Reduced FOXP3+ regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms

Sebode, Marcial; Peiseler, Moritz; Franke, B.; Schwinge, Dorothee; Schoknecht, Tanja; Wortmann, Frederike; Quaas, Alexander; Petersen, Britt‐Sabina; Ellinghaus, Eva; Baron, Udo; Olek, Sven; Wiegard, Christiane; Weiler‐Normann, Christina; Lohse, Ansgar W.; Herkel, Johannes; Schramm, Christoph

doi:10.1016/j.jhep.2013.12.027

Cited by 97 publications

(98 citation statements)

References 30 publications

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“…In PSC, there is a clear T-cell predominant infiltrate [5] but little knowledge to date of relevant auto-antigenic triggers. Fewer functioning Tregs can be demonstrated in PBC, PSC and AIH cohorts, supporting the concept of defective loss of immune tolerance [27,31] .…”

Section: Immunologymentioning

confidence: 64%

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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Section: Immunologymentioning

confidence: 64%

The Pathogenesis of Autoimmune Liver Disease

Arndtz

Hirschfield

2016

Dig Dis

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“…Since there have been no advances in new therapies for these diseases in the last three decades, observations of reduction of Treg and/or impairment of Treg function in these diseases supports the concept of Treg therapy in AILD (12, 15, 17, 85). Treg therapy is an attractive option and especially now that standard operating procedures (SOPs) and GMP reagents and equipment are in place for the automated and safe manufacture of patient-specific cell-based therapies.…”

Section: Treg Immunotherapy For Liver Transplantation and Autoimmune mentioning

confidence: 88%

Clinical Potential of Regulatory T Cell Therapy in Liver Diseases: An Overview and Current Perspectives

et al. 2016

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The increasing demand for liver transplantation and the decline in donor organs has highlighted the need for alternative novel therapies to prevent chronic active hepatitis, which eventually leads to liver cirrhosis and liver cancer. Liver histology of chronic hepatitis is composed of both effector and regulatory lymphocytes. The human liver contains different subsets of effector lymphocytes that are kept in check by a subpopulation of T cells known as Regulatory T cells (Treg). The balance of effector and regulatory lymphocytes generally determines the outcome of hepatic inflammation: resolution, fulminant hepatitis, or chronic active hepatitis. Thus, maintaining and adjusting this balance is crucial in immunological manipulation of liver diseases. One of the options to restore this balance is to enrich Treg in the liver disease patients. Advances in the knowledge of Treg biology and development of clinical grade isolation reagents, cell sorting equipment, and good manufacturing practice facilities have paved the way to apply Treg cells as a potential therapy to restore peripheral self-tolerance in autoimmune liver diseases (AILD), chronic rejection, and posttransplantation. Past and on-going studies have applied Treg in type-1 diabetes mellitus, systemic lupus erythematosus, graft versus host diseases, and solid organ transplantations. There have not been any new therapies for the AILD for more than three decades; thus, the clinical potential for the application of autologous Treg cell therapy to treat autoimmune liver disease is an attractive and novel option. However, it is fundamental to understand the deep immunology, genetic profiles, biology, homing behavior, and microenvironment of Treg before applying the cells to the patients.

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“…Although reduced numbers of T reg have been reported in pediatric autoimmune hepatitis patients, other groups have demonstrated even increased numbers of Treg in adult patients with AIH, which correlated with inflammatory activity within the liver [216,217]. Therefore, impairment of T reg does not seem to be a general phenomenon in patients with AIH, whereas it has been reported in patients with PSC, a disease which is associated with polymorphisms within the IL-2RA locus, which may impair the delivery of IL-2 induced signals to T reg [218,219].…”

Section: Immunological Backgroundmentioning

confidence: 98%

Immunology of hepatic diseases during pregnancy

2016

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The mother's immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.

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Reduced FOXP3+ regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms

Cited by 97 publications

References 30 publications

The Pathogenesis of Autoimmune Liver Disease

The Pathogenesis of Autoimmune Liver Disease

Clinical Potential of Regulatory T Cell Therapy in Liver Diseases: An Overview and Current Perspectives

Immunology of hepatic diseases during pregnancy

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