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SCIENTIFIC PUBLICATIONS BY ALR FUNDED RESEARCHERS

Defining Functional Implications of a Human SLE Risk Allele in Mice

Siminovitch, Kathernine, MD

University Health Network (Canada)

Among the many genes now shown to contribute to the development of lupus is PTPN22, a gene that codes for a tyrosine phosphatase called Lyp. Lyp is found only in blood cells and is important for suppressing T lymphocyte activity. Many people with lupus express a variant form of Lyp called Lyp620W. However, we don’t know how this variant contributes to the disease process. 

With this grant, Dr. Siminovitch and her team hope to identify the pathways that link the Lyp620W variant to risk for lupus. To do so, they will study mice that express this variant. Initial work with these animals found numerous immune cell defects, particularly, “hyper” activation of T and B lymphocytes. Analysis of these mice also revealed that the variant protein is unstable and is broken down too quickly ,resulting in very low levels in the mouse lymphocytes. The team then showed that these abnormalities also occur in cells from humans expressing the Lyp620 variant. These findings suggest that the PTPN22gene variant causes reduction in Lyp levels and in the ability of Lyp to suppress immune cell activation. The result is immune cell hyperactivity.

Dr. Siminovitch and her team will now further define the Lyp variant’s effects on T and B cell functions, particularly activation, movement, and development. For instance, they will compare how cells from mutant and normal mice divide or migrate in response to select stimuli, and examine the cells’ secretion of inflammatory cytokines involved in autoimmune responses.

They will also study T and B lymphocyte development in the mouse model to assess whether the variant alters early elimination of autoreactive cells, which occurs in people with normal immune systems, but may be reduced in those with lupus.

Another set of studies will define the variant protein’s effects on autoimmunity and how this genetic variant interacts with other genetic variants to cause lupus. 

What this study means for people with lupus: Defining the pathways related to a specific genetic variant could identify new targets for treatment.


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