Combined Deficiency of Proapoptotic Regulators Bim and Fas Results in the Early Onset of Systemic Autoimmunity

Jack Hutcheson; John C. Scatizzi; Akbar M. Siddiqui; G. Kenneth Haines; Tianfu Wu; Quan Zhen Li; Laurie S. Davis; Chandra Mohan; Harris Perlman

doi:10.1016/j.immuni.2007.12.015

Combined Deficiency of Proapoptotic Regulators Bim and Fas Results in the Early Onset of Systemic Autoimmunity

Jack Hutcheson, John C. Scatizzi, Akbar M. Siddiqui, G. Kenneth Haines, Tianfu Wu, Quan Zhen Li, Laurie S. Davis, Chandra Mohan, Harris Perlman

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

196 Scopus citations

Abstract

Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11^-/-Fas^lpr/lpr) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11^-/-) and and with an lpr mutation in the gene encoding Fas (Fas^lpr/lpr) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11^-/- or Fas^lpr/lpr mice. Bcl2l11^-/-Fas^lpr/lpr antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11^-/-Fas^lpr/lpr mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.

Original language	English (US)
Pages (from-to)	206-217
Number of pages	12
Journal	Immunity
Volume	28
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2007.12.015
State	Published - Feb 15 2008

Keywords

MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Infectious Diseases
Immunology

Access to Document

10.1016/j.immuni.2007.12.015

Cite this

@article{02a7fbf317864379aab77fb46d5afc6f,

title = "Combined Deficiency of Proapoptotic Regulators Bim and Fas Results in the Early Onset of Systemic Autoimmunity",

abstract = "Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11-/-Faslpr/lpr) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11-/-) and and with an lpr mutation in the gene encoding Fas (Faslpr/lpr) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11-/- or Faslpr/lpr mice. Bcl2l11-/-Faslpr/lpr antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11-/-Faslpr/lpr mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.",

keywords = "MOLIMMUNO",

author = "Jack Hutcheson and Scatizzi, \{John C.\} and Siddiqui, \{Akbar M.\} and Haines, \{G. Kenneth\} and Tianfu Wu and Li, \{Quan Zhen\} and Davis, \{Laurie S.\} and Chandra Mohan and Harris Perlman",

note = "Funding Information: We would like to thank J. Eslick and S. Koehm for technical assistance in preparing and collecting flow-cytometry data for this project, as well as I. Rifkin and M. Rauchman for their help in interpreting our preliminary data. Our thanks also go to M. Green, L. Morrison, G. Chinnadurai, and T. Ferguson for providing advice in the preparation of this work. The authors thank A.W. Becker for assistance with patient sample collection and A. Mobley of the UTSW flow-cytometry core for cell sorting. We thank K.H. Dao and B.K. Han for patients' clinical evaluations. We thank D.R. Karp and E.K. Wakeland and the members of the Simmons Arthritis Research Center for their support. This project is supported from a predoctoral American Heart Association grant to J.H. (0710060Z), from a predoctoral American Heart Association grant to J.C.S. (0515499Z), and from National Institutes of Health (NIH) (AR050250, AI067590) and the Saint Louis University Autoimmune Disease fund to H.P. L.D. was supported in part by AR45293 and the Simmons Arthritis Research Center. This work was also supported by NIH grant U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research. ",

year = "2008",

month = feb,

day = "15",

doi = "10.1016/j.immuni.2007.12.015",

language = "English (US)",

volume = "28",

pages = "206--217",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Combined Deficiency of Proapoptotic Regulators Bim and Fas Results in the Early Onset of Systemic Autoimmunity

AU - Hutcheson, Jack

AU - Scatizzi, John C.

AU - Siddiqui, Akbar M.

AU - Haines, G. Kenneth

AU - Wu, Tianfu

AU - Li, Quan Zhen

AU - Davis, Laurie S.

AU - Mohan, Chandra

AU - Perlman, Harris

N1 - Funding Information: We would like to thank J. Eslick and S. Koehm for technical assistance in preparing and collecting flow-cytometry data for this project, as well as I. Rifkin and M. Rauchman for their help in interpreting our preliminary data. Our thanks also go to M. Green, L. Morrison, G. Chinnadurai, and T. Ferguson for providing advice in the preparation of this work. The authors thank A.W. Becker for assistance with patient sample collection and A. Mobley of the UTSW flow-cytometry core for cell sorting. We thank K.H. Dao and B.K. Han for patients' clinical evaluations. We thank D.R. Karp and E.K. Wakeland and the members of the Simmons Arthritis Research Center for their support. This project is supported from a predoctoral American Heart Association grant to J.H. (0710060Z), from a predoctoral American Heart Association grant to J.C.S. (0515499Z), and from National Institutes of Health (NIH) (AR050250, AI067590) and the Saint Louis University Autoimmune Disease fund to H.P. L.D. was supported in part by AR45293 and the Simmons Arthritis Research Center. This work was also supported by NIH grant U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research.

PY - 2008/2/15

Y1 - 2008/2/15

N2 - Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11-/-Faslpr/lpr) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11-/-) and and with an lpr mutation in the gene encoding Fas (Faslpr/lpr) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11-/- or Faslpr/lpr mice. Bcl2l11-/-Faslpr/lpr antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11-/-Faslpr/lpr mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.

AB - Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11-/-Faslpr/lpr) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11-/-) and and with an lpr mutation in the gene encoding Fas (Faslpr/lpr) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11-/- or Faslpr/lpr mice. Bcl2l11-/-Faslpr/lpr antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11-/-Faslpr/lpr mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.

KW - MOLIMMUNO

UR - https://www.scopus.com/pages/publications/38949209522

UR - https://www.scopus.com/inward/citedby.url?scp=38949209522&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2007.12.015

DO - 10.1016/j.immuni.2007.12.015

M3 - Article

C2 - 18275831

AN - SCOPUS:38949209522

SN - 1074-7613

VL - 28

SP - 206

EP - 217

JO - Immunity

JF - Immunity

IS - 2

ER -

Combined Deficiency of Proapoptotic Regulators Bim and Fas Results in the Early Onset of Systemic Autoimmunity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this