Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis

Zhang, Weici; Sharma, Rahul; Ju, Shyr Te; He, Xiaosong; Yan-yan, Tao; Tsuneyama, Koichi; Tian, Zhigang; Lian, Zhe Xiong; Fu, Shu Man; Gershwin, M. Eric

doi:10.1002/hep.22651

Cited by 88 publications

(74 citation statements)

References 56 publications

(51 reference statements)

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“…We administered recombinant TGF-b into scurfy mice on a daily basis. It is well known that scurfy mice develop fatal autoimmune diseases, and that various cytokines secreted by excessively activated CD4 + T cells play an important role in their pathologies (40,41). Notably, exogenously administered TGF-b efficiently suppressed severe autoimmune phenotypes of scurfy mice (Fig.…”

Section: Tgf-b Suppresses Th1 Cell Differentiation By Foxp3-independementioning

confidence: 91%

Smad2 and Smad3 Are Redundantly Essential for the TGF-β–Mediated Regulation of Regulatory T Plasticity and Th1 Development

Takimoto

Wakabayashi

Sekiya

et al. 2010

The Journal of Immunology

297

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Although it has been well established that TGF-β plays a pivotal role in immune regulation, the roles of its downstream transcription factors, Smad2 and Smad3, have not been fully clarified. Specifically, the function of Smad2 in the immune system has not been investigated because of the embryonic lethality of Smad2-deficient mice. In this study, we generated T cell-specific Smad2 conditional knockout (KO) mice and unexpectedly found that Smad2 and Smad3 were redundantly essential for TGF-β–mediated induction of Foxp3-expressing regulatory T cells and suppression of IFN-γ production in CD4+ T cells. Consistent with these observations, Smad2/Smad3-double KO mice, but not single KO mice, developed fatal inflammatory diseases with higher IFN-γ production and reduced Foxp3 expression in CD4+ T cells at the periphery. Although it has been suggested that Foxp3 induction might underlie TGF-β–mediated immunosuppression, TGF-β still can suppress Th1 cell development in Foxp3-deficient T cells, suggesting that the Smad2/3 pathway inhibits Th1 cell development with Foxp3-independent mechanisms. We also found that Th17 cell development was reduced in Smad-deficient CD4+ T cells because of higher production of Th17-inhibotory cytokines from these T cells. However, TGF-β–mediated induction of RORγt, a master regulator of Th17 cell, was independent of both Smad2 and Smad3, suggesting that TGF-β regulates Th17 development through Smad2/3-dependent and -independent mechanisms.

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Section: Tgf-b Suppresses Th1 Cell Differentiation By Foxp3-independementioning

confidence: 91%

Smad2 and Smad3 Are Redundantly Essential for the TGF-β–Mediated Regulation of Regulatory T Plasticity and Th1 Development

Takimoto

Wakabayashi

Sekiya

et al. 2010

The Journal of Immunology

297

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“…In addition, the ratio of hepatic Tregs over hepatic CD8 + cells was also lower in PBC patients than in patients with chronic hepatitis C and autoimmune hepatitis [18]. Moreover, recent experimental evidence suggests that deficiency of Tregs results in the development of anti-mitochondrial antibodies and autoimmune cholangitis [19]. Recently, it has been suggested that CXCL10 could mediate the hepatic recruitment of Tregs expressing CXCR3 after natural killer (NK) T cell activation in mice liver [20].…”

Section: Discussionmentioning

confidence: 99%

CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid

Manousou

Kolios

Drygiannakis

et al. 2013

Clinical and Experimental Immunology

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“…The increased presence of TGF-β3 instead of TGF-β1 could be a further mechanism that favors Th17 activity since one can postulate that TGF-β3 could either be associated with functionally defective Tregs or could directly favor the increase of Th17. Further evidence for such a hypothesis is provided by a report that mice with mutation of the gene encoding the FoxP3 transcriptional factor developed AMA positivity and features resembling PBC with increased levels of IL-17 and IL-23, cytokines associated with Th17 cells [104] . The proposed model requires that additional aspects have to be verified in future.…”

Section: Pathogenesis Of Pbc: a Unifying Hypothesismentioning

confidence: 99%

“…Equally important is the role of T regulatory cells. Animal experiments indicate that deficiency of regulatory T cells (Tregs) results in the development of AMA +ve, autoimmune bile ductular lesions anti [104] . Moreover a reduction of Tregs has been found in the portal tracts of PBC patients [105] .…”

Section: Cd4mentioning

confidence: 99%

Primary biliary cirrhosis: From bench to bedside

Notas

2015

WJGPT

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Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient's genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. Core tip: Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis of largely unknown pathophysiology. We examined the epidemiological and geoepidemiological data as well as the pathogenetic aspects of PBC. A novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.

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Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis

Cited by 88 publications

References 56 publications

Smad2 and Smad3 Are Redundantly Essential for the TGF-β–Mediated Regulation of Regulatory T Plasticity and Th1 Development

Smad2 and Smad3 Are Redundantly Essential for the TGF-β–Mediated Regulation of Regulatory T Plasticity and Th1 Development

CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid

Primary biliary cirrhosis: From bench to bedside

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