Murder is like opium

 And fine wine and look

Aid

Your doctor health insurers and hospitals want you dead land have a joe biden brain

Enjoy life shoot BCG and taliban

West Point ponders whether real homicidal people 

Can let the good times roll in Afghanistan 

Shooting unarmed people is like collecting from strip clubs

Bring beer and neutron bombs to Afghanistan and let people do as the please

tachment

BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation

22 July 2021

Abstract

Induction of immunosuppressive T-regulatory cells (Tregs) is a desirable goal in autoimmunity, and perhaps other immune diseases of activation. One promising avenue is with the bacille-calmette-guérin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with gradual clinical improvements in human autoimmunity over a 2–3 year post-vaccination period. We hypothesize that those improvements, and their unusually long time course to fully materialize, are partially attributable to BCG’s induction of Tregs. Here we report on a 3 year-long longitudinal cohort of T1Ds and examine the mechanism by which Treg induction occurs. Using the Human Infinium Methylation EPIC Bead Chip, we show that BCG vaccination is associated with gradual demethylation of most of 11 signature genes expressed in highly potent Tregs: Foxp3, TNFRSF18, CD25, IKZF2, IKZF4, CTLA4, TNFR2, CD62L, Fas, CD45 and IL2; nine of these 11 genes, by year 3, became demethylated at the majority of CpG sites. The Foxp3 gene was studied in depth. At baseline Foxp3 was over-methylated compared to non-diabetic controls; 3 years after introduction of BCG, 17 of the Foxp3 gene’s 22 CpG sites became significantly demethylated including the critical TSDR region. Corresponding mRNA, Treg expansion and clinical improvement supported the significance of the epigenetic DNA changes. Taken together, the findings suggest that BCG has systemic impact on the T cells of the adaptive immune system, and restores immune balance through Treg induction.

Introduction

Exposure to chronic infectious diseases can result in increases in host Treg cells^1,2. The Treg and infectious disease link is thought to result from the co-evolutionary existence of pathogens developing mechanisms for long-term survival within host cells without host-immune recognition. In tuberculosis, the granuloma is surrounded by host-induced Treg cells. Infection with tuberculosis (Mycobacterium tuberculosis), as well as leprosy (Mycobacterium leprae), is accompanied by an increase in circulating Treg cells^3,4 Mice experimentally infected with tuberculosis show expansion of Tregs⁵.

Induction of Treg cells, in numbers or activation state, is a one type of therapeutic approach in human inflammatory diseases. One possible way to increase the numbers or function of Tregs is to use microorganisms that typically with infection already uses this mechanism for host immune escape. Strategic introduction of long-lived organisms that are not harmful to hosts, such as the attenuated Mycobacterium bovis of the BCG vaccine, might be beneficial for host Treg induction. Increasing Tregs numbers or function maybe one solution to inflammation. Underlying defects in Treg function, sometimes related to Foxp3 expression or function, are common in severe human immune diseases. The first disorder associated with dysfunction of the Foxp3 gene impacting Tregs, is IPEX syndrome (immunodysregulation polyendocrinopathy enteropathy X-linked). This syndrome of autoimmune driven diarrhea, eczema and often type 1 diabetes, is caused by a multitude of now identified germline mutation in the Foxp3 gene with over 70 mutations⁶. Subsequent studies support the Foxp3 gene as the defining protein of the Treg cellular lineage and identify potent Tregs with suppressive function⁷. The Foxp3 gene works in concert with other signature genes of potent Tregs. In other immune diseases, specific genetic mutations in single Treg-associated genes have not been identified, suggesting other genetic mechanisms for the poor Treg function in inflammatory diseases. This paves the way for alternative therapeutic approaches with quantitative defects to overcome the lackluster performance of Tregs in autoimmunity.

The BCG vaccine is being increasingly used in autoimmune clinical trials as an anti-inflammatory drug^{8,9,10,11,12,13}. BCG vaccines are also being used for combatting childhood asthma and allergies^14,15,16. Evidence exists especially in at least two human autoimmune diseases, multiple sclerosis (MS) and type 1 diabetes (T1D), of BCG’s therapeutic effects manifesting gradually over a post-infection period of 3 or so years^10,12. In autoimmune diabetic subjects, 8 weeks after two BCG vaccinations, CpG sites in Treg signature genes have shown statistically significant but small early demethylation changes¹². This, along with corresponding increases in mRNA, supports increased Treg function to control inflammation. Although this time course is short, similarly short time courses with BCG therapy also suggest, at the protein level, that inflammatory cytokines expressed for 2 or 3 months are also changing which could be a consequence of BCG impact on cytokines produced by monocytes¹⁶. Long-term and multi-year effects of BCG vaccines for durable boosting of the Treg response have not been studied. A vaccine with an avirulent version of the microorganism might show benefit by Treg induction if these benefits could be sustained on a multi-year basis. BCG’s apparent control over Treg signature genes, including Foxp3, appears to be a path to understanding its clinical success in multiple human inflammatory diseases.

Traditionally the BCG vaccine has been thought to have influence over the innate immune response, meaning lasting changes predominantly in host monocytes. The innate immune response of BCG on the host is certainly controlled in part by the histone activity of key genes involved in cytokine secretion^18,19,20. The methylation changes in monocytes have been coined “trained innate immunity”. BCG’s impact on the host immune response may also involve the adaptive immune system. Indeed the impact of BCG on glycolysis can be monitored both within T cells and monocytes suggesting adaptive immune changes from BCG vaccine therapy^12,13,17. The MYC pathway for