With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of t...With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage.In recent years,population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity,providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways.In this review,we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics.An overview of the genetic basis of autoimmunity is followed by3 chapters detailing susceptibility genes involved in innate immunity,adaptive immunity and inflammatory cell death processes respectively.With such attempts,we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the‘usual suspects’of a limited subset of validated therapeutic targets.展开更多
Rheumatoid arthritis(RA)is a relatively common inflammatory disease that affects the synovial tissue,eventually results in joints destruction and even long-term disability.Although Janus kinase inhibitors(Jakinibs)sho...Rheumatoid arthritis(RA)is a relatively common inflammatory disease that affects the synovial tissue,eventually results in joints destruction and even long-term disability.Although Janus kinase inhibitors(Jakinibs)show a rapid efficacy and are becoming the most successful agents in RA therapy,high dosing at frequent interval and severe toxicities cannot be avoided.Here,we developed a new type of fully compatible nanocarriers based on recombinant chimeric proteins with outstanding controlled release of upadacitinib.In addition,the fluorescent protein component of the nanocarriers enabled noninvasive fluorescence imaging of RA lesions,thus allowing real-time detection of RA therapy.Using rat models,the nanotherapeutic is shown to be superior to free upadacitinib,as indicated by extended circulation time and sustained bioefficacy.Strikingly,this nanosystem possesses an ultralong half-life of 45 h and a bioavailability of 4-times higher than pristine upadacitinib,thus extending the dosing interval from one day to 2 weeks.Side effects such as over-immunosuppression and leukocyte levels reduction were significantly mitigated.This smart strategy boosts efficacy,safety and visuality of Jakinibs in RA therapy,and potently enables customized designs of nanoplatforms for other therapeutics.展开更多
Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overvi...Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA. We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.展开更多
Ankylosing spondylitis(AS)is a prototype of spondyloarthritis(SpA)with long-term joint inflammation of the spine.SpA manifestations also include psoriasis,uveitis,and inflammatory bowel disease,which suggest these dis...Ankylosing spondylitis(AS)is a prototype of spondyloarthritis(SpA)with long-term joint inflammation of the spine.SpA manifestations also include psoriasis,uveitis,and inflammatory bowel disease,which suggest these diseases may share some common genetic background.展开更多
文摘With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage.In recent years,population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity,providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways.In this review,we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics.An overview of the genetic basis of autoimmunity is followed by3 chapters detailing susceptibility genes involved in innate immunity,adaptive immunity and inflammatory cell death processes respectively.With such attempts,we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the‘usual suspects’of a limited subset of validated therapeutic targets.
基金supported by the National Key R&D Program of China(Nos.2022YFA0913200,2021YFF0701800,2022YFF0710000,and 2020YFA0908900)the National Natural Science Foundation of China(Nos.22107097,22020102003,22277064,82272161,and 22125701)+1 种基金Tsinghua University Spring Breeze Fund grant(No.2021Z99CFZ005),and the Youth Innovation Promotion Association of CAS(No.2021226)All animal experiments were conducted in compliance with the Animal Management Rules of the Ministry of Health of the People's Republic of Chinawith the approval of the Institutional Animal Care and Use Committee of the Animal Experiment Center of Jilin University(No.PZPX20180929070).
文摘Rheumatoid arthritis(RA)is a relatively common inflammatory disease that affects the synovial tissue,eventually results in joints destruction and even long-term disability.Although Janus kinase inhibitors(Jakinibs)show a rapid efficacy and are becoming the most successful agents in RA therapy,high dosing at frequent interval and severe toxicities cannot be avoided.Here,we developed a new type of fully compatible nanocarriers based on recombinant chimeric proteins with outstanding controlled release of upadacitinib.In addition,the fluorescent protein component of the nanocarriers enabled noninvasive fluorescence imaging of RA lesions,thus allowing real-time detection of RA therapy.Using rat models,the nanotherapeutic is shown to be superior to free upadacitinib,as indicated by extended circulation time and sustained bioefficacy.Strikingly,this nanosystem possesses an ultralong half-life of 45 h and a bioavailability of 4-times higher than pristine upadacitinib,thus extending the dosing interval from one day to 2 weeks.Side effects such as over-immunosuppression and leukocyte levels reduction were significantly mitigated.This smart strategy boosts efficacy,safety and visuality of Jakinibs in RA therapy,and potently enables customized designs of nanoplatforms for other therapeutics.
基金This work was supported by the National Natural Science Foundation of China (Nos. 31770988 and 31500716)the National Basic Research Program (973 Program) of China (H. Xu, No. 2014CB541802).
文摘Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA. We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.
文摘Ankylosing spondylitis(AS)is a prototype of spondyloarthritis(SpA)with long-term joint inflammation of the spine.SpA manifestations also include psoriasis,uveitis,and inflammatory bowel disease,which suggest these diseases may share some common genetic background.
