TY - JOUR
T1 - Cross-regulation of TNF and IFN-α in autoimmune diseases
AU - Palucka, A. Karolina
AU - Blanck, Jean Philippe
AU - Bennett, Lynda
AU - Pascual, Virginia
AU - Banchereau, Jacques
PY - 2005/3/1
Y1 - 2005/3/1
N2 - Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-α production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-α release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-α secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-α-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.
AB - Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-α production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-α release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-α secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-α-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.
KW - Autoimmunity
KW - Cytokines
KW - Dendritic cells
UR - http://www.scopus.com/inward/record.url?scp=14744276518&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=14744276518&partnerID=8YFLogxK
U2 - 10.1073/pnas.0408506102
DO - 10.1073/pnas.0408506102
M3 - Article
C2 - 15728381
AN - SCOPUS:14744276518
SN - 0027-8424
VL - 102
SP - 3372
EP - 3377
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
IS - 9
ER -