Do Long COVID and Gulf War Illness Share an Underlying Mechanism?

In 2023, immunologist James Iredell Moss published a hypothesis suggesting that symptoms of long COVID may be driven by an autoimmune-like mechanism. He proposed that SARS-CoV-2 may disrupt the immune system by reactivating B cells that are usually kept in an inactive, or “anergic,” state to prevent them from attacking the body [1]. He has also pointed to research showing that disruption of PTEN—a gene that helps regulate immune cell signaling—can activate inflammatory pathways like PI3K/AKT and may contribute to loss of immune tolerance [2].

According to the hypothesis, COVID-19 may elevate levels of angiotensin II, which can activate signaling pathways in these inactive B cells. This may reverse their tolerance, triggering the production of autoantibodies—a possible explanation for the lingering symptoms seen in Long COVID, such as fatigue, brain fog, and joint pain.

This idea aligns with growing research showing new-onset autoantibodies in COVID-19 patients [3], the presence of diverse autoreactive antibodies affecting different body systems [4], and the wide range of long COVID symptoms being documented across patient populations [5]. Moss also draws parallels to Gulf War Illness (GWI), a chronic condition affecting many veterans from the 1991 Gulf War. In a 2019 paper, he proposed that a nerve agent protection drug taken during deployment may have caused a similar immune response by reactivating anergic lymphocytes [6].

Although this theory has not been confirmed through clinical trials, it highlights a potential mechanism worth further investigation.

Citations

1. James Iredell Moss (2023). Long Haul COVID 19 is the Result of B Lymphocyte Anergy Reversal. Mod Appl Pharm Pharmacol. 3(1). MAPP.000554.
2. Mei, P., et al. (2024). Downregulation of Serum PTEN Expression in Mercury-Exposed Population and PI3K/AKT Pathway-Induced Inflammation. Biomedical and environmental sciences : BES, 37(4), 354–366. https://doi.org/10.3967/bes2024.040
3. Chang, S.E., et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun 12, 5417 (2021). https://doi.org/10.1038/s41467-021-25509-3
4. Wang EY, et al (2021). Diverse functional autoantibodies in patients with COVID-19. Nature. https://doi.org/10.1038/s41586-021-03631-y
5. Al-Aly, Z., Xie, Y., & Bowe, B. (2021). High-dimensional characterization of post-acute sequelae of COVID-19. Nature, 594(7862), 259–264. https://doi.org/10.1038/s41586-021-03553-9
6. Moss J. I. (2019). Gulf War Illnesses are autoimmune conditions caused by the direct effect of the nerve gas prophylaxis drug (pyridostigmine bromide) on anergic immune system lymphocytes. Medical hypotheses, 132, 109373. https://doi.org/10.1016/j.mehy.2019.109373