Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα−/− mice

Yao, Yuan; Yang, Wei; Yang, Yan; Di, Hong J.; Lu, Fang; Li, Liang; Tao, Yan Yan; Tsuneyama, Koichi; Zhang, Weici; Friedman, Scott L.; Gershwin, M. Eric; Lian, Zhe Xiong

doi:10.1016/j.jaut.2014.02.009

Cited by 63 publications

(52 citation statements)

References 67 publications

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“…In mouse models, deletion of the IL-12p40 subunit appears to lead to worsening biliary inflammation and suggest that IL-12 may also have negative immunoregulatory functions [42] .…”

Section: Cytokines and Leukocyte Recruitmentmentioning

confidence: 99%

The Pathogenesis of Autoimmune Liver Disease

Arndtz

Hirschfield

2016

Dig Dis

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Background: Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. Key Messages: There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Conclusions: Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood.

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“…In mouse models, deletion of the IL-12p40 subunit appears to lead to worsening biliary inflammation and suggest that IL-12 may also have negative immunoregulatory functions [42] .…”

Section: Cytokines and Leukocyte Recruitmentmentioning

confidence: 99%

The Pathogenesis of Autoimmune Liver Disease

Arndtz

Hirschfield

2016

Dig Dis

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“…There have been significant advances in our understanding of primary biliary cirrhosis (PBC) including dissection of molecular and immunological mechanisms that lead to biliary cell destruction, development of animal models, and further details on geoepidemiology [1][2][3][4][5][6][7][8]. These advances, notwithstanding, and because of the potential presence of cirrhosis, there remain the critical questions regarding the relative frequency and risk factors for developing hepatocellular carcinoma (HCC) in PBC [9].…”

Section: Introductionmentioning

confidence: 99%

Incidence and Risk Factors for Hepatocellular Carcinoma in Primary Biliary Cirrhosis

Rong

Wang

Bowlus

et al. 2015

Clinic Rev Allerg Immunol

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The incidence, risk factors, and clinical features of hepatocellular carcinoma (HCC) in primary biliary cirrhosis (PBC) have been a long-standing subject of interest. We took advantage of a large cohort of 1865 well-defined Chinese patients with PBC for whom follow-up was conducted for up to 20 years to study the incidence of HCC. Our goal was to address the incidence and prevalence of HCC in PBC and the risk factors, including hepatitis B virus (HBV) infection, and finally to compare the tumor characteristics of PBC-related HCC, including size, location, mortality, and long-term outcomes, to that of HBV-related HCC. In this cohort, HCC occurred in 70 of 1865 PBC patients with a prevalence of 3.75 % and an incidence of 0.66 cases per 100 patient-years. The 5- and 10-year cumulative incidences were 2.6 % (95 % confidence interval (CI) 1.8-3.4) and 8.9 % (95 % CI 5.5-12.3), respectively. Age >54 years (odds ratio [OR] = 5.5, 95 % CI 3.0-10.1, p = 0.001), male sex (OR = 2.2, 95 % CI 1.2-4.0, p = 0.001), co-existence of diabetes mellitus (DM) (OR = 3.1, 95 % CI 1.6-6.2, p = 0.002), and previous HBV infection (OR = 6.6, 95 % CI 3.7-11.9, p = 0.001) were independently associated with the development of HCC. The tumor size, number, location, and 5-year survival were not significantly different in PBC-related HCC compared to HBV-related HCC. Alpha-fetoprotein was elevated in only 20 % of the cases with PBC-related HCC. Although HCC was uncommon, occurring in fewer than 5 % of patients, the risk is significantly increased by age, sex, DM, and past HBV infection.

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“…There have been extraordinary and extensive studies of the genetic basis, the immunological features, and the molecular characteristics of not only human PBC but also of several mouse models [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis

Yang

Wang

et al. 2015

Clinic Rev Allerg Immunol

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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.

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Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα−/− mice

Cited by 63 publications

References 67 publications

The Pathogenesis of Autoimmune Liver Disease

The Pathogenesis of Autoimmune Liver Disease

Incidence and Risk Factors for Hepatocellular Carcinoma in Primary Biliary Cirrhosis

The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis

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