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Objectives. The aim of the study was to analyse the cytokine memory of T-cells derived from systemic lupus erythematosus (SLE) patients and healthy donors enriched for autoantigen-specific T-cells by in vitro stimulation with SmD183–119, a common autoantigen in SLE.Methods. Autoreactive CD3+ T-cells derived from 37 SLE patients and 14 healthy donors were enriched by repetitive ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with SmD183–119. For control, PBMCs were stimulated only with interleukin-2 (IL-2). After two rounds of antigenic stimulation, cultures were stimulated with PMA/ionomycin to probe the cytokine memory by intracellular cytokine staining. Frequencies of cytokine-expressing T-cells were analysed and, in SLE patients, compared with disease activities and autoantibody levels.Results. Comparing the cytokine memory in the cultures, SLE patients displayed higher frequencies of tumour necrosis factor-α (TNF-α)+ T-cells than healthy donors and the frequencies correlated with disease activity. Frequencies of SmD183–119-specific TNF-α+ T-cells and of memory T-cells expressing interferon-γ (IFN-γ) correlated with serum anti-dsDNA antibody levels. The frequencies of IL-10 expressing SmD183–119-specific T-cells were lower among PBMCs of SLE patients. Relatively higher frequencies of IL-10+ T-cells in SLE patients correlated with low disease activities, and low anti-dsDNA and anti-SmD183–119 antibody concentrations in culture supernatants.Conclusions. The memory of autoreactive SmD183–119-specific and unspecific stimulated peripheral Th cells for re-expression of cytokines is shifted towards more cells expressing TNF-α and less IL-10+ cells, when compared SLE patients with normal donors. This shift towards proinflammatory memory effector Th cells correlates with disease severity and humoral autoimmunity. [ABSTRACT FROM AUTHOR]

In addition to releasing proteins and mediators, cells also release membrane vesicles (exosomes and apoptotic blebs) into the extracellular environment. Apoptotic blebs contain multiple autoantigens, but few data are available concerning the protein content of exosomes. Exosomes are formed during an immune response and can directly stimulate T cells or bind to dendritic cells. The aim of this study was to identify the nature of synovial exosomes from patients with different rheumatic diseases and to examine their potential autoantigenic content, which may be involved in the induction of an autoimmune response.Synovial exosomes from patients with rheumatoid arthritis (RA), patients with reactive arthritis, and patients with osteoarthritis were purified, analyzed by electron microscopy, and labeled with immunogold to detect IgG and IgM molecules. Autoantigen content was identified by 2‐dimensional electrophoresis–immunoblotting and subsequent mass spectrometry. In order to investigate the presence of citrullinated proteins, immunoblotting with anticitrulline antibodies was performed.Citrullinated proteins were observed in all exosome preparations, in contrast to other autoantigenic proteins (e.g., BiP and heterogeneous nuclear RNP A2) that were previously observed in RA and other autoimmune diseases. These citrullinated proteins included the fibrin α‐chain fragment, fibrin β‐chain, fibrinogen β‐chain precursor, fibrinogen D fragment, and the Spα (CD5 antigen‐like protein) receptor. Purification of synovial exosomes led to the detection of citrullinated fibrinogen and citrullinated Spα associated with IgM and IgG.Synovial exosomes contain citrullinated proteins, which are known to be autoantigens in RA. Although immune mechanisms in which exosomes carry citrullinated peptides could play an important role in the induction and distribution of citrullinated proteins, there must be a specific recognition of these proteins that is unique to the RA immune system. [ABSTRACT FROM AUTHOR]

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Objectives. In SSc, diagnosis and classification is based mainly on skin sclerosis. Herein, we investigated in a large multicentre cohort, to what extent skin sclerosis reflects organ involvement and additional clinical symptoms. Methods. A total of 1200 SSc patients from the register of the German Systemic Sclerosis Network (DNSS), classified as either lcSSc or dcSSc, were analysed for their serological characteristics, clinical symptoms and organ manifestations in relation to skin involvement measured by the modified Rodnan skin score (mRSS). Results. SSc patients with different mRSS did not differ significantly in their disease duration and in most of the clinical symptoms. They showed a similar distribution of most organ manifestations such as pulmonary arterial hypertension as well as cardiac, renal and nervous system involvement. More severe skin thickening was found to be associated with pulmonary fibrosis and gastrointestinal symptoms, as well as with digital ulcers and musculoskeletal involvement. Conclusions. In patients with SSc, potentially life-threatening complications and clinical symptoms with high impact on the quality of life occur independently from the extent of skin sclerosis. The diagnosis in SSc patients with a low mRSS could be missed or they could be insufficiently treated. [ABSTRACT FROM AUTHOR]

Objectives. Autoantibodies against the 20S-proteasome display a broad diversity with a remarkably low frequency of individual cross-reactivity against the different subunits of the proteasome. Although their pathogenic and diagnostic significance remains obscure, an involvement in the clearance of circulating proteasomes as well as an interaction with the activity of the proteolytic complex was assumed in previous studies. Methods. To investigate the anti-proteasome response in more detail and to disclose reactivities against former neglected subunits, two-dimensional electrophoresis followed by immunoblotting was used. As a novel antigen source, the immunosubunits LMP2 (β1i) and LMP7 (β5i) were expressed as recombinant proteins and employed in ELISA. Results. The subunits Iota (α1) and Zeta (α5) of the outer rings as well as the catalytic subunit Delta (β1) and all three immunosubunits [MECL-1 (β2i), LMP2 (β1i) and LMP7 (β5i)] of the inner rings of the proteasome were identified as autoantigens for the first time. Using a panel of anti-proteasome antibody-positive sera of patients with SLE, autoimmune myositis (PM/DM) and primary Sjögrens syndrome (pSS), an autoimmune response was documented against LMP2 (β1i) and LMP7 (β5i) in all three patient groups in ELISA. Conclusions. The frequent autoimmune response against LMP2 (β1i) and LMP7 (β5i) might indicate a role of inflammatory processes in the primary induction of the anti-proteasomal immune reaction, while the diversity of the humoral response against the proteasome system supports the assumption of a specific antigen-driven process leading to these extended autoimmune reactivities. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. Methods. ReAct (Research in Active Rheumatoid Arthritis) was a large, open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers. Patients self-administered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase. Measures of adalimumab effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, Disease Activity Score 28 (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ DI). Results. Of 6610 patients, 899 had a history of etanercept and/or infliximab therapy; these patients experienced substantial clinical benefit from adalimumab treatment. At week 12, 60% of patients had an ACR20 and 33% had an ACR50 response; 76% had a moderate and 23% had a good EULAR response. In addition, 12% achieved a DAS28 Conclusion. In typical clinical practice, adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and/or infliximab. [ABSTRACT FROM AUTHOR]