Immune system changes linked to hypermobile EDS in new study

Differences in complement proteins found in blood from women

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Hypermobile Ehlers-Danlos syndrome (EDS) is not just a problem of the connective tissue that provides structure to the body, but also involves changes in the immune response, which could provide opportunities to improve diagnosis and treatment, a study finds.

“Our study provides strong evidence that immune dysregulation plays a role in [hypermobile EDS],” researchers at the Medical University of South Carolina wrote. The study, “Proteomic discoveries in hypermobile Ehlers-Danlos syndrome reveal insights into disease pathophysiology,” appeared in ImmunoHorizons.

“These findings underscore the need for continued investigation into immune dysregulation in [hypermobile EDS], which may yield important insights into its underlying [disease mechanisms] and guide the development of targeted clinical interventions,” the researchers wrote.

Hypermobile EDS weakens the connective tissue that provides a framework for the body and holds different types of tissue together. This can make the joints overly flexible and unstable, and more likely to dislocate or cause pain. These symptoms mimic those of other diseases, often delaying a diagnosis.

Unlike other types of EDS, hypermobile EDS has no clear genetic cause. Because the condition’s molecular basis is still unclear, the researchers set out to identify biological changes that may explain it and help with its diagnosis.

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Analyzing patient and control proteins

Researchers analyzed blood proteins from 29 women with a diagnosis of hypermobile EDS and compared them with 29 age-matched control women. For the analysis, the researchers used mass spectrometry, which can detect and measure thousands of proteins at once.

Of 478 proteins, 35 were present at different levels in patients compared with controls. Fifteen were part of the complement system, a group of proteins that work in a cascade where one protein activates the next, to help in the immune response. Nine proteins were involved in blood clotting, and others played a role in inflammation and stress.

To confirm these findings, the researchers used ELISA, a standard laboratory method that measures specific proteins, in samples from 41 patients (35 women, six men) and 38 control individuals matched for age and sex. In both groups, the mean age was 37.

Five complement proteins — C1QA, C3, C8A, C8B, and C9 — were present at significantly lower levels in blood from patients compared with controls. For C1QA, C3, C8A, and C8B, the differences remained significant even after excluding women with previous diagnoses of autoimmune diseases and all the men.

The researchers also measured the levels of 105 cytokines, which are proteins that signal between immune cells and help control inflammation. Seven cytokines were present at significantly lower levels in blood from patients, supporting the idea that changes in the immune response may play a role in this disease.

“The observed complement and cytokine patterns, combined with emerging genetic insights, point to a complex interplay between genetic predisposition, immune system activation, and connective tissue dysfunction,” the researchers wrote.

By identifying specific immune changes, this study challenges the older view of hypermobile EDS as a purely structural problem. It opens new directions for developing diagnostic tests based on blood biomarkers, as well as treatments that target the immune response.

“These immune findings broaden the perspective on [hypermobile EDS],” the researchers wrote. “It is important to consider if they may be due to inherent disease processes, secondary inflammation, or associated or contributing [coexisting diseases].”