2007年国际联合研究项目人类微生物组计划(The Human Microbiome Project,HMP)和人类肠道元基因(或宏基因)组学计划(Metagenomics of The Human Intestinal Tract,MetaHIT)正式启动,标志着肠道宏基因组研究的时代已经到来。人是由90%的...2007年国际联合研究项目人类微生物组计划(The Human Microbiome Project,HMP)和人类肠道元基因(或宏基因)组学计划(Metagenomics of The Human Intestinal Tract,MetaHIT)正式启动,标志着肠道宏基因组研究的时代已经到来。人是由90%的共生微生物组成的超级生物体,微生物尤其是肠道微生物参与了人体的营养吸收和代谢,通过这种相互作用方式影响着人体的健康和疾病的发展。本文从多种途径综述肠道菌群对疾病发病机制的研究进展,旨在为寻找人类的健康和疾病的治疗靶点提供一些新的思路。展开更多
Interleukin-17(IL-17)and IL-17-producing cells have been shown to play important roles in inflammation and the immune response.IL-17 is believed to be mainly produced by T helper 17(Th17)cells,a unique helper T-cell s...Interleukin-17(IL-17)and IL-17-producing cells have been shown to play important roles in inflammation and the immune response.IL-17 is believed to be mainly produced by T helper 17(Th17)cells,a unique helper T-cell subset different from Th1 and Th2 cells.Other subsets of T cells such as cdT and natural killer T(NKT)cells have also been found to produce IL-17 in response to innate stimuli.IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines,cytokines,matrix metalloproteinases(MMPs)and antimicrobial peptides from mesenchymal and myeloid cells.This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo.Furthermore,increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies,autoimmune diseases,allograft transplantation and even malignancy.They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte(CTL)responses against cancer.Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.展开更多
Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. ...Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.展开更多
The role of vitamin D as an immune modulator has been emphasized in recent years,and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus...The role of vitamin D as an immune modulator has been emphasized in recent years,and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus.Vitamin D mediates its effect though binding to vitamin D receptor(VDR),and activation of VDR-responsive genes.While VDR gene polymorphism was found to associate with autoimmune thyroid diseases(AITDs),few studies examined levels of vitamin D in these patients and those that did yielded conflicting results.We therefore undertook to evaluate the levels of vitamin D in patients with AITDs compared to patients with non-AITDs and healthy controls.Serum vitamin D(25-OH)levels were measured in 50 patients with AITDs,42 patients with non-AITDs and 98 healthy subjects,utilizing the LIAISON chemiluminescence immunoassay(DiaSorin,Saluggia,Italy).VitaminD deficiency was designated at levels lower than 10 ng/ml.Antithyroid antibodies,thyroid functions and demographic parameters were evaluated in all patients.The prevalence of vitamin D deficiency was significantly higher in patients with AITDs compared with healthy individuals(72% versus 30.6%;P<0.001),as well as in patients with Hashimoto’s thyroiditis compared to patients with non-AITDs(79% versus 52%;P<0.05).Vitamin D deficiency also correlated to the presence of antithyroid antibodies(P=0.01)and abnormal thyroid function tests(P=0.059).Significantly low levels of vitamin D were documented in patients with AITDs that were related to the presence of anti thyroid antibodies and abnormal thyroid function tests,suggesting the involvement of vitamin D in the pathogenesis of AITDs and the advisability of supplementation.展开更多
Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as ...Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.展开更多
Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the s...Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody(ANA) and smooth muscle antibody(SMA).AIH-2 is specified by antibody to liver kidney microsomal antigen type-1(anti-LKM1) and anti-liver cytosol type 1(anti-LC1).SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies(AMA) react-ing with enzymes of the 2-oxo-acid dehydrogenase complexes(chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis(PSC) mostly affecting adult men wherein the only(and non-specific) reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody(p-ANCA),also termed peri-nuclear anti-neutrophil nuclear antibodies(p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis(ASC) with serological features resembling those of type 1 AIH.Liver diagnostic serol-ogy is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement(or even compete with) tradi-tional immunofluorescence procedures.We survey for the first time global trends in quality assurance impact-ing as it does on(1) manufacturers/purveyors of kits and reagents,(2) diagnostic service laboratories that fulfill clinicians' requirements,and(3) the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.展开更多
The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune c...The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.展开更多
Ankylosing spondylitis(AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain;additionally, in more advanced cases, it ca...Ankylosing spondylitis(AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain;additionally, in more advanced cases, it can cause spine fusion. Significant progress in its pathophysiology and treatment has been achieved in the last decade. Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen(HLA)?B27 and the interleukin?23/17 axis.However, the pathogenesis of AS remains unclear. The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways. This study also summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.展开更多
Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. MSCs can differentiate into osteoblastic, chondrogenic, an...Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. MSCs can differentiate into osteoblastic, chondrogenic, and adipogenic lineages, although recent studies have demonstrated that MSCs are also able to differentiate into other lineages, including neuronal and cardiomyogenic lineages. Since their original isolation from the bone marrow, MSCs have been successfully harvested from many other tissues. Their ease of isolation and ex vivo expansion combined with their immunoprivileged nature has made these cells popular candidates for stem cell therapies. These cells have the potential to alter disease pathophysiology through many modalities including cytokine secretion, capacity to differentiate along various lineages, immune modulation and direct cell-cell interaction with diseased tissue. Here we first review basic features of MSC biology including MSC characteristics in culture, homing mechanisms, differentiation capabilities and immune modulation. We then highlight some in vivo and clinical evidence supporting the therapeutic roles of MSCs and their uses in orthopedic, autoimmune, and ischemic disorders.展开更多
文摘2007年国际联合研究项目人类微生物组计划(The Human Microbiome Project,HMP)和人类肠道元基因(或宏基因)组学计划(Metagenomics of The Human Intestinal Tract,MetaHIT)正式启动,标志着肠道宏基因组研究的时代已经到来。人是由90%的共生微生物组成的超级生物体,微生物尤其是肠道微生物参与了人体的营养吸收和代谢,通过这种相互作用方式影响着人体的健康和疾病的发展。本文从多种途径综述肠道菌群对疾病发病机制的研究进展,旨在为寻找人类的健康和疾病的治疗靶点提供一些新的思路。
文摘Interleukin-17(IL-17)and IL-17-producing cells have been shown to play important roles in inflammation and the immune response.IL-17 is believed to be mainly produced by T helper 17(Th17)cells,a unique helper T-cell subset different from Th1 and Th2 cells.Other subsets of T cells such as cdT and natural killer T(NKT)cells have also been found to produce IL-17 in response to innate stimuli.IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines,cytokines,matrix metalloproteinases(MMPs)and antimicrobial peptides from mesenchymal and myeloid cells.This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo.Furthermore,increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies,autoimmune diseases,allograft transplantation and even malignancy.They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte(CTL)responses against cancer.Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.
文摘Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.
文摘The role of vitamin D as an immune modulator has been emphasized in recent years,and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus.Vitamin D mediates its effect though binding to vitamin D receptor(VDR),and activation of VDR-responsive genes.While VDR gene polymorphism was found to associate with autoimmune thyroid diseases(AITDs),few studies examined levels of vitamin D in these patients and those that did yielded conflicting results.We therefore undertook to evaluate the levels of vitamin D in patients with AITDs compared to patients with non-AITDs and healthy controls.Serum vitamin D(25-OH)levels were measured in 50 patients with AITDs,42 patients with non-AITDs and 98 healthy subjects,utilizing the LIAISON chemiluminescence immunoassay(DiaSorin,Saluggia,Italy).VitaminD deficiency was designated at levels lower than 10 ng/ml.Antithyroid antibodies,thyroid functions and demographic parameters were evaluated in all patients.The prevalence of vitamin D deficiency was significantly higher in patients with AITDs compared with healthy individuals(72% versus 30.6%;P<0.001),as well as in patients with Hashimoto’s thyroiditis compared to patients with non-AITDs(79% versus 52%;P<0.05).Vitamin D deficiency also correlated to the presence of antithyroid antibodies(P=0.01)and abnormal thyroid function tests(P=0.059).Significantly low levels of vitamin D were documented in patients with AITDs that were related to the presence of anti thyroid antibodies and abnormal thyroid function tests,suggesting the involvement of vitamin D in the pathogenesis of AITDs and the advisability of supplementation.
文摘Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.
文摘Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody(ANA) and smooth muscle antibody(SMA).AIH-2 is specified by antibody to liver kidney microsomal antigen type-1(anti-LKM1) and anti-liver cytosol type 1(anti-LC1).SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies(AMA) react-ing with enzymes of the 2-oxo-acid dehydrogenase complexes(chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis(PSC) mostly affecting adult men wherein the only(and non-specific) reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody(p-ANCA),also termed peri-nuclear anti-neutrophil nuclear antibodies(p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis(ASC) with serological features resembling those of type 1 AIH.Liver diagnostic serol-ogy is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement(or even compete with) tradi-tional immunofluorescence procedures.We survey for the first time global trends in quality assurance impact-ing as it does on(1) manufacturers/purveyors of kits and reagents,(2) diagnostic service laboratories that fulfill clinicians' requirements,and(3) the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.
基金supported in part by the National Natural Science Foundation of China(grants#81830016,81771732,and 81620108002 to X.M.,#81922010 and 81873561 to R.T.)supported in part by services provided by the NIH centers P30 DK120515 and P50 AA011999+1 种基金supported by the excellence initiative VASCage(Centre for Promoting Vascular Health in the Ageing Community)R8fD K-Centre(COMET program-Competence Centers for Excellent Technologies)funded by the Austrian Ministry for Transport,Innovation and Technology,the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol,Salzburg and Vienna.
文摘The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.
基金supported by the Beijing Natural Science Foundation youth project (7184325)the China Postdoctoral Foundation NO.62 general program
文摘Ankylosing spondylitis(AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain;additionally, in more advanced cases, it can cause spine fusion. Significant progress in its pathophysiology and treatment has been achieved in the last decade. Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen(HLA)?B27 and the interleukin?23/17 axis.However, the pathogenesis of AS remains unclear. The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways. This study also summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.
基金Supported by (in part) Research Grants from the Brinson Foundation (to He TC)the Orthopaedic Research and Education Foundation (to Haydon RC and Luu HH)+3 种基金the National Institutes of Health (to He TC, Haydon RC, Luu HH and Reid RR)The 863 Program of Ministry of Science and Technology of China,#2007AA2z400 (to He TC and Deng ZL)the Natural Science Foundation of China (#30901530 to Luo X, #30800658 to Luo J,and #30772211 to Deng ZL)the Natural Science Foundation Project of Chongqing Science and Technology Commission#2008BB5396 (to Chen L) and #2009BB5060 (to Luo J)
文摘Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. MSCs can differentiate into osteoblastic, chondrogenic, and adipogenic lineages, although recent studies have demonstrated that MSCs are also able to differentiate into other lineages, including neuronal and cardiomyogenic lineages. Since their original isolation from the bone marrow, MSCs have been successfully harvested from many other tissues. Their ease of isolation and ex vivo expansion combined with their immunoprivileged nature has made these cells popular candidates for stem cell therapies. These cells have the potential to alter disease pathophysiology through many modalities including cytokine secretion, capacity to differentiate along various lineages, immune modulation and direct cell-cell interaction with diseased tissue. Here we first review basic features of MSC biology including MSC characteristics in culture, homing mechanisms, differentiation capabilities and immune modulation. We then highlight some in vivo and clinical evidence supporting the therapeutic roles of MSCs and their uses in orthopedic, autoimmune, and ischemic disorders.
