I don't really see this talked about much if at all, but could a significant portion of CFS patients (as well as patients with similar symptoms) be suffering from immune overreaction to commensal bacteria and other benign antigens? There was a Harvard study that found patients with chronic sinusitis suffer from immune reaction to benign bacteria, and antibiotic therapy (low-Fodmap, rifaxmin) often provides relief for people suffering from "IBS". Women with interstitial cystitis often find short term relief when taking antibiotics. Food, probiotics, and medication intolerances are also very common in CFS, IBS, MCAD, FIBRO and other similar disease states. A number of years ago, I took a course of antibiotics for a UTI. I can't remember what it was, but I felt more "normal" than I've felt in years (no brain fog, depression, high energy, etc.) until slowly slipping back into symptoms in a couple weeks. This may point to a dyregulation of t-regs. T-regs may be higher in CFS patients to compensate, but may not be adequate or of the correct subset to stop inflammation. Rituximab increases t-regs, which may point to the reason why benefits are often not permanent. There is some interesting research right now being done looking into IL-2 low dose therapy to stimulate t-reg populations to help with overreactive immune response (specifically in autoimmune conditions). Interestingly, IL-2 KO mice had overactive immune responses to commensal bacteria. I think there is something to be said about leaky gut, dysregulated microbiome, dysregulated CNS response, neuroinflammation, but I don't think these issues will be resolved if you don't address the oral/peripheral tolerance issues at least in a significant subset of people. And honestly, a 2+ pronged approach that at very least addresses central/peripheral sensitization and the loss of immune intolerance may have to be addressed simultaneously. Unfortunately, there are no good treatments yet for either of these issues.