Increased SLAMF7+CD8+ T cells are associated with the pathogenesis of experimental autoimmune pancreatitis in mice.

BACKGROUND: IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. METHODS: A murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. RESULTS: AIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7-CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. CONCLUSIONS: Increased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.

Value of IL-1ß and IL-23 in Predicting 28-Day Mortality Due to Sepsis: A Retrospective Study.

BACKGROUND This research aimed to explore the utility of Interleukin-1ß (IL-1ß) and IL-23 as potential biomarkers for the diagnosis and prognosis of sepsis. MATERIAL AND METHODS This study included 74 adult individuals with sepsis, 45 ICU controls, and 50 healthy individuals attending routine physical examinations. IL-1ß and IL-23 levels were assessed and analyzed on the admission day. Univariate Cox regression analyses were utilized to explore the association of IL-1ß and IL-23 with sepsis survival. Furthermore, receiver operating characteristic (ROC) analysis was employed to evaluate the value of IL-1ß and IL-23 to predict 28-day mortality due to sepsis. RESULTS Serum concentrations of IL-1ß and IL-23 were significantly higher in septic patients relative to healthy and ICU controls (P<0.001). IL-1ß and IL-23 levels in non-survivors were significantly higher than in survivors (P<0.001). IL-1ß (hazard ratio; HR=1.06, P<0.001) and IL-23 (HR=1.02, P=0.031) were independent risk variables for 28-day mortality in sepsis patients, which were strongly associated with the severity of sepsis. The area under the ROC curve for predicting 28-day fatality in sepsis was 0.66 for IL-1ß (P=0.024, 95% confidence interval; CI: 0.54-0.76) and 0.77 for IL-23 (P<0.001, 95% CI: 0.65-0.86). Furthermore, compared with low serum IL-1ß (<9.41 pg/mL) and IL-23 (<6.77 pg/mL) levels, septic patients with high serum IL-1ß (≥9.41 pg/mL) and IL-23 (≥6.77 pg/mL) levels had poorer survival. CONCLUSIONS Serum IL-1ß and IL-23 values were higher in patients with sepsis and are potential diagnostic and prognostic markers for sepsis, but this needs to be confirmed by prospective studies.

Clinicopathological characteristics of IgG4-related lung disease.

BACKGROUND: Immunoglobulin G4-related lung disease (IgG4-RLD) is a rare entity. We retrospectively analyzed the clinical and histopathological characteristics of patients with pathologically confirmed IgG4-RLD to improve the diagnosis rate and reduce the risk of misdiagnosis. METHODS: We screened the pathological reports of 4838 patients with pulmonary surgery and/or biopsy specimens from April 2017 to April 2021 at Sun Yat-Sen Memorial Hospital affiliated with Sun Yat-Sen University, and specimens from 65 patients with suspected IgG4-RLD were subjected to immunohistochemical staining for IgG4 and IgG. Finally, 10 patients with definite IgG4-RLD that was pathologically confirmed were enrolled and analyzed. RESULTS: The incidence of pathologically confirmed IgG4-RLD was 0.2% (10/4838). The ten patients had an average age of 59.7 years at diagnosis, and the male-to-female ratio was 9:1. The initial clinical manifestations were nonspecific, and cough was the most common symptom (4/10). More than one organ was involved in most patients (8/10), and mediastinal/hilar lymph node involvement was often observed (7/10). Serum IgG4 was analyzed in 6 patients and found to be elevated. Serum tumor marker levels were within the normal range or were slightly elevated. Computed tomography (CT) of the chest and/or 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging revealed that 5 patients had a mixed type, 3 patients had the solid nodular type, and 2 patients had the bronchovascular type. All pulmonary masses and large nodules with solid patterns had spiculated margins and inhomogeneous enhancement with or without pleural indentation and a lobulated appearance. Abundant lymphoplasmacytic cell infiltration and fibrosis were observed in all patients. The expression of IgG4 and IgG was upregulated in the pulmonary sections. Seven patients were treated with glucocorticoids with or without additional immunosuppressants and responded well. CONCLUSIONS: The results of our study suggest that multiple imaging findings, an elevated serum IgG4 concentration, and no significant increase in serum tumor biomarkers could provide diagnostic support for IgG4-RLD, especially for isolated IgG4-RLD or IgG4-RLD that includes other organ involvement that does not aid in establishing the diagnosis.

The function of IL-33/ST2 signaling axis in treg cells activating fibrosis in IgG4-related disease.

OBJECTS: To explore whether IL-33/ST2 signaling axis can activate Treg cells in promoting tissue fibrosis in IgG4-related disease. METHODS: Peripheral blood from patients diagnosed as IgG4-related disease and healthy volunteers matched with age and sex from September 2019 to December 2020 in Sun Yat-sen Memorial Hospital was collected and disposed to separate the peripheral blood mononuclear cells and serum. The concentration of serum IL-33, IL-13 and ST2 was measured using ELISA kits. And the ratio of Treg cells was measured with flow cytometry. Patients diagnosed as type1 autoimmune pancreatitis from September 2019 to December 2020 in Sun Yat-sen Memorial Hospital were enrolled in this study. Patients diagnosed as pancreatic cancer and chronic pancreatitis were enrolled as controls. Pathological sections of these patients were collected and treated with Immunohistochemical staining and Masson trichrome staining in order to observe the expression of FoxP3, IL-33, IL-13 and ST2 as well as the grade of tissue fibrosis. RESULTS: We found that no matter in blood circulation or at the affected sites in IgG4-related disease, the expression of IL-33, IL-13 and ST2 was up regulated and Treg cells expanded. In type1 autoimmune pancreatitis, the degree of fibrosis was positively correlated to IL-33, IL-13, ST2 and FoxP3. Moreover, IL-33, IL-13, ST2 and Treg cells affected each other both in blood and in pancreas. CONCLUSIONS: IL-33/ST2 may affect the expanding of Treg and the secretion of IL-13 in the fibrosis process in IgG4-RD.

The risk of malignancy in patients with IgG4-related disease: a systematic review and meta-analysis.

BACKGROUND: The relationship between IgG4-related disease (IgG4-RD) and the risk of malignancy is still controversial. This article focused on assessing the risk of cancer in patients with IgG4-RD by meta-analysis. METHODS: We conducted a systematic review of the literature and meta-analysis characterizing the associated risk of overall malignancy and four site-specific malignancies (pancreas, lung, gastric and lymphoma) in patients with IgG4-RD. A search from 2003 to 2020 was performed using specified terms from PubMed, Embase, Web of Science and SinoMed. Random-effects model analysis was used to pool standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to clarify the heterogeneity of the included studies. Begg's funnel plot and Egger's linear regression test were used to evaluate the bias of the meta-analysis. A P value < 0.05 indicated the existence of publication bias. RESULTS: A total of 10 studies were included in the article. The overall SIR estimates suggested an increased risk of overall cancer in IgG4-RD patients (SIR 2.57 95% CI 1.72-3.84) compared with the general population. The specific SIRs for pancreas and lymphoma were higher than those of the general population in IgG4-RD patients (SIR 4.07 95% CI 1.04-15.92, SIR 69.17 95% CI 3.91-1223.04, respectively). No significant associations were revealed in respiratory and gastric cancer (SIR 2.14 95% CI 0.97-4.75, SIR 0.95 95% CI 0.24-3.95, respectively). Four studies were found to be the major sources of heterogeneity by sensitivity analysis. There was no evidence of publication bias via Egger's test. CONCLUSION: Compared with the general population, patients with IgG4-RD appear to have a higher risk of overall cancer, especially pancreatic and lymphoma. The risk of lung and gastric cancer was not different between IgG4-RD patients and the general population.

Solution-Processable Anion-doped Conjugated Polymer for Nonvolatile Organic Transistor Memory with Synaptic Behaviors.

Brain-inspired synaptic transistors have been considered as a promising device for next-generation electronics. To mimic the behavior of a biological synapse, both data processing and nonvolatile memory capability are simultaneously required for a single electronic device. In this work, a simple approach to realize a synaptic transistor with improved memory characteristics is demonstrated by doping an ionic additive, tetrabutylammonium perchlorate (TBAP), into an active polymer semiconductor without using any extra charge storage layer. TBAP doping is first revealed to improve the memory window of a derived transistor memory device from 19 to 32 V (∼68% enhancement) with an on/off current ratio over 103 at VG = -10 V. Through morphological analysis and theoretical calculations, it is revealed that the association of anion with polymers enhances the charge retention capability of the polymer and facilitates the interchain interactions to result in improved memory characteristics. More critically, the doped device is shown to successfully mimic the synaptic behaviors, such as paired-pulse facilitation (PPF), excitatory and inhibitory postsynaptic currents, and spike-rate dependent plasticity. Notably, the TBAP-doped device is shown to deliver a PPF index of up to 204% in contrast to the negligible value of an undoped device. This study describes a novel approach to prepare a synaptic transistor by doping conjugated polymers, which can promote the future development of artificial neuromorphic systems.