Inflammation is the principal hallmark of RA. Different pathways are implicated in the production of pro-inflammatory cytokines, the bona fide mediators of this inflammation. Among them are the TNF pathway and the IL-1 receptor/Toll-like receptor (IL-1R/TLR4) pathway. One of the potential negative regulators of IL-1R/TLR4 signalling is the Fas-associated death domain protein (FADD), which is the pivotal adaptor of the apoptotic signal mediated by death receptors of the TNF family. FADD can sequester myeloid differentiation primary response gene 88 (MyD88), the common adaptor of most TLRs, and hence hinder the activation of nuclear factor B (NF-B), the downstream transcription factor. We recently described a new regulatory mechanism of FADD expression, via the shedding of microvesicles, mediated by adenosine receptors. Interestingly, adenosine is found in high concentrations in the joints of RA patients and has been largely reported as a regulator of inflammation. This review discusses the possible link that could exist between the adenosine-dependent regulation of FADD in the inflammatory context of RA and the potential role of FADD as a therapeutic target in the treatment of RA. We will see that the modulation of FADD expression may be a double-edged sword by increasing apoptosis and at the same time limiting NF-B activation.

The use of Doppler techniques, including power, colour and spectral Doppler, has greatly increased in rheumatology in recent years. This is due to the ability of Doppler US (DUS) to detect pathological vascularization within joints and periarticular soft tissues, thereby demonstrating the presence of active inflammation, which has been reported to be correlated with the local neo-angiogenesis. In synovitis, DUS showed a high correlation with histological and MRI findings, thus it is considered a valid tool to detect pathological synovial vascularization. Moreover, it is more sensitive than clinical examination in detecting active joint inflammation and in the evaluation of response to treatment. In addition, DUS may be considered as a reference imaging modality in the assessment of enthesitis, MRI being not sensitive and histology not feasible. Moreover, it has been demonstrated to be able to detect changes in asymptomatic enthesis. In conclusion, DUS is a useful and sensitive tool in the evaluation and monitoring of active inflammation. Its widespread use in clinical rheumatological practice is recommended. The aim of this article is to review the current literature about the role of DUS in rheumatic diseases, analysing its validity, reliability and feasibility.

Objective. Behçet's disease is one of the major aetiologies of uveitis causing blindness in Asian countries. A genome-wide association study identified six microsatellite markers as disease susceptibility loci for Japanese patients with Behçet's disease. To confirm our recent results, these microsatellite markers were examined in a Korean population as a replication study.

Methods. Study participants included 119 Behçet's disease patients and 141 controls. All were enrolled in Korea. Association between the six reported microsatellite markers (D3S0186i, D6S0014i, D6S0032i, 536G12A, D12S0645i and D22S0104i) and Behçet's disease was analysed. HLA-B was genotyped by sequence-based typing methods.

Results. A microsatellite marker located near the HLA-B region demonstrated significant association with Behçet's disease (P = 0.028). The genotype and phenotype frequencies of the HLA-B*51 gene were significantly increased in patients (23.1 and 39.5%, respectively) compared with healthy controls (11.2 and 20.1%, respectively; P < 0.001).

Conclusion. Microsatellite analysis revealed that the HLA-B*51 gene was strongly associated with Behçet's disease in a Korean population.

Objective. Recent advances in molecular techniques have revealed that there is bi-directional transfer of cells between mother and child during pregnancy, and the presence of a mother's cells in her child has been termed maternal microchimerism (MMc). There is the potential for maternal cells to provoke inappropriate immune responses in the child, which could be a factor in autoimmunity including JDM. The aim of this study was to determine whether maternal (female) cells could be detected in frozen muscle sections from seven males (age range 3–13 years) with JDM participating in the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies and sections of muscle controls (age range 2–12 years).

Methods. At least 1000 cells from each section underwent FISH and confocal imaging through each nucleus. Concomitant IF for CD45 was used to determine whether MMc in muscle were lymphocytes. A non-parametric Mann–Whitney U-test was used to detect statistical differences.

Results. The frequency of MMc was higher in JDM muscle (0.42–1.14%) than in controls (0.08–0.42%) P = 0.01. No CD45⁺ MMc were observed.

Conclusion. These data confirm an increased frequency of MMc in JDM. More detailed characterization of MMc is required, particularly using phenotypic markers, to explain the role of these cells in JDM.

Objective. Evidence shows that defensins are involved in the pathogenesis of SLE and ANCA-associated small vasculitis (AASV). The copy number variation of DEFB4 has been proposed to be susceptible to inflammatory disorders. This study aims to investigate whether the DEFB4 genomic copy number variations associate with the susceptibility to these two autoimmune diseases.

Methods. A total of 1178 Chinese people were enrolled, including Panel 1 comprising 240 SLE patients and 275 matched controls, Panel 2 comprising 303 SLE patients and 248 matched controls and Panel 3 with 112 AASV patients. The DEFB4 copy number was typed by a paralogue ratio test (PRT), and all the subjects in Panel 1 were also typed using the restriction enzyme digest variant ratio (REDVR) for validation.

Results. The results from PRT and REDVR were highly concordant (R = 0.911, P = 3.85 x 10^–199) and allowed copy numbers to be assigned into integer classes with high confidence. Comparison of mean DEFB4 copy number revealed a small increase in cases with SLE both in Panel 1 (P = 0.063) and Panel 2 (P = 0.017). When pooling Panels 1 and 2 together, the association was reinforced (P = 0.002) in SLE. Such association was also observed in AASV (P = 0.009).

Conclusion. We found that a higher DEFB4 gene copy number was associated with both SLE and AASV.

Objective. To study the phenotypic characteristics of and the balance between systemic IL-7 receptor (IL-7R)α⁺ and IL-7Rα^– Tregs in primary SS (pSS) patients as compared with control subjects and to assess the functional consequences this has for (IL-7-induced) T-cell activation.

Methods. The functional properties of IL-7Rα⁺ and IL-7Rα^–(CD25⁺) CD4 T cells from pSS patients were tested in vitro. Expression of CD25 and FoxP3 by IL-7Rα⁺ and IL-7Rα^–CD4 T cells from pSS patients and healthy controls (HCs) were assessed. Also, the net ex vivo T-cell cytokine production and the capacity of IL-7 to activate total CD4 T cells from pSS patients compared with HCs in vitro was tested.

Results. IL-7Rα⁺ T cells from pSS patients strongly proliferated and their numbers were slightly reduced compared with HCs. This reduced number was caused by an increase in both anergic and suppressive IL-7Rα^–CD25⁺ T cells expressing high levels of FoxP3, but also by increases in IL-7Rα^–CD25^– CD4 T cells that only moderately expressed FoxP3. This altered balance in IL-7Rα⁺ and IL-7Rα^–CD4 T cells was accompanied by unchanged ex vivo Th1, Th2 and Th17 cytokine production of total CD4 T cells. Furthermore, the increased numbers of IL-7Rα^–CD25⁺ T cells did not prevent specific IL-7-induced Th1 and Th17 cytokine production by IL-7Rα⁺ T cells.

Conclusion. IL-7Rα⁺ cells are highly proliferating cells that respond strongly to IL-7 despite an increased number of IL-7Rα^– T cells that express FoxP3 and CD25. The recent finding that IL-7 and IL-7Rα⁺ T cells were both found to be increased in exocrine glands of pSS patients indicates that IL-7 could contribute to glandular inflammation by activation of IL-7Rα⁺ responder T cells despite the increased numbers of Tregs.

Objective. We explored the inhibitory effect of sulphoraphane (SFN), a potent inducer of Phase 2 enzymes, on cytokine-induced prostaglandin E₂ (PGE₂) and nitric oxide (NO) production and cartilage degradation in articular chondrocytes. The regulatory mechanism of SFN on nuclear factor (NF)-B was investigated.

Methods. Chondrocytes were obtained from patients with knee OA. Chondrocytes were stimulated with IL-1β or TNF-α with or without pre-incubation with SFN. Production of PGE₂ and NO was evaluated by the Griess reaction and an ELISA. The expression of microsomal PGE synthase (mPGES), cyclo-oxygenase (COX)-2 and inducible NO synthase (iNOS) was evaluated by real-time RT–PCR and western blot analysis. The regulation of NF-B activity was explored using luciferase and chromatin immunoprecipitation assays as well as a western blot for phosphorylated IB kinase (IKK), IB and the degradation of IB. Proteoglycan and type II collagen degradation products released from explant cultures were analysed using the dimethylmethylene blue assay and an ELISA for C-terminal telopeptides of type II collagen.

Results. SFN inhibited the production of PGE₂ and NO induced by IL-1β and TNF-α. At a concentration as low as 5 μM, SFN completely inhibited mPGES, COX-2 and iNOS at the mRNA and protein levels, and proteoglycan and type II collagen degradation product release in explant culture. Various signalling pathways required for the NF-B activation were affected by SFN.

Conclusion. SFN inhibited a broad range of catabolic mechanisms in articular chondrocytes. SFN may be a safe and effective candidate drug for the inhibition of cartilage degradation in arthritic diseases.