Multifactorial Role of Carbon Dioxide in Autoimmune Diseases: From Membrane Depolarization to Gene Reprogramming

Background: The incidence of autoimmune disorders has increased alongside rising carbon dioxide (CO₂) levels over the past century. Objective: To determine whether elevated CO₂ levels are associated with autoimmune disorders. Design: Case-control study conducted at local tertiary hospitals in Egypt. Methods: A total of 150 patients diagnosed with various autoimmune disorders and 75 age- and sex-matched controls (aged 20–70 years) were enrolled. Exclusion criteria included neuromuscular disorders, critical illness, respiratory conditions, and occupational CO₂ exposure, as guided by criteria from the National Institute for Occupational Safety and Health. Recruitment occurred between November 2023 and March 2024. All participants underwent arterial blood gas analysis. Selected patients were further evaluated to confirm autoimmune status. Pa CO₂ was analyzed using two statistical methods to validate significance. Results: The mean Pa CO₂ (± SD) was 48.18 ± 12.10 mmHg in autoimmune patients, compared to 42.63 ± 11.06 mmHg in controls (p = 0.001). Elevated Pa CO₂ was found in 97 (64.7%) of cases and 30 (40%) of controls, yielding a relative risk (RR) of 1.62. The odds ratio (OR) with 95% confidence interval (CI) was 2.75 (1.55–4.86), p = 0.0005. Conclusion: Our study demonstrates a significant correlation between elevated CO₂ levels and autoimmune disorders. The underlying mechanism may involve complex interactions including CO₂-induced alterations in cell membrane integrity, calcium (Ca²⁺) homeostasis, and intracellular signaling. The thermic effect of CO₂ may enhance antibody mobility away from their original antigens. Subsequently, CO₂ protonation increases electrostatic interactions between anionic cell membranes and the positively charged antibodies, redirecting them toward host antigens and triggering autoimmune reactions. Tissues rich in negatively charged cells, such as skin and musculoskeletal tissues, are more affected. CO₂-driven changes in gene expression and mRNA translation may also contribute to diverse autoimmune phenotypes. This suggests a potential therapeutic role of targeting CO₂-related pathways. Based on these findings, a novel treatment approach for autoimmune disorders is proposed, involving membrane receptor modulation via CO₂-induced thermal oscillations of electron clouds, potentially leading to favorable phenotypic outcomes.