Search

Breakdown of tolerance is a hallmark of autoimmune diseases. Over the past 10 years, there has been increased interest in the role of FoxP3+ regulatory T cells (TRegs) in maintaining peripheral tolerance. Dysfunction of these cells is considered to play a major role in the development of autoimmune diseases. Besides their suppressive function, a fraction of these cells has the capacity to differentiate into IL-17-producing cells (Th-17), a phenomenon associated with autoimmune inflammation. The revealed plasticity of TRegs, therefore, has obvious implications when designing therapeutic strategies for restoring tolerance in autoimmune diseases using TRegs. In this review, we discuss development, classification, molecular characterization and mechanisms of suppression by TRegs. In addition, we describe recent data on their potential conversion into Th-17 cells in human systemic autoimmune diseases. We also outline a new strategy for TReg-based therapy via isolation, expansion and re-infusion of highly pure FoxP3+ TRegs free of contaminating effector T cells. [ABSTRACT FROM PUBLISHER]

Objectives. To investigate whether maintaining the chondrocyte’s native pericellular matrix prevents collagen-induced up-regulation of collagenase-3 (MMP-13) and whether integrin α1 (ITGα1) and/or discoidin domain receptor 2 (DDR2) modulate MMP-13 expression and which signalling pathway plays a role in collagen-stimulated MMP-13 expression.Methods. Goat articular chondrocytes and chondrons were cultured on collagen coatings. Small interfering RNA (siRNA) oligonucleotides targeted against ITGα1 and DDR2 were transfected into primary chondrocytes. Chemical inhibitors for mitogen-activated protein kinase kinase (MEK1) (PD98059), focal adhesion kinase (FAK) (FAK inhibitor 14), mitogen-activated protein kinase 8 (JNK) (SP600125) and protein kinase C (PKC) (PKC412), and a calcium chelator (BAPTA-AM) were used in cell cultures. Real-time PCR was performed to examine gene expression levels of MMP-13, ITGα1 and DDR2 and collagenolytic activity was determined by measuring the amount of hydroxyproline released in the culture medium.Results. Maintaining the chondrocyte’s native pericellular matrix prevented MMP-13 up-regulation and collagenolytic activity when the cells were cultured on a collagen coating. Silencing of ITGα1 and DDR2 reduced MMP-13 gene expression and collagenolytic activity by primary chondrocytes cultured on collagen. Incubation with the PKC inhibitor strongly reduced MMP-13 gene expression levels. Gene expression levels of MMP-13 were also decreased by chondrocytes incubated with the MEK, FAK or JNK inhibitor.Conclusion. Maintaining the native pericellular matrix of chondrocytes prevents collagen-induced up-regulation of MMP-13. Both ITGα1 and DDR2 modulate MMP-13 expression after direct contact between chondrocytes and collagen. PKC, FAK, MEK and JNK are involved in collagen-stimulated expression of MMP-13. [ABSTRACT FROM PUBLISHER]

Objective. To investigate the effect of a moderate to high intensive exercise program on two primary outcomes (aerobic capacity, fatigue), and three secondary outcomes [anxiety, depression and health-related quality of life (HRQoL)] in women with primary Sjögren's syndrome (primary SS).Methods. Twenty-one women with primary SS were ranked according to degree of fatigue and allocated to an exercise group (TG; n = 11) or a control group (CG; n = 10). The exercise method was Nordic walking for 45 min three times a week for 12 weeks. Outcome measures assessed at baseline and after 12 weeks were aerobic capacity, fatigue, ratings of perceived exertion (RPE), anxiety, depression and HRQoL.Results. Nine women in the TG and 10 women in the CG completed the study. Analysis showed significant differences between the groups regarding aerobic capacity (P = 0.03), fatigue (P = 0.03), RPE (P = 0.03), and depression (P = 0.02) with the better values for the TG. There were no differences in anxiety or HRQoL.Conclusion. Our findings support the use of appropriate aerobic exercise in the treatment of primary SS. [ABSTRACT FROM AUTHOR]

The article describes the cases of a woman with systemic lupus erythematosus and discoid lupus and a man with nephrotic syndrome that were administered belimumab B cell targeted maintenance treatment. Rituximab is indicated as the primary treatment in the refractory lupus nephritis cases along with information issued by the European League Against Rheumatism. Synergic effect of the two drugs is speculated from the pathophysiological control of B cell hyperactivity.

The article describes the case of girl diagnosed with poly-juvenile idiopathic arthritis (JIA) treated with tacrolimus T cell-specific calcineurin inhibitor as therapeutic alternative. Prior treatment with prednisolone, acyclovir and MTX for polyarticular remission induced by varicella infection is described. Efficacy of the drug in organ and marrow transplantation applications and rheumatoid arthritis are cited in support of its potential in suppressing poly-JIA.

The article describes the case of a 31-year-old woman with migratory arthalgias, development of puffy fingers and fast, progressive centripetal skin thickening. Topics discussed include the patient being diagnosed with systemic sclerosis (SSC) with diffuse cutaneous involvement. Also mentioned are the patient receiving high-dose cyclophospamide followed by autologous haematopoletic stem cell transplantation (aHSCT) as well as possible cause of cytomegalovirus-associated pneumonia (CMV-P).

The authors discuss whether positron emission tomography (PET) scan along with a magnetic resonance imaging (MRI) scan is the key to detect heart involvement in Churg-Strauss syndrome (CSS). They mention that for clinicians, heart involvement in CSS is difficult to detect. They state that MRI is a non-invasive and low-risk technique that has is used for detection of CSS; they cite a study by Marmursztejn and colleagues which showed that PET imaging may be used additionally in some patients.

The article discusses the connection between the B-lymphocyte stimulator (BLyS) and primary Sjögren's syndrome (pSS). According to the author, BLyS us critical to the survival of B cells, its binding to receptors provides survival signals to B cells, and excess serum BLyS (sBLyS) levels were higher in patients with pSS. This was associated with the main immunological markers but also with disease activity, and further investigations of the of BLyS usefulness in patients with pSS is needed.

A letter to the editor is presented which describes the case of a 58-year old Japanese man who had a heliotrope rash and Gottron's papules of the metacarpophalangeal (MCP), elbow and knee joints.

The article cites studies on immune homeostasis which include "Unconventional T Cells," "Innate Lymphoid Cells and Stroma in Inflammation and Tissue Pathology" and "NKT Cells."

The article presents abstracts of studies on rheumatology which include the cost of treating juvenile idiopathic arthritis, the economic evaluation of self-management in people with rheumatoid arthritis (RA) and the response to TNF-Alpha inhibitors in patients with RA.

The authors reflect on the role of the antigen-experienced CD4+ T cells follicular T helper (TFH) cells in the diagnosis and treatment of autoimmune diseases. Topics discussed include the generation of TFH cells from the periphery of naive CD4+T cells, the inability of TFH cells to promote self-tolerance and autoimmunity, and the role of modified B cell function in the advancement of autoimmune diseases. Also mentioned is the potential of unsettled TFH cells to influence autoimmune diseases.

A letter to the editor is presented in response to the article "Role of Activated Macrophage and Inflammatory Cytokines in the Development of Calcinosis in Juvenile Dermatomyositis" in the previous issue.

The author reflects on the study entitled "The Arthritis-Associated HLA-B*27:05 Allele Forms More Cell Surface B27 Dimer and Free Heavy Chain (FHC) Ligands for KIR3DL2 Than HLA-B*27:09," by Alberto Cauli et alia. He gives a brief summary of the study and explains the interaction between HLA-B27 molecular forms and receptors of innate immunity. He foresees a diagnostic test that uses KIR3DL2 tetramers to detect elevated levels of B27 FHC forms in patients with spondyloarthropaties.

An abstract of the study "Investigating the Chondroprotective Potential of Mesenchymal Stem Cells in Arthritis," by Sweta S. Parida and Oksana Kehoe is presented.

The article presents abstracts of the studies "The Role of the Gut Microbiome in Axial Spondyloarthritis," by Simon Milling and "The Role of the Gut Microbione in the Differentiation of Regulatory B Cells in Arthritis," by Claudia Mauri.

The article presents a study which examined the pathogenesis of giant cell arteritis (GCA), an immune-mediated chronic inflammatory disease of large vessels. It analyzes the role played by activated macrophages, chemokines, and endothelial adhesion molecules in GCA. It cites glucocorticoids as a treatment for GCA.

The article presents the study which monitored the role of neutrophils in giant cell arteritis (GCA) over a six-month period in Great Britain as of May 2014.

The article presents the study which examined the increased rho kinase (ROCK) activity in temporal arterial biopsies (TAB) in patients with giant cell arteritis (GCA). In the study, the subjects were formed into three groups, namely, GCA with positive TAB, GCA with negative TAB, and age- and sex-matched controls. Based on the results, GCA subjects have higher phospho-ezrin/radixin/moesin (pERM) intensity scores than the controls.

The article presents the study which analyzed the normal frequencies of IFN-ϒ producing (Th1) and IL-17 producing T-cells (T-17) in patients with giant cell arteritis (GCA) in stimulated whole blood samples as of May 2014.

The article presents the study which examined the distribution of defined B cell subsets in patients with giant cell entiritis (GCA) before and after corticosteroid treatment as of May 2014.

RA is a progressive inflammatory autoimmune disease with articular and systemic effects. Its exact cause is unknown, but genetic and environmental factors are contributory. T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naïve T cells into Th 17 (TH17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production. Joint damage begins at the synovial membrane, where the influx and/or local activation of mononuclear cells and the formation of new blood vessels cause synovitis. Pannus, the osteoclast-rich portion of the synovial membrane, destroys bone, whereas enzymes secreted by synoviocytes and chondrocytes degrade cartilage. Antigen-activated CD4+ T cells amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes and osteoclasts. The release of cytokines, especially TNF-α, IL-6 and IL-1, causes synovial inflammation. In addition to their articular effects, pro-inflammatory cytokines promote the development of systemic effects, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamic–pituitary–adrenal axis, resulting in fatigue and depression. [ABSTRACT FROM PUBLISHER]

This section presents abstracts on medical topics which include scleroderma, dermal fibrosis and pulmonary arterial hypertesnion.

Background. β-catenin is the central integrator of canonical Wnt signalling. Since recent evidence suggests a central role of Wnts in fibrosis, we examined the β-catenin/Wnt pathway in SSc and focused on the role of β-catenin in fibroblast activation.Methods. We performed qPCR for several Wnt ligands and axin-2 to examine Wnt expression in SSc skin. We further studied protein levels of Wnt-1, -4, -10b and β-catenin by IHC. To establish the effects of β-catenin/Wnt signalling on collagen release, we created mice with fibroblast-specific stabilization of β-catenin (dEx3 β-catenin (wt/fl) × Col1a2; Cre-ER) as well as mice carrying fibroblast-specific deletion of β-catenin [Ctnnb1(fl/fl) × Col1a2; Cre-ER].Summary of the results. We could demonstrate mRNA overexpression of Wnt-1, -2, -9a, -9b, -10a, -10b and -16 in SSc skin. Wnt-1, -4 and -10b consistently showed strong expression in SSc skin when compared with healthy skin. On protein level, however, Wnt-4 was indistinguishable between SSc patients and healthy controls, whereas Wnt-1 and Wnt-10b protein levels were increased in SSc skin. The overexpression of Wnt-1 and Wnt-10b resulted in a prominent nuclear accumulation of β-catenin in fibroblasts. Finally, increased mRNA levels of the target gene axin-2 confirmed the activation of canonical Wnt signalling.In dEx3 β-catenin (wt/ex) mice, we addressed the consequences of enhanced Wnt signalling and increased accumulation of β-catenin in SSc. We selectively targeted β-catenin in fibroblasts. Cre-activated dEx3 β-catenin (wt/fl) × Col1a2; Cre-ER mice showed massive and spontaneous dermal thickening even 2 weeks after Cre activation. Eight weeks after Cre-activation, skin thickening cumulated at 102.6% (P < 0.001). In line with the dermal thickening, hydroxyproline content and myofibroblast counts showed strong increases.To test the therapeutic potential of targeting β-catenin/Wnt signaling, we created Ctnnb1(fl/fl) x Col1a2;Cre-ER mice to specifically delete β-catenin in fibroblasts. After Cre activation and β-catenin deletion in fibroblasts, mice were challenged with bleomycin subcutaneously for 4 weeks. We found that Cre-activated Ctnnb1(fl/fl) × Col1a2; Cre-ER mice were protected from bleomycin-induced dermal with a reduction of skin thickening by 71% (P < 0.05).Conclusions. We demonstrated a prominent activation of canonical Wnt signalling in SSc with nuclear accumulation of β-catenin in fibroblasts and activation of the target gene axin-2. Our results showed that fibroblast-specific stabilization of β-catenin resulted in enhanced collagen release, whereas deletion of β-catenin potently reduced collagen production. Together, our findings highlight a key role of β-catenin in fibroblast activation and fibrosis. Thus, β-catenin may be promising molecular target for anti-fibrotic therapies. [ABSTRACT FROM PUBLISHER]

Objectives. Objective of this multicentre, observational study was to assess effects and safety of rituximab (RTX) using the European Scleroderma Trial and Research Group (EUSTAR) cohort.Methods. EUSTAR centres were asked to provide specific data about SSc patients treated with RTX. Primary endpoints were predefined for different disease manifestations and compared between baseline and follow-up. Normally distributed data, analysed by paired t-test, are shown as mean (s.d.), and non-parametric data, analysed by Wilcoxon matched paired signed-rank test, are shown as median and interquartile range.Results. Data on 72 SSc patients treated with RTX were captured from 27 EUSTAR centres (51 females/21 males, 52 diffuse/19 limited, age 51 (44–60) years, disease duration 6 (3–10) years, 47 anti-Scl-70 positive).The most frequent RTX application scheme was 1000 mg × 2 within 2 weeks (57/72 patients). Co-treatment with other immunosuppressive drugs was reported in 28 patients.The modified Rodnan skin score (mRSS) significantly decreased vs baseline at 7 (5–9) months follow-up (n = 47, 18.2 + 10.9 vs 14.5 + 9.9, P = 0.0002). This was true for both patients with later disease stages and also for patients with earlier, extended skin fibrosis (dSSc with mRSS >16 at baseline, n = 26; 26.5 + 6.8 vs 20.4 + 8.9, P < 0.0001, reduction by 29.9%). S-HAQ was unchanged, but the European SSc activity score improved after rituximab treatment [n = 10; 3.7 (2.6–6.4) vs 1.7 (0.9–2.5), P = 0.01]. RTX had no effects on lung fibrosis (FVC, DLCO, TLC, HRCT score) in n = 11 patients with evidence for SSc-ILD.In SSc-polyarthritis patients, the DAS-28 declined at 6 months follow-up without reaching statistical significance [n = 8; 4.8 (2.5–7.5) vs 3.7 (2.6–6.6); p = 0.3]. Of 8, 5patients were RF and/or anti-CCP antibody positive. Similar results were obtained for secondary outcome measures (tender and swollen joint count, VAS, CRP, ESR).Additional positive effects of RTX were seen on SSc-related myopathy (CK levels, 273 + 177 vs 184 + 139; n = 12, P = 0.03) and on digital ulcers [total number per patient 1 (1–3) vs 0 (0–1); n = 23; P = 0.0086].During RTX treatment 14 patients had infections, 3 serum sickness, 2 allergic reactions and 1 lung fibrosis aggravation, 29 fatigue and 9 nausea. Four patients died, one possibly related to RTX treatment (pneumonia and cardiac failure 1.5 months after RTX infusion).Conclusion. This large EUSTAR cohort study points at positive effects of RTX in particular on skin fibrosis, and suggests randomized controlled trial in SSc patients. [ABSTRACT FROM PUBLISHER]

Ischaemic ulcerations of the fingertips are common in SSc and a source of pain and disability. Healing has been demonstrated with intravenous iloprost and two studies with bosentan have demonstrated reduction in the occurrence of new digital ulcers (DUs) over 4–6 months of treatment. Both bosentan studies showed no benefit in healing DU and because of this, net DU burden is no different between drug and placebo and accordingly secondary measures of outcome including pain and hand functionality are inconsistently affected. While it is likely an artefact, it remains unclear that current outcome measures including the Scleroderma Health Assessment Questionnaire (SHAQ), the UK Functional Score and the Michigan Hand Questionnaire are sensitive to change in the domain of digital ischaemia. Major events including amputation and hospitalization occur too infrequently to serve as practical measures of outcome in trials. Future studies of DU therapies will benefit from development of an ulcer-specific measure of outcome. [ABSTRACT FROM PUBLISHER]