Xiao

Common variable immunodeficiency and autoimmunity – an inconvenient truth ☆

Coexisting morbidities in CVID include bronchiectasis, autoimmunity and malignancies. The incidence of autoimmune disease in CVID patients may approach 20% of cases. The most common autoimmune disease found in CVID patients is autoimmune cytopenia, but rheumatoid arthritis, lupus, and now primary biliary cirrhosis have also been reported. The coexistence of immunodeficiency and autoimmunity appears paradoxical, since one represents a hypoimmune state and the other a hyperimmune state. However, this paradox may not actually be all that implausible due to the complex nature of immune cells, signaling pathways and their interactions. The cellular alterations in combined variable immunodeficiency include a range of T and B cell abnormalities. Selective immune derangements found in CVID include a downregulation of regulatory T cells (Treg cells), accelerated T cell apoptosis, abnormal cytokine production secondary to cytokine gene polymorphisms and increased autoreactive B cell production. The impact of these abnormalities on T and B cell interaction may not only explain the immunodeficiency but also the development of autoimmunity in select groups of patients with CVID. The variability in the clinical manifestations of CVID as a result of this immune interaction suggests that CVID is not one disease but many. This is important because it follows that the treatment of CVID may not always be the same, but may need to be directed specifically towards each individual patient.

Diagnosis and classification of drug-induced autoimmunity (DIA)

Since sulfadiazine associated lupus-like symptoms were first described in 1945, certain drugs have been reported to interfere with the immune system and induce a series of autoimmune diseases (named drug-induced autoimmunity, DIA), exemplified by systemic lupus erythematosus (SLE). Among the drugs, procainamide and hydralazine are considered to be associated with the highest risk for developing lupus, while quinidine has a moderate risk, and all other drugs have low or very low risk. More recently, drug-induced lupus has been associated with the use of newer biological modulators, such as tumor necrosis factor (TNF)-alpha inhibitors and cytokines. In addition to lupus, other major autoimmune diseases, including vasculitis and arthritis, have also been associated with drugs. Because resolution of symptoms generally occurs after cessation of the offending drugs, early diagnosis is crucial for treatment strategy and improvement of prognosis. Unfortunately, it is difficult to establish standardized criteria for DIA diagnosis. Diagnosis of DIA requires identification of a temporal relationship between drug administration and the onset of symptoms, but the relative risk with respect to dose and duration for each drug has rarely been determined. DIA is affected by multiple genetic and environmental factors, leading to difficulties in establishing a list of global clinical features that are characteristic of most or all DIA patients. Moreover, the distinction between authentic DIA and unmasking of a latent autoimmune disease also poses challenges. In this review, we summarize the highly variable clinical features and laboratory findings of DIA, with an emphasis on the diagnostic criteria.

Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy

Objective A close relationship between gut microbiota and some chronic liver disorders has recently been described. Herein, we systematically performed a comparative analysis of the gut microbiome in primary biliary cholangitis (PBC) and healthy controls. Design We first conducted a cross-sectional study of 60 ursodeoxycholic acid (UDCA) treatment-naïve patients with PBC and 80 matched healthy controls. Second, an independent cohort composed of 19 treatment-naïve patients and 34 controls was used to validate the results. Finally, a prospective study was performed in a subgroup of 37 patients with PBC who underwent analysis before and after 6 months of UDCA treatment. Faecal samples were collected, and microbiomes were analysed by 16S ribosomal RNA gene sequencing. Results A significant reduction of within-individual microbial diversity was noted in PBC (p=0.03). A signature defined by decreased abundance of four genera and increased abundance of eight genera strongly correlated with PBC (area under curve=0.86, 0.84 in exploration and validation data, respectively). Notably, the abundance of six PBC-associated genera was reversed after 6 months of UDCA treatment. In particular, Faecalibacterium, enriched in controls, was further decreased in gp210-positive than gp210-negative patients (p=0.002). Of interest was the finding that the increased capacity for the inferred pathway, bacterial invasion of epithelial cells in PBC, highly correlated with the abundance of bacteria belonging to Enterobacteriaceae. Conclusions This study presents a comprehensive landscape of gut microbiota in PBC. Dysbiosis was found in the gut microbiome in PBC and partially relieved by UDCA. Our study suggests that gut microbiota is a potential therapeutic target and diagnostic biomarker for PBC.

The risk predictive values of UK-PBC and GLOBE scoring system in Chinese patients with primary biliary cholangitis: the additional effect of anti-gp210

Adequate risk stratification is critical for the management of the patients with primary biliary cholangitis (PBC). The UK‐PBC and GLOBE scoring systems for prognosis of PBC have been proposed recently, but have not been validated in Asian population.

Clinical and histological features of autoantibody-negative autoimmune hepatitis in Chinese patients: a single center experience.

This study aimed to define the clinical features of Chinese patients with autoantibody‐negative autoimmune hepatitis (AIH) and to refine the diagnosis and management of these atypical patients in a single Chinese center.

RNA Sequencing and Bioinformatics Analysis Implicate the Regulatory Role of a Long Noncoding RNA-mRNA Network in Hepatic Stellate Cell Activation

Background/Aims: To analyze the long noncoding (lncRNA)-mRNA expression network and potential roles in rat hepatic stellate cells (HSCs) during activation. Methods: LncRNA expression was analyzed in quiescent and culture-activated HSCs by RNA sequencing, and differentially expressed lncRNAs verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) were subjected to bioinformatics analysis. In vivo analyses of differential lncRNA-mRNA expression were performed on a rat model of liver fibrosis. Results: We identified upregulation of 12 lncRNAs and 155 mRNAs and downregulation of 12 lncRNAs and 374 mRNAs in activated HSCs. Additionally, we identified the differential expression of upregulated lncRNAs (NONRATT012636.2, NONRATT016788.2, and NONRATT021402.2) and downregulated lncRNAs (NONRATT007863.2, NONRATT019720.2, and NONRATT024061.2) in activated HSCs relative to levels observed in quiescent HSCs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that changes in lncRNAs associated with HSC activation revealed 11 significantly enriched pathways according to their predicted targets. Moreover, based on the predicted co-expression network, the relative dynamic levels of NONRATT013819.2 and lysyl oxidase (Lox) were compared during HSC activation both in vitro and in vivo. Our results confirmed the upregulation of lncRNA NONRATT013819.2 and Lox mRNA associated with the extracellular matrix (ECM)-related signaling pathway in HSCs and fibrotic livers. Conclusion: Our results detailing a dysregulated lncRNA-mRNA network might provide new treatment strategies for hepatic fibrosis based on findings indicating potentially critical roles for NONRATT013819.2 and Lox in ECM remodeling during HSC activation.

Comparative clinical characteristics and natural history of three variants of sclerosing cholangitis: IgG4-related SC, PSC/AIH and PSC alone

There is increased interest and recognition of the clinical variants of Sclerosing Cholangitis (SC) namely IgG4-SC, PSC/AIH overlap and PSC. For most Centers, the characteristic of IgG4-SC has not been thoroughly clinically compared with other sclerosing cholangitis variants. Further there are relatively few PSC/AIH overlap patients and the clinical outcome is not well characterized, especially for the PSC/AIH overlap syndrome. Our objective herein is to clarify the differences and similarities of the natural history of IgG4-SC, the PSC/AIH overlap and PSC alone. We also place in perspective the diagnostic value of serum IgG4 for IgG4-SC and investigate biomarkers for predicting the prognosis of sclerosing cholangitis. In this study, we took advantage of our large and well-defined patient cohort to perform a retrospective cohort study including 57 IgG4-SC, 36 PSC/AIH overlap patients, and 55 PSC patients. Firstly, as expected, we noted significant differences among immunoglobulin profiles and all patients exhibited similar cholestatic profiles at presentation. Cirrhotic events were found in 20 of total 57 IgG4-SC, 15 of 36 PSC/AIH overlap, and 18 of 55 PSC patients. Serum IgG4 was elevated in 92.65% of IgG4-SC patients with an 86% sensitivity and 98% specificity for diagnosis. IgG4-SC patients had a better treatment response at 6-month and 1-year than PSC/AIH patients, while the latter responded better with steroids than PSC patients. Importantly the adverse outcome-free survival of IgG4-SC patients was reduced, unlike earlier reports, and therefore similar to the PSC/AIH overlap syndrome. Serum IgG and total bilirubin were useful to predict long-term survival of IgG4-SC and PSC/AIH, respectively. In conclusion, serum IgG4≧1.25 ULN shows an excellent predictability to distinguish IgG4-SC among SC patients. IgG4-SC appears to be immune-mediated inflammatory process, while PSC/AIH overlap more tends to be cholestatic disease.

The immunobiology of mucosal-associated invariant T cell (MAIT) function in primary biliary cholangitis: Regulation by cholic acid-induced Interleukin-7

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.

The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid‐Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis

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.

Performance of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome

AIM To investigate the performance of transient elastography (TE) for diagnosis of fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome. METHODS A total of 70 patients with biopsy-proven AIH-PBC overlap syndrome were included. Spearman correlation test was used to analyze the correlation of liver stiffness measurement (LSM) and fibrosis stage. Independent samples Student’s t-test or one-way analysis of variance was used to compare quantitative variables. Receiver operating characteristics (ROC) curve was used to calculate the optimal cut-off values of LSM for predicting individual fibrosis stages. A comparison on the diagnostic accuracy for severe fibrosis was made between LSM and other serological scores. RESULTS Patients with AIH-PBC overlap syndrome had higher median LSM than healthy controls (11.3 ± 6.4 kPa vs 4.3 ± 1.4 kPa, P < 0.01). LSM was significantly correlated with fibrosis stage (r = 0.756, P < 0.01). LSM values increased gradually with an increased fibrosis stage. The areas under the ROC curves of LSM for stages F ≥ 2, F ≥ 3, and F4 were 0.837 (95%CI: 0.729-0.914), 0.910 (0.817-0.965), and 0.966 (0.893-0.995), respectively. The optimal cut-off values of LSM for fibrosis stages F ≥ 2, F ≥ 3, and F4 were 6.55, 10.50, and 14.45 kPa, respectively. LSM was significantly superior to fibrosis-4, glutaglumyl-transferase/platelet ratio, and aspartate aminotransferase-to-platelet ratio index scores in detecting severe fibrosis (F ≥ 3) (0.910 vs 0.715, P < 0.01; 0.910 vs 0.649, P < 0.01; 0.910 vs 0.616, P < 0.01, respectively). CONCLUSION TE can accurately detect hepatic fibrosis as a non-invasive method in patients with AIH-PBC overlap syndrome.