Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling

J Immunol. 2009 Mar 15;182(6):3343-7. doi: 10.4049/jimmunol.0713370.


PTPN22 is a gene encoding the protein tyrosine phosphatase Lyp. A missense mutation changing residue 1858 from cytosine to thymidine (1858C/T) is associated with multiple autoimmune disorders. Studies have demonstrated that Lyp has an inhibitory effect on TCR signaling; however, the presence of autoantibodies in all of the diseases associated with the 1858T variant and recent evidence that Ca(2+) flux is altered in B cells of 1858T carriers indicate a role for Lyp in B cell signaling. In this study we show that B cell signal transduction is impaired in individuals who express the variant. This defect in signaling is characterized by a deficit in proliferation, a decrease in phosphorylation of key signaling proteins, and is reversed by inhibition of Lyp. These findings suggest that the PTPN22 1858T variant alters BCR signaling and implicate B cells in the mechanism by which the PTPN22 1858T variant contributes to autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocyte Subsets / pathology
  • Genetic Variation / immunology*
  • Humans
  • Immunologic Memory / genetics
  • Lymphocyte Activation / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / biosynthesis
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / physiology
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / physiology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*


  • Receptors, Antigen, B-Cell
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22