Mucosal-associated invariant T (MAIT) cells are novel innate-like T cells constituting a significant proportion of circulating and hepatic T cells. Herein, we extensively examine the phenotypical and ...functional alterations of MAIT cells and their regulation in a cohort of 56 patients with Primary Biliary Cholangitis (PBC) and 53 healthy controls (HC). Additionally alterations of MAIT cells were assessed before and after UDCA treatment. Finally the localization of MAIT cell in liver was examined using specific tetramer staining and the underlying mechanisms of these alterations in PBC were explored. Our data demonstrated that the frequency and number of circulating MAIT cells were decreased, whereas hepatic MAIT cells were increased in PBC compared to HC. Moreover, circulating MAIT cells were more activated in PBC than HC, reflected by elevated expression levels of granzyme B. Six months of UDCA treatment significantly attenuated the circulating MAIT cells differences in PBC. Of note, the expression levels of IL-7 were significantly increased in both plasma and liver from PBC as compared to HC, which promoted the production of inflammatory cytokines and granzyme B by inducing signal transduction and activation of transcription 5 (STAT5) phosphorylation in MAIT cells. Finally, cholic acid, one of the major bile acids in liver, upregulated IL-7 expression in hepatocyte cell line L02 by inducing Farnesoid X Receptor (FXR) binding to the IL-7 promoter. Hence MAIT cells are activated and enriched in the liver of PBC. Cholic acid-induced IL-7 production in hepatocytes plays a critical role in regulating MAIT cell function, highlighting that hepatocytes may bridge cholangiocyte injury and innate immunity through a bile acid signaling pathway.
•An indispensable role of MAIT cells in PBC was suggested.•MAIT cells are more activated with increased cytokine production in PBC.•IL-7 enhanced cytokine production in MAIT cells in PBC.•Bile acids can affect MAIT cell functions through regulating expression of IL-7.
In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver ...transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy.
We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response.
This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5–58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5–48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ −0.163. The predictive value was validated internally and externally.
Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.
Display omitted
•Combining ursodeoxycholic acid with immunosuppressants improves outcomes in primary biliary cholangitis with moderate-to-severe interface hepatitis.•Baseline IgG>1.3×ULN and ALP<2.4×ULN predict fibrosis regression.•A developed Fibrosis Regression Score (FRS), incorporating IgG and ALP, identifies individuals achieving fibrosis regression.
Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T ...cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC.
Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model.
Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFβR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFβ-Smad signaling.
CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC.
Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.
Display omitted
•CD103+ TRM cells are the dominant population of PDC-E2-specific autoreactive cytotoxic T cells in livers of patients with PBC.•CD103+ TRM cells exhibit cytotoxicity against autologous cholangiocytes in PBC.•Upon antigenic stimulation, metabolic reprogramming and DNA damage response of CD103+ TRM cells is orchestrated by NUDT1.•NUDT1-dependent DNA damage resistance promotes long-term survival of CD103+ TRM cells via PARP1-TGFβ-Smad axis.
Gastric cancer (GC) is a globally important disease. It is the 5th most common malignancy and the 4th most common cause of death from cancer in the world. Patients with GC are often at an advanced ...stage when they are first diagnosed, and their overall prognosis is poor due to locally advanced and distant metastasis. This study sought to establish a predictive model of GC distant metastasis and survival that can be used to guide individualized treatment.
Patients diagnosed with GC from the Surveillance, Epidemiology, and End Results database were enrolled in the study. Univariate and multivariate logistic regression analyses were used to identify risk and prognostic factors for GC patients with distant metastasis. The factors were then used to construct nomograms to predict the probability of distant metastasis and the survival time of GC patients. Receiver operating characteristic (ROC) curve and decision curve analyses were used to verify the prediction ability of the nomograms.
We established a comprehensive nomogram to predict the survival time of GC patients and 4 nomograms to predict distant metastasis. Nomograms could help oncologists to formulate treatment strategies and provide hospice care under an overall management model.
Establishing a prediction model for distant metastasis and the survival of GC patients is of great clinical significance. The prediction of distant metastasis could help clinicians to make individualized assessments of patients and formulate individualized examination measures. Survival prediction models could help oncologists to formulate good treatment strategies and provide hospice care.
Emperipolesis has been widely described in patients with autoimmune hepatitis, but the significance and the diagnostic value have not been quantitated. The goal of this study was to define the ...features and clinical significance of emperipolesis in autoimmune hepatitis (AIH). A retrospective histological evaluation of 101 patients with AIH and 184 controls was performed. Confocal staining for CD4, CD8, CD19, CD56, CD163, and CD11b, CK8/18 and cleaved caspase-3 was performed. Emperipolesis was observed in 65.3 % of the patients with AIH in haematoxylin and eosin (H&E)-stained slides, which was significantly higher than in patients with primary biliary cirrhosis (17.9 %), chronic hepatitis B (14.9 %), and drug-induced liver injury (25.6 %). Among AIH patients, the patients with emperipolesis had significantly higher serum (alanine aminotransferase/aspartate aminotransferase ALT/AST) levels. Histologically, emperipolesis was associated with more severe necroinflammatory features and more advanced fibrosis. The lymphocytes in hepatocytes were predominantly as CD8 T cells. Emperipolesis of CD8 T cells induced cleaved caspase-3 expression, and was prominent in areas apoptosis. Emperipolesis is a characteristic feature of AIH which is often seen in conjunction with interface hepatitis, plasmacytic infiltration and hepatocyte rosetting and is associated with more severe necroinflammatory and fibrotic changes. In AIH, emperipolesis is predominantly mediated by CD8 T cells, appears to induce apoptosis and may be another mechanism of autoimmune-mediated hepatocyte injury.
In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we ...assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL,
P
< 0.0001), primary biliary cholangitis (7.32 ng/mL,
P
< 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL,
P
< 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.
Although a variant of primary biliary cirrhosis (PBC) characterized by features of autoimmune hepatitis (AIH) has been recognized for many years, few studies with ample numbers of patients have ...focused on its natural history. This study aimed to clarify the natural history, prognosis, and response to therapy in a cohort of patients with PBC with AIH features. We retrospectively analyzed 277 PBC patients without AIH features and 46 PBC patients with AIH features seen between September 2004 and April 2014. The 5-year adverse outcome-free survival of PBC patients with AIH features was 58 % compared to 81 % in PBC patients without AIH features. Multivariate analysis in the patients with AIH features indicated that total bilirubin ≥2.70× the upper limit of normal predicted a poor prognosis (
p
= 0.008, relative risk 8.39, 95% confidence interval (CI) 1.73, 40.73). Combination therapy with ursodeoxycholic acid (UDCA) and immunosuppression provided better short-term responses in PBC patients with AIH features, defined by multiple criteria. Higher aspartate aminotransferase (AST) level at accession suggested better prognosis for PBC patients with AIH features while worse prognosis for PBC patients without AIH features. PBC patients with AIH features differ from those without AIH features in terms of natural history, prognostic indicators, and response to therapy.
The primary function of myeloid‐derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune‐mediated diseases. In immunoglobulin G4 (IgG4)–related disease ...(IgG4‐RD), it has been hypothesized that there are selective regulatory defects that lead to a T helper 2 (Th2) bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4‐related sclerosing cholangitis (IgG4‐SC), the most common extrapancreatic involvement of IgG4‐RD, as well as controls consisting of primary sclerosing cholangitis, autoimmune hepatitis, and healthy volunteers, to study MDSCs. We report dramatically increased levels of receptor activator for nuclear factor kappa B ligand (RANKL) expression in serum and liver from patients with IgG4‐SC compared to both liver‐disease and healthy controls. Moreover, in IgG4‐SC liver, RANKL‐secreting cells specifically colocalized with cluster of differentiation 38–positive plasma cells and MDSCs, particularly monocytic MDSCs, and express the RANKL receptor in liver. Similarly, the frequency and number of peripheral blood MDSCs were significantly increased. Importantly, serum expression levels of RANKL were inversely correlated with the serum level of gamma‐glutamyltransferase but significantly positively correlated with the frequency of MDSCs. Moreover, we confirmed that RANKL induced the expansion and activation of MDSCs through the RANKL/RANK/nuclear factor kappa B signal pathway. Of note, RANKL‐treated MDSCs suppressed T‐cell proliferation and induced Th2 differentiation. Conclusion: Our data suggest that plasma cell–derived RANKL induces the expansion and activation of MDSCs, which suppress T‐cell proliferation and contribute to the Th2‐type response characteristic of IgG4‐SC.
Several articles have been published about the reorganization of surgical activity during the coronavirus disease 2019 (COVID-19) pandemic but little is known about the operative volume, distribution ...of cases, or capacity of The Department of Thoracic Surgery to deliver surgical services in the time of COVID-19.
A retrospective operative logbook review was completed in department of thoracic in a designated COVID-19 hospital. We reviewed and analyzed the operative logbook and discussed our countermeasures during the outbreak. A prediction model was established to discuss the time consuming about delayed surgeries during the pandemic.
One thousand two hundred and seventy-five operation records were collected. The thoracic surgeries of this year has decreased (43.4%) during the Wuhan lockdown. From Jan 23
to Apr 8
in 2020, there were 461 surgeries performed in The Department of Thoracic in our hospital with 0 cases of nosocomial COVID-19 infection. Prediction model showed that it will take 6 weeks to solve the backlog if department can reach the 85% of maximum of operations per week.
An understanding of operative case volume and distribution is essential in facilitating targeted interventions to strengthen surgical capacity in the time of COVID-19. A proper guideline is imperative to ensure access to safe, timely surgical care. By developing a scientific and effective management of hospital, it is possible to ensure optimal surgical safety during this crisis. Regular updates and a further study include multicenter is required.
ChiCTR2000034346.
PDF
