Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Roberto Baccala, Rosana Gonzalez-Quintial, Amanda L. Blasius, Ivo Rimann, Keiko Ozato, Dwight H. Kono, Bruce Beutler, Argyrios N. Theofilopoulos

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effectswere observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and-independent antigens. Moreover, Slc15a4 mutant C57BL/6-Faslpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.

Original languageEnglish (US)
Pages (from-to)2940-2945
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
StatePublished - Feb 19 2013

Fingerprint

Dendritic Cells
Autoantibodies
Toll-Like Receptor 7
Inbred NZB Mouse
T Independent Antigens
Toll-Like Receptors
Splenomegaly
Kidney Diseases
Autoimmunity
Histidine
Chromatin
B-Lymphocytes
Erythrocytes
Ligands
Mutation
Survival
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. / Baccala, Roberto; Gonzalez-Quintial, Rosana; Blasius, Amanda L.; Rimann, Ivo; Ozato, Keiko; Kono, Dwight H.; Beutler, Bruce; Theofilopoulos, Argyrios N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 8, 19.02.2013, p. 2940-2945.

Research output: Contribution to journalArticle

Baccala, Roberto ; Gonzalez-Quintial, Rosana ; Blasius, Amanda L. ; Rimann, Ivo ; Ozato, Keiko ; Kono, Dwight H. ; Beutler, Bruce ; Theofilopoulos, Argyrios N. / Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 8. pp. 2940-2945.
@article{c95c2b671d604d2184e859b09f15e07f,
title = "Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus",
abstract = "In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effectswere observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and-independent antigens. Moreover, Slc15a4 mutant C57BL/6-Faslpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.",
author = "Roberto Baccala and Rosana Gonzalez-Quintial and Blasius, {Amanda L.} and Ivo Rimann and Keiko Ozato and Kono, {Dwight H.} and Bruce Beutler and Theofilopoulos, {Argyrios N.}",
year = "2013",
month = "2",
day = "19",
doi = "10.1073/pnas.1222798110",
language = "English (US)",
volume = "110",
pages = "2940--2945",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "8",

}

TY - JOUR

T1 - Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

AU - Baccala, Roberto

AU - Gonzalez-Quintial, Rosana

AU - Blasius, Amanda L.

AU - Rimann, Ivo

AU - Ozato, Keiko

AU - Kono, Dwight H.

AU - Beutler, Bruce

AU - Theofilopoulos, Argyrios N.

PY - 2013/2/19

Y1 - 2013/2/19

N2 - In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effectswere observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and-independent antigens. Moreover, Slc15a4 mutant C57BL/6-Faslpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.

AB - In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effectswere observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and-independent antigens. Moreover, Slc15a4 mutant C57BL/6-Faslpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.

UR - http://www.scopus.com/inward/record.url?scp=84874229894&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874229894&partnerID=8YFLogxK

U2 - 10.1073/pnas.1222798110

DO - 10.1073/pnas.1222798110

M3 - Article

VL - 110

SP - 2940

EP - 2945

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 8

ER -