In the preprint of (1): Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID
there is a list of "candidate core genes" which means that Single Nucleotide Polymorphisms (SNPs) within or near these genes were found to be associated with an increased risk of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). The study specifically identified over 22,000 "reproducible disease signatures," which are combinations of 1 to 4 SNPs that were more common in people with ME/CFS than in healthy individuals. The genes that these highly associated SNPs map to were identified as the "candidate core genes".
Here are the genes from the list "candidate core genes" most closely related to the failure of antigen processing and the resulting persistence of antigens:
- ABCA1: Essential for maintaining the "lipid rafts" on cell membranes where immune signaling occurs; its dysfunction prevents the proper organization and display of antigens to T-cells.
- BAG6: A critical "triage" chaperone; it captures defective proteins and ensures they are delivered for processing. A deficiency in BAG6 means viral or bacterial proteins are not "tagged" correctly, allowing them to linger in the cell.
- C3 (Complement Component 3): Involved in "opsonization" (coating pathogens to be recognized). Persistent antigens cause chronic C3 activation, leading to the "collateral damage" of healthy synapses in the brainstem.
- COLEC12: A scavenger receptor that helps clear cell debris and pathogens; its dysfunction allows "antigenic trash" to accumulate in the tissues, triggering constant immune responses.
- CSMD1: A master regulator that should dampen the response to antigens. Its loss allows the immune system to "over-respond" to persistent viral markers, driving runaway neuroinflammation.
- LAIR1: An inhibitory receptor that should signal the immune system to "stand down" once an antigen is presented; variants prevent this "off-switch," leading to chronic activation.
- MICB: An immune "stress signal"; if antigens persist, MICB remains on the cell surface, marking healthy regulatory neurons for destruction by the body's own killer cells.
- PDI3: It is an essential component of the MHC Class I peptide-loading complex (PLC). Peptide Editing: It forms a stable disulfide-linked complex with tapasin to stabilize the MHC class I molecule until it is loaded with a high-affinity antigenic peptide.
- PSMB9: The "shredder" that breaks down proteins into small fragments for the immune system to see. Variants in PSMB9 lead to incomplete shredding, meaning the immune system never gets the "clear signal" it needs to finish the job.
- TAP1 (Transporter associated with Antigen Processing 1): The "gatekeeper" that moves protein fragments into the compartment where they are loaded onto the cell surface. TAP1 SNPs are the most common cause of persistent antigen signaling, as the body cannot effectively "show" the infection to the immune system to get it cleared. (TAP2 is on the orignal "long list")
- TLR3: The primary sensor for viral signals; variants cause the system to stay "locked" in a hyper-responsive inflammatory state even when only tiny amounts of antigen remain.
- USP45 / USP47: Deubiquitinating enzymes that regulate protein stability; their disruption leads to the accumulation of misfolded proteins in the ER, directly feeding the WASF3-mediated ER stress cycle.
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.
This is the analysis from AI
1. BAG, PSMB9: The Processing Failure
Normal Function: When a virus enters a cell, proteins like BAG6 "capture" the viral pieces and feed them into the PSMB9 (immunoproteasome), which acts as a molecular shredder.
ME/CFS Context: In ME/CFS, SNPs in these genes mean the viral proteins aren't shredded or "tagged" correctly. Instead of being cleared, these viral fragments accumulate inside the cell like toxic waste, creating chronic proteostatic stress.
2. TAP1, TAP2, PDIA3: The "Gatekeeper" Failure
2. TAP1, TAP2, PDIA3: The "Gatekeeper" Failure
Normal Function: The TAP1 protein works as a subunit of the Transporter associated with Antigen Processing (TAP) complex:
- Peptide Translocation: It forms a heterodimer with the TAP2 protein to act as an ATP-dependent "pump". This pump moves degraded protein fragments (peptides) from the cell's cytosol into the endoplasmic reticulum (ER).
- MHC Class I Loading: Once inside the ER, these peptides are loaded onto MHC class I molecules. The TAP complex also acts as a molecular scaffold, stabilizing the MHC class I molecules until they successfully bind a peptide.
- Immune Surveillance: The peptide-bound MHC class I proteins are then transported to the cell surface, where they allow CD8+ cytotoxic T cells to recognize and destroy infected or malignant cells.
The protein encoded by the PDIA3 gene, commonly known as ERp57 or GRP58, is a multifunctional enzyme primarily located in the endoplasmic reticulum (ER) that is critical for protein folding and immune system function:
- Peptide Editing: It forms a stable disulfide-linked complex with tapasin to stabilize the MHC class I molecule until it is loaded with a high-affinity antigenic peptide.
- T-Cell Activation: By ensuring proper peptide loading, it allows cells to present antigens to CD8+ cytotoxic T cells, which is vital for detecting viral infections and cancerous cells.
These genes form the Peptide Loading Complex (PLC), which prepares viral and bacterial fragments for display to the immune system.
ME/CFS Context: In the ME/CFS pathomechanism, TAP1, TAP2, and PDIA3 SNPs act as the "gatekeeper" failure. They prevent the immune system from successfully "checking out" of an infection, leading to the chronic immune dysregulation, T-cell exhaustion, and neuroinflammation identified by the deep phenotyping study (2).
ME/CFS Context: In the ME/CFS pathomechanism, TAP1, TAP2, and PDIA3 SNPs act as the "gatekeeper" failure. They prevent the immune system from successfully "checking out" of an infection, leading to the chronic immune dysregulation, T-cell exhaustion, and neuroinflammation identified by the deep phenotyping study (2).
3. MICB: The "Kill Me" Signal
Normal Function: MICB is a stress-induced protein that acts like a "flare." When a cell is infected or cancerous, it displays MICB on its surface to alert Natural Killer (NK) cells and cytotoxic T cells to destroy it.
ME/CFS Context: SNPs in MICB may result in a weakened signal to the immune system. If cells harboring a persistent virus (like EBV of VZV) cannot effectively signal for their own destruction, the infection remains uncleared—directly supporting the antigen persistence hypothesis.
4. TLR3, C3: The "Ifinite" Alert
Normal Function: When TLR3 detects a virus, it sends a signal to the cell's nucleus to "turn on" the production of more C3 protein. It also helps activate the enzymes that break C3 into its active forms, providing more material to mark and attack pathogens.
Normal Function: When TLR3 detects a virus, it sends a signal to the cell's nucleus to "turn on" the production of more C3 protein. It also helps activate the enzymes that break C3 into its active forms, providing more material to mark and attack pathogens.
Once C3 is activated, the C3b fragment acts as a physical "tag" that sticks to the surface of viruses or infected cells. Simultaneously, TLR3 signals recruit immune cells to the area. These cells then use specialized receptors to find the C3b tags, allowing them to quickly identify and eat (phagocytose) the target.
ME/CFS Context: SNPs in TLR3 may reduce the receptor's ability to recognize viral dsRNA.
SNPs in C3 may result in lower levels of functional C3, the body cannot effectively "tag" (opsonize) bacteria or viruses with C3b.And because the "clearance" signal is never sent, sensors like TLR3 and C3 stay permanently activated.
The body remains in a state of chronic innate immune activation. This consumes massive amounts of cellular energy (ATP) and produces constant inflammatory cytokines. This is why patients feel like they have a "permanent flu" that never resolves.
5. CSMD1, LAIR1: The Loss of the "Off-Switch"
Normal Function: CSMD1 is a large protein that regulates the complement system (preventing it from attacking healthy cells) and is heavily involved in neurodevelopment and synaptic maintenance.
LAIR1 is an inhibitory receptor that acts as a "brake" on almost all immune cells (T cells, B cells, and NK cells). It prevents the immune system from overreacting and causing self-damage.
ME/CFS Context: SNPs in CSMD1 link the immune system to the nervous system. In ME/CFS, a failure to regulate complement in the brain could lead to neuroinflammation and the cognitive "brain fog" reported by patients.
Combinatorial SNPs in LAIR1 could lead to an "over-active brake" or a "faulty brake." This leads to T-cell exhaustion (where the immune system is too inhibited to fight) or chronic inflammation (where the system can't turn itself off).
Hit, Stay and Sabotage
Hit, Stay and Sabotage
In 2025, a unified pathomechanism for ME/CFS has emerged, centering on a "failure to clear" pathogens/viral fragments. This model moves away from the "hit-and-run" theory toward a "Sustained Antigen Persistence" framework.
The DecodeME study proves that ME/CFS is not caused by one "broken gene" but by a combination of subtle genetic weaknesses.
This genetic "profile" creates the exact conditions needed for the sustained antigen persistence seen in the NIH's deep phenotyping (2) research: an immune system that is perpetually "on" but never "successful.
More information
Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?
Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction
Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?
Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction
Suppression of the host antiviral response by non-infectious varicella zoster virus extracellular vesicles
Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus
References
1) Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID
https://www.medrxiv.org/content/10.64898/2025.12.01.25341362v1
2) Walitt B, Singh K, LaMunion SR, Hallett M, Jacobson S, Chen K, Enose-Akahata Y, Apps R, Barb JJ, Bedard P, Brychta RJ, Buckley AW, Burbelo PD, Calco B, Cathay B, Chen L, Chigurupati S, Chen J, Cheung F, Chin LMK, Coleman BW, Courville AB, Deming MS, Drinkard B, Feng LR, Ferrucci L, Gabel SA, Gavin A, Goldstein DS, Hassanzadeh S, Horan SC, Horovitz SG, Johnson KR, Govan AJ, Knutson KM, Kreskow JD, Levin M, Lyons JJ, Madian N, Malik N, Mammen AL, McCulloch JA, McGurrin PM, Milner JD, Moaddel R, Mueller GA, Mukherjee A, Muñoz-Braceras S, Norato G, Pak K, Pinal-Fernandez I, Popa T, Reoma LB, Sack MN, Safavi F, Saligan LN, Sellers BA, Sinclair S, Smith B, Snow J, Solin S, Stussman BJ, Trinchieri G, Turner SA, Vetter CS, Vial F, Vizioli C, Williams A, Yang SB; Center for Human Immunology, Autoimmunity, and Inflammation (CHI) Consortium; Nath A. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun. 2024 Feb 21;15(1):907. doi: 10.1038/s41467-024-45107-3. PMID: 38383456; PMCID: PMC10881493.
Ingen kommentarer:
Send en kommentar
Bemærk! Kun medlemmer af denne blog kan sende kommentarer.