مستخلص: Although effector CD4+ T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown. Here we show the process of intravascular antigen recognition using intravital multiphoton microscopy of glomeruli. CD4+ T cells undergo intravascular migration within uninflamed glomeruli. Similarly, while MHCII is not expressed by intrinsic glomerular cells, intravascular MHCII-expressing immune cells patrol glomerular capillaries, interacting with CD4+ T cells. Following intravascular deposition of antigen in glomeruli, effector CD4+ T-cell responses, including NFAT1 nuclear translocation and decreased migration, are consistent with antigen recognition. Of the MHCII+ immune cells adherent in glomerular capillaries, only monocytes are retained for prolonged durations. These cells can also induce T-cell proliferation in vitro. Moreover, monocyte depletion reduces CD4+ T-cell-dependent glomerular inflammation. These findings indicate that MHCII+ monocytes patrolling the glomerular microvasculature can present intravascular antigen to CD4+ T cells within glomerular capillaries, leading to antigen-dependent inflammation.Copyright © 2018 The Author(s).

مصطلحات الفهرس: CD4+ T lymphocyte, animal cell, animal experiment, animal model, antigen presenting cell, antigen recognition, article, controlled study, glomerulonephritis/et [Etiology], glomerulus, glomerulus capillary, in vitro study, inflammation, lymphocyte migration, lymphocyte proliferation, male, microvasculature, monocyte, mouse, multiphoton microscopy, nonhuman, protein expression, antigen/ec [Endogenous Compound], major histocompatibility antigen class 2/ec [Endogenous Compound], Article

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/37424Test
Nature Communications
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مستخلص: Although effector CD4+ T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown. Here we show the process of intravascular antigen recognition using intravital multiphoton microscopy of glomeruli. CD4+ T cells undergo intravascular migration within uninflamed glomeruli. Similarly, while MHCII is not expressed by intrinsic glomerular cells, intravascular MHCII-expressing immune cells patrol glomerular capillaries, interacting with CD4+ T cells. Following intravascular deposition of antigen in glomeruli, effector CD4+ T-cell responses, including NFAT1 nuclear translocation and decreased migration, are consistent with antigen recognition. Of the MHCII+ immune cells adherent in glomerular capillaries, only monocytes are retained for prolonged durations. These cells can also induce T-cell proliferation in vitro. Moreover, monocyte depletion reduces CD4+ T-cell-dependent glomerular inflammation. These findings indicate that MHCII+ monocytes patrolling the glomerular microvasculature can present intravascular antigen to CD4+ T cells within glomerular capillaries, leading to antigen-dependent inflammation.Copyright © 2018 The Author(s).

مصطلحات الفهرس: CD4+ T lymphocyte, animal cell, animal experiment, animal model, antigen presenting cell, antigen recognition, article, controlled study, glomerulonephritis/et [Etiology], glomerulus, glomerulus capillary, in vitro study, inflammation, lymphocyte migration, lymphocyte proliferation, male, microvasculature, monocyte, mouse, multiphoton microscopy, nonhuman, protein expression, antigen/ec [Endogenous Compound], major histocompatibility antigen class 2/ec [Endogenous Compound], Article

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/37424Test
Nature Communications
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مستخلص: Regulatory T cells (Tregs) play indispensable roles in the immune system, in limiting excessive or inappropriate immune and inflammatory responses. They achieve this function via effects on other immune cells in the secondary lymphoid system, and in peripheral locations such as skin, gut and bone marrow. As for the more extensively studied cellular players in the immune system, particularly dendritic cells and conventional T cells, in vivo imaging of Tregs via two-photon (or multiphoton) microscopy (MPM) has been central to the development of understanding how these cells function. In this brief review, we will describe the studies that have utilised MPM to examine Treg behaviour in vivo. These studies have investigated Treg behaviour in lymph nodes and spleen, as well as in peripheral organs such as skin, small intestine and bone marrow. The findings from these experiments underline how assumptions made about Treg function based on results of in vitro experiments are often not supported by direct visualisation of these cells in their normal in vivo settings. Together this work reveals that only via MPM analysis can Treg function be investigated in the complicated multicellular environments where conventional T cells, antigen-presenting cells and other potential cellular targets of Tregs are present with each undergoing their own specific actions.Copyright © 2017 Australasian Society for Immunology Inc. All rights reserved.

مصطلحات الفهرس: spleen, human, antigen presenting cell, bone marrow, cell function, experimental model, human cell, imaging, immunoregulation, in vitro study, lymph node, microscopy, organ, regulatory T lymphocyte, skin, small intestine, Review

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/38641Test
Immunology and Cell Biology
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مستخلص: Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell selfepitope derived from the a3 chain of type IV collagen (a3135-145)1-4. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive a3135-145-specific T cells expand in patients with Goodpasture disease and, in a3135-145- immunized HLA-DR15 transgenic mice, a3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the a3135-145 epitope in different binding registers. HLA-DR15-a3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLADR1- a3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered a3135-145-specific T-cell antigen receptor usage, HLADR15- a3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-a3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded a3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative ab

مصطلحات الفهرس: autoimmunity, allele, antigen presenting cell, antigen specificity, article, CD4+ T lymphocyte, Goodpasture syndrome, helper cell, heterozygote, HLA system, homozygote, human, lymphocyte proliferation, nonhuman, phenotype, priority journal, regulatory T lymphocyte, collagen type 4/ec [Endogenous Compound], gamma interferon/ec [Endogenous Compound], HLA DR1 antigen/ec [Endogenous Compound], HLA DR15 antigen/ec [Endogenous Compound], interleukin 10/ec [Endogenous Compound], interleukin 17/ec [Endogenous Compound], interleukin 6/ec [Endogenous Compound], T lymphocyte receptor/ec [Endogenous Compound], transforming growth factor beta/ec [Endogenous Compound], unclassified drug, collagen type 4 alpha3 chain/ec [Endogenous Compound], Article

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/39426Test
Nature
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مستخلص: Regulatory T cells (Tregs) play indispensable roles in the immune system, in limiting excessive or inappropriate immune and inflammatory responses. They achieve this function via effects on other immune cells in the secondary lymphoid system, and in peripheral locations such as skin, gut and bone marrow. As for the more extensively studied cellular players in the immune system, particularly dendritic cells and conventional T cells, in vivo imaging of Tregs via two-photon (or multiphoton) microscopy (MPM) has been central to the development of understanding how these cells function. In this brief review, we will describe the studies that have utilised MPM to examine Treg behaviour in vivo. These studies have investigated Treg behaviour in lymph nodes and spleen, as well as in peripheral organs such as skin, small intestine and bone marrow. The findings from these experiments underline how assumptions made about Treg function based on results of in vitro experiments are often not supported by direct visualisation of these cells in their normal in vivo settings. Together this work reveals that only via MPM analysis can Treg function be investigated in the complicated multicellular environments where conventional T cells, antigen-presenting cells and other potential cellular targets of Tregs are present with each undergoing their own specific actions.Copyright © 2017 Australasian Society for Immunology Inc. All rights reserved.

مصطلحات الفهرس: spleen, human, antigen presenting cell, bone marrow, cell function, experimental model, human cell, imaging, immunoregulation, in vitro study, lymph node, microscopy, organ, regulatory T lymphocyte, skin, small intestine, Review

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/38641Test
Immunology and Cell Biology
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مستخلص: Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell selfepitope derived from the a3 chain of type IV collagen (a3135-145)1-4. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive a3135-145-specific T cells expand in patients with Goodpasture disease and, in a3135-145- immunized HLA-DR15 transgenic mice, a3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the a3135-145 epitope in different binding registers. HLA-DR15-a3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLADR1- a3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered a3135-145-specific T-cell antigen receptor usage, HLADR15- a3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-a3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded a3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative ab

مصطلحات الفهرس: autoimmunity, allele, antigen presenting cell, antigen specificity, article, CD4+ T lymphocyte, Goodpasture syndrome, helper cell, heterozygote, HLA system, homozygote, human, lymphocyte proliferation, nonhuman, phenotype, priority journal, regulatory T lymphocyte, collagen type 4/ec [Endogenous Compound], gamma interferon/ec [Endogenous Compound], HLA DR1 antigen/ec [Endogenous Compound], HLA DR15 antigen/ec [Endogenous Compound], interleukin 10/ec [Endogenous Compound], interleukin 17/ec [Endogenous Compound], interleukin 6/ec [Endogenous Compound], T lymphocyte receptor/ec [Endogenous Compound], transforming growth factor beta/ec [Endogenous Compound], unclassified drug, collagen type 4 alpha3 chain/ec [Endogenous Compound], Article

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/39426Test
Nature
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مستخلص: Introduction: In contrast to other areas in rheumatology, the therapeutic armamentarium in systemic lupus erythematosus (SLE) has lagged behind due to a number of reasons. While SLE is the prototypical multi-system autoimmune disease, its low incidence and the heterogeneity in its clinical manifestations have made it difficult to study. Despite advances in the understanding and application of immunology, the emergence of new targets has not been successfully validated largely due to the difficult-to-use outcome measures. Among the many targets studied, co-stimulation blockade that prevents activation of T cells by antigen-presenting cells, poses an interesting concept that is plausible based on basic science, animal and early human studies. Areas covered: The authors hereby review the development of abatacept in the treatment of SLE and possible future directions. Expert opinion: Despite failure to achieve primary efficacy end points, the studies of abatacept in lupus provided tantalising evidence that co-stimulatory blockade is a feasible option worthy of further exploration. © 2012 Informa UK, Ltd.

مصطلحات الفهرس: nonhuman, pathogenesis, review, rheumatoid arthritis/dt [Drug Therapy], systemic lupus erythematosus/dt [Drug Therapy], systemic lupus erythematosus/et [Etiology], T lymphocyte activation, treatment outcome, treatment response, abatacept/ae [Adverse Drug Reaction], abatacept/ct [Clinical Trial], abatacept/cb [Drug Combination], abatacept/do [Drug Dose], abatacept/dt [Drug Therapy], abatacept/pd [Pharmacology], abatacept/sc [Subcutaneous Drug Administration], azathioprine/cb [Drug Combination], azathioprine/dt [Drug Therapy], CD28 antigen/ec [Endogenous Compound], corticosteroid/cb [Drug Combination], corticosteroid/dt [Drug Therapy], cyclophosphamide/cb [Drug Combination], cyclophosphamide/dt [Drug Therapy], HLA B7 antigen/ec [Endogenous Compound], methotrexate/cb [Drug Combination], methotrexate/dt [Drug Therapy], mycophenolic acid 2 morpholinoethyl ester/cb [Drug Combination], mycophenolic acid 2 morpholinoethyl ester/dt [Drug Therapy], immune response, antigen presenting cell, B lymphocyte, disease severity, drug efficacy, drug indication, drug safety, drug treatment failure, human, immunosuppressive treatment, infection/si [Side Effect], loading drug dose, lupus erythematosus nephritis/co [Complication], lupus erythematosus nephritis/dt [Drug Therapy], Review

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/28344Test
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مستخلص: MHC II and CD4+ T cells are required for anti-glomerular basement membrane (GBM) globulininitiated crescentic glomerulonephritis (GN) in mice, but the role of MHC I and CD8+ T cells is unclear. The cytolytic function of CD8+ T cells requires recognition of peptide antigens presented on MHC I. CD8+ T cells can also perform helper functions via cytokine production. The contribution of MHC I to crescentic GN was investigated using TAP-1 gene knock out (TAP-1-/-) mice, which have deficient MHC I antigen presentation. Heterozygous TAP-1 mice have normal MHC I expression and developed GN with crescents in 42 +/- 4% of glomeruli (normal 0%), proteinuria (9.1 +/- 1.6 mg/20 h, normal 1.5 +/- 0.3 mg/20 h) and impaired renal function (creatinine clearance 110 +/- 8 mul/min, normal 193 +/- 10 mul/min) following administration of sheep anti-mouse GBM globulin. TAP-1-/- mice, which have extremely low MHC I expression and reduced CD8+ T cells, developed similar GN with 39 +/- 3% crescents, proteinuria (12.7 +/- 4.3 mg/20 h) and impaired renal function (creatinine clearance 123 +/- 20 mul/min). In vivo antibody-induced CD8 depletion did not attenuate crescent formation or protect renal function in C57B1/6 mice developing GN, although significant reduction in proteinuria (5.3 +/- 1.2 mg/20 h, P = 0.012) and glomerular recruitment of CD4+ T cells and macrophages were observed compared with control treated mice with GN. These data demonstrate that MHC I is not required for development of crescentic GN in mice. The MHC I-independent contribution of CD8+ T cells to proteinuria and inflammatory cell recruitment suggests that they may serve a 'helper' rather than cytolytic role in this disease.

مصطلحات الفهرس: article, controlled study, creatinine clearance, cytokine production, glomerulonephritis/di [Diagnosis], major histocompatibility complex, major histocompatibility complex restriction, mouse, nonhuman, priority journal, CD4 antigen/ec [Endogenous Compound], CD8 antigen/ec [Endogenous Compound], creatinine/ec [Endogenous Compound], major histocompatibility antigen class 1/ec [Endogenous Compound], proteinuria/di [Diagnosis], animal cell, animal tissue, antigen presenting cell, Article

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/33365Test
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LibKey Link

مستخلص: Introduction: In contrast to other areas in rheumatology, the therapeutic armamentarium in systemic lupus erythematosus (SLE) has lagged behind due to a number of reasons. While SLE is the prototypical multi-system autoimmune disease, its low incidence and the heterogeneity in its clinical manifestations have made it difficult to study. Despite advances in the understanding and application of immunology, the emergence of new targets has not been successfully validated largely due to the difficult-to-use outcome measures. Among the many targets studied, co-stimulation blockade that prevents activation of T cells by antigen-presenting cells, poses an interesting concept that is plausible based on basic science, animal and early human studies. Areas covered: The authors hereby review the development of abatacept in the treatment of SLE and possible future directions. Expert opinion: Despite failure to achieve primary efficacy end points, the studies of abatacept in lupus provided tantalising evidence that co-stimulatory blockade is a feasible option worthy of further exploration. © 2012 Informa UK, Ltd.

مصطلحات الفهرس: nonhuman, pathogenesis, review, rheumatoid arthritis/dt [Drug Therapy], systemic lupus erythematosus/dt [Drug Therapy], systemic lupus erythematosus/et [Etiology], T lymphocyte activation, treatment outcome, treatment response, abatacept/ae [Adverse Drug Reaction], abatacept/ct [Clinical Trial], abatacept/cb [Drug Combination], abatacept/do [Drug Dose], abatacept/dt [Drug Therapy], abatacept/pd [Pharmacology], abatacept/sc [Subcutaneous Drug Administration], azathioprine/cb [Drug Combination], azathioprine/dt [Drug Therapy], CD28 antigen/ec [Endogenous Compound], corticosteroid/cb [Drug Combination], corticosteroid/dt [Drug Therapy], cyclophosphamide/cb [Drug Combination], cyclophosphamide/dt [Drug Therapy], HLA B7 antigen/ec [Endogenous Compound], methotrexate/cb [Drug Combination], methotrexate/dt [Drug Therapy], mycophenolic acid 2 morpholinoethyl ester/cb [Drug Combination], mycophenolic acid 2 morpholinoethyl ester/dt [Drug Therapy], immune response, antigen presenting cell, B lymphocyte, disease severity, drug efficacy, drug indication, drug safety, drug treatment failure, human, immunosuppressive treatment, infection/si [Side Effect], loading drug dose, lupus erythematosus nephritis/co [Complication], lupus erythematosus nephritis/dt [Drug Therapy], Review

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/28344Test
LibKey Link

مستخلص: MHC II and CD4+ T cells are required for anti-glomerular basement membrane (GBM) globulininitiated crescentic glomerulonephritis (GN) in mice, but the role of MHC I and CD8+ T cells is unclear. The cytolytic function of CD8+ T cells requires recognition of peptide antigens presented on MHC I. CD8+ T cells can also perform helper functions via cytokine production. The contribution of MHC I to crescentic GN was investigated using TAP-1 gene knock out (TAP-1-/-) mice, which have deficient MHC I antigen presentation. Heterozygous TAP-1 mice have normal MHC I expression and developed GN with crescents in 42 +/- 4% of glomeruli (normal 0%), proteinuria (9.1 +/- 1.6 mg/20 h, normal 1.5 +/- 0.3 mg/20 h) and impaired renal function (creatinine clearance 110 +/- 8 mul/min, normal 193 +/- 10 mul/min) following administration of sheep anti-mouse GBM globulin. TAP-1-/- mice, which have extremely low MHC I expression and reduced CD8+ T cells, developed similar GN with 39 +/- 3% crescents, proteinuria (12.7 +/- 4.3 mg/20 h) and impaired renal function (creatinine clearance 123 +/- 20 mul/min). In vivo antibody-induced CD8 depletion did not attenuate crescent formation or protect renal function in C57B1/6 mice developing GN, although significant reduction in proteinuria (5.3 +/- 1.2 mg/20 h, P = 0.012) and glomerular recruitment of CD4+ T cells and macrophages were observed compared with control treated mice with GN. These data demonstrate that MHC I is not required for development of crescentic GN in mice. The MHC I-independent contribution of CD8+ T cells to proteinuria and inflammatory cell recruitment suggests that they may serve a 'helper' rather than cytolytic role in this disease.

مصطلحات الفهرس: article, controlled study, creatinine clearance, cytokine production, glomerulonephritis/di [Diagnosis], major histocompatibility complex, major histocompatibility complex restriction, mouse, nonhuman, priority journal, CD4 antigen/ec [Endogenous Compound], CD8 antigen/ec [Endogenous Compound], creatinine/ec [Endogenous Compound], major histocompatibility antigen class 1/ec [Endogenous Compound], proteinuria/di [Diagnosis], animal cell, animal tissue, antigen presenting cell, Article

URL: https://repository.monashhealth.org/monashhealthjspui/handle/1/33365Test
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