New insights on the role of human leukocyte antigen complex in primary biliary cholangitis.

Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.

Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis.

OBJECTIVE: Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. DESIGN: We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. RESULTS: Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. CONCLUSIONS: Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.

Morphological, Functional, and Tissue Characterization of Silent Myocardial Involvement in Patients With Primary Biliary Cholangitis.

BACKGROUND & AIMS: Cirrhotic cardiomyopathy is a major complication and cause of morbidity in end-stage primary biliary cholangitis (PBC). However, it is unclear whether there is clinically silent myocardial involvement at the early stage of PBC before cirrhosis and cardiac manifestations. This prospective, three-center, multi-modality cardiac imaging study on the early identification of myocardial impairment in PBC (EARLY-MYO-PBC) was designed to identify silent myocardial impairment in PBC patients without cardiac manifestations. METHODS: A total of 112 subjects (56 with PBC and 56 age- and sex-matched controls) undergoing cardiovascular magnetic resonance (CMR) were enrolled. Demographic, serologic, and cardiac imaging data were prospectively collected. All participants had no cardiac discomfort or previous heart disease and had normal electrocardiographic findings. RESULTS: Subclinical myocardial involvement, as evidenced by cardiac morphologic, functional, and tissue characterization changes on CMR, including hyperdynamic left ventricular (LV) ejection fraction (median, 75% in PBC patients vs 69% in controls, P = .029), subclinical myocardial edema by T2-short tau inversion recovery (21% vs 2% in controls, P = .001), elevated extracellular matrix indices (30% vs 26% in controls, P < .001), and impaired myocardial viability by positive late gadolinium enhancement (LGE) (36%), was detected in PBC patients. Importantly, a mid-wall "stripe" at the LV septum was identified as a PBC-specific LGE pattern that differs from other known cardiomyopathies. In multivariate analysis, gp210 positivity (odds ratio [OR] = 9.909, P = .010), lower hemoglobin (OR = 0.919, P = .004), and body mass index (OR = 0.638, P = .005) were independent predictors of cardiac abnormalities in PBC. CONCLUSIONS: This study demonstrates clinically silent cardiac impairment with specific CMR patterns in PBC, allowing optimal screening for early myocardial impairment and potentially timely therapies. (Trial registration no.: NCT03545672).

Primary biliary cholangitis.

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

Immunity to commensal skin fungi promotes psoriasiform skin inflammation.

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.

Alterations of gut microbiome in autoimmune hepatitis.

OBJECTIVE: The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls. DESIGN: We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy. RESULTS: The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including Veillonella were associated with disease status. Of note, Veillonella dispar, the most strongly disease-associated taxa (p=8.85E-8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites. CONCLUSION: Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.

Autoantibodies in patients with interleukin 12 receptor beta 1 deficiency.

OBJECTIVE: Interleukin 12 receptor beta 1 (IL-12Rß1) deficiency is a primary immunodeficiency that exposes affected individuals to an augmented risk of intracellular pathogen-mediated infections. The paradoxical presence of autoimmune manifestations in immune-deficient patients has been recognized, but the basis of this phenomenon is unclear, with the role of frequent infections being a possible trigger to break tolerance. Our study aimed to analyze extensively a profile of autoantibodies in a clinically well-defined case series of patients with IL-12Rß1 deficiency. METHODS: Eight patients with IL-12Rß1 deficiency referred to Children's Medical Center in Tunis, Tunisia, during 1995-2012 were enrolled in the study. Sixteen age- and gender-matched blood donors served as controls. Serum, liver-related autoantibodies immunoglobulin (Ig)G, IgM, IgA were tested by ELISA and by standard indirect immunofluorescence on Hep-2 cells. RESULTS: We found a significant prevalence of liver autoantibodies in the study group. Regarding primary biliary cholangitis (PBC), two of eight patients were positive for MIT3 autoantibodies, both confirmed by immunofluorescence, and one patient was positive for PBC-specific antinuclear antibodies, sp100. Moreover, two patients had significantly increased gamma-glutamyltransferase levels and one had IgM levels twice the upper limit of normal. Intriguingly two patients were positive for anti-actin antibodies; a typical feature of autoimmune hepatitis type 1, along with a significant increase in IgG levels. CONCLUSIONS: This is the first report of a serological analysis in patients with an IL-12Rß1 deficiency. Despite the difficulty in interpreting the role of the IL-12, the evidence of liver-specific autoantibodies confirms the importance its signal in liver autoimmunity.

The genetics of primary biliary cholangitis.

PURPOSE OF REVIEW: Primary biliary cholangitis (PBC) is a female predominant chronic autoimmune disease of the intrahepatic bile ducts and with a long latent period. It is crucial to understand how genetics contribute to the disease. RECENT FINDINGS: Geo-epidemiological studies in PBC have provided evidence of familial risk; case-control studies and genome wide association studies have identified various human leukocyte antigen (HLA) and non-HLA alleles that are associated with PBC. However, these alleles are non-PBC specific and most of the identified non-HLA loci were also found to be susceptible genes in other autoimmune diseases and different between study populations. SUMMARY: Patients with PBC are often asymptomatic and often left undiagnosed. There are no known HLA and non-HLA alleles specific for PBC. Global effort and novel approaches such as epigenetics directed at identification of genetic risk factors will greatly facilitate accurate and timely diagnosis, which will improve prognosis and increase treatment options.

The Genetics and Epigenetics of Primary Biliary Cholangitis.

Both genetic background and environmental factors contribute to primary biliary cholangitis (PBC). Recent innovative technologies, such as genome-wide association studies, identified a remarkable number of susceptible nonhuman leukocyte antigen genes contributing to the development of PBC; however, they are primarily indicators of active immunologic responses commonly involved in autoimmune reactions. Thus, recent studies have focused on epigenetic mechanisms that would link genetic predisposition and environmental triggering factors. In PBC, methylation profiling and altered X chromosome architecture have been intensively explored in conjunction with a striking female predominance. Further, microRNAs have been found to be associated with the etiology of PBC.

The Critical Role of Chemokine (C-C Motif) Receptor 2-Positive Monocytes in Autoimmune Cholangitis.

The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6Chi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6Chi monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.

Contextual control of skin immunity and inflammation by Corynebacterium.

How defined microbes influence the skin immune system remains poorly understood. Here we demonstrate that Corynebacteria, dominant members of the skin microbiota, promote a dramatic increase in the number and activation of a defined subset of γδ T cells. This effect is long-lasting, occurs independently of other microbes, and is, in part, mediated by interleukin (IL)-23. Under steady-state conditions, the impact of Corynebacterium is discrete and noninflammatory. However, when applied to the skin of a host fed a high-fat diet, Corynebacterium accolens alone promotes inflammation in an IL-23-dependent manner. Such effect is highly conserved among species of Corynebacterium and dependent on the expression of a dominant component of the cell envelope, mycolic acid. Our data uncover a mode of communication between the immune system and a dominant genus of the skin microbiota and reveal that the functional impact of canonical skin microbial determinants is contextually controlled by the inflammatory and metabolic state of the host.

Utility of arterial stiffness assessment in children.

Atherosclerotic cardiovascular disease is a leading cause of death and disability worldwide, and the atherosclerotic process begins in childhood. Prevention or containment of risk factors that accelerate atherosclerosis can delay the development of atherosclerotic cardiovascular disease. Although current recommendations are to periodically screen for commonly prevailing risk factors for atherosclerosis in children, a single test that could quantify the cumulative effect of all risk factors on the vasculature, thus assessing arterial health, would be helpful in further stratifying risk. Measurement of pulse wave velocity and assessment of augmentation index - measures of arterial stiffness - are easy-to-use, non-invasive methods of examining arterial health. Various studies have assessed pulse wave velocity and augmentation index in children with commonly occurring conditions including obesity, hypertension, insulin resistance, diabetes mellitus, dyslipidaemia, physical inactivity, chronic kidney disease, CHD and acquired heart diseases, and in children who were born premature or small for gestational age. This article summarises pulse wave velocity and augmentation index assessments and the effects of commonly prevailing chronic conditions on arterial health in children. In addition, currently available reference values for pulse wave velocity and augmentation index in healthy children are included. Further research to establish widely applicable normative values and the effect of lifestyle and pharmacological interventions on arterial health in children is needed.

Rheumatic Manifestations in Autoimmune Liver Disease.

Autoimmune liver diseases coexist with rheumatic disorders in approximately 30% of cases and may also share pathogenic mechanisms. Autoimmune liver diseases result from an immune-mediated injury of different tissues, with autoimmune hepatitis (AIH) targeting hepatocytes, and primary biliary cholangitis (PBC) and primary sclerosing cholangitis targeting cholangiocytes. Sjogren syndrome is diagnosed in 7% of AIH cases and serologic autoimmunity profiles are a common laboratory abnormality, particularly in the case of serum antimitochondrial (PBC) or anti-liver kidney microsomal antibodies (AIH). Therapeutic strategies may overlap between rheumatic and autoimmune liver diseases and practitioners should be vigilant in managing bone loss.

Geoepidemiology and changing mortality in primary biliary cholangitis.

Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic disease characterized by an autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts. Originally PBC was considered to be rare and almost invariably fatal, mainly because the diagnosis was made in patients presenting with advanced symptomatic disease (jaundice and decompensated cirrhosis). However, the development of a reproducible indirect immunofluorescence assay for antimitochondrial antibody made it possible to diagnose the disease at an earlier stage, and introduction of ursodeoxycholic acid therapy as the first-line therapy for PBC drastically changed PBC-related mortality. At present, patients with an early histological stage have survival rates similar to those of an age- and sex-matched control population. Although 30% of patients treated with ursodeoxycholic acid may exhibit incomplete responses, obeticholic acid and drugs currently in development are expected to be effective for these patients and improve outcomes. Meanwhile, more etiology and immunopathology studies using new technologies and novel animal models are needed to dissect variances of clinical course, treatment response, and outcome in each patient with PBC. Precision medicine that is individualized for each patient on the basis of the cause identified is eagerly awaited.

The epigenetics of PBC: The link between genetic susceptibility and environment.

Primary biliary cholangitis (PBC) previously known as primary biliary cirrhosis is an autoimmune disease-associated with progressive cholestasis, the presence of autoreactive T cell and characteristic serological autoantibodies. Genetic and genome-wide association studies (GWAS) have recently shed light on the genetic background of PBC. Besides that some causal nucleotide changes and mechanisms remain largely unknown as suggested for example, by the observation that monozygotic twins have an identical DNA sequence even if presents some phenotypic differences that may be consequences of different exposures to environmental stressors. For this reason, it is believed that epigenetic mechanisms may be involved in PBC pathogenesis, as already demonstrated in many autoimmune diseases and can eventually provide an understanding that has been missed from genetics alone. This review will focus on the most commonly studied epigenetic modifications already demonstrated in PBC; special attention will be paid also to other epigenetic mechanisms so far not demonstrated in PBC patients, but that could increase our understanding in PBC pathogenesis.

Vitamin D, Low-Grade Inflammation and Cardiovascular Risk in Young Children: A Pilot Study.

Vitamin D has anti-inflammatory properties, and deficiency is prevalent in children. There is a paucity of data regarding vitamin D status and its correlation with low-grade inflammation and vasculature. We prospectively enrolled 25 children, 9-11 years old (13 male); 21 obese. Eight atherosclerosis-promoting risk factors were scored as categorical variables with the following thresholds defining abnormality: body mass index Z score ≥ 1.5; systolic blood pressure ≥ 95th percentile (for age, sex, and height); triglyceride ≥ 100 mg/dL; low-density lipoprotein cholesterol (LDL-C) ≥ 110 mg/dL; high-density lipoprotein cholesterol ≤ 45 mg/dL; hemoglobin A1C (HBA1C) ≥ 5.5; 25-hydroxyvitamin D [25(OH) D] ≤ 30 ng/mL, and tobacco smoke exposure. High-sensitivity C-reactive protein (hsCRP) was measured to assess low-grade inflammation and classified as low- (<1 mg/L), average- (1-3 mg/L), and high-risk (>3 to <10 mg/L) groups. The proportion of children within each hsCRP group who had above threshold risk factors was calculated. Carotid artery ultrasound was performed to measure carotid artery intima-media thickness (CIMT). Median (range) for 25(OH) D was 24 (17-45) ng/mL. Eighteen were either 25 (OH) D deficient (<20 ng/mL) or insufficient (20-30 ng/mL), and seven were sufficient (>30 ng/mL). hsCRP was 1.7 (0.2-9.1) mg/L, with 11 being <1.0 mg/L, 8 between 1.0-3.0 and 6 > 3.0 to < 10.0 mg/L. Risk factor score was 3.9 ± 1.7 out of eight. 25(OH) D levels did not correlate with hsCRP or CIMT. While vitamin D deficiency, inflammation, and risk factors coexist at a very young age, causative mechanisms remain unclear.

Outcomes after prolonged extracorporeal membrane oxygenation support in children with cardiac disease--Extracorporeal Life Support Organization registry study.

OBJECTIVE: Extracorporeal membrane oxygenation remains the mainstay of mechanical circulatory support initiation and maintenance in children with cardiac insufficiency. However, the outcomes after prolonged extracorporeal membrane oxygenation for cardiac insufficiency in children remain ill defined. METHODS: We reviewed the International Extracorporeal Life Support Organization data from January 1, 2000, through December 31, 2011. We defined prolonged extracorporeal membrane oxygenation as uninterrupted support for ≥14 days. RESULTS: A total of 777 children aged <18 years required extracorporeal membrane oxygenation support for ≥14 days. Of these, 176 (23%) survived to hospital discharge. Compared with the nonsurvivors, the survivors were older (median age, 0.64 vs 0.10 years; P < .01), weighed more (median weight, 7.0 kg; range, 2-90; vs median, 4.0; range, 1.4-100 kg; P < .01), had a shorter duration of support (mean, 20 ± 6 vs 22 ± 9 days; P < .01), and a fewer number of organ system complications (mean, 2.8 ± 1.7 vs 3.6 ± 1.6, P < .01). Children with congenital heart disease had worse survival than those with cardiomyopathy and myocarditis (15% vs 42% and 52%, respectively; P < .01), and those with 1-ventricle physiology had worse survival than those with 2-ventricle physiology (10% vs 18%, P = .01). Seven percent (n = 56) reached cardiac transplantation, with 66% surviving to hospital discharge versus 19% of those not transplanted (P < .01). CONCLUSIONS: The attrition is high after prolonged extracorporeal membrane oxygenation support for cardiac insufficiency in children. Cardiac transplantation in this cohort was rarely achieved and was associated with high mortality compared with benchmarks for cardiac transplantation survival. Earlier redirection of care or conversion to other modes of mechanical support as a bridge to transplantation should be considered.