Hi all, Have a theory I would like to run by anyone willing to read it (hopefully @nandixon @Valentijn would be willing to lend their expertise): Do you think CFS could be due to CTLA4 mutations? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668597/ From what I've seen and read, a lot of CFS/ME patients have both autoimmunity and CVID-like immune deficiency. CFS also tends to run in families with autoimmune histories. CTLA4 mutations appear to be in the 1-2% prevalence range, I think. From the paper above, it looks like the immune dysregulation caused by CTLA4 is autosomal dominant with variable penetrance because 2 functional copies of CTLA4 are required for Tregs to actually be able to supress T cell activity. So even having one bad copy can make a person's Treg cells somewhat useless at preventing autoimmune disease. Thus with bad CTLA4 function, you get persistence and proliferation of autoreactive T cells in several target organs and induction of an array of auto-antibodies by B Cells. This would fit with why Rituxan works well in a good chunk of CFS patients, but isn't curative. The autoreactive B cells will keep being made and activated as long as auto-reactive T cells are still there. Unfortunately, even killing the autoreactive T cells once over won't be curative if CTLA4 is to blame, because the Tregs (although normal or even increased in number) are powerless to inactivate any new autoreactive Tcells that crop up. There are 2 CTLA4 protein replacement products out there, currently used for RA -- Orencia (Abetacept) is one of them. Orancia was used to successfully treat a girl with multiple autoimmune diseases found to have a novel CTLA4 mutation who wasn't responding to immune suppressive medications (http://www.sciencedirect.com/science/article/pii/S0091674915012610). Orencia can take 3-6mos to affect joint symptoms...which is curiously similar to how long Rituxan takes to work in CFS patients. Interestingly, Orencia anecdotally relieves fatigue in RA patients quite well, and often faster than it relieves their joint pain. Has anyone with CFS been on Orencia? If so, what has your experience been? And does anyone know their CTLA4 mutation status? (A search for CTLA4 on the forums yielded a few 23&me results showing at least one bad CTLA4 copy. I have 2 mutated copies.) I ask because Orencia is cheaper than Rituxan and would theoretically treat the root cause of the disease (if due to ctla4), possibly fixing the autoimmunity and immune deficiency. Thanks in advance for your input!