Risk factors of adult isoniazid-resistant and rifampicin-susceptible tuberculosis in Nanjing, 2019-2021.

INTRODUCTION: This study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults. METHOD: The clinical data of 1,844 adult inpatients diagnosed with culture-positive pulmonary tuberculosis (PTB) in Nanjing Second Hospital from January 2019 and December 2021 were collected. All culture positive strain from the patient specimens underwent drug susceptibility testing (DST). Among them, 166 patients with Hr-TB were categorized as the Hr-TB group, while the remaining 1,678 patients were classified as having drug-susceptible tuberculosis (DS-TB). Hierarchical logistic regression was employed for multivariate analysis to identify variables associated with Hr-TB. RESULTS: Multivariate logistic regression analysis revealed that individuals with diabetes mellitus (DM) (OR 1.472, 95% CI 1.037-2.088, p = 0.030) and a history of previous tuberculosis treatment (OR 2.913, 95% CI 1.971-4.306, p = 0.000) were at higher risk of developing adult Hr-TB, with this risk being more pronounced in male patients. Within the cohort, 1,640 patients were newly treated, and among them, DM (OR 1.662, 95% CI 1.123-2.461, p = 0.011) was identified as risk factors for Hr-TB. CONCLUSIONS: Diabetes mellitus is a risk factor for Hr-TB in adults, and the contribution of diabetes as a risk factor was more pronounced in the newly treatment or male subgroup. And previous TB treatment history is also a risk factor for Hr-TB in adults.

Factors associated with 25-hydroxyvitamin D level in Chinese hospitalized patients with systemic lupus erythematosus: a retrospective cohort study.

We aimed to investigate the factors associated with vitamin D deficiency and changes in 25 (OH)D levels, as well as the impact of those changes on disease activity and renal function among SLE patients. This retrospective cohort study was based on the medical records of SLE patients hospitalized between 2010 and 2021. We collected relevant information from this patient population. Logistic regression analysis was employed to determine the factors associated with vitamin D deficiency and increased 25 (OH)D levels, and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) accordingly. At baseline, among the 1257 SLE patients, the median and interquartile range of 25 (OH)D levels were 14 (9, 20) ng/ml, with 953 (75.8%) patients exhibiting 25 (OH)D deficiency (< 20 ng/ml). The presence of 25 (OH)D deficiency was found to be associated with renal involvement and a high glucocorticoid (GC) maintenance dose. Among the 383 patients who were followed up for an average of 18 months, an increase of at least 100% in 25 (OH)D levels was positively associated with a decreased GC maintenance dose and vitamin D3 supplementation, with adjusted odds ratios(OR) (95% confidence interval [CI]) of 2.16 (1.02, 4.59) and 1300 (70, 22300), respectively. Furthermore, an increased level of 25 (OH)D was significantly associated with a decrease in the Disease Activity Index 2000 score and the urinary protein/creatinine ratio. Patients with SLE have low vitamin D levels, especially those with impaired kidney function. Increased 25 (OH)D levels can be achieved through supplementation with high doses of vitamin D3 and are associated with improvements in disease activity and the urinary protein/creatinine ratio.

Serosal involvement in adult-onset Still's disease: A multicentre and retrospective study.

OBJECTIVES: This study evaluated the characteristics of serosal involvement in adult-onset Still's disease (AOSD). METHODS: Patients meeting the Yamaguchi classification criteria were classified into AOSD with and without serosal involvement according to their manifestations and sonography/radiography. Clinical data was retrospectively reviewed from 102 patients with AOSD in two centres. RESULTS: Forty-two patients (41.2%) had serosal involvement. The frequencies of pulmonary infiltrate and impaired liver function were significantly higher in patients with serosal involvement (p = .002 and p = .007, respectively), who also had a higher modified systemic score (p = .009). In addition, the percentages of CD3+ T cells (p < .001) and, especially, the CD8+ T cells (p = .004) were significantly increased in the peripheral blood of AOSD patients with serosal involvement. Notably, patients with serosal involvement were more likely to develop macrophage activation syndrome (p = .047) and a chronic pattern (p = .016) during the follow-up. CONCLUSIONS: Patients with serosal involvement demonstrated the more severe disease activity and different immune phenotypes; these patients were more likely to develop macrophage activation syndrome, and they may require more aggressive treatment at an early time to control their systemic inflammation.

Human SLE variant NCF1-R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages.

OBJECTIVES: We previously identified a hypomorphic variant, p.Arg90His (p.R90H) of neutrophil cytosolic factor 1 (NCF1, a regulatory subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex), as an putative causal variant for systemic lupus erythematosus (SLE), and established a knock-in (KI) H90 variant in the C57BL/6 background to study how this variant promotes lupus development. METHODS: Wild type (WT) and KI littermates were assessed for immune profiles and lupus-like features. Disease activity and renal damage of patients with SLE were assessed by systemic lupus erythematosus disease activity index (SLEDAI) and renal items of systemic lupus international collaborating clinics (SLICC), respectively. RESULTS: Compared with WT littermates, 5-week-old homozygous KI mice had reduced oxidative burst, splenomegaly, elevated type I interferon (IFN-I) scores, increased ratios of splenic follicular T helper 2 (Tfh2) to either T follicular regulatory (Tfr) or Tfh1 cells, increased ANA+ follicular, germinal centre and plasma cells without spontaneous kidney disease up to 1 year of age. Pristane treatment exacerbated the immune dysregulation and induced IFN-I-dependent kidney disease in 36-week-old H90 KI female mice. Decreased efferocytosis of macrophages derived from KI mice and patients with homozygous H90 SLE promoted elevated ratios of Tfh2/Tfr and Tfh2/Tfh1 as well as dysregulated humoral responses due to reduced voltage-gated proton channel 1 (Hv1)-dependent acidification of phagosome pH to neutralise the decreased electrogenic effect of the H90 variant, resulting in impaired maturation and phagosome proteolysis, and increased autoantibody production and kidney damage in mice and patients with SLE of multiple ancestries. CONCLUSIONS: A lupus causal variant, NCF1-H90, reduces macrophage efferocytosis, enhances Tfh2 responses and promotes autoantibody production and kidney damage in both mice and patients with SLE.

Global, regional and national trends in sex- and age-specific disability-adjusted life years of musculoskeletal disorders, 1990-2019.

OBJECTIVE: To quantify the temporal trend of sex- and age-specific disability-adjusted life years (DALYs) for musculoskeletal (MSK) disorders by region and cause. METHODS: Data were collected from the Global Burden of Diseases Study 2019. The estimated annual percentage change (EAPC) by sex, age, region and cause was calculated to examine the temporal trend of the age-standardized DALYs rate (ASDR). The sociodemographic index (SDI) and risk exposures were also examined. RESULTS: Between 1990 and 2019, the global ASDR for MSK disorders remained almost stable by sex and age group but decreased among females ages 0-14 years (EAPC = -0.27). Such age and sex patterns were nearly the same by SDI, except for high SDI regions, where ASDR increased in all subgroups except those ages 15-49 years. The trend in ASDR of MSK disorders for females and males ages 50-74 and ≥75 years increased in ∼80% of countries and territories. The greatest increase was in El Salvador for males ages 15-49 years (EAPC = 1.30), followed by Nicaragua. The association between EAPC and SDI was positive in developing regions, particularly among females ages 15-49 years, and negative in developed regions. A decreasing trend in ASDR was mainly driven by the decrease in low back pain, while the increasing trend was largely due to other MSK disorders and gout across sexes and age groups. CONCLUSIONS: There are great disparities in the age- and sex-specific trends in ASDR by cause on the global, regional and national levels. More differentiated prevention and management strategies are needed for MSK disorders.

Clinical significance of HScore and MS score comparison in the prognostic evaluation of anti-MDA5-positive patients with dermatomyositis and interstitial lung disease.

OBJECTIVES: To evaluate the clinical significance of the HScore and MS score in the prognosis of anti-melanoma differentiation-associated gene 5 (MDA5) positive patients with dermatomyositis (DM) and interstitial lung disease (ILD). METHODS: The clinical features as well as HScore and MS score were compared between the survivors (n = 61) and nonsurvivors (n = 36) among 97 anti-MDA5-positive DM-ILD patients. Potential prognostic factors were analysed. RESULTS: Compared with survivors, nonsurvivors had significantly older age, tended to be male, and had a significantly higher frequency of fever at disease onset, higher levels of aspartate transaminase, lactate dehydrogenase, and serum ferritin, as well as higher values of HScore and MS score but had a significantly lower frequency of arthritis at disease onset. Multivariate analysis revealed that age ≥50 years [hazard ratio (HR) = 2.70, p = .040, 95% confidence interval (CI) 1.05-6.97)], male gender (HR = 3.20, p = .017, 95% CI 1.23-8.28), and higher HScore (HR = 3.72, p = .003, 95% CI 1.56-8.86) were independent risk factors for mortality. Patients with more risk factors had significantly poorer survival (p < .001). CONCLUSIONS: Older age, high HScore, and male gender are risk factors for poor survival among anti-MDA5-positive DM-ILD patients, suggesting the potential role of macrophage activation in the pathogenesis.

Decreased serum ACE2 levels in patients with connective tissue diseases.

OBJECTIVE: To evaluate serum concentration and activity of angiotensin-converting enzyme 2 (ACE2) in patients with connective tissue diseases (CTDs). METHODS: Serum samples from healthy subjects and patients with SLE, systemic sclerosis (SSc), primary Sjögren's syndrome (SS) and RA were collected. The concentration and activity of ACE2 were measured by ELISA and fluorometric method, respectively, and analysed for associations with clinical features and concurrent medications. RESULTS: In total, 66 SLE, 55 SSc, 31 SS and 31 RA patients were involved. ACE2 concentration was significantly decreased in patients with either of the four CTDs compared with healthy subjects. The concentration was not linked to special clinical features expect that it was slightly lower in patients with lupus nephritis than those without. In SLE patients, ACE2 concentration elevated with the increase of glucocorticoids, and was not associated with other treatments. Different from the concentration, ACE2 activity was increased in CTD patients. A weak correlation of ACE2 activity with SLE disease activity index score was also observed. CONCLUSION: The clinical significance of ACE2 concentration and activity looks quite different among CTD patients. Preliminary data suggest ACE2 levels are not affected by most of the treatments.

Association of antimalarial drugs with decreased overall and cause specific mortality in systemic lupus erythematosus.

OBJECTIVE: To evaluate the association and dose-response pattern between antimalarial drugs and overall and cause specific mortality in SLE patients. METHODS: Medical records including information on HCQ/chloroquine (CQ) prescription were extracted from Jiangsu Lupus database. The database was designed to collect data from SLE patients that first-hospitalized during 1999-2009 in Jiangsu province, China, and a follow-up for survival status was performed in 2010 and 2015. Cox and restricted cubic spline models were used to estimate the hazard ratio and 95% CI. RESULTS: We identified 221 deaths among 2446 SLE patients in total. Compared with non-users, decreased overall mortality was associated with either HCQ or CQ users, with adjusted hazard ratio (95% CI) of 0.49 (0.35, 0.67) and 0.49 (0.27, 0.87), respectively. The association between HCQ/CQ and overall mortality was similar across subgroups, such as patients with comorbidities and organ involvements. Interestingly, both the time and the daily dosage of HCQ/CQ use were related to decreased mortality of SLE in a linear dose-response relationship. In cause specific analyses, HCQ/CQ was inversely associated with death from renal insufficiency and other organ (cardiopulmonary, gastrointestinal and haematological) involvements, with adjusted hazard ratio (95% CI) of 0.23 (0.09, 0.55) and 0.25 (0.10, 0.62), respectively, yet it was not significantly associated with mortality from infection and neuropsychiatric involvements. CONCLUSION: Antimalarial drugs were associated with lower risk of SLE mortality, especially renal insufficiency- and other organ involvement-related death. The protective effects for survival might be augmented by adherence and full dosage of these drugs.

Impaired olfactory neural circuit in patients with SLE at early stages.

OBJECTIVE: To investigate the changes of olfactory function and odor-induced brain activation in patients with systemic lupus erythematosus (SLE) at early stages compared with healthy controls. MATERIALS AND METHODS: Olfactory function and odor-induced brain activation in 12 SLE patients at early stages and 12 age, gender and education matched healthy controls were evaluated using olfactory behavior test and odor-induced task-functional magnetic resonance imaging (task-fMRI). RESULTS: No significant differences in olfactory behavior scores (including olfactory threshold, olfactory identification, and olfactory memory) were found in the patients with SLE at early stages compared with the healthy controls, while significantly decreased odor-induced activations in olfactory-related brain regions were observed in the patients. In the SLE group, the patients with better performance in the olfactory threshold test had significantly lower levels of anti-dsDNA antibody. CONCLUSION: The current study demonstrated that significant alterations in odor-induced brain activations occurred prior to measurable olfactory decline in SLE at early stages, which provided a new method for early diagnosis of olfactory dysfunction in SLE.

Anti-Ro52 antibodies in clinical practice: A single-centre experience.

INTRODUCTIONS: To analyse the clinical significance of anti-Ro52 autoantibodies that target TRIM21 protein and occur in a variety of connective tissue diseases (CTD), 4782 cases with blood tested positive for anti-Ro52 antibodies between January 2016 and September 2017 in Drum Tower Hospital were enrolled. METHODS: Anti-Ro52 and anti-Ro60 were measured using the immunoblotting method together with antibodies against other extractable nuclear antigens at the time of the patient's first visit. RESULTS: In this cohort, females accounted for the majority of all subjects (75.9%) and the average age was 47.25 years old. About 97.4% were diagnosed as having various diseases, in which around 2/3 were CTDs. The incidence of CTD in patients with merely anti-Ro52 was lower than those with both anti-Ro52 and anti-Ro60 (54.7% vs 85.5% for all patients and 53.3% vs 87.1% for inpatients, both P < .0001). Amongst CTDs, the incidence of systemic lupus erythematosus was significantly decreased, while the incidence of inflammatory myositis as well as undifferentiated connective tissue diseases was increased in anti-Ro52 single-positive group. For patients with either CTDs or non-CTDs, respiratory involvement was more common in patients with merely anti-Ro52 (67.6% vs 34.7%, P < .0001 and 53.2% vs 36.3%, P < .01). Sub-analysis revealed that both interstitial lung disease and pulmonary infection were related to anti-Ro52 in CTD inpatients (P < .0001 and P < .05). CONCLUSIONS: Our study shows that anti-Ro52 could occur in various clinical conditions. These antibodies may appear in the early stage of CTD with the lung an important target organ, thus their presence warrants long-term follow-up.

Incidence trend of five common musculoskeletal disorders from 1990 to 2017 at the global, regional and national level: results from the global burden of disease study 2017.

OBJECTIVE: To assess cause-specific incidence and its trend of musculoskeletal (MSK) disorders at global, regional and national levels. METHODS: Data on MSK disorders were downloaded from the Global Burden of Disease 2017 study website. Estimated annual percentage change (EAPC) was calculated to quantify the temporal trend in age-standardised incidence rate (ASR) of MSK disorders, by age, sex, region and cause. RESULTS: Between 1990 and 2017 incident cases of MSK disorders increased globally by 58% from 211.80 million to 334.74 million, with a decreasing ASR of 0.18% annually (95% CI -0.21% to -0.15%). The ASR decreased for low back pain (LBP), remained stable for neck pain (NP), and increased for rheumatoid arthritis (RA), osteoarthritis (OA) and gout, with EAPCs (95% CI) of -0.24 (-0.29 to -0.20), -0.09 (-0.13 to -0.05), 0.36 (0.28 to 0.43), 0.32 (0.28 to 0.36) and 0.22 (0.21 to 0.23), respectively. It appears women have higher increase in EAPC than men for RA (1.3 times) and gout (1.6 times). The absolute EAPC was strikingly high in high or high-middle sociodemographic index (SDI) regions for overall, LBP and gout, and in low SDI regions for NP. EAPC was significantly associated with baseline ASR for LBP (nonlinear), RA (ρ=-0.41) and gout (ρ=-0.42), also with 2017 human development index for LBP (ρ=-0.53) and gout (ρ=0.15). CONCLUSIONS: Globally, MSK disorders remain a public health burden. The ASR is decreasing for MSK disorders overall, mainly in high-middle SDI regions, but increasing for RA, OA and gout.

Mesenchymal stem cells prevent podocyte injury in lupus-prone B6.MRL-Faslpr mice via polarizing macrophage into an anti-inflammatory phenotype.

BACKGROUND: Podocyte injury plays a pathogenic role in the development of lupus nephritis (LN). Mesenchymal stem cells (MSCs) have shown promising therapeutic potential for LN. However, whether MSCs can prevent podocyte injury in LN remains unknown. METHODS: Human umbilical cord-derived MSCs (UC-MSCs) were infused into lupus-prone B6.MRL-Faslpr (B6.lpr) mice to investigate the influences of UC-MSCs on podocyte injury in LN. Podocytes and macrophages were co-cultured with UC-MSCs in vitro to study the mechanism by which UC-MSC protect podocytes. We further explored the effects of UC-MSCs on macrophage polarization. RESULTS: We found that UC-MSCs promoted the expression of podocyte-specific markers, podocin and synaptopodin, in lupus-prone B6.lpr mice, along with the improvement of lupus renal pathology in terms of reduced IgG and C3 deposition in glomeruli and decreased anti-dsDNA antibody level. Besides, UC-MSC treatment decreased podocyte foot process effacement, as UC-MSCs-treated macrophages led to less podocyte injury in vitro. Interestingly, we further found that UC-MSCs-treated macrophages exhibited an anti-inflammatory phenotype with higher expression of CD206, and lower expression of tumor necrosis factor-α and interleukin-1ß. Additionally, UC-MSCs-treated lupus mice showed reduced renal macrophage infiltration and elevated CD206 expression in kidney. CONCLUSIONS: Our results demonstrated that UC-MSCs ameliorated LN by preventing podocyte injury possibly through reducing macrophage infiltration and polarizing macrophage into an anti-inflammatory phenotype.

Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor.

Bone marrow mesenchymal stem cells (BMSC) have been shown to possess immunomodulatory activities, while its role in rheumatoid arthritis (RA) remains unknown. Citrullinated fibrinogen (cfb) has been considered as a specific autoantigen in RA pathogenesis. Our study aims to determine the role of cfb on immunomodulatory function of BMSC. We demonstrated the specific role of toll-like receptor 4 (TLR4)-NFκB pathway in the pro-inflammatory response of BMSC to cfb with increased production of interleukin (IL)-6, IL-8 and chemokine CC motif ligand 2 (CCL2). Moreover, cfb impaired BMSC-mediated suppression of peripheral blood mononuclear cells (PBMC) proliferation and reduced the production of the key immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO) in BMSC. We have uncovered a previously unrecognized role of cfb in interfering BMSC-mediated immunoregulation in RA. Cfb could act as a damage-associated molecule pattern (DAMP) for BMSC and thereby contribute to the propagation of inflammation in RA.

Mesenchymal stem cells induced CD4+ T cell apoptosis in treatment of lupus mice.

Umbilical cord-derived mesenchymal stem cell transplantation (UCMSCT) has been used to treat human autoimmune diseases like lupus for example, but little is known about its effect on cell apoptosis. Here we evaluated the efficacy of UCMSCT for lupus treatment and explored the mechanism by which mesenchymal stem cells (MSCs) modulate T cell apoptosis in lupus mice. 1 × 106 human umbilical cord-derived mesenchymal stem cells (UC-MSCs) were injected into B6.MRL-Faslpr (B6.lpr) mice via tail vein. 6 h, 24 h or 4 weeks later, the mice were sacrificed and the apoptosis of lymphocytes in peripheral blood and spleen were detected by flow cytometry. The immune cell subpopulations in spleen were also measured at 6 h and 24 h, respectively. The therapeutic effects were assessed after 4 weeks. The frequency of peripheral blood CD4+ T cell apoptosis was reduced in lupus-prone B6.lpr mice. UCMSCT alleviated the disease phenotypes in B6.lpr mice, decreased the ratio of Th1 as well as Th2 cells, and increased percentages of apoptotic CD4+ T cells in vivo and vitro. Collectively, our findings unravel that UCMSCT alleviate lupus disease and reverse immune imbalance possibly by promoting T cell apoptosis in B6.lpr mice.

Comparable therapeutic potential of umbilical cord mesenchymal stem cells in collagen-induced arthritis to TNF inhibitor or anti-CD20 treatment.

OBJECTIVES: The effects of mesenchymal stem cell (MSC) transplantation on established collagen-induced arthritis (CIA) were evaluated and compared to biologic therapies. METHODS: CIA was induced with the immunisation of type II collagen (CII) in DBA/1 mice. Human umbilical cord MSC, anti-TNF antibody, rhTNFR:Fc fusion protein and anti-CD20 antibody were respectively injected intraperitoneally into CIA mice. Arthritis severity was assessed by clinical and histological scoring. The frequencies of lymphocytes in spleen were analysed, and serum concentrations of cytokines and autoantibody to CII were also measured. The ability of MSC to regulate the balance of T helper cell subsets in CII stimulated CIA CD4+ T cells was assessed in vitro. RESULTS: MSC treatment significantly decreased the severity of arthritis, which was comparable to biologic treatments. All the treatments down-regulated Th1 subset. Except anti-CD20 all the treatments decreased Th17 subset. MSC treatment enhanced the proportion of regulatory T (Treg) cells and inhibited the generation of T follicular helper (Tfh) cells. The decrease in autoantibody level was detectable in all the treated groups. In vitro MSC induced Foxp3+ T cells, and down-regulated IL-17+, IFNγ+ T cells and pathogenic IL-17+IFNγ+ or IL-17+Foxp3+ T cells. MSC also reduced the secretion of IL-1ß, IL-6, IL-17 and TNF-α among collagen-specific T cells. CONCLUSIONS: MSC show comparable effects to the known biologic treatments and correct immune imbalance in CIA. MSC might provide a promising approach for the treatment of rheumatoid arthritis.

Hypoxia-inducible factor 1 in autoimmune diseases.

Autoimmune disorders are a complicated and varied group of diseases arising from inappropriate immune responses. Recent studies have demonstrated that ongoing inflammatory and immune responses are associated with increased oxygen consumption, a process resulting in localized tissue hypoxia within inflammatory lesions ("inflammatory hypoxia"), in which hypoxia-inducible factor 1 (HIF-1), an oxygen-sensitive transcription factor that allows adaptation to hypoxia environments, has been shown to play an important function. HIF-1 is a regulator of angiogenesis and immune system. Besides, HIF-1-mediated metabolic shift and fibrosis may also play crucial roles in some autoimmune disorders. Firstly, we briefly summarize the role of HIF-1 in angiogenesis, immune responses and fibrosis. Secondly, we will show the major recent findings demonstrating a role for HIF-1 signaling in autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, systemic sclerosis and multiple sclerosis. The growing evidences may prompt HIF-1 to be a new target for treatment of autoimmune diseases.

Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus.

Human umbilical cord-derived mesenchymal stem cells (UCMSCs) show therapeutic effects on systemic lupus erythematosus (SLE). Deficiency in functional polarization and phagocytosis in macrophages has been suggested in the pathogenesis of SLE. We found that macrophages from B6.MRL-Fas(lpr) mice exhibited lower level of CD206, the marker for alternatively activated macrophage (AAM, also called M2). In addition, the phagocytic activity of B6.MRL-Fas(lpr) macrophages was also decreased. UCMSC transplantation improved the proportion of CD206(+) macrophages and their phagocytic activity in B6.MRL-Fas(lpr) mice. Importantly, macrophages from SLE patients also showed lower expression of CD206 and reduced phagocytic activity, which were corrected by being co-cultured with UCMSCs in vitro and in SLE patients receiving UCMSC transplantation. Mechanistically, we demonstrated that IL-6 was required for the up-regulation of CD206 expression and phagocytic activity of UCMSC-treated SLE macrophages. Our results indicate that UCMSCs alleviate SLE through promoting CD206 expression and phagocytic activity of macrophages in an IL-6 dependent manner.

Umbilical cord mesenchymal stem cells inhibit the differentiation of circulating T follicular helper cells in patients with primary Sjögren's syndrome through the secretion of indoleamine 2,3-dioxygenase.

OBJECTIVE: The aim of this study was to investigate the effect of umbilical cord mesenchymal stem cells (UC-MSCs) on circulating T follicular helper (cTfh) cells in primary SS (pSS) patients. METHODS: The percentage of CXCR5(+)PD-1(+)CD4(+) T cells in peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry. PBMCs were co-cultured with UC-MSCs by cell-to-cell contact or in a trans-well system. Naive CD4(+) T cells were isolated from PBMCs and then co-cultured with UC-MSCs under Tfh cell-polarizing conditions. The percentage of CXCR5(+)PD-1(+)CD4(+) T cells, carboxyfluorescein succinimidyl ester (CFSE) fluorescence intensity and annexin V were determined by flow cytometric analysis. Real-time PCR and Luminex cytokine assay were performed to detect mRNA expression and supernatant protein levels. The activity of indoleamine 2,3-dioxygenase (IDO) was measured by HPLC. RESULTS: Increased frequency of cTfh cells was found in pSS patients and was positively correlated with serum anti-La/SSB levels and the European League Against Rheumatism SS Disease Activity Index score. In vitro, UC-MSCs suppressed the differentiation and proliferation of cTfh cells. Real-time PCR analysis showed significantly higher IDO mRNA expression on UC-MSCs when co-cultured with naive CD4(+) T cells under Tfh cell-polarizing conditions in pSS patients. However, IDO mRNA expression on UC-MSCs was only a little higher when UC-MSCs were co-cultured with naive CD4(+) T cells in a trans-well system. In addition, HPLC showed increased IDO enzymic activity in the supernatant of UC-MSCs co-cultured with naive CD4(+) T cells under Tfh cell-polarizing conditions in pSS. The addition of the IDO inhibitor 1-MT partly reversed the suppressive effect of UC-MSCs on the differentiation of cTfh cells. CONCLUSION: These results suggest an inhibitory effect of UC-MSCs on the differentiation of cTfh cells via the secretion of IDO, and soluble factors secreted by activated CD4(+) T cells might contribute to IDO secretion by UC-MSCs.

CTLA-4 SNPs (CT60A/G, -1722T/C, -1661G/A, and -318C/T) and systemic lupus erythematosus: a meta-analysis.

In this meta-analysis, we investigated the association between CTLA-4 polymorphisms (CT60A/G, -1722T/C, -1661G/A, and -318C/T) and SLE susceptibility. Data were extracted independently by two reviewers. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in fixed or random effects models. Seventeen studies involving of 3931 cases and 4619 controls were identified. Significant association of promoter -1722T/C polymorphism and SLE was observed for TT vs. CC (OR=1.63, 95% CI 1.63-2. 30, P<0.05) in the overall study population and in the Asians subgroups (OR=2. 18, 95% CI 1.70-2. 81, P<0.05); the OR for the allele T vs. C in Asians was 1.66 (95% CI 1.33-2. 07, P<0.05). For the CT60A/G polymorphism, significant association was observed for AA vs. AG (OR=0.64, 95% CI 0.46-0.88, P<0.05) in Asians. These results suggest that -1722T/C and CT60A/G polymorphisms in CTLA-4 are associated with SLE, particularly in Asians.