Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Ritu Bohat; Xiaofang Liang; Yanping Chen; Chunyu Xu; Ningbo Zheng; Ashley Guerrero; Jiakai Hou; Roshni Jaffery; Nicholas A. Egan; Yaxi Li; Yitao Tang; Esra Unsal; Adolfo Robles; Si Chen; Angela M. Major; Hadil Elldakli; Sang Hyuk Chung; Han Liang; M. John Hicks; Yong Du; Jamie S. Lin; Xiqun Chen; Chandra Mohan; Weiyi Peng

doi:10.1016/j.clim.2023.109874

Fas^lpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Ritu Bohat, Xiaofang Liang, Yanping Chen, Chunyu Xu, Ningbo Zheng, Ashley Guerrero, Jiakai Hou, Roshni Jaffery, Nicholas A. Egan, Yaxi Li, Yitao Tang, Esra Unsal, Adolfo Robles, Si Chen, Angela M. Major, Hadil Elldakli, Sang Hyuk Chung, Han Liang, M. John Hicks, Yong DuJamie S. Lin, Xiqun Chen, Chandra Mohan, Weiyi Peng

Research output: Contribution to journal › Article › peer-review

Abstract

Sle1 and Fas^lpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Fas^lpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Fas^lpr/+ (Sle1^homo.lpr^het) and compared it with B6.Fas^lpr/lpr (lpr^homo), B6.Sle1/Sle1 (Sle1^homo), and B6.Sle1/Sle1.Fas^lpr/lpr (Sle1^homo.lpr^homo) strains. Whereas Sle1^homo.lpr^homo mice exhibited profound lymphoproliferation and early mortality, Sle1^homo.lpr^het mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1^homo.lpr^het mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1^homo.lpr^het T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Fas^lpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1^homo.lpr^het strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

Original language	English (US)
Article number	109874
Journal	Clinical Immunology
Volume	258
DOIs	https://doi.org/10.1016/j.clim.2023.109874
State	Published - Jan 2024

Keywords

Autoimmune disease
FAS
Genetics
Lupus

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/j.clim.2023.109874

Cite this

Bohat, R., Liang, X., Chen, Y., Xu, C., Zheng, N., Guerrero, A., Hou, J., Jaffery, R., Egan, N. A., Li, Y., Tang, Y., Unsal, E., Robles, A., Chen, S., Major, A. M., Elldakli, H., Chung, S. H., Liang, H., Hicks, M. J., ... Peng, W. (2024). Fas^lpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus. Clinical Immunology, 258, Article 109874. https://doi.org/10.1016/j.clim.2023.109874

Bohat, R, Liang, X, Chen, Y, Xu, C, Zheng, N, Guerrero, A, Hou, J, Jaffery, R, Egan, NA, Li, Y, Tang, Y, Unsal, E, Robles, A, Chen, S, Major, AM, Elldakli, H, Chung, SH, Liang, H, Hicks, MJ, Du, Y, Lin, JS, Chen, X, Mohan, C & Peng, W 2024, 'Fas^lpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus', Clinical Immunology, vol. 258, 109874. https://doi.org/10.1016/j.clim.2023.109874

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title = "Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus",

abstract = "Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.",

keywords = "Autoimmune disease, FAS, Genetics, Lupus",

author = "Ritu Bohat and Xiaofang Liang and Yanping Chen and Chunyu Xu and Ningbo Zheng and Ashley Guerrero and Jiakai Hou and Roshni Jaffery and Egan, {Nicholas A.} and Yaxi Li and Yitao Tang and Esra Unsal and Adolfo Robles and Si Chen and Major, {Angela M.} and Hadil Elldakli and Chung, {Sang Hyuk} and Han Liang and Hicks, {M. John} and Yong Du and Lin, {Jamie S.} and Xiqun Chen and Chandra Mohan and Weiyi Peng",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = jan,

doi = "10.1016/j.clim.2023.109874",

language = "English (US)",

volume = "258",

journal = "Clinical Immunology",

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T1 - Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

AU - Bohat, Ritu

AU - Liang, Xiaofang

AU - Chen, Yanping

AU - Xu, Chunyu

AU - Zheng, Ningbo

AU - Guerrero, Ashley

AU - Hou, Jiakai

AU - Jaffery, Roshni

AU - Egan, Nicholas A.

AU - Li, Yaxi

AU - Tang, Yitao

AU - Unsal, Esra

AU - Robles, Adolfo

AU - Chen, Si

AU - Major, Angela M.

AU - Elldakli, Hadil

AU - Chung, Sang Hyuk

AU - Liang, Han

AU - Hicks, M. John

AU - Du, Yong

AU - Lin, Jamie S.

AU - Chen, Xiqun

AU - Mohan, Chandra

AU - Peng, Weiyi

PY - 2024/1

Y1 - 2024/1

N2 - Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

AB - Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

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KW - Genetics

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