IL-2 receptor alpha deficiency and features of primary biliary cirrhosis

Aoki, Christopher A.; Roifman, Chaim M.; Lian, Zhe‐Xiong; Bowlus, Christopher L.; Norman, Gary L.; Shoenfeld, Yehuda; Mackay, Ian R.; Gershwin, M. Eric

doi:10.1016/j.jaut.2006.04.005

Cited by 161 publications

(127 citation statements)

References 25 publications

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“…In 6BH-BSA-immunized guinea pigs, the presence of liver-specific histological lesions, the presence of lymphoid cell infiltrations surrounding damaged portal tracts together with mitochondrial autoantigen-specific AMA, implicates the involvement of cell-mediated immune responses in the liver. Future studies using reagents that demonstrate specificity for guinea pig CD4 ϩ and CD8 ϩ T cells will be designed to address the important role of T cell-mediated immune responses in this model (35,36). However, we need to emphasize several limitations in the study of T cell responses and guinea pigs.…”

Section: Discussionmentioning

confidence: 99%

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Leung

Park

Tsuneyama

et al. 2007

The Journal of Immunology

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Although significant advances have been made in dissecting the effector mechanisms in autoimmunity, the major stumbling block remains defining the etiological events that precede disease. Primary biliary cirrhosis (PBC) illustrates this paradigm because of its high degree of heritability, its female predominance, and its extraordinarily specific and defined immune response and target destruction. In PBC, the major autoantigens belong to E2 components of the 2-oxo-acid dehydrogenase family of mitochondrially located enzymes that share a lipoylated peptide sequence that is the immunodominant target. Our previous work has demonstrated that synthetic mimics of the lipoate molecule such as 6-bromohexoanate demonstrate a high degree of reactivity with PBC sera prompted us to immunize groups of guinea pigs with 6-bromohexoanate conjugated to BSA. In this study, we provide serologic and immunohistochemical evidence that such immunized guinea pigs not only develop antimitochondrial autoantibody responses similar to human PBC, but also develop autoimmune cholangitis after 18 mo. Xenobiotic-immunized guinea pigs are the first induced model of PBC and suggest an etiology that has implications for the causation of other human autoimmune diseases. The data also reflect the likelihood that, in PBC, the multilineage antimitochondrial response is a pathogenic mechanism and that loss of tolerance and subsequent development of biliary lesions depends on either modification of the host mitochondrial Ag or a similar breakdown due to molecular mimicry.

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Section: Discussionmentioning

confidence: 99%

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Leung

Park

Tsuneyama

et al. 2007

The Journal of Immunology

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“…In addition, allogenic stem cell transplantation was found to lead to full recovery from primary biliary cirrhosis where peripheral blood lymphocytes were completely deficient in the -subunit of the IL-2R (CD25) [102].…”

Section: Interleukin-2 and Interleukin-2 Receptormentioning

confidence: 99%

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

111

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Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes.Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.4

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“…4 To reprove this point, a group of women with chronic viral disease was included in this further analysis to further rule out the possibility that chronic inflammation or liver injury per se interferes with preferential X chromosome loss.…”

Section: Chromosome Analysesmentioning

confidence: 99%

“…1 Importantly, the critical importance of genetic susceptibility to PBC is supported by the high concordance rate in monozygotic twins, 2 the tendency to observe multiple cases in pedigrees, 3 and recent observations in case reports of specific mutations. 4 We do know, however, that PBC is likely a combination of genetic and environmental factors. 5,6 Indeed, we previously submitted that sex chromosome defects would provide clues in the search for loci involved in PBC susceptibility and sex ratios 7 and have reported that women with PBC and two other female-predominant autoimmune diseases, systemic sclerosis and autoimmune thyroid disease, are characterized by an enhanced X monosomy rate in peripheral blood mononuclear cells (PBMC), particularly T and B lymphocytes 8,9 compared to healthy age-matched women.…”

mentioning

confidence: 99%

Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis†

et al. 2007

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Recent work has demonstrated enhanced X monosomy in women with primary biliary cirrhosis (PBC) as well as two other female-predominant autoimmune diseases, systemic sclerosis and autoimmune thyroid disease. To further our understanding of these events, we have investigated the mechanisms of X chromosome loss and X chromosome inactivation (XCI) in 166 women with PBC and 226 rigorously age-matched healthy and liver disease controls. X chromosome analysis and determination of loss pattern was performed by quantitative fluorescent polymerase chain reaction (QF-PCR) with 4 X-linked short tandem repeats. Further definition of the XCI was based on analysis of methylation-sensitive restriction sites. Importantly, in PBC the X chromosome loss occurs not only more frequently but also in a preferential fashion. This observation supports our thesis that the enhanced X monosomy involves only one parentally derived chromosome and is not secondary to a constitutive non random pattern of XCI. In fact, in the presence of monosomy, the lost X chromosome is necessarily the inactive homologue. Conclusion: The finding that the X chromosome loss is preferential suggests the critical involvement of X chromosome gene products in the female predisposition to PBC and also emphasizes the need to determine the parental origin of the maintained chromosome to investigate the role of imprinting. (HEPATOLOGY 2007;46:456-462.)

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IL-2 receptor alpha deficiency and features of primary biliary cirrhosis

Cited by 161 publications

References 25 publications

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis†

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