Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance

IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain...
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Autor*in:	Abhimanyu Amarnani [verfasserIn] Maria Lopez-Ocasio [verfasserIn] Ramile Dilshat [verfasserIn] Kamala Anumukonda [verfasserIn] Jonathan Davila [verfasserIn] Nikita Malakhov [verfasserIn] Chongmin Huan [verfasserIn] Erna Magnusdottir [verfasserIn] Eirikur Steingrimsson [verfasserIn] Christopher A. Roman [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon

Übergeordnetes Werk:	In: Frontiers in Immunology - Frontiers Media S.A., 2011, 15(2024)
Übergeordnetes Werk:	volume:15 ; year:2024

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fimmu.2024.1339325

Katalog-ID:	DOAJ100810268

Internformat


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520			\|a IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.
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653		0	\|a Immunologic diseases. Allergy
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700	0		\|a Eirikur Steingrimsson \|e verfasserin \|4 aut
700	0		\|a Christopher A. Roman \|e verfasserin \|4 aut
700	0		\|a Christopher A. Roman \|e verfasserin \|4 aut
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allfields	10.3389/fimmu.2024.1339325 doi (DE-627)DOAJ100810268 (DE-599)DOAJ83bee28e926c4e8daccfe4b66b70ad74 DE-627 ger DE-627 rakwb eng RC581-607 Abhimanyu Amarnani verfasserin aut Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity. B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon Immunologic diseases. Allergy Abhimanyu Amarnani verfasserin aut Abhimanyu Amarnani verfasserin aut Maria Lopez-Ocasio verfasserin aut Maria Lopez-Ocasio verfasserin aut Ramile Dilshat verfasserin aut Kamala Anumukonda verfasserin aut Kamala Anumukonda verfasserin aut Jonathan Davila verfasserin aut Jonathan Davila verfasserin aut Nikita Malakhov verfasserin aut Nikita Malakhov verfasserin aut Chongmin Huan verfasserin aut Erna Magnusdottir verfasserin aut Eirikur Steingrimsson verfasserin aut Christopher A. Roman verfasserin aut Christopher A. Roman verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 15(2024) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:15 year:2024 https://doi.org/10.3389/fimmu.2024.1339325 kostenfrei https://doaj.org/article/83bee28e926c4e8daccfe4b66b70ad74 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2024.1339325/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024
spelling	10.3389/fimmu.2024.1339325 doi (DE-627)DOAJ100810268 (DE-599)DOAJ83bee28e926c4e8daccfe4b66b70ad74 DE-627 ger DE-627 rakwb eng RC581-607 Abhimanyu Amarnani verfasserin aut Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity. B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon Immunologic diseases. Allergy Abhimanyu Amarnani verfasserin aut Abhimanyu Amarnani verfasserin aut Maria Lopez-Ocasio verfasserin aut Maria Lopez-Ocasio verfasserin aut Ramile Dilshat verfasserin aut Kamala Anumukonda verfasserin aut Kamala Anumukonda verfasserin aut Jonathan Davila verfasserin aut Jonathan Davila verfasserin aut Nikita Malakhov verfasserin aut Nikita Malakhov verfasserin aut Chongmin Huan verfasserin aut Erna Magnusdottir verfasserin aut Eirikur Steingrimsson verfasserin aut Christopher A. Roman verfasserin aut Christopher A. Roman verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 15(2024) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:15 year:2024 https://doi.org/10.3389/fimmu.2024.1339325 kostenfrei https://doaj.org/article/83bee28e926c4e8daccfe4b66b70ad74 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2024.1339325/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024
allfields_unstemmed	10.3389/fimmu.2024.1339325 doi (DE-627)DOAJ100810268 (DE-599)DOAJ83bee28e926c4e8daccfe4b66b70ad74 DE-627 ger DE-627 rakwb eng RC581-607 Abhimanyu Amarnani verfasserin aut Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity. B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon Immunologic diseases. Allergy Abhimanyu Amarnani verfasserin aut Abhimanyu Amarnani verfasserin aut Maria Lopez-Ocasio verfasserin aut Maria Lopez-Ocasio verfasserin aut Ramile Dilshat verfasserin aut Kamala Anumukonda verfasserin aut Kamala Anumukonda verfasserin aut Jonathan Davila verfasserin aut Jonathan Davila verfasserin aut Nikita Malakhov verfasserin aut Nikita Malakhov verfasserin aut Chongmin Huan verfasserin aut Erna Magnusdottir verfasserin aut Eirikur Steingrimsson verfasserin aut Christopher A. Roman verfasserin aut Christopher A. Roman verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 15(2024) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:15 year:2024 https://doi.org/10.3389/fimmu.2024.1339325 kostenfrei https://doaj.org/article/83bee28e926c4e8daccfe4b66b70ad74 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2024.1339325/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024
allfieldsGer	10.3389/fimmu.2024.1339325 doi (DE-627)DOAJ100810268 (DE-599)DOAJ83bee28e926c4e8daccfe4b66b70ad74 DE-627 ger DE-627 rakwb eng RC581-607 Abhimanyu Amarnani verfasserin aut Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity. B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon Immunologic diseases. Allergy Abhimanyu Amarnani verfasserin aut Abhimanyu Amarnani verfasserin aut Maria Lopez-Ocasio verfasserin aut Maria Lopez-Ocasio verfasserin aut Ramile Dilshat verfasserin aut Kamala Anumukonda verfasserin aut Kamala Anumukonda verfasserin aut Jonathan Davila verfasserin aut Jonathan Davila verfasserin aut Nikita Malakhov verfasserin aut Nikita Malakhov verfasserin aut Chongmin Huan verfasserin aut Erna Magnusdottir verfasserin aut Eirikur Steingrimsson verfasserin aut Christopher A. Roman verfasserin aut Christopher A. Roman verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 15(2024) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:15 year:2024 https://doi.org/10.3389/fimmu.2024.1339325 kostenfrei https://doaj.org/article/83bee28e926c4e8daccfe4b66b70ad74 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2024.1339325/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024
allfieldsSound	10.3389/fimmu.2024.1339325 doi (DE-627)DOAJ100810268 (DE-599)DOAJ83bee28e926c4e8daccfe4b66b70ad74 DE-627 ger DE-627 rakwb eng RC581-607 Abhimanyu Amarnani verfasserin aut Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity. B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon Immunologic diseases. Allergy Abhimanyu Amarnani verfasserin aut Abhimanyu Amarnani verfasserin aut Maria Lopez-Ocasio verfasserin aut Maria Lopez-Ocasio verfasserin aut Ramile Dilshat verfasserin aut Kamala Anumukonda verfasserin aut Kamala Anumukonda verfasserin aut Jonathan Davila verfasserin aut Jonathan Davila verfasserin aut Nikita Malakhov verfasserin aut Nikita Malakhov verfasserin aut Chongmin Huan verfasserin aut Erna Magnusdottir verfasserin aut Eirikur Steingrimsson verfasserin aut Christopher A. Roman verfasserin aut Christopher A. Roman verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 15(2024) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:15 year:2024 https://doi.org/10.3389/fimmu.2024.1339325 kostenfrei https://doaj.org/article/83bee28e926c4e8daccfe4b66b70ad74 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2024.1339325/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024
language	English
source	In Frontiers in Immunology 15(2024) volume:15 year:2024
sourceStr	In Frontiers in Immunology 15(2024) volume:15 year:2024
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon Immunologic diseases. Allergy
isfreeaccess_bool	true
container_title	Frontiers in Immunology
authorswithroles_txt_mv	Abhimanyu Amarnani @@aut@@ Maria Lopez-Ocasio @@aut@@ Ramile Dilshat @@aut@@ Kamala Anumukonda @@aut@@ Jonathan Davila @@aut@@ Nikita Malakhov @@aut@@ Chongmin Huan @@aut@@ Erna Magnusdottir @@aut@@ Eirikur Steingrimsson @@aut@@ Christopher A. Roman @@aut@@
publishDateDaySort_date	2024-01-01T00:00:00Z
hierarchy_top_id	657998354
id	DOAJ100810268
language_de	englisch
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However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. 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callnumber-first	R - Medicine
author	Abhimanyu Amarnani
spellingShingle	Abhimanyu Amarnani misc RC581-607 misc B lymphocyte misc tolerance misc germinal center misc transcriptome misc microphthalmia transcription factor (Mitf) misc type-I-interferon misc Immunologic diseases. Allergy Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance
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topic_title	RC581-607 Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance B lymphocyte tolerance germinal center transcriptome microphthalmia transcription factor (Mitf) type-I-interferon
topic	misc RC581-607 misc B lymphocyte misc tolerance misc germinal center misc transcriptome misc microphthalmia transcription factor (Mitf) misc type-I-interferon misc Immunologic diseases. Allergy
topic_unstemmed	misc RC581-607 misc B lymphocyte misc tolerance misc germinal center misc transcriptome misc microphthalmia transcription factor (Mitf) misc type-I-interferon misc Immunologic diseases. Allergy
topic_browse	misc RC581-607 misc B lymphocyte misc tolerance misc germinal center misc transcriptome misc microphthalmia transcription factor (Mitf) misc type-I-interferon misc Immunologic diseases. Allergy
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title	Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance
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title_full	Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance
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author_browse	Abhimanyu Amarnani Maria Lopez-Ocasio Ramile Dilshat Kamala Anumukonda Jonathan Davila Nikita Malakhov Chongmin Huan Erna Magnusdottir Eirikur Steingrimsson Christopher A. Roman
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title_sort	mitf regulates gene expression networks implicated in b cell homeostasis, germinal center responses, and tolerance
callnumber	RC581-607
title_auth	Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance
abstract	IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.
abstractGer	IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.
abstract_unstemmed	IntroductionThe microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.MethodsTwo complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.ResultsBoth models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.DiscussionThese studies clarify Mitf’s role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.
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title_short	Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance
url	https://doi.org/10.3389/fimmu.2024.1339325 https://doaj.org/article/83bee28e926c4e8daccfe4b66b70ad74 https://www.frontiersin.org/articles/10.3389/fimmu.2024.1339325/full https://doaj.org/toc/1664-3224
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author2	Abhimanyu Amarnani Maria Lopez-Ocasio Ramile Dilshat Kamala Anumukonda Jonathan Davila Nikita Malakhov Chongmin Huan Erna Magnusdottir Eirikur Steingrimsson Christopher A. Roman
author2Str	Abhimanyu Amarnani Maria Lopez-Ocasio Ramile Dilshat Kamala Anumukonda Jonathan Davila Nikita Malakhov Chongmin Huan Erna Magnusdottir Eirikur Steingrimsson Christopher A. Roman
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up_date	2024-07-03T16:49:08.079Z
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Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance

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