What If Connective Tissue Isn't Where the Story Starts? Rethinking hEDS Pathophysiology

hEDS is a little wonky.

Okay. Maybe a lot wonky.

We recognize a clinical pattern. We have diagnostic criteria. We know that hypermobility and connective tissue manifestations are part of that pattern.

But when we ask the much harder question—why is this happening?—the answer gets considerably fuzzier.

Unlike several other types of Ehlers-Danlos syndrome, we have not identified one clear genetic or molecular pathway that explains hEDS. Increasingly, research is suggesting there may not be one.

hEDS may represent multiple biological pathways eventually arriving at a similar clinical presentation.

For a long time, we’ve approached that clinical presentation by looking primarily at the connective tissue. That makes sense. Hypermobility is visible. Joint instability is measurable. Connective tissue exists throughout the body, so differences in connective tissue could potentially help explain why symptoms aren’t limited to the joints.

For several connective tissue disorders, we can even trace the problem backward.

A genetic variant affects a particular protein. That changes the extracellular matrix. That changes the tissue. That creates the clinical presentation.

Nice, tidy biological pathway.

hEDS hasn’t given us that.

Despite years of research, we still don’t have one established molecular explanation that accounts for the hEDS population.

And that leaves open the possibility that the connective tissue we’re observing may not always be where the story begins.

This is where the work of allergist and immunologist Dr. Anne Maitland gets really interesting.

Before we go any further, though, this needs a giant flashing disclaimer:

What we’re about to discuss is an emerging hypothesis.

It has not been established as the mechanism of hEDS. It does not mean hEDS has been reclassified. It does not mean researchers have discovered that hEDS “isn’t actually a connective tissue disorder.”

And it absolutely does not mean we’ve solved hEDS.

What Maitland is proposing is a different framework through which researchers might investigate the biology.

Instead of assuming that abnormal connective tissue must sit at the beginning of the pathway, she has proposed investigating whether, in at least some people, the tissue changes we observe could develop within a much larger problem involving the epithelial, immune, and nervous systems.

In other words, maybe we need to stop staring only at the lumber and start paying attention to the environment the lumber lives in.

Back to our Hypermobile House.

We usually think about walls as passive structures. They separate the inside from the outside.

But your epithelial barriers are much more sophisticated than drywall.

Epithelium covers the surfaces of the body and lines many of the places where your internal environment interacts with the outside world: your skin, gastrointestinal tract, respiratory tract, and other mucosal surfaces.

These barriers have a surprisingly complicated job.

They have to determine what gets through, what stays out, and what deserves an alarm.

Think about the gastrointestinal tract. Your intestinal barrier needs to allow nutrients to cross while simultaneously interacting with food proteins, bacteria, microbial products, chemicals, medications, and everything else moving through your gut.

So the epithelial barrier isn’t simply a physical wall.

It’s an active surveillance system.

And there is a LOT happening at that wall.

Epithelial cells communicate with each other. Sensory nerves detect changes in the environment. Immune cells survey for potential threats. Mast cells can release powerful signaling molecules. Blood vessels respond to inflammatory and neurological signals.

And underneath all of this is extracellular matrix and connective tissue providing structural support.

These systems aren’t living in separate rooms.

They’re communicating constantly.

The epithelial system can signal the immune system. The immune system can influence nerves. Nerves can influence immune cells. Immune mediators can influence blood vessels. Inflammatory signaling can influence how extracellular matrix is produced, broken down, and remodeled.

The wall, alarm system, electrical system, plumbing, and framing are all interacting.

That interaction is sometimes described as an epithelial-neuroimmune axis.

Normally, that communication is a good thing.

When an epithelial barrier is damaged or encounters something potentially threatening, epithelial cells can release signals that recruit and activate immune responses. Immune cells release their own chemical messengers. Sensory nerves can detect inflammatory signals and communicate back with immune cells. Blood flow and vascular permeability can change. Cells within the surrounding tissue respond to this changing chemical environment.

The goal is to identify a problem, respond to it, repair the barrier, and eventually settle everything back down.

But Maitland’s proposed framework asks us to consider what could happen if that system doesn’t completely settle.

If epithelial barrier disruption persists, the underlying immune and nervous systems may continue receiving signals that something is wrong. Persistent immune activation can change the inflammatory environment. Neuroimmune signaling can amplify or modify those responses. Cells responsible for maintaining the extracellular matrix are sitting right in the middle of that environment.

And connective tissue isn’t static.

We sometimes talk about it like the lumber used to build a house: you build the house, and that’s the lumber you’ve got.

Biology doesn’t work quite like that.

The extracellular matrix is constantly being maintained and remodeled. Proteins are produced. Proteins are degraded. Collagen is reorganized. Cells respond to mechanical load, hormones, inflammatory mediators, neurological signals, and their surrounding environment.

Maitland has proposed investigating whether chronic epithelial barrier disruption and abnormal neuroimmune signaling could create an environment that changes how that extracellular matrix is maintained and remodeled.

That distinction matters.

She is not saying that epithelial dysfunction has been proven to cause hEDS.

She is proposing that researchers investigate a pathway that could look something like:

epithelial barrier disruption → persistent immune activation → altered neuroimmune signaling → changes in the local inflammatory environment → altered extracellular matrix remodeling → changes in tissue behavior

And those arrows need a giant asterisk.

Many of them have not been established in hEDS.

This is a proposed biological pathway that researchers still need to test. We don’t know whether epithelial changes would be a cause, a consequence, an amplifier, or simply something present in a subset of patients.

But the framework changes the perspective.

Instead of only studying what is different about the connective tissue, we can also study the biological environment responsible for maintaining that tissue.

And suddenly the Hypermobile House becomes much more complicated.

Maybe some houses were built with different lumber.

Maybe something in the environment is changing how the lumber is maintained.

Maybe both are happening.

And maybe different houses that look remarkably similar from the street have entirely different things happening behind their walls.

That possibility becomes particularly interesting when we look at the clinical complexity of hEDS.

People with hEDS frequently don’t present with an isolated musculoskeletal problem. Gastrointestinal dysfunction, autonomic dysfunction, pain, migraine, fatigue, and allergic or immune symptoms are commonly reported alongside the connective tissue manifestations.

Historically, it has been tempting to draw a bunch of lines between those diagnoses and create one giant explanation.

We need to be careful there.

Association does not establish a shared mechanism. Having hEDS and POTS does not prove one caused the other. Having hEDS and mast-cell-related symptoms does not prove mast cells caused the connective tissue changes. And the frequent overlap of these conditions does not establish the social-media version of a universal “hEDS-POTS-MCAS trifecta.”

But the overlap gives researchers something worth studying.

Why do these systems keep appearing in the same patient populations?

Some may be consequences. Some may be comorbidities. Some may eventually turn out to share underlying biology. And different patients may arrive at a similar clinical phenotype through completely different pathways.

We don’t know yet.

That’s important.

Maitland’s hypothesis also isn’t occurring in a vacuum. Recent hEDS research has started identifying biological signals that don’t fit neatly inside a simple “defective connective tissue” model.

Proteomic research has identified differences involving complement, coagulation, inflammatory, and immune pathways in people with hEDS.

A recent genetic preprint has suggested a much more complex architecture than a single-gene disorder, with signals involving connective tissue, neurological, pain, and neuroimmune pathways. The researchers proposed the phrase neuroimmune-stromal dysregulation as one way of conceptualizing some of these findings.

None of this proves Maitland’s epithelial-neuroimmune hypothesis.

That’s worth saying again: none of this proves Maitland’s hypothesis.

These are separate lines of research asking related questions.

But together, they make it increasingly reasonable to investigate hEDS beyond a straightforward structural model of connective tissue.

And maybe that’s ultimately where hEDS is headed.

We’ve spent years searching for the cause.

There may not be one.

One person’s biology might begin primarily within extracellular matrix regulation.

Another may eventually be found to have neuroimmune signaling playing a larger role. Another may have a mechanism we haven’t identified yet.

Several biological roads could potentially lead to patients who look remarkably similar in the clinic.

From the sidewalk, the houses might look almost identical.

But when science finally gets far enough to open the walls, we may discover that they were never the same house at all.

For now, Dr. Maitland’s epithelial-neuroimmune model remains exactly what it should be called:

an emerging hypothesis.

It needs to be tested.

Researchers still need to determine whether epithelial barrier abnormalities are consistently present in hEDS, whether they precede or follow other manifestations, which signaling pathways might be involved, and whether those pathways actually alter extracellular matrix biology in ways capable of contributing to the hEDS phenotype.

The evidence may ultimately support parts of this theory.

It may reject parts of it.

Or hEDS may eventually be divided into biological subgroups that require completely different explanations.

But Maitland’s theory gives researchers something incredibly valuable:

a different framework to investigate.

We’ve spent a long time examining the framing because that’s where we can see the movement.

Now we’re beginning to look more closely at the walls, the wiring, the security system, and the biological environment surrounding that framing.

Because hypermobility tells us what a joint does.

It still doesn’t tell us why.

And with hEDS, the why remains very much an open question.

Want to go down the rabbit hole?

1. Maitland, A. (2026). The Epithelial-Neuroimmune Axis in Ehlers-Danlos Syndromes: Bridging Barrier Dysfunction and Systemic Inflammation to Structural Spinal Pathology. Presented at the American Syringomyelia & Chiari Alliance Project 2026 Conference.ASAP 2026 presentation information

2. Griggs, M., Daylor, V., Petrucci, T., et al. (2025). Proteomic discoveries in hypermobile Ehlers-Danlos syndrome reveal insights into disease pathophysiology. ImmunoHorizons, 9(10), vlaf044.DOI: 10.1093/immhor/vlaf044 PubMed

3. Petrucci-Nelson, T., Guilhaumou, S., Berrandou, T. E., et al. (2025). Complex genetics and regulatory drivers of hypermobile Ehlers-Danlos syndrome: Insights from genome-wide association study meta-analysis. medRxiv [Preprint].DOI: 10.1101/2025.09.19.25336146

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About the Author

Allyson Barnes, PT, DPT is the founder of BAR Therapies and BAR Institute. She is a physical therapist specializing in the evaluation and treatment of symptomatic hypermobility and related connective tissue disorders. Through The Floppy Files, Allyson translates complex research into practical, evidence-informed education that helps patients, families, and healthcare professionals better understand hypermobility and participate more fully in everyday life.

Learn more about Allyson, explore more articles in The Floppy Files, or browse continuing education courses through BAR Institute.

Disclaimer

This content is intended for educational purposes only and is not medical advice. It is not a substitute for individualized evaluation, diagnosis, or treatment. Always consult your qualified healthcare provider regarding your specific health concerns.