Proteomic analysis reveals distinctive protein profiles involved in CD8^(+) T cell-mediated murine autoimmune cholangitis

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver,and T cells are critical drivers in this process.However,little is known about the regulation of their functional behavior during disease development.We previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type Ⅱ(dnTGFβ RII)spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis(PBC).Adoptive transfer of CD8^(+) but not CD4^(+) T cells into Rag1^(−/−)mice reproduced the disease,demonstrating a critical role for CD8^(+) T cells in PBC pathogenesis.Herein,we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFβRII and B6 control mice at different ages.In addition,we analyzed CD8 protein profiles after adoptive transfer of splenic CD8^(+) cells into Rag1^(−/−)recipients.The use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of CD8 cells,which are key to biliary mediation.In total,254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic CD8^(+) cells compared to donor splenic CD8^(+) cells.In contrast to donor splenic CD8^(+) cells,recipient hepatic CD8^(+) cells expressed distinct profiles for proteins involved in chemokine signaling,focal adhesion,T cell receptor and natural killer cell-mediated cytotoxicity pathways.

Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis

BACKGROUND： Sclerosing cholangitis（SC） is a chronic cholestatic hepatobiliary disease with uncertain long-term prognosis in pediatric patients. This study aimed to evaluate longterm results in children with SC according to the types of SC.METHODS： We retrospectively followed up 25 children with SC over a period of 4-17 years（median 12）. The diagnosis of SC was based on biochemical, histological and cholangiographic findings. Patients fulfilling diagnostic criteria for probable or definite autoimmune hepatitis at the time of diagnosis were defined as having autoimmune sclerosing cholangitis（ASC）; other patients were included in a group of primary sclerosing cholangitis（PSC）. The incidence of the following complications was studied： obstructive cholangitis, portal hypertension, advanced liver disease and death associated with the primary disease.RESULTS： Fourteen（56%） patients had PSC and 11（44%） had ASC. Patients with ASC were significantly younger at the time of diagnosis（12.3 vs 15.4 years, P=0.032） and had higher Ig G levels（22.7 vs 17.2 g/L, P=0.003）. The mentioned complications occurred in 4（16%） patients with SC, exclusively in the PSC group： one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, twoother children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications.CONCLUSION： In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC.

Autoantibodies in primary sclerosing cholangitis

The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients,but the specifi city of these antibodies is generally low,and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecifi c dysregulation of the immune system,but the literature in PSC points to the possible presence of specifi c antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC,with a particular emphasis on the prevalence,clinical relevance and possible pathogenetic importance of each individual marker.

Use of oral vancomycin in children with autoimmune liver disease:A single centre experience

BACKGROUND Previous reports showed some beneficial effect of oral vancomycin treatment(OVT)in children with primary sclerosing cholangitis;conversely,the experience in patients with other autoimmune liver diseases(AILD),including autoimmune hepatitis(AIH)and autoimmune sclerosing cholangitis(ASC),is scant.AIM To assess the response to immunosuppressive treatment(IS)and to OVT in children diagnosed with AILD.METHODS Retrospective study of children diagnosed with AIH(normal biliary tree at cholangiography)and ASC(abnormal biliary tree at cholangiography)in the last 10 years.All underwent standard immunosuppressive therapy(IS),but nonresponders received also OVT.Biochemical remission[normal aspartate aminotransferase(AST)]and immunological remission(normal IgG and negative autoantibodies)rates and Sclerosing Cholangitis Outcomes in Pediatrics(SCOPE)index were assessed and compared during the follow up.RESULTS 75 children were included[69%female,median age 10.5 years(5.6-13.4 years),AIH=54,ASC=21].Sixty-three patients(84%,AIH=52,ASC=11)were treated with standard IS and 61 achieved biochemical remission,whereas 12 not responding to IS[16%,F=75%,median age 13.5 years,(12.2-15.7),10 with ASC]required OVT and 8 achieved biochemical remission.Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81%(61/75)to 92%(69/75).Median values of AST,alanine aminotransferase(ALT)and gamma-glutamyl transferase(GGT)decreased significantly after OVT start(P<0.05).Complete normalization of livers enzymes(AST,ALT and GGT)was observed in 6/12 patients(50%).Decrease in SCOPE index score was reported in 5/12 patients(42%).At last follow up(median of 4.4 years,range 0.6-13.8 years)all 75 patients are alive,6(8%,1 with ASC)successfully discontinued medications,1(with ASC)required liver transplantation.CONCLUSION Children with AIH and ASC respond well to IS treatment.OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS.These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.