<i>Escherichia coli</i>infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (<i>Idd10/Idd18</i>) mice

Wang, J. J.; Yang, Guo Xiang; Zhang, W. C.; Lü, Ling; Tsuneyama, Koichi; Kronenberg, M.; Vela, José Luis; López‐Hoyos, Marcos; He, Xiao; Ridgway, William M.; Leung, Patrick S.C.; Gershwin, M. Eric

doi:10.1111/cei.12224

Cited by 63 publications

(63 citation statements)

References 71 publications

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“…+ and CD8 + T cells are noted in the liver of both patients with PBC and murine models of autoimmune cholangitis [5][6][7]15,18,[25][26][27][28][29][30][31][32]. In this study, 2-OA-BSA/α-GalCer-immunized mice had significant increases in CD4 + and CD8 + T cells.…”

Section: T Cell Infiltrates Including Cd4mentioning

confidence: 51%

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

Chang

Chen

et al. 2014

Clinical and Experimental Immunology

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SummaryAlthough primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well-known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2-octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2-OA-BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2-OA-BSA in the presence or absence of α-galactosylceramide (α-GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock-out mice immunized with 2-OA-BSA/PBS or 2-OA-BSA/α-GalCer develop anti-mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α-GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways.

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Section: T Cell Infiltrates Including Cd4mentioning

confidence: 51%

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

Chang

Chen

et al. 2014

Clinical and Experimental Immunology

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“…The theory is based on the fact that PBC patients have a higher incidence of recurrent UTIs . The animal models of E coli ‐infected NOD.B6 Idd10/Idd18 develop liver lesions strikingly similar to the portal infiltrates of humans with PBC, this clearly supports the hypothesis of microbial involvement in the development of PBC . Furthermore, Shimoda et al .…”

Section: Discussionmentioning

confidence: 60%

TCRβ repertoire of memory T cell reveals potential role for Escherichia coli in the pathogenesis of primary biliary cholangitis

Hou

Yang

Chen

et al. 2019

Liver International

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Background Primary biliary cholangitis (PBC) is an organ‐specific, T cell‐mediated autoimmune disease which is characterized by the breakdown of self‐tolerance to the highly conserved pyruvate dehydrogenase complex, especially the pyruvate dehydrogenase E2 complex (PDC‐E2). However, the molecular mechanism of breakdown of self‐tolerance is still unclear. Methods A combination of multiplex‐PCR and immune repertoire sequencing (IR‐seq) was used for a standardized analysis of memory T cell receptor (TCR) β‐chain repertoire of PBC patient and healthy volunteers. In vitro induction and expansion of human PDC‐E2163‐176 (human PDC‐E2)‐specific T cells and E coli PDC‐E231‐44/134‐147/235‐248 (E coli PDC‐E2)‐specific T cells, and identified the human (and E coli) PDC‐E2‐specific TCRβ repertoire by IR‐seq. Results Primary biliary cholangitis patients have shorter complementarity‐determining region 3s (CDR3s), and higher degree of sequence overlap in the TCRβ repertoire of memory T cell. Moreover, altered insertion patterns and skewed TRBV segment usage were observed in PBC patients. With regard to the pathogenesis, the concentration of E coli was higher in PBC patients’ faecal. The frequency of E coli (and human)‐specific TCRs was higher in the memory TCRβ repertoire of PBC patients compared with healthy controls. Importantly, the TCRβ repertoire characteristics were almost identical between E coli PDC‐E2‐related TCRs and human PDC‐E2‐related TCRs, including the patterns of TRBV usage, CDR3 length and amino acid composition. Conclusion Our findings comprehensively revealed the TCRβ repertoire characterization of PBC patients, and provided a TCR molecular basis to understand the mechanism of cross‐recognition between human PDC‐E2 and E coli PDC‐E2, and the imbalance of immune tolerance in PBC.

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“…9,10 The primary autoantigen of PBC has been identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). [11][12][13][14][15] Data from human studies and animal models demonstrate that the pathogenesis of PBC involves not only autoreactive T cells and other immune cells [16][17][18][19][20][21][22] but also biliary epithelial cells. 12,18,19,[23][24][25][26][27][28][29][30] Herein, we demonstrate that circulating exosomes from PBC could be taken up by antigenpresenting cells (APCs) and affect the expression of cell surface co-stimulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

et al. 2015

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Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls (HCs), and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA (miRNA) populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14 1 monocytes, whereas CD40 up-regulated on CD11c 1 dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease. Cellular & Molecular Immunology

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Escherichia coliinfection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice

Cited by 63 publications

References 71 publications

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

TCRβ repertoire of memory T cell reveals potential role for Escherichia coli in the pathogenesis of primary biliary cholangitis

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

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