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Nagano, Takuya; Yamamoto, Kazuhide; Matsumoto, Seiji; Okamoto, Ryoichi; Tagashira, Masafumi; Ibuki, Naofumi; Matsumura, Shuji; Yabushita, Kazuhisa; Okano, Nobuaki; Tsuji, Takao

doi:10.1023/a:1020511002025

Cited by 97 publications

(21 citation statements)

References 27 publications

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“…The monocyte PAMP-induced cytokine production observed in our study appears compatible with previously obtained data [76][77][78][79][80], which implicate a significant role of Th-1 cytokines in the pathogenesis of PBC. We note, however, that Th-2 cytokines, such as IL-5, IL-6, and IL-10 have also been detected in PBC livers [77,79], thus indicating that both Th-1 and Th-2 cytokines, possibly during different stages of the disease, might be involved in the pathogenesis of PBC. A longitudinal study will therefore be necessary to evaluate whether the observed differences are secondary to other mechanisms that contribute to the pathogenesis of PBC.…”

Section: Monocytessupporting

confidence: 92%

Innate Immunity and Primary Biliary Cirrhosis

Selmi¹,

Lleo²,

Pasini³

et al. 2009

CMM

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There has been a rapid growth in our understanding of the molecular bases of primary biliary cirrhosis (PBC). These efforts were initiated when the immunodominant mitochondrial autoantigen was cloned and sequenced. Using the recombinant cloned antigen as a tool, research has focused on the effector mechanisms of disease and the uniqueness of the primary target tissue, the intrahepatic bile ducts. Most recently, there have been experimental data suggesting that innate immunity changes may be critical to the initiation and perpetuation of the autoimmune injury, as in the case of the enhanced response of monocytes and memory B cells to infectious stimulation and environmental mimics. These observations are important as they help fill in the many gaps which remain on the most difficult subject of autoimmunity, etiology. Indeed, based on the available data, several experimental models of PBC have been developed. These models illustrate and suggest that PBC can be initiated by several mechanisms, all of which lead to loss of tolerance to the mitochondrial antigens. However, once this adaptive response develops, it appears that much of the subsequent pathology is exacerbated by innate responses. We suggest that future therapeutic efforts in PBC will depend heavily on understanding the nature of this innate immune responses and methodology to blunt their cytotoxicity.

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Section: Monocytessupporting

confidence: 92%

Innate Immunity and Primary Biliary Cirrhosis

Selmi¹,

Lleo²,

Pasini³

et al. 2009

CMM

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“…Cytokine expression in the liver of primary biliary cirrhosis patients is similarly mixed. Compared to other liver diseases, increased hepatic expression of IL-5, IL-6, IFNγ, TGFβ, and IL-2 has been noted (257, 258). Recent studies also identified key Th1 and Th17 cytokines in the liver (259) and on blood cells (260) and a decreased T regulatory to Th17 cell balance in peripheral blood cells (261).…”

Section: Role Of Eosinophils In Autoimmune Diseasesmentioning

confidence: 99%

“…Eosinophil infiltration is higher in the early stages of the disease (stages I–II versus III–IV) (263, 265). Increased eosinophil infiltration was positively associated with liver IL-5 expression (258) and mast cell infiltration (264). Infiltrating eosinophils are degranulating, releasing ECP, MBP, and EDN, which can also be detected in the serum (262, 265).…”

Section: Role Of Eosinophils In Autoimmune Diseasesmentioning

confidence: 99%

Eosinophils in Autoimmune Diseases

2017

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Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.

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“…Analysis of RNA expression in explanted PBC liver samples has consistently revealed skewing of the cytokine profile with reduced IL-10 (a predominantly Th2 cytokine) and increased interferon gamma (IFNγ; a Th1 cytokine) in comparison to chronic hepatitis C explants [16], [17]. Levels of serum IL-18 – which acts to release IL-12 and activate the Th1 pathway – and IFNγ are also elevated in PBC patients relative to levels detected in healthy controls and chronic viral hepatitis patients [18], [19].…”

Section: Introductionmentioning

confidence: 99%

The immunogenetics of primary biliary cirrhosis: A comprehensive review

Webb

Siminovitch

Hirschfield

2015

Journal of Autoimmunity

105

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Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.

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Untitled

Cited by 97 publications

References 27 publications

Innate Immunity and Primary Biliary Cirrhosis

Innate Immunity and Primary Biliary Cirrhosis

Eosinophils in Autoimmune Diseases

The immunogenetics of primary biliary cirrhosis: A comprehensive review

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