DUSP22 protein may help assess disease severity in AS: Study

Low protein levels tied to worse disease in ankylosing spondylitis

Marisa Wexler MS avatar

by Marisa Wexler MS |

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Low levels of the protein DUSP22 in certain immune cells may contribute to more severe ankylosing spondylitis (AS), according to a new study.

The findings suggest that measuring DUSP22 levels could be useful as a way to assess disease activity and responses to treatments, the researchers said, noting that “early diagnostic biomarkers … of AS are lacking.”

DUSP22 “levels were significantly lower in [the] AS group than healthy controls,” the team wrote, adding “Several DUSPs (particularly DUSP22) were identified to be potential biomarkers of disease activity for AS.”

The study, “Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis,” was published in the journal BMC Medicine.

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New Inflammation Biomarker May Be Useful in AS, Study Suggests

DUSP22 shows promise as biomarker

Dual-specificity phosphatases, known as DUSPs, are a group of 25 proteins that help to regulate biochemical signaling inside cells. They work by applying a type of modification called dephosphorylation to other molecules.

This class of proteins are known to help regulate the activity of T cells, a type of immune cell, and the production of proinflammatory signaling molecules, which play central roles in the development of ankylosing spondylitis and other forms of inflammatory arthritis.

Now, a team of scientists in Taiwan conducted a series of experiments aiming to better understand how DUSPs may be involved in AS. The study included samples from 60 people with AS and 45 healthy individuals, who served as controls. In both groups, the average age was in the late 30s, and about three-quarters of participants were men.

The scientists analyzed levels of messenger RNA (mRNA) for 23 DUSP genes. mRNA is an intermediary molecule made when genes are read to make protein.

Results showed that levels of mRNA for several DUSPs — namely DUSP 4, DUSP5, DUSP6, DUSP7, and DUSP14 — were significantly higher in T cells from AS patients compared with controls. Meanwhile, mRNA for another protein, DUSP22, was significantly lower in T cells from AS patients. Cell-by-cell analyses showed that AS patients had fewer T cells expressing the DUSP22 protein.

Statistical tests indicated that levels of DUSP22 showed the greatest distinction between AS patients and controls among all the tested mRNAs.

“These findings provide strong evidence for the notable role of DUSPs, particularly DUSP22, in the pathogenesis [development] of AS,” the researchers wrote.

According to the team, these findings suggest that measuring DUSP levels in T cells could be helpful in diagnosing AS, though they stressed a need for further studies to test this idea.

Taken together, the reduction of DUSP22 levels may reflect the inflammatory status and disease activity of AS and could be used as a biomarker for disease activity and treatment response.

Cellular analyses showed that lower levels of DUSP22 mRNA was significantly correlated with higher expression of a pro-inflammatory signaling molecule called TNF-alpha. Higher levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 were likewise associated with higher TNF-alpha expression.

“These data imply that several DUSP-family phosphatases are associated with proinflammatory cytokine expression and are involved in pathogenesis of AS through regulation of T cell-mediated inflammation,” the researchers wrote.

Additional statistical assessments showed that lower DUSP22 expression was significantly associated with higher levels of other inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), as well as worse scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a measure of disease severity. Levels of the other DUSPs did not significantly correlate with disease severity measures.

In four of the AS patients, samples were available from both before and after starting anti-inflammatory biologic therapy. Analyses of these samples indicated that mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 decreased in T-cells following treatment, while levels of DUSP22 increased after treatment.

“These results suggest that expression of the DUSP4, DUSP5, DUSP6, DUSP7, DUSP14, and DUSP22 genes is correlated with the disease activity of AS patients,” the researchers wrote.

“Taken together, the reduction of DUSP22 levels may reflect the inflammatory status and disease activity of AS and could be used as a biomarker for disease activity and treatment response,” they added.

Given the findings that suggested a connection between low DUSP22 and AS, the researchers used mice engineered to lack that protein in T cells to investigate further. As they got older, these mice showed signs of damage and bone overgrowth on their spines, as well as higher levels of T cells producing pro-inflammatory signaling molecules in their vertebrae.

“These results suggest that aged (1-year-old) DUSP22 [laboratory] mice spontaneously develop AS-like bone disease,” the scientists concluded.

The researchers noted that this study is limited by its small size, highlighting a need for additional studies to explore the biological and clinical ramifications of DUSPs in AS.