Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis

Tornai, Tamás; Tornai, Dávid; Sipeki, Nóra; Tornai, István; Alsulaimani, Rayan; Fechner, Kaï; Roggenbuck, Dirk; Norman, Gary L.; Veres, Gábor; Pár, Gabriella; Pár, Alajos; Szalay, Ferenç; Lakatos, László; Antal‐Szalmás, Péter; Papp, Mária

doi:10.1038/s41598-017-18622-1

Cited by 24 publications

(35 citation statements)

References 38 publications

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“…Another intriguing finding was the correlation of GP2 IgA occurrence with elevated levels of secretory IgA (three times the normal value) which could be a sign of an increased IgA secretion by epithelia and/or reabsorption of IgA from mucosal surfaces. In contrast, this phenomenon was not revealed for all investigated microbial Abs and autoAbs including ANCA [101].…”

Section: Autoantigenic Targets In Psc-lessons From Humoral Autoimmunimentioning

confidence: 65%

“…Finally, an elevated secretion and re-absorption of secretory IgA was reported in patients with PSC [52]. The majority of GP2 IgA in the serum of CD patients bears a secretory piece [101]. This indicates that this particular GP2 IgA was secreted onto mucosal surfaces and later re-adsorbed.…”

Section: Putative Role Of Gp2 Iga In the Pathophysiology Of Pscmentioning

confidence: 89%

“…This hints at an involvement of the mucosa-associated lymphoid tissue (MALT). Recently, Tornai et al [101] confirmed the association of GP2 IgA with the severity of PSC in a prospective study demonstrating a significant correlation with shorter transplant-free survival for GP2 autoAbs. GP2 IgA was the only independent predictor for liver transplantation after adjusting for Mayo risk score with a hazard ratio of 4.69.…”

Section: Autoantigenic Targets In Psc-lessons From Humoral Autoimmunimentioning

confidence: 90%

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The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia

Lopens

Krawczyk

Papp

et al. 2020

Autoimmun Highlights

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Unlike in other autoimmune liver diseases such as autoimmune hepatitis and primary biliary cholangitis, the role and nature of autoantigenic targets in primary sclerosing cholangitis (PSC), a progressive, chronic, immune-mediated, life threatening, genetically predisposed, cholestatic liver illness, is poorly elucidated. Although anti-neutrophil cytoplasmic antibodies (ANCA) have been associated with the occurrence of PSC, their corresponding targets have not yet been identified entirely. Genome-wide association studies revealed a significant number of immune-related and even disease-modifying susceptibility loci for PSC. However, these loci did not allow discerning a clear autoimmune pattern nor do the therapy options and the male gender preponderance in PSC support a pathogenic role of autoimmune responses. Nevertheless, PSC is characterized by the co-occurrence of inflammatory bowel diseases (IBD) demonstrating autoimmune responses. The identification of novel autoantigenic targets in IBD such as the major zymogen granule membrane glycoprotein 2 (GP2) or the appearance of proteinase 3 (PR3) autoantibodies (autoAbs) have refocused the interest on a putative association of loss of tolerance with the IBD phenotype and consequently with the PSC phenotype. Not surprisingly, the report of an association between GP2 IgA autoAbs and disease severity in patients with PSC gave a new impetus to autoAb research for autoimmune liver diseases. It might usher in a new era of serological research in this field. The mucosal loss of tolerance against the microbiota-sensing GP2 modulating innate and adaptive intestinal immunity and its putative role in the pathogenesis of PSC will be elaborated in this review. Furthermore, other potential PSC-related autoantigenic targets such as the neutrophil PR3 will be discussed. GP2 IgA may represent a group of new pathogenic antibodies, which share characteristics of both type 2 and 3 of antibody-mediated hypersensitive reactions according to Coombs and Gell.

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Section: Autoantigenic Targets In Psc-lessons From Humoral Autoimmunimentioning

confidence: 65%

Section: Putative Role Of Gp2 Iga In the Pathophysiology Of Pscmentioning

confidence: 89%

Section: Autoantigenic Targets In Psc-lessons From Humoral Autoimmunimentioning

confidence: 90%

See 1 more Smart Citation

The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia

Lopens

Krawczyk

Papp

et al. 2020

Autoimmun Highlights

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“…TSPAN8 is expressed in the gastrointestinal tract and several carcinomas (Agaësse et al, 2017;Zhu et al, 2017;Zhao et al, 2018) and GP2 is expressed in the pancreas and gastrointestinal tract (Cogger et al, 2017;Ohno & Hase, 2010); loss of tolerance to GP2 is associated with Crohn's disease and primary sclerosing cholangitis (Werner et al, 2013;Tornai et al, 2018). Expression of both TRAs is enhanced in mTEC by the presence of AIRE and can be detected on their cell surface by flow cytometry.…”

Section: Large Scale Single-cell Rna-sequencing Data From Facs Sortedmentioning

confidence: 99%

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

Dhalla

Baran-Gale

Maio

et al. 2019

Preprint

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During thymic negative selection, medullary thymic epithelial cells (mTEC) collectively express most protein coding genes, a process termed promiscuous gene expression (PGE). Although PGE is crucial for inducing central T-cell tolerance, this process has not been established definitively as being either stochastic or coordinated. To resolve this question, we sequenced the transcriptomes of 6,894 single mTEC, including 1,795 rare cells expressing either of two tissue-restricted antigens, TSPAN8 or GP2. Transcriptional heterogeneity allowed partitioning of mTEC into 15 robustly-defined subpopulations representing distinct maturational stages and subtypes. Although 50 gene co-expression groups were robustly identified, few could be explained by chromosomal location, biological pathway, or tissue specificity. Further, GP2+ mTEC were randomly dispersed spatially within medullary islands. Thus although PGE exhibits ordered co-expression, biologically it is indeterminate. This likely enhances the presentation of diverse antigens to passing thymocytes during their medullary residency, while simultaneously maintaining mTEC identity throughout PGE.

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“…Pathogenic mutations in the UMOD gene have been shown to affect the structure and polymerization of uromodulin, resulting in kidney disease 24 . Given the similarity in the amino acid sequence as well as the expected functionality between these two proteins, genetic However, accumulating evidence has demonstrated the effects of GP2 on the innate immune response 28,29 . The GP2 is also expressed in the membranous (M) cells of the intestinal epithelium in humans and mice, where it acts as an uptake receptor for a subset of commensal and pathogenic bacteria 30 .…”

mentioning

confidence: 99%

Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

Lin

Nakatochi

Ito

et al. 2018

Preprint

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The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P<5.0×10 -8 ) and 4 suggestive loci (P<1.0×10 -6 ) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28×10 -9 ), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel 5 gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus. IntroductionWith approximately 33,000 related deaths every year, pancreatic cancer is the fourth leading cause of cancer deaths in Japan, after lung, colorectal, and stomach cancers 1 . The incidence and mortality rates of pancreatic cancer have increased steadily over the past decades, while those of other gastrointestinal cancers have shown a decreasing trend 1 . Despite the increasing burden levied by pancreatic cancer, few modifiable risk factors other than smoking and type 2 diabetes mellitus (T2D) have been identified, and the 5-year survival rates remain the worst (<10%) among major malignancies.Genome-wide association studies (GWASs) have increasingly revealed the role of inherited genetic variations in pancreatic cancer susceptibility. Since the first GWAS, conducted by the PanScan consortium, identified common variants in the gene coding for the ABO blood group system in 2009, 2 at least 23 genome-wide significant susceptibility loci have been linked to pancreatic cancer risk 3 . However, fewer loci have been identified for pancreatic cancer than for other common cancers, including breast and colorectal cancers 4,5 . Furthermore, the identified risk variants explained approximately 13% of the total heritability on the basis of GWAS-identified SNPs in a population of European ancestry 6 . These observations suggest that additional risk loci can be identified by increasing the sample size,

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Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis

Cited by 24 publications

References 38 publications

The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia

The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

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