For the first time ever, I've created tolerance to self

[crowneagle]

The threat of being on preds for the rest of my life is highly motivating. RTX has a hard time crossing my blood brain barrier. It's like Arnold Schwarzenegger trying to enter your home through the water line. Well, like I once told my rheumy, necessity is the mother of invention.


Wegener's attacks our mucosal tissues, normally the sinuses and airways. Being the black sheep of the family, WG decided to attack another mucosal tissue, my colon. I've been dealing with colitis for a long time.

Colitis: an unusual presentation of Wegener's granulomatosis
https://www.ncbi.nlm.nih.gov/pmc/art...nal%20function.

.................................................. .................................................. .........................................

Recently, I've been investigating alternative ways to reduce the B cell burden in my brain. There is a family of enzymes called PI3K, that promote cellular differentiation and proliferation. "Phosphoinositide 3-kinase (PI3K) signalling has been shown to be a key pathway in the regulation of the immune response and continues to be the focus of intense research."

"Data from gene-targeted mice, pharmacological inhibitors, as well as studies of human and mice expressing activating mutants have revealed that PI3Kδ is a key regulator of Tfh cell differentiation." The extra symbol on the end of PI3K denotes a lower tense Delta isoform. I'll mention it again at the end of this post. All mentions of the two lead characters, PI3K and Tfh have been marked in bold for visual clarity.

In WG, Tfh cells are elevated and unbalanced, as opposed by Tfh regulatory cells. "Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high affinity antibodies and memory B cells. Follicular T-helper (Tfh) cells are required for the development of the germinal centre where B-lymphocyte antigenic affinity undergoes maturation. The role of these cells is being investigated in autoimmunity and seems to be more prominent in diseases with a higher participation of autoantibodies."

"T follicular helper (Tfh) cells are a specialized population of CD4+ T cells that provide help to B cells for the formation and maintenance germinal centers, and the production of high affinity class-switched antibodies, long-lived plasma cells, and memory B cells. As such, Tfh cells are essential for the generation of successful long-term humoral immunity and memory responses to vaccination and infection. Conversely, overproduction of Tfh cells has been associated with the generation of autoantibodies and autoimmunity."

Recently my neurologist put me on a 60mg pred taper. By a slip of the tongue, she inferred the taper would be the first of many. I didn't think much of it at the time. But when I ordered a bottle of Nystatin from my vasculitis doctor, he sent me a case. Mentally, it was all starting to sink in. We all know how difficult it is to get off preds. I worked very hard to be pred free. Maybe there was a better way. The wheels started spinning in my head. I needed to find a self treatment that suppresses the PI3K pathway and rebalances my Tfh cells. The answer was right under my nose.

I've been using fisetin for years, mainly as adjuvant therapy during flareups. I've always kept the doses low. But with my future hanging in the balance, I figured what do I have to lose? I tripled my dose of fisetin(300mg) and coupled that with low dose preds(5mg). After a couple of weeks, not only has my colitis disappeared but the triggers that aggravate it, don't trigger it anymore. As a test, I filled my face with potato chips and peanuts. No reaction whatsoever! I know it wasn't the preds, because three rounds of solumedrol and a pred taper didn't do anything for my colitis, this past summer.

Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009086/

Fisetin suppresses PI3K and by association, also suppresses Tfh differentiation. Since Tfh cells accumulate in my mucosal tissues, my conclusion leads me to believe fisetin played a role in ridding myself of colitis. It should be noted that fisetin suppresses all isoforms of PI3K, alpha, beta, delta and gamma. When I entered into this little project, my primary goal was reducing B cell proliferation and differentiation. But like all things in life, one thing led to another. This post is an over-simplification of a complex subject; but with time, I'm going to see how far I can take it. Reducing my B cell burden remains my number one goal. Unlike RTX, fisetin readily crosses the blood brain barrier. My next goal is to reduce CD19+ B cells in my brain. By any measure, I'm off to a good start.

Additional observations and outlook: This treatment appears to be cumulative. It's 6pm now and I'm usually not feeling very well. My symptoms generally get worse at night. However, the longer I'm on this regimen, the better I feel. I've been taking 100mg fisetin at lunch and 200mg at suppertime. I might be able to reduce my dosage in the near future or even reduce the 5mg dose of preds. I take fisetin with meals because it needs fat to be absorbed properly. I take it twice a day because its half-life is short. Life Extension developed an improved formula(Bio-Fisetin) that increases both its bioavailability and half-life, all at a lower dosage. I'm also wondering if some of the benefits can be attributed to a reduction in autoantibodies. e.g. Short lived B plasma cells have a 3-5 day lifespan, while mature peripheral B cells have a halflife of 5-6 weeks. Research on fisetin is exploding, with 372 entries on PubMed in just the last couple of years. I'm particularly interested in its senolytic properties in regards to senescent T cells in anca vasculitis. Senescent T cells are inflammatory in weggies. There is also a clinical trial going on right now, using much higher doses for a few days using a hit and run approach in nursing home residents, to see if they get an improvement in age related degeneration.

Disclaimer:

Always discuss supplements with your doctor. The information contained in this post is complex and much of it is theoretical in nature. I have found no reported ill effects from fisetin, but that doesn't mean they don't exist. Pharmaceutical grade PI3K inhibitors have reported side effects. e.g. "The most commonly seen toxicities with the PI3K isoform-specific inhibitor, alpelisib, are hyperglycemia, rash, and diarrhea." Or just maybe, nature does it better.



PI3K Orchestrates T Follicular Helper Cell Differentiation in a Context Dependent Manner: Implications for Autoimmunity
https://pubmed.ncbi.nlm.nih.gov/30666254/