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Mechanical ventilation can induce a cytokine response that may be attenuated by a strategy to minimize overdistention and recruitment/derecruitment of the lung. Whether these physiological improvements are associated with improvements in clinical end points should be determined in future studies.

Mammalian circadian behavior is governed by a central clock in the suprachiasmatic nucleus of the brain hypothalamus, and its intrinsic period length is believed to affect the phase of daily activities. Measurement of this period length, normally accomplished by prolonged subject observation, is difficult and costly in humans. Because a circadian clock similar to that of the suprachiasmatic nucleus is present in most cell types, we were able to engineer a lentiviral circadian reporter that permits characterization of circadian rhythms in single skin biopsies. Using it, we have determined the period lengths of 19 human individuals. The average value from all subjects, 24.5 h, closely matches average values for human circadian physiology obtained in studies in which circadian period was assessed in the absence of the confounding effects of light input and sleep–wake cycle feedback. Nevertheless, the distribution of period lengths measured from biopsies from different individuals was wider than those reported for circadian physiology. A similar trend was observed when comparing wheel-running behavior with fibroblast period length in mouse strains containing circadian gene disruptions. In mice, inter-individual differences in fibroblast period length correlated with the period of running-wheel activity; in humans, fibroblasts from different individuals showed widely variant circadian periods. Given its robustness, the presented procedure should permit quantitative trait mapping of human period length.

Systemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disorder, which often involves referral to multiple medical specialists. Lupus nephritis (LN) occurs in ~35% of adults with SLE and predicts poor survival. There is currently no consensus on how to manage patients with SLE or LN across specialties and across different European countries. The Lupus Nephritis Terminology Advisory Group was formed to address this issue as it impacts upon LN treatment. It has developed consensus statements based on opinions from expert panel meetings with nephrologists, nephropathologists, rheumatologists, clinical immunologists and internal medicine specialists from many European countries, after reviewing current guidelines from the European League Against Rheumatism, the American College of Rheumatology and the participants' experience. In this article, we report consensus statements that were developed in six important areas: classification of patients with LN, how classification affects the selection of treatment options and definitions of induction, response, flare and maintenance. We have also proposed a consensus for the terminology involved in the management of LN that is consistent with clinical opinion gathered from multidisciplinary expert meetings and with existing guidelines. We believe this consensus approach provides agreed expert opinion to clinicians and will form the basis for optimising LN treatment.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of several autoantibodies. Among the multiple factors involved in SLE development, apoptotic defects and impaired clearance of cellular debris have gained considerable interest, as they contribute to autoantigen overload. Several molecules of the innate immunity, also participate in the removal of damaged and apoptotic cells. Among them are C1q, C-reactive protein (CRP), serum amyloid P protein (SAP), mannose-binding lectin (MBL), and apolipoprotein A1 (APO A1). To evaluate the prevalence of autoantibodies against CRP, SAP, MBL, APO A1, and C1q among SLE patients, and their relationship with disease activity, a total of 150 SLE patients were screened for the presence of elevated antibody titers against C1q, CRP, SAP, MBL, and APO A1, utilizing the enzyme-linked immunosorbent assay (ELISA) method. Disease activity was assessed using the ECLAM or SLEDAI scores. The study population comprised two groups of patients: 100 patients with quiescent disease (median ECLAM score 2) comprised the first group, and 50 patients with active disease (median SLEDAI score 16) comprised group 2. Elevated titers of anti-CRP antibodies were significantly elevated only in group 1 (10% versus 4% of controls). Antibodies against SAP were evaluated only among patients in group 1, and were found at a significant high prevalence (20%). Elevated titers of anti-MBL antibodies were significantly elevated only in group 1 (15% versus 3.6%); and antibodies directed against APO A1 were significantly elevated in 21% of group 1, and 50% of group 2 patients. Elevated titers of anti-C1q were evaluated only in group 2, and were found at a significant prevalence of 66%. Significant correlation with disease activity was found only for anti-APO A1 antibodies, and only in group 1. Several patients harbored more than one of the autoantibodies tested. In patients with SLE, autoantibodies directed against protective molecules, that is, acute-phase proteins involved in the disposal of cellular and nuclear debris, can be detected. These autoantibodies may play a pathogenic role in the development or perpetuation of autoimmunity in SLE.

The changes in synovial tissue after IFNbeta treatment and the in vitro data support the view that IFNbeta therapy has immunomodulating effects on rheumatoid synovium and might help to diminish both joint inflammation and destruction. Larger well-controlled studies are warranted to show the efficacy of IFNbeta treatment for RA.

Objective. Previous studies have revealed the presence of IgG antifibroblast antibodies (AFAs) capable of binding to the surface of fibroblasts in systemic sclerosis (SSc) sera. Since chemokines may directly or indirectly affect the development of fibrosis, this study was undertaken to investigate the production of chemokines induced by AFAs in fibroblasts, and to characterize the signaling pathways and surface molecules involved.Methods. AFA-positive and AFA-negative IgG were tested on fibroblasts. Chemokine messenger RNA expression was screened by microarray and quantitative reverse transcription-polymerase chain reaction. Production of CCL2, CXCL8, and CXCL10 proteins was assessed by enzyme-linked immunosorbent assay. Pharmacologic inhibitors were used to study signal transduction, with results assessed by Western blotting and immunofluorescence analysis. Fibroblasts with defective expression of Toll-like receptors (TLRs) and anti-TLR monoclonal antibodies (mAb) were used to assess AFA specificity.Results. In human fibroblasts, AFA-positive IgG induced the preferential transcription of chemokines with profibrotic and proangiogenic potential, including, but not exclusively, CCL2, CXCL1, CXCL8, CKLF, and ECGF1, which were distinctly different from those induced by interferon-␥. Levels of CCL2 and CXCL8 proteins were increased in AFA-stimulated fibroblast culture supernatants. AFA binding to fibroblasts resulted in concomitant activation of ERK-1/2, c-Jun, and NF-B. CCL2 production was sensitive to inhibition of both proteasome and JNK, while CXCL8 production was sensitive only to inhibition of proteasome. AFAs failed to up-regulate CCL2 expression in TLR-4-deficient fibroblasts but not in TLR-6-or TLR-2-deficient fibroblasts. Moreover, anti-TLR-4 mAb, but not anti-TLR-2 mAb, partially inhibited the production of CCL2 induced by AFAs in human fibroblasts. Conclusion.Autoantibodies that bind to the surface of fibroblasts may contribute to the pathogenesis of SSc by up-regulating the fibroblast production of profibrotic and proangiogenic chemokines, in a proteasomeand TLR-4-dependent manner.

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