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18-08-2011 | Internal medicine | Article

Researchers discover genetic clue in rheumatoid arthritis

Abstract

Free abstract

MedWire News: Canadian researchers have identified the mechanism by which a mutation in the gene encoding Lyp phosphatase (PTPN22) increases the risk for rheumatoid arthritis (RA) and other autoimmune disorders.

Katherine Siminovitch (University of Toronto, Ontario) and colleagues explain that Lyp has been shown to negatively regulate T-cell antigen receptor (TCR) signaling, and a variant in PTPN22 (Lyp620W) confers risk for autoimmune disease.

"Although a regulatory role for Lyp in T-cell activation has been established, the effect of the autoimmune disease-associated Lyp620W variant on T-cell responses remains unclear," they add.

To better understand the impact of the Lyp variant on T cells, Siminovitch and team generated mice harboring a PTPN22 allele encoding Pep619W (the mouse equivalent of Lyp620W).

Initially, the Pep619W mutant mice appeared healthy but progressive enlargement of the thymus and spleen appeared at 2 months of age, accompanied by increases in T-cell number, activation, and positive selection, and in dendritic- and B-cell activation, report the researchers.

In addition, Pep protein levels were dramatically reduced in the mutant mice, despite similar levels of PTPN22 expression between Pep619W and wild-type Pep619R mice.

This was because the Pep619W protein degraded more rapidly, and showed greater association with, and in vitro cleavage by, calpain 1, than Pep619R, say Siminovitch et al.

Next, the researchers investigated whether similar processes occur in humans. They found that, like Pep, the Lyp variant Lyp620W degraded at a faster rate than wild-type Lyp (Lyp620R) in peripheral blood mononuclear cells from healthy or RA-affected individuals.

Furthermore, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type Lyp620R.

"Collectively, our results show a loss-of-function effect of the Lyp620W and Pep619W variants… rendering Lyp/Pep more susceptible to calpain- and proteosome-mediated cleavage and degradation, thus lowering Lyp/Pep levels and diminishing its inhibitory effects on T- and to a lesser extent B-cell activation," write Siminovitch and co-authors in the journal Nature Genetics.

"Our findings also identify a role for Lyp/Pep in dendritic cell activation and function and suggest that the Lyp620W/Pep619W variant's influence on immune responses relevant to autoimmune disease susceptibility may be mediated in part through effects on dendritic cell function," they add.

Taken together these findings suggests that the Lyp/Pep variant induces a lymphocyte and dendritic cell hyper-responsive phenotype that may not induce autoimmune disease per se, but may instead create an immunologic environment that favors the emergence of such disease.

"This is one of the first studies in which we have traced the steps that connect a specific genetic lesion to the development of a common, complex autoimmune condition," said Siminovitch.

Study co-author Edward Keystone, also from the University of Toronto added: "Measuring levels of [Lyp] will help us monitor disease severity in patients with autoimmune disorders, test the effects of various therapies including new drugs, and determine which treatments work best in specific patients."

By Laura Dean

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