The Expression and Clinical Significance of Different Forms of Mer Receptor Tyrosine Kinase in Systemic Lupus Erythematosus

Objective. To investigate the expression and clinical significance of trans-membrane MerTK (mMer) on circulating CD14+ monocytes/macrophages and soluble MerTK (sMer) levels in plasma in systemic lupus erythematosus (SLE). Method. 108 SLE patients and 42 healthy controls were recruited in this study. The expression of mMer on the surfaces of CD14+ monocytes/macrophages was evaluated by flow cytometry (FCM). The sMer levels were measured by ELISA. Real-time quantitative PCR was applied to evaluate the mRNA levels of MerTK and ADAM17. Results. Both mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma significantly increased in SLE patients compared to healthy subjects. The frequency of anti-inflammatory MerTK expressing CD14+CD16+ monocytes decreased in SLE. mMer expression was positively correlated with CD163 expression on CD14+ cells. Both the mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma were positively correlated with SLEDAI. Furthermore, more elevated mMer and sMer levels were found in patients with higher SLEDAI, presence of anti-SSA, anti-Sm autoantibodies, and lupus nephritis. Conclusion. Both mMer and sMer levels significantly increased in SLE and positively correlated with disease activity and severity. The upregulation of MerTK expression may serve as a biomarker of the disease activity and severity of SLE

Burnout and Associated Factors among Family Doctor Team Members in Different Types of Primary Healthcare Institutions：a Comparative Study

BackgroundBurnout has become a prominent issue as the increase of workload in family doctor team members in primary healthcare institutions during the promotion of contracted family doctor services. There is still a lack of research comparing the differences in burnout among family doctor team members in different types of primary healthcare institutions.ObjectiveTo compare burnout prevalence and associated factors between family doctors in community/township health centers, and those in community health stations/village clinics, providing a basis for improving the mental health status and team stability of family doctors, as well as the quality of services provided by them.MethodsFrom August 1 to 21, 2020, a multistage cluster random sampling method was used to select 760 family doctor team members〔201 (26.4%) working at community/township health centers, and 559 (73.6%) working at community health stations/village clinics〕 as the participants from primary healthcare institutions in 6 counties/county-level cities /districts of Taian City, Shandong Province. They were invited to attend a survey to complete Demographic Questionnaire and the Chinese version of Maslach Burnout Inventory-General Survey (MBI-GS) .ResultsOverall, the prevalence of burnout among the participants was 68.9% (524/760) . Overall, the prevalence of burnout among the participants was 68.9% (524/760) , and the prevalence of burnoutof family doctor team members in community/township health centers and community health stations/village clinics was 63.7% (128/201) and 70.8% (396/559) , respectively. The levels of burnout of family doctor team members in community health stations/village clinics was higher than that of those in community/township health centers, with a statistically significant difference (P<0.05) . Family doctor team members in community health stations/village clinics had higher total score of MBI-GS and higher subscale score of reduction of professional efficacy than did those in community /township health centers, with a statistically significant difference (P<0.05) . Multivariate Logistic regression analysis showed that: for family doctor team members in community/township health centers, the risk of burnout of those aged 41-50 years is higher than that aged≤30 years〔OR (95%CI) =7.119 (1.770, 28.638) 〕, the risk of burnout of those with monthly income >4 000 yuan is lower than that with monthly income <2 000 yuan〔OR (95%CI) =0.194 (0.040, 0.941) 〕, the risk of burnout of those with high/very high self-rated work pressure is higher than that of those without/little self-rated work pressure〔OR (95%CI) =3.629 (1.475, 8.929) 〕, the risk of job burnout of those who evaluated the incentive mechanism as ordinary and relative effective/very effective was lower than that evaluated the incentive mechanism as very ineffective/less effective〔OR (95%CI) were 0.196 (0.052, 0.739) and 0.235 (0.066, 0.834) 〕. For the family doctor team members in community health stations/village clinics, the risk of burnout in women is lower than that in men〔OR (95%CI) =0.603 (0.396, 0.920) 〕, the risk of job burnout of those with general and relatively high/very high self-assessment residents' recognition is lower than that with very low/relatively low self-assessment residents' recognition〔OR (95%CI) were 0.258 (0.113, 0.590) and 0.428 (0.199, 0.918) 〕, the risk of burnout of those with high/very high self-rated job stress is higher than that without/little self-rated job stress〔OR (95%CI) =2.320 (1.368, 3.935) 〕.ConclusionFamily doctor team members in community health stations/village clinics demonstrated higher burnout prevalence, and lower professional efficacy. To reduce the burnout prevalence and improve professional efficacy in family doctor team members, it is suggested to strengthen trainings, increase salary and further improve incentive mechanism for those in community/township health centers, and to increase the number of officially budgeted posts, and promotion opportunities as well as the propaganda of contracted family doctor services for those in community health stations/village clinics. Moreover, the workflow of contracting family doctor services should be simplified in all these institutions

The Expression and Clinical Significance of Different Forms of Mer Receptor Tyrosine Kinase in Systemic Lupus Erythematosus

Objective. To investigate the expression and clinical significance of trans-membrane MerTK (mMer) on circulating CD14+ monocytes/macrophages and soluble MerTK (sMer) levels in plasma in systemic lupus erythematosus (SLE). Method. 108 SLE patients and 42 healthy controls were recruited in this study. The expression of mMer on the surfaces of CD14+ monocytes/macrophages was evaluated by flow cytometry (FCM). The sMer levels were measured by ELISA. Real-time quantitative PCR was applied to evaluate the mRNA levels of MerTK and ADAM17. Results. Both mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma significantly increased in SLE patients compared to healthy subjects. The frequency of anti-inflammatory MerTK expressing CD14+CD16+ monocytes decreased in SLE. mMer expression was positively correlated with CD163 expression on CD14+ cells. Both the mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma were positively correlated with SLEDAI. Furthermore, more elevated mMer and sMer levels were found in patients with higher SLEDAI, presence of anti-SSA, anti-Sm autoantibodies, and lupus nephritis. Conclusion. Both mMer and sMer levels significantly increased in SLE and positively correlated with disease activity and severity. The upregulation of MerTK expression may serve as a biomarker of the disease activity and severity of SLE

Impairment of Granzyme B-Producing Regulatory B Cells Correlates with Exacerbated Rheumatoid Arthritis

Hyperactivated B cells have been demonstrated the contribution to the development of rheumatoid arthritis (RA). While the recognition of the negative regulatory function of B cells further promoted our understanding of their pathogenic role in RA. Recently, a new population of granzyme B (GrB)-producing B cells was identified, which was proved to be involved in cancer and infectious diseases. However, their characteristics and roles in RA remain to be elucidated. In the present study, we aim to further characterize whether B cells could produce GrB and reveal their potential role in the pathogenesis of RA. Here, we further demonstrated peripheral blood B cells from healthy individuals could produce and secrete GrB, which could be enhanced by IL-21 and/or anti-B-cell receptor stimulation. These cells could negatively regulate Th1 and Th17 cells partly via downregulating TCR zeta chain and inducing T cell apoptosis, which might be termed as GrB-producing regulatory B cells (Bregs). These GrB-producing Bregs were significantly decreased under RA circumstance concomitant of lower levels of IL-21 receptor, with impaired regulatory functions on Th1 and Th17 cells. Moreover, the frequencies of these cells were negatively correlated with RA patient disease activity and clinical features. After effective therapy with disease remission in RA, these GrB-producing Bregs could be recovered. Therefore, our data revealed that B cells could produce GrB with immunosuppressive functions, and the impairment of this Breg subset was correlated with RA pathogenesis

Increased IL-33 in Synovial Fluid and Paired Serum Is Associated with Disease Activity and Autoantibodies in Rheumatoid Arthritis

National Basic Research Program of China (973 Program) [2010CB529104]; National Natural Science Foundation of China [31170840, 81072401]Objectives. IL-33, a newly found cytokine which is involved in joint inflammation, could be blocked by a decoy receptor-sST2. The expression and correlation of IL-33 and sST2 in rheumatoid arthritis (RA) are of great interest. Methods. Synovial fluid (SF) was obtained from 120 RA and 30 osteoarthritis (OA) patients, and paired sera were collected from 54 of these RA patients. The levels of IL-33 and sST2 were measured by ELISA. Results. SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. Serum IL-33 was correlated positively with SF IL-33 in RA. Furthermore, it was correlated with RF-IgM and GPI. sST2 was partly detectable in RA (13 out of 54, 24.1%), while not in OA. Serum sST2 in RA had no significant correlation with serum IL-33 or SF IL-33. However, SFs from both RA and OA patients did not express sST2. Conclusions. This study supported that IL-33 played an important role in the local pathogenesis of RA. Considering the tight correlation between IL-33 and clinical features, it may become a new target of local treatment

Hypoxia-inducible factor-1α and interleukin 33 form a regulatory circuit to perpetuate the inflammation in rheumatoid arthritis.

Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease