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Eric Meffre, PhD

Associate Professor of Immunobiology and of Medicine

Yale School of Medicine

Immunology

https://medicine.yale.edu/immuno/people/eric_meffre.profile

PTPN22 function in human B cells and inhibition to reset tolerance in SLE

We are investigating why patients with lupus fail to remove destructive B cells, called autoreactive B cells, that naturally form in the body. Some evidence suggests that a protein called PTPN22 may be responsible for this failure. Our preliminary studies of mice “humanized” with human lupus cells suggest that inhibiting PTPN22 could restore the ability to destroy B cells that attack patients’ own healthy cells. One goal of the proposed research is to find out more about PTPN22’s function in B cells, such as how it interacts with other molecules in the cells and how these interactions are affected by a specific mutation in PTPN22’s gene that increases patients’ risk of developing lupus. Those results might point to new ways to block PTPN22. We also intend to determine whether inhibiting PTPN22 stimulates the “humanized” mice to eliminate autoreactive B cells. Targeting PTPN22 to restore patients’ ability to remove autoreactive B cells may represent a unique approach to prevent lupus development and reduce autoimmunity.

What this study means for people with lupus

“We are testing whether a protein called PTPN22 prevents patients with lupus from destroying harmful B cells that can attack a person’s own healthy cells. Our findings could help researchers develop new lupus treatments that block PTPN22 and eliminate self-destructive B cells.”

Genetic studies have identified the 1858T polymorphism in the PTPN22 gene (PTPN22 T) to be associated with the development of many autoimmune diseases including systemic lupus erythematosus (SLE) patients. This polymorphism encodes PTPN22 phosphatases with a tryptophan at position 620 (620W PTPN22) instead of an arginine in the common 620R PTPN22 variant and was shown to interfere with the removal of developing human autoreactive B cells in a B-cell intrinsic manner. In addition, the substitution of the conserved arginine by a tryptophan at the similar position 619 in murine Ptpn22 called PEP also promotes autoimmunity in knockin mice and even the restricted expression of 619W PEP to only B cells was sufficient to impair immune tolerance and to produce anti-dsDNA autoantibodies. All these observations demonstrate an essential role for PTPN22 and its 620W variant in the development of autoimmunity by regulating autoreactive B cell selection, differentiation and activation. However, while some reports have studied the molecular involvement of PTPN22 in T cells and monocytes, nothing is known about PTN22 function in B cells, which pathways and molecules its phosphatase activity may regulate, and how the R620W amino acid replacement alters B cell responses. Our initial findings show that LYN, PKCΔ, SYK and BTK, which are well known to control BCR signaling, B cell development and activation, bind PTPN22 in human B cells, thereby suggesting that PTPN22 is an important regulator of B cell responses. In addition, our preliminary data suggest that inhibiting PTPN22 enhances BCR signaling and appears to result in the elimination of developing autoreactive B cells in humanized mice engrafted with hematopoietic stem cells (HSCs) isolated from the bone marrow of an SLE patient, whereas humanized mice transplanted with HSCs from the same SLE patients and which were not injected with the PTPN22 inhibitor displayed elevated frequencies of autoreactive B cells that were similar to counterparts isolated from the blood of the same SLE patient. Targeting PTPN22 may therefore represent a novel therapeutic strategy that would specifically prevent the production of autoreactive B cells in SLE. The goals of the proposed research are to characterize the dynamic interactions between PTPN22 and other signaling molecules in B cells and how they are affected by the R620W amino acid replacement. We also intend to assess the efficacy of PTPN22 inhibition in resetting the B cell tolerance checkpoints defective in SLE. Indeed, since a second PTPN22 allele, R263Q, which encodes loss-of-function enzymes was reported to protect against RA and SLE, our working hypothesis is that PTPN22 blockade could represent a novel approach to thwart autoimmunity.

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