Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity

William Stohl, Noam Jacob, William J. Quinn, Michael P. Cancro, Huaxin Gao, Chaim Putterman, Xiaoni Gao, Luminita Pricop, Michael N. Koss

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.

Original languageEnglish (US)
Pages (from-to)833-841
Number of pages9
JournalJournal of Immunology
Volume181
Issue number1
StatePublished - 2008

Fingerprint

Autoimmunity
Systemic Lupus Erythematosus
Immunoglobulin G
T-Lymphocytes
Autoantibodies
B-Cell Activating Factor
Hypergammaglobulinemia
Interstitial Nephritis
Transgenes
Kidney
Serum

ASJC Scopus subject areas

  • Immunology

Cite this

Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. / Stohl, William; Jacob, Noam; Quinn, William J.; Cancro, Michael P.; Gao, Huaxin; Putterman, Chaim; Gao, Xiaoni; Pricop, Luminita; Koss, Michael N.

In: Journal of Immunology, Vol. 181, No. 1, 2008, p. 833-841.

Research output: Contribution to journalArticle

Stohl, William ; Jacob, Noam ; Quinn, William J. ; Cancro, Michael P. ; Gao, Huaxin ; Putterman, Chaim ; Gao, Xiaoni ; Pricop, Luminita ; Koss, Michael N. / Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. In: Journal of Immunology. 2008 ; Vol. 181, No. 1. pp. 833-841.
@article{533777b9c026470ab68dace26cd7bcfe,
title = "Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity",
abstract = "In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.",
author = "William Stohl and Noam Jacob and Quinn, {William J.} and Cancro, {Michael P.} and Huaxin Gao and Chaim Putterman and Xiaoni Gao and Luminita Pricop and Koss, {Michael N.}",
year = "2008",
language = "English (US)",
volume = "181",
pages = "833--841",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

TY - JOUR

T1 - Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity

AU - Stohl, William

AU - Jacob, Noam

AU - Quinn, William J.

AU - Cancro, Michael P.

AU - Gao, Huaxin

AU - Putterman, Chaim

AU - Gao, Xiaoni

AU - Pricop, Luminita

AU - Koss, Michael N.

PY - 2008

Y1 - 2008

N2 - In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.

AB - In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.

UR - http://www.scopus.com/inward/record.url?scp=47949087445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=47949087445&partnerID=8YFLogxK

M3 - Article

C2 - 18566449

AN - SCOPUS:47949087445

VL - 181

SP - 833

EP - 841

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -