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Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-Ⅱexpression on dendritic cells in chronic hepatitis C infection

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World Journal of Gastroenterology 2016年第22期22卷 5173-5182页

作者： Shallu Tomer yogesh k chawla Ajay Duseja Sunil k Arora Department of Immunopathology Postgraduate Institute of Medical Education and Research Department of Hepatology Postgraduate Institute of Medical Education and Research

AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells(DCs) in chronic hepatitis C(CHC) patients infected with genotype 3 ***: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c(BDCA1)+ DC isolation kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus(HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time ***: Non-responders [sustained virological response(SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1(6-fold) and negative regulators of JAk-STAT pathway such as SOCS(6-fold) as compared to responders(SVR+ve) to antiviral therapy. The downregulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex(MHC) Class-Ⅱ family as HLA-DP, HLA-DQ(2-fold) and superoxide dismutase(2-fold). Cells grown in the presence of HCV viral proteins had genes downregulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors(4-fold) were upregulated as compared to cells grown in absence of viral ***: Underexpressed MHC class-Ⅱ genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs.

关键词： Dendritic cells Hepatitis C Non-responders Negative regulators Major histocompatibility complex Class-Ⅱ genes

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A new technique of combined endoscopic sclerotherapy and ligation for variceal bleeding

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World Journal of Gastroenterology 2003年第5期9卷 1090-1093页

作者： Radha k.Dhiman yogesh k.chawla Department of Hepatology Postgraduate Institute of Medical Education & ResearchChandigarh 160012India

AIM: To develop a technique of combined endoscopic sclerotherapy and ligation (ESL) in which both techniques of endoscopic sclerotherapy (ES) and endoscopic variceal ligation (EVL) can be optimally ***: ESL was performed in 10 patients (age 46.4±7.9;9 males, 1 female) with cirrhosis of liver using sclerotherapy needle and Speedband, Superview multiple band ligater (Boston Scientific, Microvasive, Watertown, MA). A single band was placed 5-10 cm proximal to the gastro-esophageal junction over each varix from proximal to distal margin,followed by intravariceal injection of 1.5 % ethoxysclerol (4 ml each) 2 to 3 cm proximal to the gastroesophageal junction on the ligated varices distal to deployed band. EVL was then performed at the injection site. Similarly other varices were also injected and ligated from distal to proximally. In the subsequent sessions, ES alone was performed to sclerose small varices at the gastroesophageal ***: ESL was successfully performed in all patients.A median of 3 (ESL 1, ES 2) sessions (ranged 1-4) were required to eradicate the varices in 9 (90 %) of 10 *** of varices without bleed was seen in 1 patient during a mean follow-up of 10.3 months (ranged 6-15).Two patients died of liver failure. None died of variceal bleeding. None of the patients had procedure related ***: ESL may be useful in the fast eradication of esophageal varices. However, randomised controlled trials are required to find out its relative efficacy and impact on variceal recurrence in comparison to ES or EVL.

关键词： Adult Endoscopy, Digestive System Esophageal and Gastric Varices Female Gastrointestinal Hemorrhage Humans Ligation Liver Cirrhosis Male Middle Aged Pilot Projects Sclerotherapy

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Immunology of hepatocellular carcinoma

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World Journal of Hepatology 2015年第17期7卷 2080-2090页

作者： Meenakshi Sachdeva yogesh k chawla Sunil k Arora Department of Immuno- pathology Postgraduate Institute of Medical Education and Research Department of Hepatology Postgraduate Institute of Medical Education and Research

Hepatocellular carcinoma(HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system(including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells(e.g., dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC.

关键词： Hepatocellular carcinoma Immune cells Immune-dysregulation Adaptive immunity Innateimmunity

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Dendritic cells: The warriors upfront-turned defunct in chronic hepatitis C infection

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World Journal of Hepatology 2015年第19期7卷 2202-2208页

作者： Meenakshi Sachdeva yogesh k chawla Sunil k Arora Department of Immuno-pathology Post Graduate Institute of Medical Education and Research Department of Hepatology Post Graduate Institute of Medical Education and Research

Hepatitis C virus(HCV) infection causes tremendousmorbidity and mortality with over 170 million people infected worldwide. HCV gives rise to a sustained, chronic disease in the majority of infected individuals owing to a failure of the host immune system to clear the virus. In general, an adequate immune response is elicited by an efficient antigen presentation by dendritic cells(DCs), the cells that connect innate and adaptive immune system to generate a specific immune response against a pathogen. However, HCV seems to dysregulate the activity of DCs, making them less proficient antigen presenting cells for the optimal stimulation of virusspecific T cells, hence interfering with an optimal antiviral immune response. There are discordant reports on the functional status of DCs in chronic HCV infection(CHC), from no phenotypic or functional defects to abnormal functions of DCs. Furthermore, the molecular mechanisms behind the impairment of DC function are even so not completely elucidated during CHC. Understanding the mechanisms of immune dysfunction would help in devising strategies for better management of the disease at the immunological level and help to predict the prognosis of the disease in the patients receiving antiviral therapy. In this review, we have discussed the outcomes of the interaction of DCs with HCV and the mechanisms of DC impairment during HCV infection with its adverse effects on the immune response in the infected host.

关键词： Dendritic cells Hepatitis C Mechanism of functiona

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Chronic Liver Failure-Sequential Organ Failure Assessment is better than the Asia-Pacific Association for the Study of Liver criteria for defining acute-on-chronic liver failure and predicting outcome

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World Journal of Gastroenterology 2014年第40期20卷 14934-14941页

作者： Radha k Dhiman Swastik Agrawal Tarana Gupta Ajay Duseja yogesh chawla Department of Hepatology Postgraduate Institute of Medical Education and Research Chandigarh 160012 India

AIM: To compare the utility of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) and Asia-Pacific Association for the Study of Liver (APASL) definitions of acute-on-chronic liver failure (ACLF)... 详细信息

关键词： Cirrhosis Acute decompensation Mortality Prognosis Acute on chronic liver failure

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The incidence of sporadic viral hepatitis in North India:a preliminary study

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Hepatobiliary & Pancreatic Diseases International 2007年第6期6卷 596-599页

作者： Subrat kumar Radha kanta Ratho yogesh kumar chawla Anuradha Chakraborti Department of Virology Department of Hepatology Department of Experimental Medicine and Biotechnology

BACkGROUND: Viral hepatitis is one of the major causes of mortality and morbidity in developing countries. Hepatitis E virus (HEV) among the major etiological agents is responsible for both sporadic and epidemic outbreaks. The epidemic outbreak is water-borne whereas the sporadic outbreak is possibly through contact. Various diagnostic tools at times fail to pinpoint the cause of viral hepatitis. This study was carried out to evaluate the utility of ELISA and nRT-PCR (nested reverse transcriptase polymerase chain reaction) for the diagnosis of sporadic and acute viral hepatitis (AVH) caused by HEV in an endemic situation in North India. METHODS: Serum samples were collected from all the affected and suspected persons and subjected to serological detection of HAV IgM, HBsAg, HCV antibody and HEV IgM. The samples that were positive for HEV IgM were further processed for the detection of HEV RNA by nRT-PCR. RESULTS: A total of 843 samples were collected from 685 patients with AVH, 70 patients with fulminant hepatic failure (FHF), 53 patients with chronic liver disease (CLD), 11 patients with antituberculosis therapy (ATT)-induced jaundice, and 24 pregnant women. The percentage of positivity for anti-HEV IgM was 58.3% in the pregnant women, 41.4% in the paients with FHF, 38.6% in the patients with AVH, 9.4% in the patients with CLD and 18.2% in the patients with ATT induced jaundice. 9.4% of HBsAg carriers were positive for anti-HEV IgM. Males outnumbered females (62.8% vs. 37.1%). Furthermore, the rates of fulminant and acute outbreaks of hepatitis with HEV RNA positivity were 41.4% and 9.4%, respectively. CONCLUSION: Serological and molecular analysis should be combined for the diagnosis of viral infections, especially in endemic areas.

关键词： viral hepatitis fulminant liver failure pregnancy

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Genetic polymorphism in CD14 gene, a co-receptor of TLR4 associated with non-alcoholic fatty liver disease

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World Journal of Gastroenterology 2016年第42期22卷 9346-9355页

作者： Shweta kapil Ajay Duseja Bal krishan Sharma Bhupesh Singla Anuradha Chakraborti Ashim Das Pallab Ray Radha k Dhiman yogesh chawla Department of Hepatology Postgraduate Institute of Medical Education and Research Experimental Medicine and Biotechnology Postgraduate Institute of Medical Education and Research Histopathology Postgraduate Institute of Medical Education and Research Microbiology Postgraduate Institute of Medical Education and Research

AIM To evaluate the pathogenic role of toll-like receptor(TLR) gene polymorphisms in patients with nonalcoholic fatty liver disease(NAFLD).METHODS Two hundred and fifty subjects(NAFLD = 200, healthy volunteers = 50) underwent polymerase chain reaction and restriction fragment length polymorphism to assess one polymorphism in the toll-like receptor 2(TLR2) gene(A753G), two polymorphisms in the TLR4 gene(TLR4 Asp299 Gly and Thr399 Ile allele), and two polymorphisms in the cluster of differentiation 14(CD14)(C-159 T and C-550T) gene, a co-receptor of TLR4. Association of TLR gene polymorphisms with NAFLD and its severity was evaluated by genetic models of *** On both multiplicative and recessive models of gene polymorphism association, there was significant association of CD14 C(-159) T polymorphism with NAFLD; patients with TT genotype had a 2.6 fold increased risk of developing NAFLD in comparison to CC genotype. There was no association of TLR2 Arg753 Gln, TLR4 Asp299 Gly, Thr399 Ile, and CD14 C(-550) T polymorphisms with NAFLD. None of the TLR gene polymorphisms had an association with histological severity of *** Patients with CD14 C(-159) T gene polymorphism, a co-receptor of TLR4, have an increased risk of NAFLD development.

关键词： Non-alcoholic steatohepatitis Nonalcoholic fatty liver disease Toll-like receptors Obesity Cirrhosis Insulin resistance Bacterial overgrowth

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Indian patients with nonalcoholic fatty liver disease presenting with raised transaminases are different at presentation

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World Journal of Gastroenterology 2007年第4期13卷 649-650页

作者： Ajay Duseja Ashim Das Radha krishan Dhiman yogesh kumar chawla Reena Das Sanjay Bhadada Ravinder Sialy kiran kumar Thumburu Anil Bhansali Naveen kalra Department of Hepatology Postgraduate Institute of Medical Education and Research Chandigarh India Department of Histopathology Postgraduate Institute of Medical Education and Research Chandigarh India Department of Hematology Postgraduate Institute of Medical Education and Research Chandigarh India Department of Endocrinology Postgraduate Institute of Medical Education and Research Chandigarh India Department of Radiodiagnosis and Imaging Postgraduate Institute of Medical Education and Research Chandigarh India

We read with great interest the article, ＂Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians＂ by Madan et at in the recent issue of WJG. Twenty-eight （55%） out of 51 patients with nonalcoholic fatty liver disease （NAFLD） who presented with abnormal transaminases had histological evidence of nonalcoholic steatohepatitis （NASH）. The majority of patients had grade 1 [32 （63%）] or grade 2 [16 （31%）] inflammation and either had no [23 （45%）] fibrosis or stage I [19 （37%）] fibrosis. None of the patients had cirrhosisf11. We agree with Madan et al that Asian Indians with NAFLD who present with unexplained increase in transaminases may have mild disease at presentation on the basis of similar observations made by us. NAFLD has a spectrum which includes patients with only steatosis and NASH that can progress to cirrhotic and hepatocellular carcinoma.

关键词： Gastroenterology

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Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

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World Journal of Gastroenterology 2005年第3期11卷 393-395页

作者： Ajay Duseja Reena Das Mohit Nanda Ashim Das Gurjeewan Garewal yogesh chawla Department of Hepatology Department of Hematology Department of Histopathology

AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

关键词： Nonalcoholic steatohepatitis Iron overload HFE gene Mutation

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Anti-HBc screening in Indian blood donors:Still an unresolved issue

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World Journal of Gastroenterology 2008年第34期14卷 5327-5330页

作者： Hari krishan Dhawan Neelam Marwaha Ratti Ram Sharma yogesh chawla Beenu Thakral karan Saluja Sanjeev kumar Sharma Manish k Thakur Ashish Jain Department of Transfusion Medicine PGIMER Department of Hepatology PGIMER

AIM:To study the seroprevalence of antibody to hepatitis B core antigen (anti-HBc) in healthy blood donors negative for HBsAg and to evaluate whether anti-HBc detection could be adopted in India as a screening assay for HBV in addition to HBsAg. METHODS: A total of 1700 serum samples collected from HBsAg-negative healthy blood donors were tested for the presence of anti-HBc antibody (IgM + IgG). All samples reactive for anti-HBc antibody were then investigated for presence of anti-HBs and for liver function tests (LFTs). One hundred serum samples reactive for anti-HBc were tested for HBV DNA by PCR method. RESULTS: Out of 1700 samples tested, 142 (8.4%) blood samples were found to be reactive for anti-HBc. It was signif icantly lower in voluntary (6.9%) as compared to replacement donors (10.4%, P = 0.011). Seventy- two (50.7%) anti-HBc reactive samples were also reactive for anti-HBs with levels > 10 mIU/mL and 70 (49.3%) samples were non-reactive for anti-HBs, these units were labeled as anti-HBc-only. These 142 anti-HBc reactive units were also tested for liver function test. HBV DNA was detected in only 1 of 100 samples tested. CONCLUSION: keeping in view that 8%-18% of donor population in India is anti-HBc reactive, inclusion of anti- HBc testing will lead to high discard rate. Anti-HBs as proposed previously does not seem to predict clearance of the virus. Cost effectiveness of introducing universalanti-HBc screening and discarding large number of blood units versus considering ID NAT (Individual donor nuclic acid testing) needs to be assessed.

关键词： Hepatitis B core antigen Hepatitis B surface antigen Hepatitis B virus Transfusion-associated hepatitis B virus Blood donors

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