The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex‐biased autoimmunity

Bae, Heekyong; Hodge, Deborah L.; Yang, Guo Xiang; Leung, Patrick S.C.; Chodisetti, Sathi Babu; Valencia, Julio C.; Sanford, Michael; Fenimore, John M.; Rahman, Ziaur S. M.; Tsuneyama, Koichi; Norman, Gary L.; Gershwin, M. Eric; Young, Howard A.

doi:10.1002/hep.29524

Cited by 49 publications

(33 citation statements)

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“…( 38 ) The interplay of type I and type II interferons is also implicated as a cause of human PBC ( 40 ) and in a murine model of autoimmune cholangitis. ( 39 ) This study strongly supports the importance of IFNG as a key cytokine in PBC development and disease activity. Hierarchical clustering of gene expression in livers with PBC in conjunction with data on single‐cell RNA sequences in the human liver identified several cell type–specific genes in the downstream of IFNG (Table 5), thus providing a rationale for the development of anti‐IFNG pathway therapies in a cell type–specific manner.…”

Section: Discussionsupporting

confidence: 80%

“…( 5,12,13 ) Correspondingly, IFNG has been implicated in the pathogenesis of PBC in both human and mice models. ( 36‐39 ) IFNG protein expression was up‐regulated in infiltrating mononuclear cells and small bile ducts in livers with PBC. ( 36,37 ) Chronic expression of IFNG leads to murine autoimmune cholangitis with a female predominance that mimics human PBC, manifested by portal inflammation, liver granulomas, elevated bile salt and serum immunoglobulin M (IgM) levels, and production of antimitochondrial antibodies in IFNG‐3′‐untranslated region adenylate‐rich element‐deleted mice.…”

Section: Discussionmentioning

confidence: 99%

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Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

et al. 2020

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Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets. (Hepatology Communications 2020;4:724-738). P rimary biliary cholangitis (PBC) is a rare chronic autoimmune cholestatic liver disease that predominantly affects middle-aged females. PBC is characterized by lymphocytic cholangitis and gradual destruction of the small intrahepatic bile ducts, which leads to fibrosis, cirrhosis, and

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

et al. 2020

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“…This model presents an overexpression of IFN that determines features of autoimmune cholangitis similar to human PBC with a strong female predominance and the classical histological lesions, that is, portal inflammation, small bile ducts destruction, and granuloma. The same group reported in this issue of H epatology the development of a novel model obtained by mating ARE‐Del ‐/‐ mice with IFN type I receptor alpha chain knockout mice, called Ifnar1 ‐/‐ . They compared histological changes of male and female double‐knockout ARE‐Del ‐/‐ Ifnar1 ‐/‐ mice with those of ARE‐Del ‐/‐ mice.…”

mentioning

confidence: 98%

“…In this scenario, the study by Bae et al has the great merit of being one of the few studies trying to address the issue of female preponderance in PBC. In particular, the investigators have highlighted the type I interferon (IFN) signaling as a key component of the sex bias in a murine model of autoimmune cholangitis.…”

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confidence: 99%

Female preponderance of primary biliary cholangitis is all about our understanding of its autoimmune nature

2018

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“…In human PBC, gene expression analysis on liver biopsy tissues has also identified IFNγ signalling being significantly detectable in both early and late stages of disease[28][29][30] and recent GWAS studies have revealed several single -23-nucleotide variants enriched in CD4 T cell signalling, such as the IL12-JAK-STAT4 signalling pathway[31]. Loss of type I IFN receptor (IFN-a/β) receptor signalling using double knock out ARE-Del -/-Ifnr1 -/mice has been shown to reduce liver pathology, abrogate sex bias and correct germinal centre (sites implicated in loss of tolerance) abnormalities[32].Overall, these animal and human studies provide strong evidence that IFNγ-induced Th1 responses via CD4 T cell activation plays a critical role in early stages and progression of PBC and possibly other Th1-mediated autoimmune diseases. Given that IL-12 is one of the major inducers of IFNγ production, which in turn primes additional antigen presenting cells to produce IL-12 and thus facilitate Th1 cell differentiation[15], our data confirm an important role for IL-12 in disease.We demonstrate that although PBC and pSS are the two diseases in which, amongst others, risk variants in the IL12A locus have been identified, the monocytes from those patients were able to respond to TLR4 and TLR7/8 stimulation and secrete normal levels of IL-12p70 protein compared to healthy controls.…”

mentioning

confidence: 99%

Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells

Liaskou

Patel

Webb

et al. 2018

Journal of Autoimmunity

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IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n = 17) and pSS monocytes (n = 6) resulted in significant induction of IL12A mRNA (p < 0.05, p < 0.01, respectively) compared to PSC monocytes (n = 13) and at similar levels to HC monocytes (n = 8). PSC monocytes expressed significantly less IL-12p70 (108 pg/ml, mean) and IL-23 (358 pg/ml) compared to HC (458 pg/ml and 951 pg/ml, respectively) (p < 0.01, p < 0.05). Treg cells from patients with PBC (n = 16) and pSS (n = 3) but not PSC (n = 10) and HC (n = 8) responded to low dose (10 ng/ml) IL-12 stimulation by significant upregulation of IFNγ (mean 277 and 254 pg/ml, respectively) compared to PSC and HC Treg cells (mean 22 and 77 pg/ml, respectively)(p < 0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (p < 0.05) but not PSC and HC. In the liver of patients with PBC (n = 7) a significantly higher proportion of IL-12Rβ2Tregs (16% on average) was detected (p < 0.05) compared to other liver disease controls (5%)(n = 18) which also showed ex vivo high IFNG and TBET expression. CONCLUSION: Our data show an increased sensitivity of PBC and pSS Treg cells to low dose IL-12 stimulation, providing ongoing support for the importance of the IL12-IL-12Rβ2-STAT4 pathway on Treg cells in disease pathogenesis and potentially treatment.

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The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex‐biased autoimmunity

Cited by 49 publications

References 47 publications

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Female preponderance of primary biliary cholangitis is all about our understanding of its autoimmune nature

Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells

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