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Article ; Online: Analysis of Regulatory B Cells in Experimental Autoimmune Uveitis.

Choi, Jin Kyeong / Egwuagu, Charles E

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2270, Page(s) 437–450

Abstract: Regulatory B cells (Bregs) that produce IL-35 and IL-10 (i35-Bregs) regulate central nervous system (CNS) autoimmune diseases including uveitis. In the mouse model of uveitis, i35-Breg cells suppress intraocular inflammation by inducing expansion of IL- ... ...

Abstract	Regulatory B cells (Bregs) that produce IL-35 and IL-10 (i35-Bregs) regulate central nervous system (CNS) autoimmune diseases including uveitis. In the mouse model of uveitis, i35-Breg cells suppress intraocular inflammation by inducing expansion of IL-10-producing B cells (B10), IL-10-producing T cells (Tregs), and IL-35-producing T cells (iT
MeSH term(s)	Adoptive Transfer ; Animals ; Autoimmune Diseases/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes, Regulatory/cytology ; B-Lymphocytes, Regulatory/immunology ; B-Lymphocytes, Regulatory/pathology ; Central Nervous System Diseases ; Disease Models, Animal ; Female ; Inflammation/pathology ; Interleukin-10/immunology ; Male ; Mice ; Mice, Inbred NOD ; T-Lymphocytes, Regulatory/immunology ; Uveitis/immunology ; Uveitis/metabolism ; Uveitis/therapy
Chemical Substances	Interleukin-10 (130068-27-8)
Language	English
Publishing date	2021-01-07
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1237-8_23
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Interleukin 35 Regulatory B Cells.

Choi, Jin Kyeong / Egwuagu, Charles E

Journal of molecular biology

2020 Volume 433, Issue 1, Page(s) 166607

Abstract: B lymphocytes play a central role in host immunity. They orchestrate humoral immune responses that modulate activities of other immune cells and produce neutralizing antibodies that confer lasting immunity to infectious diseases including smallpox, ... ...

Abstract	B lymphocytes play a central role in host immunity. They orchestrate humoral immune responses that modulate activities of other immune cells and produce neutralizing antibodies that confer lasting immunity to infectious diseases including smallpox, measles and poliomyelitis. In addition to these traditional functions is the recent recognition that B cells also play critical role in maintaining peripheral tolerance and suppressing the development or severity of autoimmune diseases. Their immune suppressive function is attributed to relatively rare populations of regulatory B cells (Bregs) that produce anti-inflammatory cytokines including interleukin 10 (IL-10), IL-35 and transforming growth factor-β. The IL-35-producing B cell (i35-Breg) is the newest Breg subset described. i35-Bregs suppress central nervous system autoimmune diseases by inducing infectious tolerance whereby conventional B cells acquire regulatory functions that suppress pathogenic Th17 responses. In this review, we discuss immunobiology of i35-Breg cell, i35-Breg therapies for autoimmune diseases and potential therapeutic strategies for depleting i35-Bregs that suppress immune responses against pathogens and tumor cells.
MeSH term(s)	Animals ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; B-Lymphocytes, Regulatory/immunology ; B-Lymphocytes, Regulatory/metabolism ; Cell Plasticity/immunology ; Cytokines/genetics ; Cytokines/metabolism ; Disease Management ; Disease Susceptibility ; Humans ; Immune System Diseases/diagnosis ; Immune System Diseases/etiology ; Immune System Diseases/metabolism ; Immune System Diseases/therapy ; Immunomodulation ; Immunotherapy ; Interleukins/metabolism ; Signal Transduction/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Cytokines ; Interleukins ; interleukin-35, human
Language	English
Publishing date	2020-08-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2020.07.019
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Article ; Online: IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis.

Kang, Minkyung / Yadav, Manoj Kumar / Mbanefo, Evaristus C / Yu, Cheng-Rong / Egwuagu, Charles E

Frontiers in immunology

2023 Volume 14, Page(s) 1071162

Abstract: Introduction: IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a ... ...

Abstract	Introduction: IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize Methods: To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy. Results: Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion. Discussion: Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.
MeSH term(s)	Mice ; Animals ; Interleukin-27 ; Exosomes/metabolism ; Autoimmune Diseases ; Th1 Cells ; Uveitis
Chemical Substances	Interleukin-27
Language	English
Publishing date	2023-06-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1071162
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Uveitis: Molecular Pathogenesis and Emerging Therapies.

Egwuagu, Charles E / Alhakeem, Sahar A / Mbanefo, Evaristus C

Frontiers in immunology

2021 Volume 12, Page(s) 623725

Abstract: The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from ... ...

Abstract	The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/therapeutic use ; Autoimmunity/drug effects ; Biological Products/therapeutic use ; Cytokines/antagonists & inhibitors ; Cytokines/metabolism ; Disease Models, Animal ; Humans ; Immune Tolerance/drug effects ; Immunotherapy ; Inflammation Mediators/antagonists & inhibitors ; Inflammation Mediators/metabolism ; Molecular Targeted Therapy ; Signal Transduction ; Uvea/drug effects ; Uvea/immunology ; Uvea/metabolism ; Uveitis/immunology ; Uveitis/metabolism ; Uveitis/therapy
Chemical Substances	Anti-Inflammatory Agents ; Biological Products ; Cytokines ; Inflammation Mediators
Language	English
Publishing date	2021-04-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.623725
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Article: Chronic intraocular inflammation and development of retinal degenerative disease.

Egwuagu, Charles E

Advances in experimental medicine and biology

2014 Volume 801, Page(s) 417–425

Abstract: Elevated levels of inflammatory cytokines in the vitreous of patients with chronic intraocular inflammatory (uveitis) have long been suspected to contribute to the pathogenesis of retinal degenerative diseases. However, direct connection between chronic ... ...

Abstract	Elevated levels of inflammatory cytokines in the vitreous of patients with chronic intraocular inflammatory (uveitis) have long been suspected to contribute to the pathogenesis of retinal degenerative diseases. However, direct connection between chronic inflammation and development of retinal degenerative diseases has been difficult to establish because we lack an appropriate animal model of co-existing chronic intraocular inflammation and neurodegeneration. This report discusses new developments in immunological and diabetic research that suggest that persistent secretion of pro-inflammatory cytokines during uveitis might induce insulin resistance and retinal degenerative changes that contribute to the pathogenesis of Diabetic Retinopathy (DR), a retinal dystrophy of significant public health importance.
MeSH term(s)	Animals ; Diabetic Retinopathy/immunology ; Diabetic Retinopathy/pathology ; Disease Models, Animal ; Humans ; Insulin Resistance/immunology ; Interferon-gamma/immunology ; Mice ; Rats ; Retinal Degeneration/immunology ; Retinal Degeneration/pathology ; Retinitis/immunology ; Retinitis/pathology ; Signal Transduction/immunology ; Suppressor of Cytokine Signaling Proteins/immunology ; Uveitis/immunology ; Uveitis/pathology
Chemical Substances	Suppressor of Cytokine Signaling Proteins ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-3209-8_53
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege.

Yu, Cheng-Rong / Yadav, Manoj Kumar / Kang, Minkyung / Jittayasothorn, Yingyos / Dong, Lijin / Egwuagu, Charles E

International journal of molecular sciences

2022 Volume 23, Issue 15

Abstract: Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, ...

Abstract	Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the
MeSH term(s)	Animals ; Autoimmune Diseases ; Disease Models, Animal ; Gene Expression Regulation ; Immune Privilege ; Inflammation/metabolism ; Interleukin-27/metabolism ; Interleukins/genetics ; Interleukins/metabolism ; Mice ; Mice, Inbred C57BL ; Photoreceptor Cells/metabolism ; Retina/metabolism ; Th17 Cells ; Uveitis/metabolism
Chemical Substances	Interleukin-27 ; Interleukins
Language	English
Publishing date	2022-07-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23158156
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Interleukin 35-Producing Exosomes Suppress Neuroinflammation and Autoimmune Uveitis.

Kang, Minkyung / Choi, Jin Kyeong / Jittayasothorn, Yingyos / Egwuagu, Charles E

Frontiers in immunology

2020 Volume 11, Page(s) 1051

Abstract: Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with ... ...

Abstract	Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; B-Lymphocytes, Regulatory/immunology ; B-Lymphocytes, Regulatory/transplantation ; Cells, Cultured ; Disease Models, Animal ; Exosomes/metabolism ; Humans ; Immune Tolerance ; Immunomodulation ; Immunotherapy, Adoptive/methods ; Interleukin-10/metabolism ; Interleukins/metabolism ; Mice ; Mice, Inbred C57BL ; Neurogenic Inflammation/immunology ; Neurogenic Inflammation/therapy ; T-Lymphocytes, Regulatory/immunology ; Uveitis/immunology
Chemical Substances	Interleukins ; interleukin-35, human ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2020-05-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01051
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Deletion of

Kang, Minkyung / Lee, Hyun-Su / Choi, Jin Kyeong / Yu, Cheng-Rong / Egwuagu, Charles E

International journal of molecular sciences

2021 Volume 22, Issue 5

Abstract: Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion ... ...

Abstract	Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of
MeSH term(s)	Animals ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Autoimmune Diseases/metabolism ; Autoimmune Diseases/pathology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/pathology ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Gene Deletion ; Interferon Regulatory Factors/deficiency ; Interferon Regulatory Factors/immunology ; Interferon Regulatory Factors/metabolism ; Mice ; Mice, Knockout ; Transcription, Genetic/immunology ; Uveitis/genetics ; Uveitis/immunology ; Uveitis/metabolism ; Uveitis/pathology
Chemical Substances	Interferon Regulatory Factors ; interferon regulatory factor-4
Language	English
Publishing date	2021-03-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22052775
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Interleukin 35 Regulatory B Cells

Choi, Jin Kyeong / Egwuagu, Charles E

Journal of molecular biology. 2021 Jan. 08, v. 433, no. 1

2021

Abstract	B lymphocytes play a central role in host immunity. They orchestrate humoral immune responses that modulate activities of other immune cells and produce neutralizing antibodies that confer lasting immunity to infectious diseases including smallpox, measles and poliomyelitis. In addition to these traditional functions is the recent recognition that B cells also play critical role in maintaining peripheral tolerance and suppressing the development or severity of autoimmune diseases. Their immune suppressive function is attributed to relatively rare populations of regulatory B cells (Bregs) that produce anti-inflammatory cytokines including interleukin 10 (IL-10), IL-35 and transforming growth factor-β. The IL-35-producing B cell (i35-Breg) is the newest Breg subset described. i35-Bregs suppress central nervous system autoimmune diseases by inducing infectious tolerance whereby conventional B cells acquire regulatory functions that suppress pathogenic Th17 responses. In this review, we discuss immunobiology of i35-Breg cell, i35-Breg therapies for autoimmune diseases and potential therapeutic strategies for depleting i35-Bregs that suppress immune responses against pathogens and tumor cells.
Keywords	B-lymphocytes ; autoimmune diseases ; central nervous system ; humoral immunity ; immune response ; interleukin-10 ; measles ; neoplasm cells ; neutralization ; neutralizing antibodies ; pathogens ; smallpox ; therapeutics ; transforming growth factor beta
Language	English
Dates of publication	2021-0108
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2020.07.019
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: STAT3 deficiency in B cells exacerbates uveitis by promoting expansion of pathogenic lymphocytes and suppressing regulatory B cells (Bregs) and Tregs.

Oladipupo, Favour O / Yu, Cheng-Rong / Olumuyide, Ezekiel / Jittaysothorn, Yingyos / Choi, Jin Kyeong / Egwuagu, Charles E

Scientific reports

2020 Volume 10, Issue 1, Page(s) 16188

Abstract: STAT3 transcription factor induces differentiation of naïve T cells into Th17 cells and loss of STAT3 in T cell prevents development of CNS autoimmune diseases. However, function of STAT3 in the B lymphocyte subset is not well understood. In this study, ... ...

Abstract	STAT3 transcription factor induces differentiation of naïve T cells into Th17 cells and loss of STAT3 in T cell prevents development of CNS autoimmune diseases. However, function of STAT3 in the B lymphocyte subset is not well understood. In this study, we have generated mice lacking STAT3 in CD19
MeSH term(s)	Animals ; Autoimmune Diseases/etiology ; Autoimmune Diseases/metabolism ; Autoimmune Diseases/pathology ; B-Lymphocytes, Regulatory/immunology ; Cell Differentiation ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Retina/immunology ; Retina/pathology ; STAT3 Transcription Factor/physiology ; T-Lymphocytes, Regulatory/immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Uveitis/etiology ; Uveitis/metabolism ; Uveitis/pathology
Chemical Substances	STAT3 Transcription Factor ; Stat3 protein, mouse
Language	English
Publishing date	2020-10-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-73093-1
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