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Anti-microbial antibodies in celiac disease:Trick or treat?

World Journal of Gastroenterology 2009年第31期15卷 3891-3900页

作者： Maria Papp Ildiko Foldi Istvan Altorjay Eszter Palyu Miklos Udvardy Judit Tumpek Sandor Sipka Ilma Rita Korponay-Szabo Eva Nemes Gabor Veres Tamas Dinya Attila Tordai Hajnalka Andrikovics Gary L Norman Peter Laszlo Lakatos 2nd Department of Medicine University of Debrecen Laboratory of Clinical Immunology University of Debrecen Department of Pediatrics University of DebrecenDebrecenH-4032HungaryIlma Rita Korponay-SzaboCeliac Disease CenterHeim Pal Children's Hospital 1st Department of Pediatrics Semmelweis University Institute of Surgery University of Debrecen Department of Molecular diagnostics Hungarian National Blood Transfusion Service inova diagnostics Inc. 1st Department of Medicine Semmelweis University

AIM:To determine the prevalence of a new set of anti-glycan and anti-outer membrane protein (anti-OMP) antibodies in a Hungarian cohort of adult Celiac disease (CD) ***:190 consecutive CD patients [M/F:71/119, age:39.9 (SD:14.1) years], 100 healthy, and 48 gastrointestinal controls were tested for glycan anti-Saccharomyces cerevisiae (gASCA), anti-laminaribioside (ALCA), anti-chitobioside, anti-mannobioside, anti-OMP antibodies and major NOD2/CARD15 mutations. Thirty out of 82 CD patients enrolled at the time of diagnosis were re-evaluated for the same antibodies after longstanding gluten-free diet (GFD).RESULTS: 65.9% of the CD patients were positive for at least one of the tested antibodies at the time of the diagnosis. Except anti-OMP and ALCA, anti-microbial antibodies were exclusively seen in untreated CD; however, the overall sensitivity was low. Any glycan positivity (LR+:3.13;95% CI:2.08-4.73) was associated with an increased likelihood ratio for diagnosing CD. Significant correlation was found between the levels of anti-glycan and anti-endomysial or anti-transglutaminase antibodies. Anti-glycan positivity was lost after longstanding GFD. Anti-glycan antibody titers were associated with symptoms at presentation, but not the presence of NOD2/CARD15 mutations. Patients with severe malabsorption more frequently had multiple antibodies at diagnosis (P=0.019).CONCLUSION: The presence of anti-glycan antibodies in CD seems to be secondary to the impaired small bowel mucosa which can lead to increased antigen presentation. Furthermore, anti-glycan positivity may be considered an additional marker of CD and dietary adherence.

关键词：抗微生物疾病腹腔抗体蛋糖

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Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

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World Journal of Gastroenterology 2017年第29期23卷 5412-5421页

作者： Tamas Tornai Eszter Palyu Zsuzsanna Vitalis Istvan Tornai David Tornai Peter Antal-Szalmas Gary L Norman Zakera Shums Gabor Veres Antal Dezsofi Gabriella Par Alajos Par Peter Orosz Ferenc Szalay Peter Laszlo Lakatos Maria Papp Institute of Internal Medicine Department of Gastroenterology University of Debrecen Faculty of Medicine Department of Laboratory Medicine University of Debrecen Faculty of Medicine Debrecen inova diagnostics Inc.San Diego 1^st Department of Pediatrics Semmelweis University 1^st Department of Medicine University of Pecs Gastroenterology Department of Medicine Borsod-Abauj Zemplen County Hospital 1^st Department of Medicine Semmelweis University

AIM To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis(PSC) *** Sera of 67 PSC patients [median age(range): 32(5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin(AAA Ig A/Ig G) and gliadin(AGA Ig A/Ig G)] and for serum level of intestinal fatty acid-binding protein(I-FABP) by ELISA. Markers of lipopolysaccharide(LPS) exposure [LPS binding protein(LBP)] and various antimicrobial antibodies [anti-OMP Plus Ig A and endotoxin core Ig A antibody(Endo CAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99(14-106) mo]. One hundred and fifty-three healthy subjects(HCONT) and 172 ulcerative colitis(UC) patients were the controls. RESULTS A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA Ig A, AAA Ig G, AGA Ig A and AGA Ig G, respectively. Frequencies of AAA Ig A and AAA Ig G(P < 0.001, for both) and AGA Ig G(P = 0.01, for both) but not AGA Ig A were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA Ig A-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15(1.27-20.86), P = 0.022 or for the Mayo risk score(HR = 4.24(0.99-18.21), P = 0.052]. AAA Ig A-positivity was significantly associated with higher frequency of antimicrobial antibodies(P < 0.001 for Endo Cab Ig A and P = 0.012 for anti-OMP Plus Ig A) and higher level of the enterocyte damage marker(median I-FABP_(AAA Ig A pos vs neg): 365 vs 166 pg/m L, P = 0.011), but not with serum LBP level. CONCLUSION Presence of Ig A type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and e

关键词：主要 sclerosing 胆管炎毁坏障碍机能障碍肠的丰满的酸绑定的蛋白质 Anti-F-actin 抗体反麦胶蛋白质抗体

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Utility of serological markers in inflammatory bowel diseases: Gadget or magic?

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World Journal of Gastroenterology 2007年第14期13卷 2028-2036页

作者： Maria Papp Gary L Norman Istvan Altorjay Peter Laszlo Lakatos Department of Gastroenterology University of Debrecen DebrecenHungary inova diagnostics Inc. San Diego United States Department of Medicine Semmelweis University BudapestHungary

为煽动性的肠疾病(IBD ) 的血清学标记的面板很快正在膨胀。尽管 anti-Saccharomyces 啤酒抗体(ASCA ) 和不正常的仙子细胞质的抗体(P-ANCA ) 仍然是的原子反 neutrophil 广泛地调查的大多数，试验性的数据的增加的数量在对各种各样的... 详细信息

为煽动性的肠疾病(IBD ) 的血清学标记的面板很快正在膨胀。尽管 anti-Saccharomyces 啤酒抗体(ASCA ) 和不正常的仙子细胞质的抗体(P-ANCA ) 仍然是的原子反 neutrophil 广泛地调查的大多数，试验性的数据的增加的数量在对各种各样的微生物引起的抗原指导的最新发现的抗体上是可得到的。对在当前的 IBD 诊断算法的各种各样的抗体的评价的角色由于他们的有限敏感经常是可疑的。相反，有疾病行为和显型的血清学标记的协会正在变得逐渐地生长得很好。越来越多的观察证实有 Crohn 在高乳头 ers 表示多重血清学标记的疾病的病人是更可能的有复杂的小肠疾病(例如苛评或穿孔) 并且没有，或与抗体的低乳头 ers，比那些在为外科的更高的风险。基于血清学反应创造同质的疾病亚群可以帮助开发更多的标准化治疗学的途径并且可以在 IBD 的 pathomechanism 的更好的理解帮助。进一步未来的临床的研究被需要在 IBD 建立 serologic 的临床的角色。

关键词：炎症性肠病血清标记物 ASCA P-ANCA 抗体

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Golgi protein-73:A biomarker for assessing cirrhosis and prognosis of liver disease patients

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World Journal of Gastroenterology 2020年第34期26卷 5130-5145页

作者： Nikolaos K Gatselis Tamás Tornai Zakera Shums Kalliopi Zachou Asterios Saitis Stella Gabeta Roger Albesa Gary L Norman Mária Papp George N Dalekos Department of Medicine and Research Laboratory of Internal Medicine National Expertise Center of Greece in Autoimmune Liver DiseasesGeneral University Hospital of LarissaLarissa 41110Greece Institute of Internal Medicine and Hepatology Larissa 41447Greece Department of Internal Medicine Division of GastroenterologyUniversity of DebrecenFaculty of MedicineDebrecen H-4032Hungary Department of Research and Development Inova DiagnosticsInc.San DiegoCA 92131United States

BACKGROUND Reliable biomarkers of cirrhosis,hepatocellular carcinoma(HCC),or progression of chronic liver diseases are *** this context,Golgi protein-73(GP73)also called Golgi phosphoprotein-2,was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial *** a result,GP73 expression was found primarily in biliary epithelial cells,with only slight detection in ***,in patients with acute or chronic liver diseases and especially in HCC,the expression of GP73 is significantly up-regulated in *** far,few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease *** To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease *** GP73 serum levels were retrospectively determined by a novel GP73 ELISA(QUANTA Lite®GP73,inova diagnostics,Inc.,Research Use Only)in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa,Greece(n=366)and Debrecen,Hungary(n=266).Aspartate aminotransferase(AST)/Platelets(PLT)ratio index(APRI)was also calculated at the relevant time points in all *** hundred and three patients had chronic hepatitis B,183 chronic hepatitis C,198 alcoholic liver disease,28 autoimmune cholestatic liver diseases,15 autoimmune hepatitis,and 5 with other liver-related *** duration of follow-up was 50(57)mo[median(interquartile range)].The development of cirrhosis,liver decompensation and/or HCC during follow-up were assessed according to internationally accepted *** particular,the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein(AFP)determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic *** Increased serum levels of GP73(>20 units)were detected at initial evaluation in 277 out of

关键词： Biomarker Golgi protein-73 Hepatic fibrosis Cirrhosis Hepatocellular carcinoma Hepatitis B Hepatitis C Aspartate aminotransferase/Platelets ratio index score

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Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease

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World Journal of Gastroenterology 2015年第22期21卷 6952-6964页

作者： Nora Sipeki Laszlo Davida Eszter Palyu Istvan Altorjay Jolan Harsfalvi Peter Antal Szalmas Zoltan Szabo Gabor Veres Zakera Shums Gary L Norman Peter L Lakatos Maria Papp Division of Gastroenterology Department of Internal Medicine Faculty of Medicine University of Debrecen Clinical Research Center Faculty of MedicineUniversity of Debrecen Department of Laboratory Medicine Faculty of Medicine University of Debrecen Division of Emergency Medicine Department of Internal Medicine Faculty of Medicine University of Debrecen 1~(st) Department of Medicine Semmelweis University inova diagnostics Inc. San Diego California

AIM: To assess the prevalence and stability of different antiphospholipid antibodies(APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases(IBD) ***: About 458 consecutive patients [Crohn's disease(CD): 271 and ulcerative colitis(UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course(development f complicated disease phenotype and need for surgery),occurrence of thrombotic events, actual state of diseaseactivity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up,(median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls(HC) were tested on individual anti-β2-Glycoprotein-I(anti-β2-GPI IgA/M/G), anti-cardiolipin(ACA IgA/M/G)and anti-phosphatidylserine/prothrombin(anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies(ASCA IgA/G) by enzyme-linked immunosorbent assay(ELISA). In a subgroup of CD(n = 198) and UC patients(n = 103), obtaining consecutive samples over various arbitrary timepoints during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally,we provide an overview of studies, performed so far, in which significance of APLAs in IBD were ***: Patients with CD had significantly higher prevalence of both ACA(23.4%) and anti-PS/PT(20.4%) antibodies than UC(4.8%, p < 0.0001 and10.2%, p = 0.004) and HC(2.9%, p < 0.0001 and15.5%, p = NS). No difference was found for the prevalence of anti-β2-GPI between different groups(7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the *** of a

关键词： Crohn's disease Ulcerative colitis Diseaseprogression Antiphospholipid antibodies Anti-β2-Glycoprotein-I antibodies Anti-phosphatidylserine/prothrombin Anti-cardiolipin antibodies Thrombosis

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Comprehensive review of autoantibodies in patients with hyper-IgM syndrome

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Cellular & Molecular Immunology 2018年第6期15卷 610-617页

作者： Mohamed-Ridha Barbouche Qubo Chen Marco Carbone Imen Ben-Mustapha Zakera Shums Mehdi Trifa Federica Malinverno Francesca Bernuzzi Haiyan Zhang Nourhen Agrebi Gary L Norman Christopher Chang M Eric Gershwin Pietro Invernizzi Laboratory of Immunology Institute Pasteur de Tunis and Faculty of MedicineUniversity Tunis El Manar1002 TunisTunisia Humanitas Clinical and Research Center 20089 RozzanoItaly Clinical Laboratory Guangdong Provincial Hospital of Chinese medicine510000 GuangzhouChina Division of Gastroenterology and Center for Autoimmune Liver Diseases Department of Medicine and SurgeryUniversity of Milan-Bicocca20900 Monza(MB)Italy Department of Research and Development Inova Diagnostics92131 San DiegoCAUSA Department of Anesthesia and Intensive Care Children Hospital Bechir HamzaTunis and Faculty of MedicineUniversity Tunis El Manar1007 TunisTunisia Division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthStateKey Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Institute of Digestive Disease200001 ShanghaiChina Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California at Davis95616 DavisCAUSA

Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand *** CD40 ligand has been recently highlighted as playing a key role in the pathogenesis of primary biliary *** the present study,we assessed an extensive set of serum autoantibodies in a series of well-defined patients with hyper-immunoglobulin M ***,liver-related and liver-not-related autoantibodies IgG,IgM and IgA were tested by ELISA and standard indirect immunofluorescence in HEp-2 cells in 13 Tunisian patients(8 males and 5 females,aged 1–12 years)with hyper-immunoglobulin M syndrome during 1995–2012 and,as controls,21 age-and gender-matched blood *** level of IgM antibody against MIT3 was significantly higher in patients than in controls(35.8 vs 10.7,P=0.002).Half of the hyperimmunoglobulin M syndrome patients were found to be anti-MIT3 IgM positive vs none of the controls(Po0.0001).Twenty-three percent of patients were found to be anti-sp100 antibody positive vs only 0.05%of *** immunofluorescence,92.3%of patients were MIT3 IgM positive vs none of the *** conclusion,the IgM class of anti-MIT3 antibodies was shown to be present by both ELISA and immunofluorescence in most of the patients with hyper-immunoglobulin M *** presence of the hallmark of primary biliary cholangitis,a disease where the CD40 ligand is a key player,in an immunodeficiency disease caused by mutations in the CD40 ligand gene is very intriguing and opens new scenarios in understanding the immune pathogenesis of primary biliary cholangitis.

关键词： immunoglobulin M autoantibodies immunodeficiency hyper-immunoglobulin M syndrome primary biliary cholangitis

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Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma

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World Journal of Hepatology 2015年第14期7卷 1875-1883页

作者： Gary L Norman Nikolaos K Gatselis Zakera Shums Christos Liaskos Dimitrios P Bogdanos George K Koukoulis George N Dalekos inova diagnostics Inc. Department of Medicine and Research Laboratory of Internal Medicine School of MedicineUniversity of Thessaly Division of Rheumatology School of MedicineUniversity of Thessaly Division of Transplantation Immunology and Mucosal Biology Institute of Liver StudiesKing’s College London School of MedicineDenmark Hill Campus Department of Pathology School of MedicineUniversity of Thessaly

AIM: To assess serum cartilage oligomeric matrix protein(COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma(HCC). METHODS: A COMP enzyme-linked immunosorbentassay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range(IQR)] duration of 96.5(102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study ***: COMP positivity(> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7%(14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age(P < 0.001), advanced fibrosis(P = 0.001) and necroinflammatory activity(P = 0.001), higher aspartate aminotransferase(P < 0.001), alanine aminotransferase(P < 0.02), γ-glutamyl transpeptidase(P = 0.003), alkaline phosphatase(P = 0.001), bilirubin(P < 0.05), international normalized ratio(P = 0.002) and alpha-fetoprotein levels(P < 0.02), and lower albumin(P < 0.001), and platelet count(P = 0.008). COMP levels [median(IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8(7.9) U

关键词： Hepatic fibrosis Hepatocellular carcinoma Viral hepatitis Enzyme-linked immunosorbent assay Biomarker Cirrhosis

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