The Norris Lab published yet another new research finding regarding hypermobile EDS: the involvement of the complement system. Chronic Pain Partners has recently reported about the Lab’s groundbreaking discovery of Kallikrein, a gene believed to cause hEDS. We shared the initial findings and a later updated version of it. 

Published in ImmunoHorizons, this additional research provides yet another fresh biological insight into hypermobile Ehlers–Danlos syndrome (hEDS), the most common but least understood form of EDS. HEDS is a multi-system condition leading to dozens of comorbid conditions. This study found clear markers for system immune dysregulation in patients with hEDS. 

Researchers at the Medical University of South Carolina analyzed blood samples from 29 female hEDS patients and matched controls using advanced proteomic techniques. They found 35 proteins with altered expression in hEDS, nearly half belonging to the complement system, a core part of the body’s immune defense. In total, 80% of the affected proteins were linked to immune function, inflammation, or blood clotting, rather than structural collagen defects traditionally associated with connective tissue disorders.

Follow-up testing confirmed that complement proteins C1QA, C3, C8A, C8B, and C9 were lower in hEDS patients. Cytokine profiling further revealed altered immune signaling. These findings challenge the traditional view of hEDS as solely a connective tissue disorder and instead point to innate immune dysfunction as a central factor.

The authors suggest that this immune involvement could explain many of the multi systemic issues experienced by hEDS patients, including chronic pain, vascular fragility, mast cell activation, and higher infection risk. The identification of measurable biological markers also opens the door to earlier diagnosis and future targeted therapies.

This research, funded by the NIH, the Fullerton Foundation, and the Maltz Foundation, marks an important step toward unraveling the biology of hEDS and offers hope for better diagnostic tools and treatments in the future.

What This Means for You

• hEDS is not “just” a connective tissue disorder. The immune system—especially the complement system—appears to play a big role.
• Objective tests may be developed based on these findings. Blood proteins like C1QA, C3, C8A, C8B, and C9 could one day serve as biomarkers to support faster, more accurate diagnoses.
• Widespread symptoms explained. Immune dysfunction may contribute to pain, inflammation, infections, mast cell activation, and vascular issues seen in many patients. This may validate the experience of so many EDSers out there. 
• Future treatments. Though not available yet, therapies targeting any of these pathways may become new treatment options.

The Norris Lab has once again laid crucial groundwork for advancing our understanding of EDS. With continued research, the hope is that these insights will translate into real diagnostic and therapeutic advances for patients worldwide. Thanks to the relentless work by researchers such as Dr. Cortney Gensemer, one day, we might actually get there. Chronic Pain Partners speaks for the whole community when we say, we are entirely grateful for the hard work. 

Read the full article here:

Griggs M, Daylor V, Petrucci T, Weintraub A, Huff M, Willey S, Byerly K, Loizzi B, Morningstar J, Ball LE, Bethard JR, Drake R, Sharma A, Eichinger JK, Nichols M, Kautz S, Shapiro S, Maitland A, Patel S, Norris RA, Gensemer C. Proteomic discoveries in hypermobile Ehlers-Danlos syndrome reveal insights into disease pathophysiology. Immunohorizons. 2025 Sep 17;9(10):vlaf044. doi: 10.1093/immhor/vlaf044. PMID: 40972649; PMCID: PMC12448790.

https://pubmed.ncbi.nlm.nih.gov/40972649/

Karina Sturm

September 2025