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The autoimmune disorder, rheumatoid arthritis (RA), has been associated with multiple pathophysiological factors. Here the authors show that deficiency in endophilin A2 in rodents protects them from experimental arthritis by altering T cell activation threshold and effector functions, thereby hinting a potential target for RA therapy.

Abstract Objective Exercise can improve immune health and is beneficial for physical function in patients with rheumatoid arthritis (RA), but the immunological mechanisms are largely unknown. We evaluated the effect of moderate- to high intensity exercise with person-centred guidance on cells of the immune system, with focus on regulatory cell populations, in older adults with RA. Methods Older adults (≥65 years) with RA were randomized to either 20-weeks of moderate – to high intensity aerobic and resistance exercise (n = 24) or to an active control group performing home-based exercise of light intensity (n = 25). Aerobic capacity, muscle strength, DAS28 and CRP were evaluated. Blood samples were collected at baseline and after 20 weeks. The frequency of immune cells defined as adaptive regulatory populations, CD4 + Foxp3 + CD25 + CD127- T regulatory cells (Tregs) and CD19 + CD24hiCD38hi B regulatory cells (Bregs) as well as HLA-DR−/lowCD33 + CD11b + myeloid derived suppressor cells (MDSCs), were assessed using flow cytometry. Results After 20 weeks of moderate- to high intensity exercise, aerobic capacity and muscle strength were significantly improved but there were no significant changes in Disease Activity Score 28 (DAS28) or CRP. The frequency of Tregs and Bregs decreased significantly in the intervention group, but not in the active control group. The exercise intervention had no effect on MDSCs. The reduction in regulatory T cells in the intervention group was most pronounced in the female patients. Conclusion Moderate- to high intensity exercise in older adults with RA led to a decreased proportion of Tregs and Bregs, but that was not associated with increased disease activity or increased inflammation. Trial registration Improved Ability to Cope With Everyday Life Through a Person-centered Training Program in Elderly Patients With Rheumatoid Arthritis - PEP-walk Study, NCT02397798 . Registered at ClinicalTrials.gov March 19, 2015.

Abstract Background Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. Methods C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Results Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host’s ability to clear the infection. Conclusions Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.

Hydrogen peroxide (H2O2) and oxidative stress have been suggested as possible instigators of both the systemic inflammatory response and the increased vascular permeability associated with sepsis and septic shock. We measured H2O2 concentrations in the urine of 82 patients with severe infections, such as sepsis, septic shock, and infections not fulfilling sepsis-3 criteria, in patients with major burn injury with associated systemic inflammation, and healthy subjects. The mean concentrations of H2O2 were found to be lower in patients with severe infections compared to burn injury patients and healthy subjects. Patients with acute kidney injury (AKI), vs. those without AKI, in all diagnostic groups displayed higher concentrations of urine H2O2 (p < 0.001). Likewise, urine concentrations of H2O2 were higher in non-survivors as compared to survivors (p < 0.001) at day 28 in all diagnostic groups, as well as in patients with severe infections and burn injury (p < 0.001 for both). In this cohort, increased H2O2 in urine is thus associated with mortality in patients with sepsis and septic shock as well as in patients with burn injury.

IntroductionMatrix metalloproteinases (MMPs) -8 and -9 are released from neutrophils in acute inflammation and may contribute to permeability changes in burn injury. In retrospective studies on sepsis, levels of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) differed from those of healthy controls, and TIMP-1 showed an association with outcome. Our objective was to investigate the relationship between these proteins and disease severity and outcome in burn patients.MethodsIn this prospective, observational, two-center study, we collected plasma samples from admission to day 21 post-burn, and burn blister fluid samples on admission. We compared MMP-8, -9, and TIMP-1 levels between TBSA20% (N = 30) injured patients and healthy controls, and between 90-day survivors and non-survivors. MMP-8, -9, and TIMP-1 levels at 24-48 hours from injury, their maximal levels, and their time-adjusted means were compared between groups. Correlations with clinical parameters and the extent of burn were analyzed. MMP-8, -9, and TIMP-1 levels in burn blister fluids were also studied.ResultsPlasma MMP-8 and -9 were higher in patients than in healthy controls (P20% groups. MMP-8 and -9 were not associated with clinical severity or outcome measures. TIMP-1 differed significantly between patients and controls (P20% groups (P