Showing papers by "Rille Pullerits published in 2018"

Smoking Is Associated With Low Levels of Soluble PD-L1 in Rheumatoid Arthritis.

Abstract: Background: Smoking is a risk factor for developing rheumatoid arthritis (RA), but the mechanism remains uncertain. We previously demonstrated that smoking lowers the T cell activation threshold by limiting programmed death protein 1 (PD-1) expression. Aim: To investigate how smoking influence the levels of soluble PD-1 ligand (sPD-L1). Method: Serum levels of sPD-L1 were measured in 246 RA patients and in 168 healthy subjects. The analysis was done with respect to inflammation, smoking, treatments and autoantibody status. The effect of therapeutic TNF-inhibiting antibodies (TNFi) on sPD-L1 was studied in 16 RA patients at their first infliximab infusion. The expression of Fcγ-receptor (FcγR) subclass IIB and IIIA was analyzed with qPCR in peripheral blood mononuclear cells (PBMC) from 12 RA patients and 15 healthy controls, and in healthy PBMC exposed to IgG containing antibodies to cyclic citrullinated peptides (aCCP). Results: The negative association between smoking and sPD-L1 in RA patients was established by multiple logistic regression (OR= 0.52, p=0.038). Other covariates in the regression model were serum levels of IL-1β, representing inflammation (OR=1.6, p=0.0076), and aCCP positivity (OR=1.9, p=0.047). First infliximab infusion repressed sPD-L1 (p=0.023) in patients, and low levels of sPD-L1 were found in patients with early RA treated with TNFi (p=0.018). Treatment with TNFi was associated with higher sPD-L1 in patients with long disease duration (p=0.041) and restored levels in smokers. In vitro exposure to aCCP+IgG suppressed sPD-L1 (p=0.036), but aCCP+ patients with long disease duration had higher sPD-L1 (p=0.016). High ratio of the inhibitory FcγR subclass IIB over the stimulatory IIIA resulted in low sPD-L1 release (p=0.029). Smoking was associated with a higher FcγR IIB/IIIA ratio (p=0.00062) and lower levels of sPD-L1 (p=0.013). Conclusion: In RA, serum sPD-L1 was related to systemic inflammation and aCCP positivity. Smoking altered the expression of FcγRs and limited sPD-L1 in RA patients, permitting inappropriate T cell responses. Differential regulation of sPD-L1 during the early and late RA may indicate transposition from acute to chronic inflammation.

Survivin Measurement improves Clinical Prediction of Transition From Arthralgia to RA—Biomarkers to Improve Clinical Sensitivity of Transition From Arthralgia to RA

Abstract: Background: Arthralgia often predates development of rheumatoid arthritis (RA). A set of joint symptoms commonly found in patients during their transition from arthralgia to RA, has been recently proposed. Aim: To combine clinical and serological markers and to improve recognition of imminent rheumatoid arthritis (RA) among patients with arthralgia. Methods: The total of 1,743 first-visit patients attending the rheumatology ward in Gothenburg for joint symptoms were identified during 12 consecutive months. Among those, 63 patients were classified as RA, 73 had undifferentiated arthritis and 180 had unexplained arthralgia. New RA cases, which prospectively developed during 48 months, comprised the preclinical (pre) RA group. The joint symptoms of the first-visit were analyzed aiming to distinguish patients with arthralgia and arthritis, and patients with pre-RA, who later developed the disease. The receiver operating characteristics curves were constructed. In the model, symptoms with the odds ratio >2.0 between the arthralgia and pre-RA were combined with information about RA-specific antibodies, C-reactive protein (CRP), and survivin in serum. Results: The proposed set of clinical symptoms distinguished the arthralgia patients from RA and pre-RA. Presence of survivin in serum showed strong association with clinical joint symptoms in arthralgia. A combination of symptoms in several small joint areas, increasing number of joints with symptoms, and patient's experience of swelling in small hand joints at the first visit identified pre-RA cases with 93% specificity. Grouping those symptoms with information about survivin, RA-specific antibodies, and CRP (or gender) in the final algorithm achieved 91% specificity and 55.2% of positive prediction for transition from arthralgia to RA. Conclusion: Clinical and serological parameters in combination aid recognition of imminent RA among arthralgia patients with appropriate sensitivity.

Lack of Receptor for Advanced Glycation End Products Leads to Less Severe Staphylococcal Skin Infection but More Skin Abscesses and Prolonged Wound Healing

Abstract: Background Lack of receptor for advanced glycation end products (RAGE) ameliorates several infections including Staphylococcus aureus pneumonia. We sought to investigate the role of RAGE in staphylococcal skin infection in mice. Methods Wild-type (WT) and RAGE deficient (RAGE-/-) mice were subcutaneously inoculated with S. aureus SH1000 strain in abscess-forming dose or necrotic dose. Clinical signs of dermatitis, along with histopathological changes, were compared between the groups. Results The skin lesion size was smaller in RAGE-/- mice. Infected RAGE-/- mice expressed lower proinflammatory cytokines in local skins compared to control mice. Low dose of bacteria caused more abscess formation in RAGE-/- mice compared to skin necrosis that was more often observed in WT mice. As a result of more abscess formation, the wound healing was prolonged in RAGE-/- mice. Importantly, RAGE-/- mice had lower bacterial loads in the skin than controls, which is correlated with higher local levels of myeloperoxidase before skin infection. In vitro, enhanced phagocytic capacity of neutrophils and macrophages obtained from RAGE-/- mice compared to control mice was observed. Conclusions RAGE deficiency up-regulates phagocytic capacity of phagocytes, resulting in lower bacterial burden in local skin and milder skin lesions in mice with staphylococcal skin infection.

Complement Consumption in Systemic Lupus Erythematosus Leads to Decreased Opsonophagocytosis In Vitro

Abstract: Objective Infections remain a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The high prevalence of infections in SLE is attributed to both the disease and its treatments. The complement system plays an important role in host immune responses against invading microorganisms. We sought to provide the experimental and clinical evidence supporting the hypothesis that low levels of complement factors cause defective complement-mediated opsonization in patients with SLE. Methods Staphylococcus aureus was opsonized with sera from healthy individuals (n = 16), SLE patients with normal (n = 5) or low complement (n = 8) levels. Phagocytosis of S. aureus by healthy human neutrophils was analyzed by an imaging flow cytometry-based method. We retrospectively examined the infection incidence in relation to complement levels in a cohort of 165 patients with SLE during a 1.5-year period. The association was analyzed for infection incidence and disease-related variables. Results Uptake of S. aureus by neutrophils was decreased when S. aureus was opsonized with sera from SLE patients with low complement levels compared to sera from healthy individuals and SLE patients with normal complement. In our SLE cohort, 44% of patients had at least 1 infection during the 1.5 years. No significant association was observed between complement levels and infection risk. Importantly, high-dose glucocorticoids (GC; prednisone ≥ 10 mg/day) were the most important predictive factor for infections in patients with SLE. Conclusion Low complement levels affect bacterial opsonization in SLE blood and lead to downregulated phagocytosis by neutrophils. High-dose GC increase the infection risk in patients with SLE.

Low Serum IGF-1 in Boys with Recent Onset of Juvenile Idiopathic Arthritis.

Abstract: Background. Liver-derived insulin-like growth factor-1 (IGF-1) contributes bone formation. Decreased IGF-1 levels are common in juvenile idiopathic arthritis (JIA), but whether IGF-1 is related to sex and differ during the pathogenic progress of JIA is unknown. Objective. The aim of this study was to examine IGF-1 levels in boys and girls with newly diagnosed JIA, with established JIA and in controls. Methods. The study group included 131 patients from the Estonian population-based prevalence JIA study. Blood samples were obtained from 27 boys and 38 girls with early JIA (≤1 month from the diagnosis), 29 boys and 36 girls with established JIA (mean disease duration 18 months), and from 47 age- and sex-matched controls. Results. IGF-1 levels in boys were significantly decreased in early JIA compared to male controls, while IGF-1 levels in girls were comparable between JIA and controls. In early JIA, IGF-1 levels were 12-fold lower in boys relative to girls. In controls, IGF-1 levels correlated with both age and height, while these correlations were lost in boys with early JIA. Conclusion. We report a sex-dependent deficiency in serum IGF-1 in boys with early JIA, which argues for sex-related differences in biological mechanisms involved in the disease pathogenesis.

Low Serum Levels of Immunoglobulin D Recognize Autoantibody Production in Rheumatoid Arthritis

Abstract: Background: Immunoglobulin D (IgD) remains an enigmatic molecule due to the limited understanding of its function both in healthy and in patients with autoimmune diseases. In this study, we analyse serum IgD (sIgD) levels in rheumatoid arthritis (RA), paying special attention to clinical and serologic features of RA and treatment. Methods and finding: Serum levels of IgD, IgM, IgG and IgA were measured in 416 subjects (248 RA patients and 169 healthy controls matched by age and gender), by sandwich ELISA. Here, we show that low IgD, but not IgM, IgG and IgA, is associated with female gender and with the presence of RA-specific autoantibodies. Most prominent reduction of sIgD was found in the patients producing rheumatoid factor, alone (p=0.009) and in combination with antibodies to cyclic citrullinated peptides (p= 0.02). Low sIgD was measured in female RA patients below 50 years (p=0.01), but not in healthy females. Additionally, low sIgD was measured in RA patients treated with a combination of methotrexate and sulfasalazine/hydroxichloroquine compared to those receiving methotrexate and biologics (p=0.01). Conclusion: In RA patients, sIgD levels present clinical associations which distinct it from IgM, IgG and IgA. Low serum IgD levels appears to be pathological and is associated with autoantibodies and certain anti-rheumatic treatment.