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Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression

cellular & Molecular Immunology 2022年第10期19卷 1130-1140页

作者： Tihong shao patrick s.c.leung Weici Zhang Koichi Tsuneyama William M.Ridgway Howard A.Young Zongwen shuai Aftab A.Ansari M.Eric Gershwi Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical UniversityHefeiChina Division of Rheumatology Allergyand Clinical ImmunologySchool of MedicineUniversity of CaliforniaDavisCAUSA Department of Pathology and Laboratory Medicine Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan center for cancer Research National Cancer Institute-FrederickFrederickMDUSA

The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity.We have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγmetabolism.Importantly,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal inflammation.We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis.To study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied.JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage,associated with a significant reduction in splenic and hepatic cD4^(+)T cells and cD8^(+)T cells.Functionally,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic cD4^(+)T cells.Additionally,ruxolitinib treatment also decreased the frequencies of germinal center B(Gc B)cells and T follicular helper(Tfh)cells and led to lower serological AMA levels.Of note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment.Mechanistically,ruxolitinib inhibited the secretion of IL-6,TNF and McP1 and the expression of sTAT1 but promoted the expression of sTAT6 in macrophages in vitro,indicating that M1 macrophage polarization to M2 occurred through activation of the sTAT6-IRF4 pathway.Our data highlight the significance,both immunologically and clinically,of the JAK/sTAT signaling pathway in autoimmune cholangitis.

关键词： Primary biliary cholangitis Autoimmunity Interferons Janus Kinase Inhibitors Ruxolitinib

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原发性胆汁性胆管炎:探索个体化诊疗的最优选择

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science Bulletin 2022年第24期67卷 2498-2501页

作者：尚玉龙 patrick s.c.leung M.Eric Gershwin 韩英 National clinical Research center for Digestive Diseases and Xijing Hospital of Digestive Diseases Xijing HospitalAir Force Military Medical UniversityXi’an 710032China Division of Rheumatology Allergy and Clinical ImmunologyUniversity of CaliforniaDavis 95616USA

Primary biliary cholangitis (PBc) is a chronic cholestatic liver disease that is characterized by inflammation of the interlobular bile ducts. Although PBc is a slowly progressive disease, with a natural history of 10–15 years leading to end-stage liver disease, highrisk cases may rapidly progress to decompensated cirrhosis or even death. As the most common autoimmune liver disease, the prevalence of PBc has been increasing globally, largely due to increased disease awareness, improved diagnosis, and treatment with ursodeoxycholic acid (UDcA). PBc is more likely to occur in middle-aged women, with a female-to-male ratio ranging from 1.6 to10;however, men have a higher disease severity [1,2].

关键词： diagnosis inflammation Primary

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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 allergen.conventionally,AIT is achieved by administering escalating doses of allergen over a long treatment course.However,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 considered.The 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 capacity1.While the treatment of cancer with mimotope-based immunotherapy has already been tested in clinical trials2,mimotope-based AIT remains largely in the preclinical stage.Here,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

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Foraging valor linked with aggression:selection against completely abandoning aggression in the high-elevation ant Tetramorium alpestre?

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Insect science 2024年第3期31卷 953-970页

作者： Marie-Luise contala patrick Krapf Florian M.steiner Birgit c.schlick-steiner Molecular Ecology Group Department of EcologyUniversitat InnsbruckInnsbruckAustria rganismal&Evolutionary Biology Research Programme University of HelsinkiHelsinkiFinland

Aggression has multiple benefits and is often coupled with other behaviors("behavioral syndromes").The level of aggressiveness is influenced by an adaptive benefit-cost ratio suggesting that benefits should outweigh the costs of aggression.Here,we assess if several behaviors are coupled in two behaviorally different populations(aggressive,peaceful)of the high-elevation ant Tetramorium alpestre.For three weeks,we collected colony fragments and analyzed boldness,exploring,foraging,and risk-taking behaviors.We hypothesized that the aggressive population is bolder,more explorative and risk-prone,and forages more food than the peaceful population.To test whether(a)the combination of experiments and parameters used yields a good setup,(b)populations differ behaviorally,and(c)populations display behavioral syndromes,we assessed(a)the frequency of repeatable behaviors of each experiment,(b)the behavioral means among populations,and(c)the behavioral repeatability,respectively.We found that(a)boldness and exploring were most repeatable and represent a good experimental setup,(b)the aggressive population was bolder and more explorative and risk-prone than the peaceful population,(c)boldness and exploring behaviors were highly repeatable in both populations,thus corroborating our hypothesis.The results suggest that boldness,exploring,and risk-taking but not foraging are presumably coupled with aggression and indicate the presence of behavioral syndromes in this ant.Under specific ecological conditions,aggression may be coupled with other behaviors and important for finding food.Aggression is probably adaptive in T.alpestre,possibly indicating that selection favors aggression at least partially,which may counteract the complete loss of intraspecific aggression.

关键词： adaptive value behavioral syndromes boldness exploration repeatability trade-off

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combined Effect of Outdoor Time and Other Modifiable Factors on Myopia Incidence Among children and Adolescents—9 PLADs,china,2020

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china cDc weekly 2024年第9期6卷 151-156,I0001,I0002页

作者： Panliang Zhong Yunfei Liu Ning Ma Jiajia Dang Di shi shan cai Ziyue chen Yanhui Dong Peijin Hu Jun Ma patrick W.c Lau Randall s.stafford Yi song Institute of child and Adolescent Health School of Public HealthPeking UniversityNational Health Commission Key Laboratory of Reproductive HealthBeijingChina Department of sport Physical Education&HealthHong Kong Baptist UniversityKowloon TongHong Kong Special Administrative RegionChina Department of Medicine Stanford Prevention Research CenterStanford University School of MedicineStanfordCAUnited States

summary What is already known about this topic?Myopia has been identified as a significant emerging challenge and policy priority among children and adolescents in china by the Ministry of Education and seven other departments.Limited research has been conducted to investigate the collective impact of outdoor time and other modifiable factors on the incidence of myopia.

关键词： Incidence collective policy

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Inducing neuronal regeneration and differentiation via the BDNF/ TrkB signaling pathway: a key target against neurodegenerative diseases?

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Neural Regeneration Research 2024年第3期19卷 495-496页

作者： Mirjana Antonijevic patrick Dallemagne christophe Rochais Normandie University UNICAENCERMNCaenFrance

Brain-derived neurotrophic factor(BDNF)is one of the neurotrophins,a specific polypeptide growth factor,which plays a crucial role in the proliferation,differentiation,survival,and death of neurons and non-neuronal cells.It is not only essential to maintain the balance between death on one side and survival of neurons on the other,but also it mediates additional higher-order activities such as learning,memory,and behavior.It is initially synthesized as a precursor protein,proBDNF,that can be secreted as it is or it can be cleaved intracellularly by furin and proconvertases,or extracellularly by extracellular proteases such as matrix metalloprotease-9 and matrix metalloprotease-2,or plasmin to give mature BDNF.

关键词： death diseases degenerative

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Impact of multifocal gas-permeable lens designs on short-term choroidal response, axial length, and retinal defocus profile

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International Journal of Ophthalmology(English edition) 2024年第2期17卷 247-256页

作者： Muteb Alanazi patrick caroline Amane Alshamrani Maria Liu Optometry Department College of Applied Medical SciencesKing Saud UniversityRiyadh 14813Saudi Arabia college of Optometry Pacific UniversityForest GroveOregon 97116-1756United States Optometry school University of California at BerkeleyCalifornia 94720United States

AIM:To investigate the impact of multifocal gas permeable contact lens(MFGPcL)in various add power and distance/near area allocation on short-term changes of choroidal thickness(chT),axial length(AL),and retinal defocus profile in young adults.METHODs:seventeen young adults(2 males and 15 females;age 23.17±4.48y)were randomly assigned to wear two designs binocularly with a one-week washout period in between.Total of four MFGPcL designs were assessed.All designs were distance-center that varied in two add power(+1.50 and 3.00 D)and/or two distance zone(DZ)diameters(1.50 and 3.00 mm;design A:DZ 1.5/add 3.0,B:DZ 1.5/add 1.5,c:DZ 3.0/add 3.0,D:DZ 3.0/add 1.5).chT,AL,and peripheral refraction data were collected on each subject at baseline,on days 1 and 7 of MFGPcL daily wear.chT was assessed in four quadrants using a spectraldomain optical coherence tomography.REsULTs:AL was shortened by-26±44μm with lens c,-18±27μm with lens D,-13±29μm with lens A,and-8±30μm with lens B(all Psignificant overall increase in chT was observed with all 4 designs(lens A:+6±6μm,B:+3±7μm,c:+8±7μm,and D:+8±7μm).Temporal and superior choroid exhibited more choroidal thickening associated with MFGPcL.All designs induced significant relative peripheral myopia(RPM)beyond the central 20o across the horizontal meridian in both nasal and temporal fields(PcONcLUsION:MFGPcLs show a significant influence on chT and AL,which are associated with significant increase in RPM after short-term wear.The reliability and feasibility of quantifying short-term changes in chT support its use as a promising marker for the long-term efficacy of myopia-controlling treatments.

关键词： choroid gas-permeable contact lens retinal defocus axial length myopia

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speed and surface steepness affect internal tibial loading during running

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Journal of sport and Health science 2024年第1期13卷 118-124页

作者： Hannah Rice Markus Kurz patrick Mai Leon Robertz Kevin Bill Timothy R.Derrick steffen Willwacher Department of Physical Performance Norwegian School of Sport SciencesOslo 0806Norway sports Tech Research centre Mid Sweden UniversityÖstersund SE-83125Sweden Department of Mechanical and Process Engineering Offenburg University of Applied SciencesOffenburg 77652Germany Institute of Biomechanics and Orthopaedics German Sport University CologneCologne 50933Germany Department of Kinesiology Iowa State UniversityAmesIA 50011USA

Background:Internal tibial loading is influenced by modifiable factors with implications for the risk of stress injury.Runners encounter varied surface steepness(gradients)when running outdoors and may adapt their speed according to the gradient.This study aimed to quantify tibial bending moments and stress at the anterior and posterior peripheries when running at different speeds on surfaces of different gradients.Methods:Twenty recreational runners ran on a treadmill at 3 different speeds(2.5 m/s,3.0 m/s,and 3.5 m/s)and gradients(level:0%;uphill:+5%,+10%,and+15%;downhill:-5%,-10%,and-15%).Force and marker data were collected synchronously throughout.Bending moments were estimated at the distal third centroid of the tibia about the medial-lateral axis by ensuring static equilibrium at each 1%of stance.stress was derived from bending moments at the anterior and posterior peripheries by modeling the tibia as a hollow ellipse.Two-way repeated-measures analysis of variance were conducted using both functional and discrete statistical analyses.Results:There were significant main effects for running speed and gradient on peak bending moments and peak anterior and posterior stress.Higher running speeds resulted in greater tibial loading.Running uphill at+10%and+15%resulted in greater tibial loading than level running.Running downhill at-10%and-15%resulted in reduced tibial loading compared to level running.There was no difference between+5%or-5%and level running.conclusion:Running at faster speeds and uphill on gradients≥+10%increased internal tibial loading,whereas slower running and downhill running on gradients≥-10%reduced internal loading.Adapting running speed according to the gradient could be a protective mechanism,providing runners with a strategy to minimize the risk of tibial stress injuries.

关键词： Bending moments Gradient Musculoskeletal modeling Overuse injury Tibial stress Training factors

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Adaptive immunity in the liver

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cellular & Molecular Immunology 2016年第3期13卷 354-368页

作者： Zongwen shuai Miranda WY leung Xiaosong He Weici Zhang Guoxiang Yang patrick sc leung M Eric Gershwin Division of Rheumatology Allergy and Clinical Immunology University of California Davis School of Medicine Davis CA 95616 USA Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical University Hefei 230022 China.

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

关键词： adaptive immunity T cells immunopathogenesis antiviral immunity

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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

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