Response: increased expression or activity of PTPN22 may compromise negative selection of autoreactive CLL cells

The finding of Hebbring et al that the PTPN22 R620W autoimmunity risk allele is present at a higher frequency in chronic lymphocytic leukemia (CLL) patients originating from northern/western Europe than in matched controls¹  is very interesting and provides further support to the recent findings of Negro et al suggesting an important role for PTPN22 in the pathogenesis of CLL.² 

The study by Negro et al investigated the expression of PTPN22 in a large series of CLL patients from Italy, where the PTPN22 R620W autoimmunity risk allele is relatively infrequent, and showed that PTPN22 is markedly overexpressed in the majority of investigated CLL samples.²  Additional experiments showed that overexpression of PTPN22 attenuates BCR signals that can potentially induce leukemic cell apoptosis while simultaneously increasing the activity of the AKT kinase, a key survival signaling molecule in CLL cells. This selective uncoupling of AKT from downstream proapoptotic BCR pathways was shown to protect CLL cells from activation-induced cell death. Overall, these data suggested that the purpose of PTPN22 overexpression in CLL could be to protect the malignant B cells, which frequently express autoreactive BCRs, from immunologic tolerance mechanisms that eliminate autoreactive lymphocytes.

A similar mechanism is believed to be responsible for the increased risk of autoimmune disease in subjects carrying the PTPN22 R620W allele.³  The risk allele has been shown to inhibit antigen-receptor signaling more strongly than the wild-type protein,⁴  suggesting that it could compromise autoantigen-induced negative selection of autoreactive lymphocytes. Therefore, the finding by Hebbring et al that the PTPN22 R620W autoimmunity risk allele is present at a higher frequency in northern/western European CLL patients than in matched controls suggests that both increased expression and increased activity of PTPN22 could play a role in the pathogenesis of CLL. It will be interesting to investigate in future studies whether these 2 mechanisms operate in the same or different patients. Given the possibility of targeting PTPN22 or PTPN22-regulated pathways, this issue could be of considerable importance.