In the article titled Hydroxychloroquine Effects on TLR Signalling: Underexposed but Unneglectable in COVID-19 [1], the incorrect file for Figure 2 was used during the production process and the figure should be corrected as follows. (Figure Presented).
Burn patients with multidrug-resistant Pseudomonas aeruginosa infections commonly suffer from high morbidity and mortality, which present a major challenge to healthcare systems throughout the world. Outer membrane protein F (OprF), as a main outer membrane porin, is required for full virulence expression of P. aeruginosa. The aim of this study was to evaluate the protective efficacy of egg yolk-specific antibody (IgY) raised against recombinant OprF (r-OprF) protein in a murine burn model of infection. The hens were immunized with r-OprF, and anti-r-OprF IgY was purified using salt precipitation. Groups of mice were injected with different regimens of anti-OprF IgY or control IgY (C-IgY). Infections were caused by subcutaneous injection of P. aeruginosa strain PAO1 at the burn site. Mice were monitored for mortality for 5 days. The functional activity of anti-OprF IgY was determined by in vitro invasion assays. Immunotherapy with anti-OprF IgY resulted in a significant improvement in the survival of mice infected by P. aeruginosa from 25% to 87.5% compared with the C-IgY and PBS. The anti-OprF IgY decreased the invasion of P. aeruginosa PAO1 into the A549. Passive immunization with anti-OprF IgY led to an efficacious protection against P. aeruginosa burn infection in the burn model.
Kidney transplantation has evolved over more than half a century and remarkable progress has been made in patient and graft outcomes. Despite these advances, chronic allograft dysfunction remains a major problem. Among other reasons, de novo formation of antibodies against donor human leukocyte antigens has been recognized as one of the major risk factors for reduced allograft survival. The type of treatment in the presence of donor specific antibodies (DSA) posttransplantation is largely related to the clinical syndrome the patient presents with at the time of detection. There is no consensus regarding the treatment of stable renal transplant recipients with circulating de novo DSA. On the contrast, in acute or chronic allograft dysfunction transplant centers use various protocols in order to reduce the amount of circulating DSA and achieve long-term graft survival. These protocols include removal of the antibodies by plasmapheresis, intravenous administration of immunoglobulin, or depletion of B cells with anti-CD20 monoclonal antibodies along with tacrolimus and mycophenolate mofetil. This review aims at the comprehension of the clinical correlations of de novo DSA in kidney transplant recipients, assessment of their prognostic value, and providing insights into the management of these patients.
γ δ T cells are a minor population of T cells that express the TCR γ δ chains, mainly distributed in the mucosal and epithelial tissue and accounting for less than 5% of the total T cells in the peripheral blood. By bridging innate and adaptive immunity, γ δ T cells play important roles in the anti-infection, antitumor, and autoimmune responses. Previous research on γ δ T cells was primarily concentrated on infectious diseases and tumors, whereas their functions in autoimmune diseases attracted much attention. In this paper, we summarized the various functions of γ δ T cells in two prototypical autoimmune connective tissue diseases, that is, SLE and RA, elaborating on their antigen-presenting capacity, secretion of proinflammatory cytokines, immunomodulatory effects, and auxiliary function for B cells, which contribute to overproduction of proinflammatory cytokines and pathogenic autoantibodies, ultimately leading to the onset of these autoimmune diseases. Elucidation of the roles of γ δ T cells in autoimmune diseases is not only conducive to in-depth understanding of the pathogenesis of these diseases, but also beneficial in providing theoretical support for the development of γ δ T-cell-targeted therapy.
Immune disorder is considered the main pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA). The balance of the two special subsets of CD4+T cells, T helper cell 17 (Th17), and Regulator T cell (Treg) is the key factor of maintaining a normal immune response. Dendritic cells (DCs), which are the most powerful antigen-presenting cells, play an important role in regulating the balance of Th17 and Treg. The combination of disease modifying antirheumatic drugs (DMARDs) is an important strategy of RA therapy. In this study, we investigated the effect of MTX and CTX on DC maturation in ovalbumin (OVA) immunized mice. Th17 inflammatory response is stronger, while the level of DCs maturity is higher. In contrast, the immunosuppression of Treg is stronger. We found that MTX combined with CTX significantly inhibited the DCs maturity and downregulated the antigen presenting capacity of DCs. As a result, it reestablished a balance of Th17 and Treg. Our study adds a novel mechanism and therapeutic target of MTX combined with CTX for autoimmune disease treatment.
Previous genome-wide association study by WTCCC identified many susceptibility loci of common autoimmune diseases in British, including rheumatoid arthritis (RA). Because of the genetic heterogeneity of RA, it is necessary to replicate these susceptibility loci in other populations. Here, three SNPs with strong RA association signal in the British were analyzed in Han Chinese, and two SNPs (rs6457617 and rs11761231) were genotyped in the test cohort firstly. The rs6457617 was significantly associated with RA in the test cohort. The individuals bearing the homozygous genotype CC had 0.39-fold risk than these bearing the wild-type genotype TT (P=0.004, OR 0.39, [95% CI 0.21–0.74]). And the protective effect of allele C was confirmed in another validation cohort with 1514 samples (Pgenotye CC/TT=5.9 × 10 −10 , OR 0.34, [95% CI 0.24–0.48]). The rs6457617 can be used as a tagSNP of HLA-DQA1*03 which encoded MHC-II α chain. Since MHC restriction is important for primary T-cells in positive selection and negative selection stages, MHC protein polymorphisms may be implicated in shaping the T-cell repertoire, including the emergence of a T-cell clone involved in the inflammatory arthritis.
Background . PERP, p53 apoptosis effector related to PMP-22, is a p53-dependent apoptosis in diverse cell types and has cell type-specific roles in p53-mediated apoptosis. However, its role in PBMCs of RA patients has remained largely unclear. Objectives . The aim of this study was to detect the expression levels of PERP on PBMCs of RA patients and healthy controls and analyze the role of PERP in the pathogenesis of RA. Methods . The mRNA expression levels of PERP and IL-17 were detected by real-time PCR in PBMCs from patients with RA (n=40) and healthy controls (n=40). The correlations of PERP expression levels to IL-17 transcripts and disease activity parameters were analyzed. Results . The PERP and IL-17 expression levels in the PBMCs were significantly decreased and increased in comparison of which in healthy controls. The mRNA expression levels of PERP in PBMCs from patients with RA were negatively correlated with IL-17 and disease activity parameters DAS28, RF, CRP, and ESR rather than Anti-CCP and ANA. Conclusions . These results demonstrated that PERP might be involved in the pathogenesis and a potential therapeutic target of RA by regulating the expression of IL-17.
The prevalence of psychological problems is frequent in systemic lupus erythematosus (SLE) patients and appears to be increasing. The current study investigated the relationship among disease parameters, quality of life, and the psychological status in Chinese patients with SLE. A self-report survey design was administered to 170 SLE patients and 210 healthy individuals using the Self-Rating Anxiety Scale, the Self-Rating Depression Scale, and the Short Form 36 health survey (SF-36). Our results showed that 20.3% SLE patients had anxiety, and 32.9% had depression, which were significantly higher than the control group (7.1%, 14.3%, resp.). And there were significant correlations among socioeconomic status (SES), disease activity, and anxiety/depression in SLE patients. Meanwhile, SF-36 analysis results revealed that VT, PF, and RP scales were the most powerful predictors of anxiety of SLE patients, and SLEDAI, VT, PF, SF, and RE domains were significantly accounted for anxiety. In summary, there were significant relationships among disease parameters, quality of life, and anxiety/depression in Chinese SLE patients. Therefore, it is necessary to have psychiatric and psychological evaluations and formulate an integrated approach for managing mental health in Chinese lupus patients, especially those who have high disease activity, low SES, and poor quality of life.
Development of a vaccine against congenital cytomegalovirus (CMV) infection is a public health priority, but CMVs encode immune evasion genes that complicate live virus vaccine design. To resolve this problem, this study employed guanosyl phosphoribosyl transferase (gpt) mutagenesis to generate a recombinant guinea pig CMV (GPCMV) with a knockout of a viral chemokine gene, GPCMV MIP (gp1). MIP deletion virus replicated with wild-type kinetics in cell culture but was attenuated in nonpregnant guinea pigs, demonstrating reduced viremia and reduced inflammation and histopathology (compared to a control virus with an intact GPCMV MIP gene) following footpad inoculation. In spite of attenuation, the vaccine was immunogenic, eliciting antibody responses comparable to those observed in natural infection. To assess its protective potential as a vaccine, either recombinant virus or placebo was used to immunize seronegative female guinea pigs. Dams were challenged in the early 3rd trimester with salivary gland-adapted GPCMV. Immunization protected against DNAemia (1/15 in vaccine group versus 12/13 in the control group, P < 0.01). Mean birth weights were significantly higher in pups born to vaccinated dams compared to controls (98.7 g versus 71.2 g, P < 0.01). Vaccination reduced pup mortality, from 35/50 (70%) in controls to 8/52 (15%) in the immunization group. Congenital GPCMV infection was also reduced, from 35/50 (70%) in controls to 9/52 (17%) in the vaccine group (P < 0.0001). We conclude that deletion of an immune modulation gene can attenuate the pathogenicity of GPCMV while resulting in a viral vaccine that retains immunogenicity and demonstrates efficacy against congenital infection and disease.
Organ/tissue transplantation has become an effective therapy for end-stage diseases. However, immunosuppression after transplantation may cause severe side effects. Donor-specific transplant tolerance was proposed to solve this problem. In this study, we report a novel method for inducing and maintaining heart allograft tolerance rats. First, we induced indefinite vascularized hind-limb allograft survival with a short-term antilymphocyte serum + Cyclosporine A treatment. Peripheral blood chimerism disappeared 6-7 weeks after immunosuppression was withdrawn. Then the recipients accepted secondary donor-strain skin and heart transplantation 200 days following vascularized hind-limb transplantation without any immunosuppression, but rejected third party skin allografts, a status of donor-specific tolerance. The ELISPOT results suggested a mechanism of clone deletion. These findings open new perspectives for the role of vascularized hind-limb transplant in the induction and maintenance of organ transplantation tolerance.
Objective. To investigate the relationship between Brachial-ankle pulse wave velocity (baPWV), and its associated risk factors in Chinese patients with RA. Methods. 138 Chinese RA patients and 150 healthy subjects were included. baPWV of all the participants was measured. RA related factors were determined, as well as traditional cardiovascular risk factors. Results. baPWV was significant higher in RA group (1705.44 ± 429.20 cm/s) compared to the healthy control group (1386.23 ± 411.09 cm/s) (P<0.001). Compared with low baPWV group, high baPWV group patients were significantly older (P = 0.008) and taller (P = 0.033). Serum cholesterol (P = 0.035), triglycerides (P = 0.004), and LDL level (P = 0.006) were significantly higher in high baPWV group patients compared with low baPWV group patients. The baPWV of RA patients was positively correlated with age (r = 0.439, P<0.001), and serum cholesterol level (r = 0.231, P = 0.035), serum triglycerides level (r = 0.293, P<0.001), serum LDL level (r = 0.323, P = 0.003). Meanwhile, baPWV negatively correlated with the height of RA patients (r = −0.253, P = 0.043). Multivariate regression analysis showed that baPWV of RA group was independently associated with age and serum triglycerides level. Conclusions. The old age and high level of serum triglycerides may be the major determinants of arterial stiffness in Chinese RA patients.
The aberrant activity of CD4 + T cells in patients with systemic lupus erythematosus (SLE) is associated with DNA hypomethylation of the regulatory regions in CD11a and CD70 genes. Our previous studies demonstrated that Gadd45a contributes to the development of SLE by promoting DNA demethylation in CD4 + T cells. In this study, we identified proteins that bind to Gadd45a in CD4 + T cells during SLE flare by using the method of co-immunoprecipitation and mass spectrometry, High mobility group box protein 1 (HMGB1) is one of identified proteins. Furthermore, gene and protein expression of HMGB1 was significantly increased in SLE CD4 + T cells compared to controls, and HMGB1 mRNA was correlated with CD11a and CD70 mRNA. A significant, positive correlation was found between HMGB1 mRNA and SLEDAI for SLE patients. Our data demonstrate that HMGB1 binds to Gadd45a and may be involved in DNA demethylation in CD4 + T cells during lupus flare.
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.
O-glycosidically-linked glycans have been involved in development, maturation, homing, and immune regulation in T cells. Previous reports indicate thatAmaranthus leucocarpuslectin(ALL), specific for glycans containing galactose-N-acetylgalactosamine and N-acetylgalactosamine, recognizes human naïve CD27+CD25+CD4+T cells. Our aim was to evaluate the phenotype of CD4+T cells recognized byALLin peripheral blood mononuclear cells obtained from healthy volunteers. CD4+T cells were isolated by negative selection using magnetic beads-labeled monoclonal antibodies; the expression of T regulatory cell phenotypic markers was assessed onALL-recognized cells. In addition, IL-4, IL-10, IFN-γ, and TGF-βintracellular production inALL+cells was also evaluated. The analyses of phenotypic markers and intracellular cytokines were performed through flow cytometry.ALL-recognized CD4+T cells were mainly CD45RA+, CCR7+cells. Although52±10% CD25+Foxp3+cells were positive toALL, only34±4% ofALL+cells corresponded to CD25+Foxp3−cells. Intracellular cytokines in freshly obtainedALL+CD4+T cells exhibited 8% of IL-4, 15% of IL-10, 2% of IFN-γ, and 15% of TGF-β, whereasALL−CD4+T cells depicted 1% of IL-4, 2% of IL-10,<1% of IFN-γ, and 6% of TGF-β. Our results show that galactose-N-acetylgalactosamine and N-galactosamine-bearing CD4+T cells expressed phenotypic markers of NnTreg cells.
It was reported that IL-17 had been detected in the inflammatory infiltrates of patients with DM (dermatomyositis). In this study, we investigated the frequency of Th17 cells and the expression of microRNA-206 (miR-206) in DM patients. Firstly, we observed that the frequency of Th17 cells and the expression of transcription factors were increased significantly in the PBMCs of DM patients. Secondly, we found that there was a positive correlation between the percentages of Th17 cells and serum level of CK in DM patients. And the serum concentrations of IL-6, IL-1β, TGF-β, and IL-23, the important cytokines of Th17 differentiation, were increased in DM patients. It was predicted that Krüppel-like factor 4 (KLF4) is one of the multiple targets of miR-206. We detected the expression of miR-206 in DM patients, and it was decreased in the serum and PBMCs of DM patients. The augmented expression of KLF is accompanied by the attenuated expression of miR-206. Furthermore, a negative correlation between the percentages of Th17 cells and the expression of miR-206 in DM patients has been found. Taken together, these findings suggest the attenuated expression of miR-206, and the augmented frequency of Th17 cells in DM patients.
The purpose of this study is to investigate the possible different cellular marker expression associated with spinal cord microglial activation in different pain models. Immunohistochemistry and western blotting analysis of CD45, CD68, and MHC class I antigen as well as CD11b and Iba-1 in the spinal cord were quantitatively compared among widely used three pain animal models, complete Freund's adjuvant (CFA) injection, formalin injection, and chronic constriction injury (CCI) models. The results showed that significant upregulated expressions of CD45 and MHC class I antigen in spinal microglia as well as morphological changes with increased staining with CD11b and Iba-1 were seen in CCI and formalin models and not found in CFA-induced inflammatory pain model. CD68 expression was only detected in CCI model. Our findings suggested that different peripheral tissue injuries produced differential phenotypic changes associated with spinal microglial activation; peripheral nerve injury might induce spinal microglia to acquire these immunomolecular phenotypic changes.
Interstitial lung disease (ILD) is a common and severe complication of idiopathic inflammatory myopathies (IIM). The aim of our study was to identify risk factors for ILD by evaluating both clinical and biochemical features in IIM patients with or without ILD. From January 2008 to December 2011, medical records of 134 IIM patients in our rheumatology unit were reviewed. The patients were divided into ILD group (83 patients) and non-ILD group (51 patients). The clinical features and laboratory findings were compared. The univariable analyses indicated that arthritis/arthralgia (54.2% versus 17.6%,P<0.05), Mechanic’s hand (16.9% versus 2.0%,P<0.05), Raynaud’s phenomenon (36.1% versus 2.0%,P<0.05), heliotrope rash (44.6% versus 19.6%,P<0.05), fever (43.4% versus 21.6%,P<0.05), elevated ESR (60.2% versus 35.3%,P<0.05), elevated CRP (55.4% versus 31.4%,P<0.05), or anti-Jo-1 antibody (20.5% versus 5.9%,P<0.05) were risk factors for developing ILD in IIM. Multivariable unconditional logistic regression analysis that showed arthritis/arthralgia (OR 7.1, 95% CI 2.8–18.1), Raynaud’s phenomenon (OR 29.1, 95% CI 3.6–233.7), and amyopathic dermatomyositis (ADM) (OR 20.2, 95% CI 2.4–171.2) were the independent risk factors for developing ILD in IIM.
Sjogren's syndrome (SS) is a systemic, autoimmune disorder characterized by salivary insufficiency and lymphocytic infiltration of the exocrine glands. Even though the mechanism of its pathology and progression has been researched ever since its discovery, the roles of different parts of immune system remain inconclusive. There is no straightforward and simple theory for the pathogenesis and diagnosis of Sjogren’s syndrome because of the multiple kinds and functions of autoantibodies, changing proportion of different T-lymphocyte subsets with the progression of disease, unsuspected abilities of B lymphocytes discovered recently, crosstalk between cytokines connecting the factors mentioned previously, and genetic predisposition that contributes to the initiation of this disease. On the other hand, the number of significant reports and open-label studies of B-cell depletion therapy showing clinical efficacy in sjogren’s syndrome has continued to accumulate, which provides a promising future for the patients. In a word, further elucidation of the role of different components of the immune system will open avenues for better diagnosis and treatment of SS, whose current management is still mainly supportive.
BACKGROUND:Previous data showed that the predominance of intraglomerular T-bet or GATA3 is correlated with different mechanisms of rejection, suggesting that the ratio of T-bet/GATA3 might be used to distinguish antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR). METHODS:We compared the intraglomerular T-bet/GATA3 ratio in ABMR and TCMR. The intragraft expression of T-bet and GATA3 was studied via immunohistochemistry. The correlation of the diagnosis of AMR with the ratio of T-bet/GATA3 was examined. RESULTS:Both intraglomerular T-bet- and GATA3-expressing cells were increased during acute rejection. T-bet/GATA3>1 was strongly correlated with ABMR (93.3% versus 18.2%). The incidence of positive HLA-I/II antibodies and glomerulitis is significantly higher in T-bet/GATA3>1 group (P < 0.001, 0.013, resp.). The scores of peritubular capillary inflammation and glomerulitis were also higher in T-bet/GATA3>1 group (P = 0.052, P < 0.001, resp.). Nevertheless, T-bet/GATA3>1 is also correlated with C4d-negative ABMR and resistance to steroid treatment. Compared with C4d deposition, T-bet/GATA3>1 had a slight lower (90% versus 100%) specificity but a much higher (87.5% versus 68.8%) sensitivity. CONCLUSION:Our data suggested that intraglomerular predominance of T-bet over GATA3 might be used as diagnosis maker of ABMR in addition to C4d, especially in C4d-negative cases.
