Part II: Complex Chronic Illness-The New Roadmap

Another Tunnel, Another Light

From the patients point of view, symptoms often define a disease. “I have pain, I am exhausted, I am dizzy, I can’t find words.” Diving deep into these symptoms, interrogating them thoughtfully and sensitively, is critically important in the management of complex illness. Our patients are often miserable, their lives circumscribed by these disabling symptoms. As clinicians, it is our responsibility to consider all treatment options that may mitigate symptoms without delay. We should not and cannot postpone treatment while we search for the underlying causes. That is the very nature of medicine: we manage, we maintain, we control, but we frequently don’t understand the underlying causes and only rarely can we actually cure. Think about hypertension. We still do not fully understand what causes it but we know if we don’t treat it, patients will have strokes, heart attacks, kidney failure and other end organ damage. So we treat while we search.

This concept—treating without knowledge of cause (etiology)—is enormously frustrating for both clinicians and patients. And nowhere is it more true than in the management of patients with complex chronic illnesses like Long Covid and ME/CFS. When I prescribe a beta blocker for POTS, I may not know the underlying causes driving the pathology that results in the symptoms of dizziness, brain fog, shortness of breath, etc. But that cannot stop me from treating.

In Part I of this series on Roadmaps, Tunnels, and Light, I tried to dive into some new discoveries and new paradigms that may help us understand the underlying causes of complex illness. I sometimes refer to this dive as “The Big Picture” or “Root Causes”, the point being that we are searching for the etiology of symptoms and not focusing on the symptoms themselves.

Today we’ll take a look at another recent discovery that casts light on a possible cause of fatigue and PEM. There is a theme here in these recent discoveries.

The Big Picture in complex illness lies at the cellular, molecular and genetic level of our bodies where pathologic or maladaptive changes drive disease at the next level. From the ‘outside’, when we look at patients, we know there are metabolic, immunologic, neurologic, and bioenergetic (mitochondrial) pathologies leading to the presenting symptoms of multi system illness. But on the ‘inside’, it is molecular, cellular, and likely genetic pathologies that are foundational.

The Membrane Lockdown (The SMPDL3B Pathway)

While Paul Hwang was discovering the WASF3 mitochondrial brake, Dr. Alain Moreau’s group in Montreal (via funding from the Open Medicine Foundation) discovered a critical lipid-regulating enzyme called SMPDL3B.

Get ready for some more complicated biochemistry.

To quote from Dr. Moreau’s paper: “Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is a key immune-regulatory protein involved in sphingolipid metabolism, a signaling network that governs essential cellular processes such as growth, differentiation, apoptosis, and inflammation.”

SMPDL3B normally ‘lives’ on the cell membrane where it plays a key role in maintaining homeostasis and cellular health. Working within the innate immune system (our immunologic first responders), the molecule inhibits or antagonizes TLR4 activation. (Big Picture Hint: A go to drug in ME/CFS and Long Covid is Low Dose Naltrexone. LDN also inhibits TLR4.) At the same time, and so typical of the yin and yang of our immune system, SMPDL3B upregulates TLR3 signaling.

Ok, what does all this gibberish mean in “real life’’? The inhibition of TLR4 positively affects membrane and receptor “health” leading to a decreased inflammatory response which translates into a reduction in the release of TNF-alpha and IL-6, two major pro-inflammatory cytokines. At the same time, by activating TLR3, there is an increase in type I interferon, a key player in our antiviral immune arsenal. These are the normal actions of membrane bound SMPDL3B that promote immunologic health, decreasing inflammation and promoting antiviral activity.

Hang on now as we come to the grand finale. If the membrane bound SMPDL3B is disrupted and knocked off the membrane, then this may lead to loss of the benefits described above, that is the reduction of inflammation and the enhancing of antiviral immunity. Instead, we get the reverse, with increased inflammation via TNF alpha and IL-6, and impaired type I interferon production leading to immune dysregulation.

So what’s the big deal here? Why does this alphabet soup matter, how can it be translated into usable Big Picture information? For Dr. Moreau, a bell was ringing. He and his colleagues—and this again is where we see the elegance of science, the power of curiosity, and the importance of hypotheses—recognized that the immune dysregulation with increased inflammation and decreased antiviral activity were similar to what we find in ME/CFS and Long Covid patients. Could there be a link here? Could SMPDL3B be a potential biomarker for these complex illnesses? Could there be a quantifiable relationship between SMPDL3B levels and illness severity? And perhaps, most importantly, could this be an actionable discovery, could there be a treatment to restore the SMPDL3B to its membrane bound status?

Well, I’m asking the questions so you can guess the answers. Yes, yes, and yes. But just to add to the confusion and complexity, we need to ask the more obvious first question: what might cause the SMPDL3B disruption from cell membranes leading to the cascade of events described above. There is another enzyme called PI-PLC that, when present, can pull the SMPDL3B off the cell membranes. Under “normal” circumstances, SMPDL3B stays membrane bound and helps to moderate immune responses. The PI-PLC enzyme is encoded by a gene called PLCXD1. Ok so what do all these endless letters mean, what does it have to do with ME/CFS.

Here comes another “aha” moment: in ME patients the gene is upregulated and overactive leading to increased cleavage of SMPDL3B off the immune cell membranes. It is unclear why this gene is turned on in our patients but I suspect these groups will find the answer. I, of course, have to ask: could that upregulation be secondary to infection since that is the common denominator in the majority of ME/CFS and Long Covid patients. There is a growing body of literature to support this connection. And we are not talking about just one infection. Most often our patients have a history of an infectious onset but then also develop other reactivated infections which may be ongoing drivers of the above processes.

Another tantalizing discovery related to disrupted, circulating, soluble SMPDL3B is the impact of hormones. Estrogen up regulates the production of SMPDL3B. Read that again. See a pattern? Could this be a possible explanation for the epidemiology of ME/CFS/Long Covid where over 2/3 of the patients are female? It is hard to avoid considering this possibility.

Back to the earlier questions regarding whether SMPDL3B could be a biomarker, whether its plasma levels have any clear relation to ME/CFS patients, and whether it presents us with a druggable target. More great science here. Dr. Moreau, after working this out in his lab, teamed up with Drs. Fluge and Mella (of rituxamab fame). They looked at banked samples from 249 Canadian ME/CFS patients and 141 Norwegian patients. All patients had completed validated questionnaires assessing fatigue, PEM and other ME symptoms. They found a direct relationship between SMPDL3B plasma levels and severity of fatigue. I’ll say that again. The worse the fatigue the higher the SMPDL3B blood levels.

There is another very important fact about SMPDL3B. As a membrane associated protein it is heavily expressed in renal podocytes, cells that are intimately involved in glomerular/renal function and the handling of fluids and salts. Disruption of membrane bound SMPDL3B can lead to glomerular dysfunction and affect hydration status as the kidneys fail to adequately conserve fluid and salt. It is well known that the vast majority of ME/CFS patients struggle with hypovolemia which complicates the treatment of POTS and adds to the magnitude of hypoperfusion. Could this circulating SMPDL3B be the culprit?

So two questions possibly answered. Yes, SMPDL3B may be a diagnostic biomarker for ME/CFS and it may be an indicator of disease severity. Ok great, but can we do anything about this. Well, Dr. Moreau continued his research and discovered that an FDA approved drug that has been used for years in the treatment of diabetes could lower the circulating levels of SMPDL3B, stabilizing its membrane attachment. This work was done on cells from healthy controls and ME patients in the lab. There are no current trials in humans and given the current funding environment (thanks to you know who) I doubt we will see anything in the near future. But the drug is readily available, has a well known and relatively benign side effect profile, and could be considered for repurposing in the ME/CFS patient care world.

OK this got really complicated even as I tried to simplify it. The paper is linked below for those of you brave enough to dive in. SMPDL3B is another “Big Picture” discovery that lights up another tunnel. Focused research can translate to treatment. Science works.

https://link.springer.com/article/10.1186/s12967-025-06829-0

As always in complex illness, nothing is ever easy. There is much overlap among the pathologies, the mechanisms, and the adverse outcomes that combine to create the phenotype that is so common in ME/CFS and Long Covid. There will never be one drug, one key, one perfect intervention. That is precisely why the management of complex illness patients is driven by carefully informed trial and error supported by meticulous attention to risk and benefit while always searching for literature, experience, anecdotal reports, and consensus to guide the decisions.

The Clinical Shift: Precise De-escalation

The “Stuck Firewall” paradigm, Dr. Naviaux’s Cell Danger Response, completely rewrites the clinical playbook. If a patient’s computer network is locked down by its own security protocols, you don’t fix it by kicking the hardware, pushing through the crash, or applying broad, generic “fatigue protocols.” The collaboration between clinicians treating patients and basic scientists pursuing lab research has the power to identify the specific security protocols that are jammed and provide the system with the precise keys that may mitigate the firewall, lower the defenses, and allow the cells to successfully cycle through the cell danger response.

Full Disclosure: I used AI for some of the research while putting this together and leaned heavily on Dr. Moreau’s paper.

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Thank you.