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

http://www.ncbi.nlm.nih.gov/pubmed/18806225

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.

Pubmed ID: 18806225 RIS Download

Mesh terms: Alleles | Animals | Autoimmune Diseases | Autoimmunity | Ethylnitrosourea | Homozygote | Inflammation | Interleukin-1 | Interleukin-1 Receptor-Associated Kinases | Listeriosis | Mice | Mice, Mutant Strains | Mutagenesis | Mutation | Myeloid Differentiation Factor 88 | Protein Tyrosine Phosphatase, Non-Receptor Type 6 | Receptors, Interleukin-1 | Toll-Like Receptors

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Associated grants

  • Agency: NCI NIH HHS, Id: CA31496
  • Agency: NIGMS NIH HHS, Id: GM067759
  • Agency: PHS HHS, Id: HHSN272200700038C

Mouse Genome Informatics (Data, Gene Annotation)

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