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Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1,MyD88, and a microbial trigger


Croker, BA; Lawson, BR; Rutschmann, S; Berger, M; Eidenschenk, C; Blasius, AL; Moresco, EMY; Sovath, S; Cengia, L; Shultz, LD; Theofilopoulos, AN; Pettersson, S; Beutler, BA
2008-09-30
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Journal Article
105
39
15028-15033
A recessive phenotype called spin ( spontaneous inflammation) was induced by N-ethyl-N-nitrosourea (ENU) mutagenesis in C57BL/6J mice. Homozygotes display chronic inflammatory lesions affecting the feet, salivary glands and lungs, and antichromatin antibodies. They are immunocompetent and show enhanced resistance to infection by Listeria monocytogenes. TLR-induced TNF and IL-1 production are normal in macrophages derived from spin mice. The autoinflammatory phenotype of spin mice is fully suppressed by compound homozygosity for Myd88(poc), Irak4(otiose), and Il1r1-null mutations, but not Ticam1(Lps2), Stat1(m1Btlr), or Tnf-null mutations. Both autoimmune and autoinflammatory phenotypes are suppressed when spin homozygotes are derived into a germ-free environment. The spin phenotype was ascribed to a viable hypomorphic allele of Ptpn6, which encodes the tyrosine phosphatase SHP1, mutated in mice with the classical motheaten alleles me and me-v. Inflammation and autoimmunity caused by SHP1 deficiency are thus conditional. The SHP1-deficient phenotype is driven by microbes, which activate TLR signaling pathways to elicit IL-1 production. IL-1 signaling via MyD88 elicits inflammatory disease.
NATL ACAD SCIENCES
MOTH-EATEN MICE; TYROSINE-PHOSPHATASE; SH2 DOMAIN; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; IMMUNODEFICIENT MUTANT; SYSTEMIC AUTOIMMUNITY; RHEUMATOID-ARTHRITIS; MOTHEATEN LOCUS; I INTERFERON; T-CELLS
10.1073/pnas.0806619105
Refer to copyright notice on published article.

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Creation Date 2008-09-30 12:00:00