Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling.
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.
Arechiga
Adrian F
AF
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
Habib
Tania
T
He
Yantao
Y
Zhang
Xian
X
Zhang
Zhong-Yin
ZY
Funk
Andrew
A
Buckner
Jane H
JH
D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D011947:Receptors, Antigen, B-Cell; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22