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Xenobiotics and loss of tolerance in primary biliary cholangitis

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World Journal of Gastroenterology 2016年第1期22卷 338-348页

作者： Jinjun Wang Guoxiang Yang Alana Mari Dubrovsky Jinjung Choi patrick sc leung Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California at DavisSchool of Medicine College of Environmental science and Engineering Yangzhou University

Data from genome wide association studies and geoepidemiological studies established that a com-bination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis(PBC).The serologic hallmark of PBC are the presence of high titer anti-mitochondrial autoantibodies(AMA)that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2(PDC--E2)*** efforts have been directed to investigate the molecular basis of ***,experimental data has pointed to the thesis that the breaking of tolerance to PDC--E2 is a pivotal event in the initial etiology of PBC,including environmental xenobiotics including those commonly found in cos-metics and food additives,suggesting that chemical modification of the PDC--E2 epitope may render its vulnerable to become a neo-antigen and trigger an immune response in genetically susceptible ***,we will discuss the natural history,genetics and immunobiology of PBC and structural constraints of PDC--E2 in AMA recognition which makes it vulnerable to chemical modification.

关键词： Antimitochondrial autoantibodies Primarybiliary cholangitis Pyruvate dehydrogenase E2 Breakingof tolerance Xenobiotics

screening and identification of mimotopes of the major shrimp allergen tropomyosin using one-bead-one- compound peptide libraries

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Cellular & Molecular Immunology 2017年第3期14卷 308-318页

作者： Nicki YH leung Christine YY Wai Marco HK Ho Ruiwu Liu Kit S Lam Jin Jun Wang Shang An Shu Ka Hou Chu patrick sc leung school of Life sciences The Chinese University of Hong Kong Shatin N.T. Hong Kong SAR China Department of Pediatrics and Adolescent Medicine Queen Mary Hospital The University of Heng Kong Pokfulam Hong Kong SAR China Department of Biochemistry and Molecular Medicine University of California Davis CA 95616 USA Division of Rheumatology/Allergy School of Medicine University of California Davis CA 95616 USA

The one-bead-one-compound （OBOC） combinatorial peptide library is a powerful tool to identify ligand and receptor interactions. Here, we applied the OBOC library technology to identify mimotopes specific to the immunoglobulin E （IgE） epitopes of the major shellfish allergen tropomyosin. OBOC peptide libraries with 8-12 amino acid residues were screened with serum samples from patients with shellfish allergy for IgE mimotopes of tropomyosin. Twenty-five mimotopes were identified from the screening and their binding reactivity to tropomyosin-specific IgE was confirmed by peptide ELISA. These mimotopes could be divided into seven clusters based on sequence homology, and epitope mapping by EpiSearch of the clustered mimotopes was performed to characterize and confirm the validity of mimotopes. Five out of six of the predicted epitopes were found to overlap with previously identified epitopes of tropomyosin. To further confirm the mimicry potential of mimotopes, BALB/c mice were immunized with mimotopes conjugated to keyhole limpet hemocyanin and assayed for their capacity to induce tropomyosin-specific antibodies. BALB/c mice that received mimotope immunization were found to have an elevated level of tropomyosin-specific immunoglobulin G, but not mice that received an irrelevant mimotope. This study pioneers the successful application of the OBOC libraries using whole sera to screen and identify multiple shrimp allergen mimotopes and validates their mimicry potential using in vitro, in vivo, and in silico methods.

关键词： epitope mimotope OBOC peptide library tropomyosin

The effects of Spirulina on anemia and immune function in senior citizens

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Cellular & Molecular Immunology 2011年第3期8卷 248-254页

作者： Carlo Selmi patrick sc leung Laura Fischer Bruce German Chen-Yen Yang Thomas P Kenny Gerry R Cysewski M Eric Gershwin Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California at DavisDavisCAUSA Department of Medicine IRCCS Istituto Clinico HumanitasRozzanoMilanItaly Department of Food science and Technology University of California at DavisDavisCAUSA Cyanotech Kailua-KonaHIUSA

Anemia and immunological dysfunction(***)are commonly found in older subjects and nutritional approaches are sought to counteract these *** is a filamentous and multicellular bule-green alga capable of reducing inflammation and also manifesting antioxidant *** hypothesized that Spirulina may ameliorate anemia and immunosenescence in senior citizens with a history of *** enrolled 40 volunteers of both sexes with an age of 50 years or older who had no history of major chronic *** took a Spirulina supplementation for 12 weeks and were administered comprehensive dietary questionnaires to determine their nutritional regimen during the *** cell count(CCC)and indoleamine 2,3-dioxygenase(IDO)enzyme activity,as a sign of immune function,were determined at baseline and weeks 6 and 12 of *** study participants completed the entire study and the data obtained were *** the 12-week study period,there was a steady increase in average values of mean corpuscular hemoglobin in subjects of both *** addition,mean corpuscular volume and mean corpuscular hemoglobin concentration also increased in male *** women appeared to benefit more rapidly from Spirulina ***,the majority of subjects manifested increased IDO activity and white blood cell count at 6 and 12 weeks of Spirulina *** may ameliorate anemia and immunosenescence in older *** encourage large human studies to determine whether this safe supplement could prove beneficial in randomized clinical trials.

关键词： functional food immunosenescence red blood cell IDO

Proteomic analysis reveals distinctive protein profiles involved in CD8^(+) T cell-mediated murine autoimmune cholangitis

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Cellular & Molecular Immunology 2018年第8期15卷 756-767页

作者： Weici Zhang Ren Zhang Jun Zhang Ying Sun patrick sc leung Guo-Xiang Yang Zongwen Shuai William M Ridgway M Eric Gershwin Division of Rheumatology Allergy and Clinical ImmunologyUniversity of CaliforniaDavisCaliforniaUSA Department of Pathogenic Biology and Immunology Guangzhou University of Chinese MedicineGuangzhou 510006China Center for non-infectious liver diseases Beijing 302 HospitalBeijing 100039China Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Division of Immunology Allergy and RheumatologyUniversity of CincinnatiCincinnatiOH 45267

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver,and T cells are critical drivers in this ***,little is known about the regulation of their functional behavior during disease *** previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type Ⅱ(dnTGFβ RII)spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis(PBC).Adoptive transfer of CD8^(+) but not CD4^(+) T cells into Rag1^(−/−)mice reproduced the disease,demonstrating a critical role for CD8^(+) T cells in PBC ***,we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFβRII and B6 control mice at different *** addition,we analyzed CD8 protein profiles after adoptive transfer of splenic CD8^(+) cells into Rag1^(−/−)*** use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of CD8 cells,which are key to biliary *** total,254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic CD8^(+) cells compared to donor splenic CD8^(+) *** contrast to donor splenic CD8^(+) cells,recipient hepatic CD8^(+) cells expressed distinct profiles for proteins involved in chemokine signaling,focal adhesion,T cell receptor and natural killer cell-mediated cytotoxicity pathways.

关键词： autoimmune cholangitis CD8 dnTGFβRII mice proteomic analysis

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

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Cellular & Molecular Immunology 2017年第3期14卷 276-284页

作者： Takashi Tomiyama Guo-Xiang Yang Ming Zhao Weici Zhang Hajime Tanaka Jing Wang patrick sc leung Kazuiclli Okazaki Xiao-Song He Qianjin Lu Ross L Coppel Christopher L Bowlus M Eric Gershwin Division of Rheumatology Allergy and Clinical Immunology University of California at Davis Davis CA 95616 USA Third Department of Internal Medicine Division of Gastroenterology and Hepatology Kansai Medical University Osaka 573-1191 Japan Hunan Key Laboratory of Medical Epigenomics Department of Dermatology The Second Xiangya Hospital Central South University Changsha Hunan 410011 People's Republic of China Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya 467-8601 Japan Department of Microbiology Monash University Melbourne Australia Division of Gastroenterology and Hepatology University of California at Davis School of Medicine. Sacramento. CA 95817. USA

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＋ monocytes, whereas CD40 up-regulated on CD11c＋ 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.

关键词： autoimmunity exosome microRNA primary biliary cirrhosis

Risk of stroke after acute myocardial infarction among Chinese

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Chinese Medical Journal 2001年第2期114卷 98-99页

作者： Ping-WingNG Wai-KwongCHAN patrick Kwok-leung K WAN Department of Medicine and Geriatrics United Christian Hospital 130 Hip Wo Street Kwun Tong Kowloon Hong Kong China.

Following an acute myocardial infarction (AMI), patients have an increased risk of stroke. Estimates of risk are mainly derived from AMI treatment trials or secondary prevention studies. The reported incidence of stroke in Caucasians in the early phase after AMI ranged from 0.5% to 2.5%.1-3 Similar assessment of risk in the Chinese population is lacking. As thrombolytic therapy becomes standard treatment for AMI, there is concern that there may be an increase in haemorrhagic stroke complicating AMI treatment, especially since haemorrhagic stroke is more common in Asian populations.

关键词： acute myocardial infarction thrombolytic therapy Chinese population

Common outcome,different pathways:Social informationprocessing deficits in autism spectrum disorder and attentiondeficit/hyperactivity disorder

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World Journal of Psychiatry 2022年第2期12卷 286-297页

作者： Janice K Y Chan patrick W L leung Department of Clinical Psychology United Christian HospitalHospital AuthorityHong Kong 999077China Department of Psychology The Chinese University of Hong KongHong Kong 999077China

Social functioning is a key domain of impairment in both autism spectrum disorder(ASD)and attention-deficit/hyperactivity disorder(ADHD).This review adopts the social information-processing model as the theoretical framework to compare and contrast the deficits of ASD and ADHD at each of the six steps of social *** disorders show deficits at each step,but the nature and origins of the deficits are ***,while both disorders exhibit a common outcome of social impairment,the exact pathways that each disorder traverses along the six steps of social information-processing are *** ASD,there is a social knowledge/behaviour deficit arising from difficulties in social/emotional cue detection,encoding,and interpretation,leading to problems in joining and initiating social *** ADHD,there is a performance deficit incurred by disruption arising from the ADHD symptoms of inattention and hyperactivity/impulsivity,while its acquisition capacity on social knowledge is relatively *** inattentive,intrusive,and impulsive behaviours of ADHD unsettle social ***,this review proposes training targets for intervention along the six steps of the social information-processing model for ASD and ADHD,as well as areas for future research in further elucidating the social impairment of the two disorders.

关键词： Autism spectrum disorder Attention deficit/hyperactivity disorder Social information-processing Social impairment Social skills training Social outcome

Mimotope-based allergen-specific immunotherapy: ready for prime time?

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Cellular & Molecular Immunology 2019年第11期16卷 890-891页

作者： Nicki Y.H.leung Christine Y.Y.Wai Ka Hou Chu patrick S.C.leung Department of Paediatrics The Chinese University of Hong KongShatinHong KongChina school of Life sciences The Chinese University of Hong KongShatinHong KongChina Division of Rheumatology/Allergy School of MedicineUniversity of CaliforniaDavisCA 95616USA

INTRODUCTION Allergen-specific immunotherapy(AIT)is a therapeutic strategy to restore the normal immune response by suppressing inflammatory effector cells and inducing regulatory cells specific to the culprit ***,AIT is achieved by administering escalating doses of allergen over a long treatment ***,the use of unmodified allergens for AIT often results in severe anaphylactic side effects,and alternative approaches such as hypoallergens and T-cell epitopes with enhanced safety have been *** use of mimotopes in AIT is a relatively new concept,but earlier proof-ofconcept studies showed promising results for mimotopes,with decent safety profiles and immunomodulatory *** the treatment of cancer with mimotope-based immunotherapy has already been tested in clinical trials2,mimotope-based AIT remains largely in the preclinical ***,we revisit the pros and cons of mimotope-based AIT and describe recent findings concerning the use of mimotopes in AIT.

关键词： immunotherapy doses treatment

Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain

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Cellular & Molecular Immunology 2014年第2期11卷 141-149页

作者： Kam-leung Siu Chi-Ping Chan Kin-Hang Kok patrick Chiu-Yat Woo Dong-Yan Jin Department of Biochemistry The University of Hong Kong Pokfulam Hong Kong Department of Microbiology The University of Hong KongPokfulam Hong Kong

Coronaviruses have developed various measures to evade innate immunity, We have previously shown that severe acute respiratory syndrome （SARS） coronavirus M protein suppresses type I interferon （IFN） production by impeding the formation of functional TRAF3-containing complex. In this study, we demonstrate that the IFN-antagonizing activity is specific to SARS coronavirus M protein and is mediated through its first transmembrane domain （TM 1） located at the N terminus. M protein from human coronavirus HKU 1 does not inhibit IFN production. Whereas N-linked glycosylation of SARS coronavirus M protein has no influence on IFN antagonism, TM1 is indispensable for the suppression of IFN production. TM 1 targets SARS coronavirus M protein and heterologous proteins to the Golgi apparatus, yet Golgi localization is required but not sufficient for IFN antagonism. Mechanistically, TM 1 is capable of binding with RIG-I, TRAF3, TBK1 and IKK~, and preventing the interaction of TRAF3 with its downstream effectors. Our work defines the molecular architecture of SARS coronavirus M orotein reouired for suooression of innate antiviral re^nnn^e.

关键词： human coronavirus HKU1 innate antiviral response SARS coronavirus TRAF3 type I interferons