Athan Baillet

Interleukin-23 Mediates the Intestinal Response to Microbial β-1,3-Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin‐23 (IL‐23) receptor signaling in the development of SpA and IBD, and IL‐23 overexpression in mice is sufficient for enthesitis, driven by entheseal‐resident T cells. However, in genetically prone individuals, it is not clear where IL‐23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL‐23 production and its role in SpA pathogenesis in BALB/c ZAP‐70W163C–mutant (SKG) mice injected intraperitoneally with β‐1,3‐glucan (curdlan).

Efficacy of resistance exercises in rheumatoid arthritis: meta-analysis of randomized controlled trials

OBJECTIVE To evaluate the efficacy of resistance exercises in RA patients. METHODS A systematic literature search was done using Pubmed, Embase and Cochrane databases through November 2009 and in abstracts presented at rheumatology scientific meetings over the past 3 years. Randomized controlled trials (RCTs) comparing resistance exercise based therapy with interventions without resistance exercise for the treatment of RA patients were included. Outcomes studied were post-intervention disability on the HAQ, functional capacity assessed by walking speed, pain on the visual analogue scale (VAS), joint count, isometric, isokinetic and grip strength. Efficacy was assessed by weighted mean differences (WMDs) and tolerance was assessed by relative risk (RR). Data were pooled using the inverse of variance model, and heterogeneity was tested. RESULTS Ten RCTs, including 547 patients, met the study inclusion criteria. The mean (S.D.) Jadad score was 2.3 (0.6). Resistance exercises significantly improved isokinetic strength (WMD = 23.7%, P < 0.001), isometric strength (WMD = 35.8%, P < 0.001), grip strength (WMD = 26.4%, P < 0.001) and HAQ (WMD = -0.22, P < 0.001). Exercise also had a positive impact on the 50-foot walking test (WMD = -1.90 s, P < 0.001) and ESR (WMD = -5.17, P = 0.005). Withdrawals [RR = 0.95, 95% confidence interval (CI) 0.61, 1.48] and adverse events (RR = 1.08, 95% CI 0.72, 1.63) were well balanced in both groups. Patient and exercise characteristics did not influence the results. Subgroup analysis revealed a trend towards higher efficacy associated with high-intensity programmes. CONCLUSION Resistance exercise in RA is safe, and the improvement in most outcomes was statistically significant and possibly clinically relevant for RA disability.

Recommendations for using TNFα antagonists and French Clinical Practice Guidelines endorsed by the French National Authority for Health.

The use of TNFα antagonists must follow specific guidelines to ensure optimal effectiveness and safety. The French Society for Rheumatology (SFR) and Task Force on Inflammatory Joint Diseases (CRI), in partnership with several French learned societies, asked the French National Authority for Health (HAS) to develop and endorse good practice guidelines for the prescription and monitoring of TNFα antagonist therapy by physicians belonging to various specialties. These guidelines were developed, then, validated by two multidisciplinary panels of experts based on an exhaustive review of the recent literature and in compliance with the methodological rules set forth by the HAS. They pertain to the initial prescription of TNFα antagonists and to a variety of clinical situations that can arise during the follow-up of patients receiving TNFα antagonists (infections, malignancies, pregnancy, vaccination, paradoxical adverse events, surgery, use in older patients, and vasculitides).

Evaluation of serum interleukin-6 level as a surrogate marker of synovial inflammation and as a factor of structural progression in early rheumatoid arthritis: results from a French national multicenter cohort.

Interleukin‐6 (IL‐6) is a key cytokine in rheumatoid arthritis pathogenesis. We aimed to analyze the association between IL‐6 serum levels and joint inflammation at baseline and the correlation of time‐integrated IL‐6 values with structural damage during the first 36 months of early arthritis.

Molecular Interface of S100A8 with Cytochrome b558 and NADPH Oxidase Activation

S100A8 and S100A9 are two calcium binding Myeloid Related Proteins, and important mediators of inflammatory diseases. They were recently introduced as partners for phagocyte NADPH oxidase regulation. However, the precise mechanism of their interaction remains elusive. We had for aim (i) to evaluate the impact of S100 proteins on NADPH oxidase activity; (ii) to characterize molecular interaction of either S100A8, S100A9, or S100A8/S100A9 heterocomplex with cytochrome b 558; and (iii) to determine the S100A8 consensus site involved in cytochrome b 558/S100 interface. Recombinant full length or S100A9-A8 truncated chimera proteins and ExoS-S100 fusion proteins were expressed in E. coli and in P. aeruginosa respectively. Our results showed that S100A8 is the functional partner for NADPH oxidase activation contrary to S100A9, however, the loading with calcium and a combination with phosphorylated S100A9 are essential in vivo. Endogenous S100A9 and S100A8 colocalize in differentiated and PMA stimulated PLB985 cells, with Nox2/gp91phox and p22phox. Recombinant S100A8, loaded with calcium and fused with the first 129 or 54 N-terminal amino acid residues of the P. aeruginosa ExoS toxin, induced a similar oxidase activation in vitro, to the one observed with S100A8 in the presence of S100A9 in vivo. This suggests that S100A8 is the essential component of the S100A9/S100A8 heterocomplex for oxidase activation. In this context, recombinant full-length rS100A9-A8 and rS100A9-A8 truncated 90 chimera proteins as opposed to rS100A9-A8 truncated 86 and rS100A9-A8 truncated 57 chimeras, activate the NADPH oxidase function of purified cytochrome b 558 suggesting that the C-terminal region of S100A8 is directly involved in the molecular interface with the hemoprotein. The data point to four strategic 87HEES90 amino acid residues of the S100A8 C-terminal sequence that are involved directly in the molecular interaction with cytochrome b558 and then in the phagocyte NADPH oxidase activation.

Coupling of 6-phosphogluconate dehydrogenase with NADPH oxidase in neutrophils: Nox2 activity regulation by NADPH availability

It is well known that activation of the phagocyte NADPH oxidase requires the association of cytosolic proteins (p67‐phox, p47‐phox, p40‐phox, and Rac) with the membrane cytochrome b558, leading to its conformation change. Recently, the phagocyte NADPH oxidase complex was isolated in a constitutively active form. In this complex, 6‐phosphogluconate dehydrogenase (6PGDH), an enzyme involved in the production of intracellular NADPH, was identified. This protein was absent from the oxidase complex isolated from B lymphocytes, suggesting a specific interaction with the neutrophil NADPH oxidase. To clarify the implication of 6PGDH in the NADPH oxidase activity, a siRNA approach was conducted in neutrophil‐like PLB985 cells. NADPH oxidase activity of siRNA‐transfected cells was shown to be decreased. Similar results were obtained in vitro, after reconstitution of oxidase activity with subcellular fractions isolated from siRNA‐trans‐fected cells. Interestingly, the Michaelis constant (Km) of Nox2 for NADPH increases in 6PGDH‐depleted cells. Moreover, 6PGDH coimmunoprecipitated with oxidase cytosolic factors from cytosol of stimulated cells. Data suggested that the affinity of Nox2 for NADPH is increased in the presence of 6PGDH on cell stimulation. The present work proposes a new way of NADPH oxidase activity regulation by modulating Nox2 affinity for NADPH.—Baillet, A., Xu, R., Grichine, A., Berthier, S., Morel, F., Paclet, M.‐H. Coupling of 6‐phosphogluconate dehydrogenase with NADPH oxidase in neutrophils: Nox2 activity regulation by NADPH availability. FASEB J. 25, 2333–2343 (2011). www.fasebj.org

High Chlamydia Burden Promotes Tumor Necrosis Factor–Dependent Reactive Arthritis in SKG Mice

Chlamydia trachomatis is a sexually transmitted obligate intracellular pathogen that causes inflammatory reactive arthritis, spondylitis, psoriasiform dermatitis, and conjunctivitis in some individuals after genital infection. The immunologic basis for this inflammatory response in susceptible hosts is poorly understood. As ZAP‐70W163C–mutant BALB/c (SKG) mice are susceptible to spondylo‐arthritis after systemic exposure to microbial β‐glucan, we undertook the present study to compare responses to infection with Chlamydia muridarum in SKG mice and BALB/c mice.

Role of genetics in infection-associated arthritis

Genetic discoveries in arthritis and their associated biological pathways spanning the innate and adaptive immune system demonstrate the strong association between susceptibility to arthritis and control of exogenous organisms. The canonical theory of the aetiology of immune-mediated arthritis and other immune-mediated diseases is that the introduction of exogenous antigenic stimuli to a genetically susceptible host sets up the environment for an abnormal immune response manifesting as disease. A disruption in host-microbe homeostasis driven by disease-associated genetic variants could ultimately provide the source of exogenous antigen triggering disease development. We discuss genetic variants impacting the innate and adaptive arms of the immune system and their relationship to microbial control and arthritic disease. We go on to consider the evidence for a relationship between HLA-B27, infection and arthritis, and then emerging evidence for an interaction between microbiota and rheumatoid arthritis.

Differences in MMPs and TIMP-1 expression between intervertebral disc and disc herniation.

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 8 octobre 2012

Interleukin-23 Mediates Psoriasis-Like Inflammation in the Skg Mouse Model of Spondyloarthropathy

Robinson P1, Leo P2, Pointon J3, Harris J4, Cremin K4, Bradbury L4, Stebbings S5, Harrison A6, Duncan E4, Wordsworth P3, Brown M4 1Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland 2University of Queensland Diamantina Insititute, University of Queensland, Brisbane, Australia 3National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford, UK 4University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia 5University of Otago, Dunedin, New Zealand 6University of Otago, Wellington, New Zealand