Increased serum levels of MCTS1 and C3 in ME/CFS patients and the relation to persistent antigen presentation

...continued from the previous blog post, where persistent antigen presentation in ME/CFS patients is described:

Hit, Stay and Sabotage: A failure to clear viral fragments in ME/CFS

I continued my AI analysis and gave AI these informations:

ME/CFS patients have increased serum levels of MCTS1 and C3. This is shown in the preprint of (1): 

Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights

The serum levels of MCTS1 and C3 in ME/CFS patients at D1POST were negatively associated to VO2max1 and VO2max2 in the preprint of (2): 

Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion, Molecular & Cellular Proteomics

(I used artificial intelligence (AI) via https://www.google.com/ to get some answers. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information.)

My question: Do increased serum levels of MCST1 in ME/CFS patients fit into your explanation?

AI answer: Increased levels of MCTS1 (Malignant T-cell-amplified sequence 1) following exertion fit into the ME/CFS pathomechanism by acting as a marker of cellular stress and a driver of T-cell dysfunction.

As of 2025 research, the elevation of MCTS1—especially when negatively correlated with aerobic capacity (VO2max)—strengthens the explanation of sustained antigen persistence in several ways:

1. Impaired IFN-γ Production (Antigen Clearance Failure) 

• Molecular Role: MCTS1 is a specialized translation factor required for the synthesis of JAK2, a kinase essential for signaling through the IL-12 and IL-23 receptors.
• The Paradox: While deficiency in MCTS1 is known to cause severe susceptibility to infections due to lack of IFN-γ (the "master signal" for killing viruses), abnormal increases in plasma MCTS1 following exercise may reflect a maladaptive compensatory response.
• Mechanism: If the body is struggling to clear a persistent antigen (the persistence hypothesis), it may "over-express" MCTS1 to force the production of JAK2 and IFN-γ, but this appears ineffective or "maladaptive" in ME/CFS patients.

2. T-Cell Exhaustion and Evasion

• Immune Evasion: MCTS1 can induce PD-L1 expression, a primary "off switch" for the immune system.
• Exhaustion Link: High levels of MCTS1 may contribute to the T-cell exhaustion identified in the NIH "Deep Phenotyping" study. By increasing PD-L1, it makes cells "invisible" to T cells, allowing antigens (viruses or bacteria) to persist longer while simultaneously draining the T cells of their energy.

3. ER Stress and Protein Misfolding

• Proteostasis: Like PDIA3, MCTS1 is involved in regulating protein synthesis and folding under stress.
• Post-Exertional Crisis: In ME/CFS, exertion acts as a severe stressor. Increased MCTS1 following exercise (D1POST) suggests that the cell's "protein-making machinery" is under duress. This links back to the ER stress pathomechanism, where the system is overwhelmed by the need to handle both physical stress and potential persistent antigens.

4. Integration with Genetic Risks

MCTS1 was originally identified as a gene amplified in malignant T-cells, highlighting its powerful role in controlling T-cell life cycles. In the context of the DecodeME genetic findings (like MICB and LAIR1): 

• MICB/TAP1/2 = Failure to find the pathogen.
• MCTS1/PDIA3 = Failure to react correctly to the stress of the pathogen.

Result: A system that is genetically primed to fail at clearance, leading to the sustained antigen persistence and subsequent "crash" after exertion (PEM).

My question: How does this affect the compromised LC and hypothalmus in ME/CFS?

AI answer:The compromised state of the Locus Coeruleus (LC) and hypothalamus in ME/CFS acts as a "second hit" that locks the body into a state of chronic illness.

The genetic and protein dysfunctions (TAP1/2, PDIA3, C3, MCTS1) create a feedback loop that directly targets these two critical brain regions:

1. The Locus Coeruleus (LC) "Burnout"

The LC is the brain's main source of norepinephrine (NE), which controls arousal, focus, and the sympathetic nervous system.

• Persistent Stimulation: Ongoing systemic inflammation (from sustained antigens and C3/complement activation) acts as a constant stressor to the LC.
• Excitatory Stress: Dense noradrenergic fibers from the LC reach directly into the hypothalamus's Paraventricular Nucleus (PVN). 2025 research suggests that in severe patients, hyperactive NE neurons may over-stimulate the hypothalamus until they eventually "burn out" or reach a state of functional exhaustion.

Result: This leads to the profound cognitive "brain fog," lack of arousal, and poor blood pressure regulation (orthostatic intolerance) seen in ME/CFS.

2. The Hypothalamic "Kindling" and Connectivity Shifts

The hypothalamus is the body's master homeostatic regulator (sleep, temperature, and hormones).

• Kindling Effect: Repeated, low-intensity stimulation from persistent antigens can cause "kindling" of the limbic-hypothalamic axis. This charges the system until it sustains high arousal even without external stimuli, eventually crashing into hypocortisolism (low cortisol).
• Connectivity Changes: Recent 2024–2025 MRI studies show shifted connectivity in the hypothalamus: increased connections in the anterior hypothalamus but decreased connectivity in the posterior regions as the illness progresses.
• Homeostatic Collapse: Because the hypothalamus is compromised by neuroinflammation, its "stress threshold" drops. Even minor exertion (physical or mental) triggers a relapse (PEM) because the hypothalamus can no longer coordinate a normal physiological response to stress.

3. Crossing the Blood-Brain Barrier (BBB)

• C3 and Complement: The C3 variants and complement activation you noted are linked to increased blood-brain barrier permeability.
• The Pathway: When systemic complement and cytokines (like IL-1β and IL-6) leak into the brain, they activate microglia and astrocytes specifically in the hypothalamus and brainstem (where the LC resides).
• Integrated Pathomechanism: This turns a peripheral problem (failed viral clearance due to TAP1/2) into a central one. The persistent antigens keep the peripheral inflammation high, which then constantly "leaks" into the brain to keep the LC and hypothalamus in a state of dysfunctional neuroinflammation.

In summary, the genetic vulnerabilities in antigen presentation ensure the immune system never "finishes" its job, which chronically overstimulates the LC and hypothalamus until they lose their ability to regulate the body, resulting in the permanent fatigue and dysautonomia of ME/CFS.

More information

Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response

DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4

Quote: "We discover here that translation factors DENR, MCTS1 and eIF2D are required to induce ATF4 translation upon stress..."






References

1) Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR, Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion, Molecular & Cellular Proteomics (2025), doi: https://doi.org/10.1016/j.mcpro.2025.101467.
https://www.sciencedirect.com/science/article/pii/S1535947625005663

2) Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights
August Hoel, Fredrik Hoel, Sissel Elisabeth Furesund Dyrstad, Henrique Chapola, Ingrid Gurvin Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Karl Albert Brokstad, Hans-Peter Marti, Olav Mella, Øystein Fluge, Karl Johan Tronstad
medRxiv 2025.05.28.25328245; doi: https://doi.org/10.1101/2025.05.28.25328245
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
https://www.medrxiv.org/content/10.1101/2025.05.28.25328245v1