The role of iTr35 cells in the inflammatory response and fibrosis progression of systemic sclerosis.

OBJECTIVE: To evaluate the role of induced immunosuppressive T regulatory (iTr) 35 cells in SSc-related inflammation and fibrosis. METHODS: Sixty-eight SSc patients were enrolled in this study. Subsets of iTr35 and Tr1 were measured by flow cytometry. IL-35 and IL-10 levels were measured using ELISA. Expressions of iTr35, Tr1, fibrosis-related genes and proteins associated with signalling pathways were determined using immunofluorescence, western blot and immunohistochemistry assays. RESULTS: In peripheral blood, the proportions of the iTr35 cells were higher and Tr1 cells were lower than the control group. Similarly, IL-35 expression was increased, while IL-10 levels were decreased. In fibroblasts from skin tissue, the expression levels of EBI3, IL-12Ap35, Foxp3 and IL-10 were decreased, but collagen I, TGF-ß, alpha smooth muscle actin (α-SMA) and fibronectin levels were increased. Phosphorylated STAT3/6 were increased, but iTr35 and Tr1 cell levels were significantly decreased. When CD4+ cells were incubated with both recombinant human (rh)IL-35 and rhIL-10, the cell numbers of iTr35 and Tr1 were greater than the same type of cells treated with rhIL-35 or rhIL-10 alone. However, the viability of conventional CD4+ T cells was decreased by gradually increasing iTr35 cells. Moreover, iTr35 cells affected α-SMA expression through the STAT3/6 signalling pathway. CONCLUSION: Both iTr35 and Tr1 cells are involved in SSc-related inflammation and fibrosis. IL-35 can induce iTr35 cells, showing a synergistic effect with IL-10. We also found that iTr35 cells can inhibit T cell proliferation and differentiation via the STAT3/6 signalling pathway, thereby causing fibrosis.

APPL1 prevents pancreatic beta cell death and inflammation by dampening NFκB activation in a mouse model of type 1 diabetes.

AIMS/HYPOTHESIS: Beta cell inflammation and demise is a feature of type 1 diabetes. The insulin-sensitising molecule 'adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1' (APPL1), which contains an NH2-terminal Bin/Amphiphysin/Rvs domain, a central pleckstrin homology domain and a COOH-terminal phosphotyrosine-binding domain, has been shown to modulate inflammatory response in various cell types but its role in regulating beta cell mass and inflammation in type 1 diabetes remains unknown. Thus, we investigated whether APPL1 prevents beta cell apoptosis and inflammation in diabetes. METHODS: Appl1-knockout mice and their wild-type littermates, as well as C57BL/6N mice injected with adeno-associated virus encoding APPL1 or green fluorescent protein, were treated with multiple-low-dose streptozotocin (MLDS) to induce experimental type 1 diabetes. Their glucose metabolism and beta cell function were assessed. The effect of APPL1 deficiency on beta cell function upon exposure to a diabetogenic cytokine cocktail (CKS; consisting of TNF-α, IL-1ß and IFN-γ) was assessed ex vivo. RESULTS: Expression of APPL1 was significantly reduced in pancreatic islets from mouse models of type 1 diabetes or islets treated with CKS. Hyperglycaemia, beta cell loss and insulitis induced by MLDS were exacerbated by genetic deletion of Appl1 but were alleviated by beta cell-specific overexpression of APPL1. APPL1 preserved beta cell mass by reducing beta cell apoptosis upon treatment with MLDS. Mechanistically, APPL1 deficiency potentiate CKS-induced phosphorylation of NFκB inhibitor, α (IκBα) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFκB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFκB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. CONCLUSIONS/INTERPRETATION: APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFκB-iNOS-NO axis, representing a promising target for treating type 1 diabetes.

An Observational Study on the Clinical Characteristics and Prognosis of Patients With Interstitial Lung Disease Secondary to Dermatomyositis and Antisynthetase Syndrome.

Objective: Identify the clinical characteristics and prognostic factors in patients with idiopathic inflammatory myopathy (IIM) combined with interstitial lung disease (ILD). Methods: IIM-ILD patients who were hospitalized at Guangxi Medical University from January 2017 to December 2022 were retrospectively analyzed and classified as having dermatomyositis (DM)-ILD or -ILD. Clinical and laboratory results were analyzed. Results: There were 39 males and 111 females, the mean age of disease onset was 50.4 ± 12.3 years, and the median disease duration was 3 months (range: 1-6). Ninety-seven patients had DM-ILD, and 53 had ASS-ILD. The DM-ILD group had 72% positivity for the anti-MDA5 antibody and 5.2% positivity for the anti-Mi-2 antibody; the ASS-ILD group had 67.9% positivity for the anti-Jo-1 antibody and 17% positivity for the anti-EJ antibody. Muscle symptoms, skin ulcers, rash, rapidly progressing interstitial lung disease (RP-ILD), and elevated levels of serum carcinoembryonic antigen were more common in DM-ILD patients (all p < 0.05). However, pericardial effusion and pleural effusion, elevated creatinine kinase, and elevated C-reactive protein were more common in ASS-ILD patients. After a median follow-up of 15.5 months, there were more deaths in the DM-ILD group (42.3% vs. 13.2%, p < 0.001). Multivariate Cox regression analysis showed that RP-ILD, dyspnea, and the usual interstitial pneumonia type of ILD had negative associations with overall survival (OS), and arthralgia had a positive association with OS (all p < 0.05). Conclusion: DM-ILD patients were more prone to secondary RP-ILD and skin ulcers, had milder symptoms of myositis and less severe serositis, and had lower survival rates than the ASS-ILD patients. RP-ILD, dyspnea, and the usual interstitial pneumonia type of ILD had adverse effects on prognosis, but arthralgia was a protective factor.

Tocilizumab in the treatment of hyperferritinemic syndrome and capillary leak syndrome secondary to rheumatoid arthritis: Case report and literature review.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is mainly characterized by joint swelling, pressure pain and joint destruction. Some patients may suffer from a variety of serious complications, which require prompt diagnosis and treatment. Otherwise, the patient condition may deteriorate rapidly, leading to premature death. OBJECTIVE: We reported a case of RA combined with hyperferritinemic syndrome and capillary leak syndrome (CLS) that was successfully treated with tocilizumab (TCZ), with the aim of improving diagnostic ideas for clinicians and consequently improving the diagnosis and treatment of the hyperferritinemic syndrome and CLS. CASE SUMMARY: A 55-year-old female patient was admitted to the Department of Infectious Diseases of our hospital due to "recurrent fever for more than 1 month and aggravation for 3 days." The patient was diagnosed with fever of unknown origin (lung infection?) and received anti-infective therapy with large encirclement of anti-bacterial, antifungal and empirical anti-tuberculosis successively during hospitalization in the Department of Infectious Diseases. Yet her condition continues to progress. The patient was eventually diagnosed with RA combined with hyperferritinemic syndrome and CLS. Then she received glucocorticoids (GC) (160 mg qd) combined with intravenous immunoglobulin (IVIG, 20 g/d, for 3 days). We considered that the patient also had an overwhelming proinflammatory cytokine storm, so she received a strong anti-inflammatory treatment with TCZ (400 mg qm). The patient symptoms and follow-up chest CT showed significant improvement following treatment. CONCLUSION: TCZ has good efficacy in the treatment of RA combined with hyperferritinemic syndrome and CLS and is expected to be a promising treatment.

Clinical features and prognostic factors of systemic sclerosis in Guangxi, China: Retrospective, single-center study of long-term survival in 470 patients.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease the prevalence of which varies among populations. We analyzed SSc patients from Guangxi to improve the clinical understanding of this disease. METHODS: Data of 470 SSc patients admitted to our institution from October 1,2012 to January 1,2019 were examined. The characteristics of these patients were analyzed using Kaplan-Meier survival analysis. Cox proportional-hazard regression was used to identify prognostic factors. RESULTS: The average age was 50.44 ± 12.31 years, 285 patients (60.6%) were women, 2.1% had pneumoconiosis, 58.2% had pulmonary interstitial disease (ILD), 18.7% had pulmonary hypertension (PH), and 3.6% had renal crisis. These patients had diffuse cutaneous systemic sclerosis (dcSSc, 70.2%) or limited cutaneous systemic sclerosis (29.7%), and PH and renal crisis were more common in the dcSSc group. Patients 50 years old or more had greater prevalences of ILD, PH, and musculoskeletal damage, greater positivity of laboratory biomarkers, and increased mortality (all P < .05). Seventy-four patients (15.7%) died. The non-survivors were older, had longer disease duration, had higher prevalences of ILD, restrictive ventilation dysfunction, PH, and renal crisis, and had higher levels of creatine kinase myocardial band (CK-MB), C-reactive protein, and immunoglobin A (all P < .05). Renal crisis, PH, and high CK-MB were independent risk factors for death. CONCLUSIONS: Pneumoconiosis was more common in SSc patients than the general population from this region. Our patients had a 10-year cumulative survival rate of 74.9%, higher than reported for patients from the US. Renal crisis, PH, and high CK-MB level were independent risk factors for death.