Liver‐targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis†

Lan, Ruth Y.; Cheng, Chunmei; Lian, Zhe Xiong; Tsuneyama, Koichi; Yang, Guo Xiang; Moritoki, Yuki; Chuang, Ya Hui; Nakamura, Takafumi; Saito, Shigeru; Shimoda, Shinji; Tanaka, Atsushi; Bowlus, Christopher L.; Takano, Yasuo; Ansari, Aftab A.; Coppel, Ross L.; Gershwin, M. Eric

doi:10.1002/hep.21123

Cited by 279 publications

(210 citation statements)

References 34 publications

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“…In fact, a recent case report describes the complete lack of IL2Rα on the peripheral lymphocytes of a 5 year old boy presenting with liver dysfunction and serological expression of PBC, including the development of AMA specific for PDC-E2 (80). This case lends credence to the notion that Tregs, which are reduced in PBC patients, as well as in their sisters and daughters (25), exert a protective influence against the development of autoimmunity and particularly PBC. As a follow-up to this case report, IL2Rα deficient (IL2Rα −/− ) mice were generated and assessed for the development of clinical features found in PBC (81).…”

Section: Other Pbc Candidate Genessupporting

confidence: 71%

“…Strikingly, in the largest such study to date, AMAs were detected in 13.3% of mothers, 15.6% of sisters, and 12.5% of daughters of 127 patients with PBC with no history of familial PBC, in contrast to 1.1% of the female controls (18). Also of interest, the frequency of circulating T-regulatory cells (Tregs) has been found to be significantly reduced among sisters and daughters of PBC patients compared to age-matched controls (25). Taken together, these findings illustrate the familial predisposition to pathogenic features underlying PBC, thus providing additional evidence for the likely influence of genetics on this disease.…”

Section: The Familial Component Of Pbcmentioning

confidence: 97%

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Genetics and Genomics of Primary Biliary Cirrhosis

Juran

Lazaridis

2008

Clinics in Liver Disease

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The etiological and pathogenic factors contributing to PBC development, progression, response to treatment, and ultimately, outcome remain a mystery. This lack of knowledge can be attributed to the complexity of PBC, wherein a number of environmental triggers may be culpable, but require coexisting genetic susceptibility to exert their effect. Recognition of the genomic regions harboring these heritable risk factors has been hindered by the rarity and late onset of PBC, which has rendered the collection of adequate numbers of patients and family members for genetic analyses a difficult task. Recent advancements in the discipline of genomics holds promise to fundamentally change our understanding, prevention, and therapy of PBC. This chance arises from the development of new high-throughput approaches to genotyping, providing the means to rapidly uncover many of the genetic polymorphisms that are relevant to disease. In order to move ahead, large registries and biospecimen repositories of patients with PBC, their family members, and well-matched controls need to be established, maintained, and continually expanded. At the same time, sizeable, comprehensive haplotype mapping based association studies of functionally plausible candidate gene groups (e.g. immune function genes) as well as more far reaching genome-wide association studies will be necessary to form the basis upon which the genetic predisposition to PBC can be defined. This first set of experimental data will provide the means for future fine mapping studies, resequencing efforts, functional experimentation, and elucidation of gene-environment and gene-gene interaction; perhaps paving new paths in PBC research.

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Section: Other Pbc Candidate Genessupporting

confidence: 71%

Section: The Familial Component Of Pbcmentioning

confidence: 97%

Genetics and Genomics of Primary Biliary Cirrhosis

Juran

Lazaridis

2008

Clinics in Liver Disease

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“…Previous studies described the profiles of inflammatory cells surrounding bile ducts in PBC (9,(14)(15)(16)(17). Cellular profiles may change depending on the process of biliary inflammation.…”

Section: Immunopathological Characteristics Of Damaged Biliary Epithementioning

confidence: 99%

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

et al. 2017

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: Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an organ-specific autoimmune disease that predominantly affects middle-aged women and is characterized by the chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and, ultimately, fibrosis. The serological hallmark of PBC is the presence of anti-mitochondrial autoantibodies (AMA). Several mechanisms have been proposed for immune-mediated bile duct damage in PBC, including the roles of T cells, B cells, other cell phenotypes, and AMA. A sign of fragility of biliary epithelial cells caused by apoptosis, senescence, and autophagy has also been noted. Several complex steps and mechanisms appear to be involved in the induction and progression of cholangitis and biliary degeneration in patients with PBC.

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“…In this context, Tregs are implicated in controlling several autoimmune diseases, such as type I diabetes (4), multiple sclerosis (5,6), and rheumatoid arthritis (7). Additionally, Tregs were reported to be defective in autoimmune polyglandular syndrome type II (8), autoimmune hepatitis (9), and in patients with primary biliary cirrhosis (10). In patients with metastatic melanoma, both the number and suppressor effects of Tregs were increased (11).…”

mentioning

confidence: 99%

Expansion of CD4+CD25+and FOXP3+ Regulatory T Cells during the Follicular Phase of the Menstrual Cycle: Implications for Human Reproduction

Arruvito¹,

Sanz²,

Banham

et al. 2007

The Journal of Immunology

386

325

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Regulatory T cells (Tregs) are thought to affect the severity of various infectious and autoimmune diseases. The incidence of autoimmune disease is higher in fertile women than in men. Thus, we investigated whether Treg numbers were modulated during the menstrual cycle by sex hormones. In fertile nonpregnant women, we detected an expansion of CD4+CD25+FOXP3+ Tregs in the late follicular phase of the menstrual cycle. This increase was tightly correlated with serum levels of estradiol and was followed by a dramatic decrease in Treg numbers at the luteal phase. Women who have had recurrent spontaneous abortions (RSA) showed similarly low numbers of Tregs at both the follicular and luteal phases, comparable to numbers we observed in postmenopausal women. In addition to decreased numbers, Tregs from women with RSA were also functionally deficient, as higher numbers were required to exert a similar magnitude of suppression to CD4+CD25+FOXP3+ cells from fertile women. Consequently, reproductive failure might result from the inability of Tregs in women with RSA to expand during the preimplantatory phase combined with their lower functional capacity. Additionally, the modulation of Treg numbers we observed in fertile women suggests that the stage of the menstrual cycle should be taken into account when Treg numbers are investigated clinically.

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Liver‐targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis†

Abstract: The presence of AMAs and autoreactive T and B cells, in conjunction with the co-occurrence of other autoimmune diseases, characterizes PBC as a typical autoimmune disease. 3 Although the etiology of PBC remains obscure,

Cited by 279 publications

References 34 publications

Genetics and Genomics of Primary Biliary Cirrhosis

Genetics and Genomics of Primary Biliary Cirrhosis

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

Expansion of CD4+CD25+and FOXP3+ Regulatory T Cells during the Follicular Phase of the Menstrual Cycle: Implications for Human Reproduction

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