Recent research from the Medical University of South Carolina laboratory of Russell Norris, Ph.D. , challenges the notion that hypermobile Ehlers-Danlos Syndrome (hEDS) is an isolated connective tissue disorder, revealing that it also has an immune component that aligns much better with patient-reported symptoms.
Three recently published studies by the MUSC team take different approaches to understanding hEDS. In a Journal of Clinical Medicine article , the team explores patients' clinical experiences with the disease by analyzing the results of a survey of nearly 4,000 patients with hEDS or other disorders on the hypermobile spectrum. In an iScience article , the team identifies a genetic variant associated with the disease and links it not only to changes in connective tissue but also to disruption of the immune system. Most recently, in an ImmunoHorizons article , the team details the findings of a proteomics analysis of hEDS serum samples that suggest the involvement of the innate immune system, the body's first line of defense against invading pathogens, in hEDS.
"Although each of these three studies came at hEDS in a different way, they all point to a potential immune mechanism for the disease," said hEDS patient-scientist Cortney Gensemer, Ph.D., a postdoctoral fellow in Norris's laboratory and co-senior author of the ImmunoHorizons article.
"Our findings suggest that hypermobile Ehlers-Danlos syndrome may not originate as a primary connective tissue disorder but, instead, stem from underlying immune dysfunction, with connective tissue changes emerging as a downstream consequence," said Norris, a professor in the Department of Regenerative Medicine and Cell Biology at the Medical University of South Carolina and both senior author of the iScience article and co-senior author of the ImmunoHorizons article.
"There is a gap between what the patients report experiencing living with this disease and what the research and medical communities have historically understood it to be," said Norris Lab program coordinator Molly Griggs, who has hEDS herself and is first author of the ImmunoHorizons article. "For a long time, patients have been saying that this disease is not just stretchy skin and loose joints, which is how it is usually characterized by the health care system. Our research is a first step in bridging the gap between what the patients are experiencing and reporting and what the medical and research communities understand about the disease."
As many as 1 in 500 people have hEDS, and it can manifest as early as age 9, often as joint instability that can result in dislocations that sometimes require surgery to correct. Although this joint hypermobility gives the disease its name, its clinical presentation is usually far more complex, as the survey of 4,000 hEDS patients revealed.
"It was critical for us to incorporate patient voices from the very beginning of this research." said Victoria Daylor, a medical student at MUSC, member of the Norris Lab and first author of the Journal of Clinical Medicine article. "With the support of the patient community, this survey represents the largest dataset on this population to date, allowing us to capture a much broader and more clinically relevant picture of the reality patients live with every day."
Respondents had an average of 24 associated conditions, with 84% reporting gastrointestinal disorders, 71% dysautonomia – or disruptions to involuntary functions, such as heart rate, blood pressure, digestion and breathing – and 99% reporting chronic pain. Because these symptoms affect many different parts of the body, and often require visits to multiple specialists, the bigger picture of hEDS is easy to miss. As a result, patients wait an average of 22 years for a diagnosis.
Delayed diagnoses can leave patients in limbo, and, in worst-case scenarios, physicians can misdiagnose the disease or assume that some of the harder-to-classify symptoms exist only in the patients' imagination. A 2025 documentary, Complicated , explores the struggles of these patients as they try to navigate the health care system. Norris and Gensemer are featured in the film as evidence of a much-needed paradigm shift in the field – with a new emphasis on a patient-centered approach to research. Researchers in the Norris lab, many of whom have hEDS, root their research in the patient experience and seek to find diagnostics and therapeutics that will make a real difference in their lives.
Their findings, reported in iScience and ImmunoHorizons, begin to set the stage for an improved diagnostic tool for the disease and to paint a scientific portrait of the underlying biology of hEDS that more closely resembles patients' experiences with the disease.
The iScience article takes the first steps toward identifying the disease's genetic signature. Doing so will be important for a better assessment of a patient's risk and for an earlier and more accurate diagnosis.
The MUSC team identified a genetic change in a gene called kallikrein 15 (KLK15) in families affected by hEDS. This gene is involved in processes like inflammation, blood pressure and tissue repair. Only family members with hEDS had the variant, while unaffected relatives did not. When researchers introduced the same gene change into mice, the animals developed problems in their tendons, skin and heart valves, features similar to those seen in people with hEDS, along with signs of inflammation. These findings suggest that this genetic change may link immune system dysfunction to the connective tissue problems seen in the disease.
Although Gensemer was somewhat surprised to find a connection between KLK15 and disruptions to immune responses, she was not surprised to find an immune component to hEDS. Patients often report that the onset of disease is triggered by an infection, which suggests an immune response. Symptoms can also suddenly flare, again suggesting an immune component. Some symptoms of hEDS, like itching or gastrointestinal disorders, suggest allergic responses.
The identification of KLK15 is an important milestone in understanding the genetic signature of hEDS, particularly in the two families studied, but it alone cannot be used to diagnose hEDS. The absence of KLK15 alone does not rule out disease or disease risk. Other variants undoubtedly play a role in disease development, Norris said, and may have a greater effect in other families, underscoring the fact that a complete characterization of hEDS will take time.
Eager to explore alternative diagnostics as well as therapeutic options for patients, the MUSC team next used mass spectrometry to analyze proteins in the serum of 29 female hEDS patients and 29 age-matched women without the disease. Gensemer, who led the study published in ImmunoHorizons, thought that results of such an analysis would provide a better snapshot of the disease at a given moment and could be the first step toward identifying biomarkers that could one day be the basis for a blood test that diagnoses the disease.
Of the 35 proteins found to differ in abundance between the patients with hEDS and age-matched women without the disease, 80% were linked to causal chains of events or interactions important in immunity, clotting and inflammation. Notably, many of the protein changes seen in patients were linked to systems that control inflammation and blood clotting. About one-quarter were connected to the same family of proteins as the disease-associated gene identified earlier, while nearly half were tied to the body's complement system, a rapid, chain-reaction immune response that acts as one of the body's first lines of defense.
"Complement levels in hEDS patients are just a little bit lower than in age-matched women, but those changes are seen across two very key cascades – the clotting and complement cascades – that help with the initial innate immune response to attacks on the body," said Griggs.
Certain complement components are also important in the activation of mast cells, immune cells that act as first responders against invading pathogens, releasing chemicals such as histamines to neutralize them.
An estimated 70% of patients with hEDS have mast cell activation syndrome, in which the body's mast cells release too many inflammatory chemicals, triggering severe allergic symptoms in various body compartments, including the skin and gastrointestinal tract.
Mast cells differ from other immune cells that circulate in the blood, said Gensemer.
"Their primary residence is in connective tissues," she said, suggesting that they could play a role in hEDS.
It is too early for the proteins and pathways identified in the ImmunoHorizons article as relevant to hEDS to be used as clinical biomarkers. More mechanistic studies are needed to understand these changes and their role in the development and progression of disease.
"From these studies, we have all these snapshots of information, but we don't yet have a comprehensive picture of the progression and the onset of the disease," said Gensemer.
Once that progression is better understood, some of these proteins characteristic of hEDS could be targeted by novel drugs.
"These three recent articles suggest that it's the neuroimmune-gastrointestinal axis that is so debilitating for these patients," said Norris. "If we can use our genetic and proteomic discoveries to develop therapies that blunt pain, improve the function of the autonomic nervous system or enhance gut motility, we have the opportunity to make a significant impact on patients' lives."
