibodies were excluded. Although the bi-localised ON could be contributed to immunologic factors or trauma, the exact aetiology in this case could not be elucidated.
Full-text · Article · Dec 2013 · Osteoporosis International
[Show abstract][Hide abstract] ABSTRACT: Hodgkin's lymphoma is a lymphoid malignancy of the immune system. Its hallmark the pathognomonic Hodgkin and Reed-Sternberg cells (HRS) are derived mainly from monoclonal pre-apoptotic B-cells and carry rearranged somatically mutated immunoglobulin heavy chains. In an appropriate microenvironment HRS cells escape from apoptosis by several mechanisms, including single mutations, aberrant signaling pathways. Eventually weakened immune surveillance leads to uncontrolled, disproportional B-cell proliferation. This review summarizes the latest findings on the pathogenesis of Hodgkin's lymphoma with a special emphasis on immunological processes and depicts current and future immunotherapeutic regimes, which improve treatment outcome and reduce late toxicities.
Full-text · Article · Oct 2013 · Experimental hematology
[Show abstract][Hide abstract] ABSTRACT: A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.
No preview · Article · Aug 2013 · Human immunology