BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

The BCG (Bacille Calmette-Guérin) vaccine, introduced 100 years ago for tuberculosis prevention, has emerging therapeutic off-target benefits for autoimmunity. In randomized controlled trials, BCG vaccinations were shown to gradually improve two autoimmune conditions, type 1 diabetes (T1D) and multiple sclerosis. Here, we investigate the mechanisms behind the autoimmune benefits and test the hypothesis that this microbe synergy could be due to an impact on the host T cell receptor (TCR) and TCR signal strength. We show a quantitative TCR defect in T1D subjects consisting of a marked reduction in receptor density on T cells due to hypermethylation of TCR-related genes. BCG corrects this defect gradually over 3 years by demethylating hypermethylated sites on members of the TCR gene family. The TCR sequence is not modified through recombination, ruling out a qualitative defect. These findings support an underlying density defect in the TCR affecting TCR signal strength in T1D.

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

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.

BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes.

Myc has emerged as a pivotal transcription factor for four metabolic pathways: aerobic glycolysis, glutaminolysis, polyamine synthesis, and HIF-1α/mTOR. Each of these pathways accelerates the utilization of sugar. The BCG vaccine, a derivative of Mycobacteria-bovis, has been shown to trigger a long-term correction of blood sugar levels to near normal in type 1 diabetics (T1D). Here we reveal the underlying mechanisms behind this beneficial microbe-host interaction. We show that baseline glucose transport is deficient in T1D monocytes but is improved by BCG in vitro and in vivo. We then show, using RNAseq in monocytes and CD4 T cells, that BCG treatment over 56 weeks in humans is associated with upregulation of Myc and activation of nearly two dozen Myc-target genes underlying the four metabolic pathways. This is the first documentation of BCG induction of Myc and its association with systemic blood sugar control in a chronic disease like diabetes.

Undisclosed conflicts of interest among biomedical textbook authors.

BACKGROUND: Textbooks are a formative resource for health care providers during their education and are also an enduring reference for pathophysiology and treatment. Unlike the primary literature and clinical guidelines, biomedical textbook authors do not typically disclose potential financial conflicts of interest (pCoIs). The objective of this study was to evaluate whether the authors of textbooks used in the training of physicians, pharmacists, and dentists had appreciable undisclosed pCoIs in the form of patents or compensation received from pharmaceutical or biotechnology companies. METHODS: The most recent editions of six medical textbooks, Harrison's Principles of Internal Medicine (HarPIM), Katzung and Trevor's Basic and Clinical Pharmacology (KatBCP), the American Osteopathic Association's Foundations of Osteopathic Medicine (AOAFOM), Remington: The Science and Practice of Pharmacy (RemSPP), Koda-Kimble and Young's Applied Therapeutics (KKYAT), and Yagiela's Pharmacology and Therapeutics for Dentistry (YagPTD), were selected after consulting biomedical educators for evaluation. Author names (N = 1,152, 29.2% female) were submitted to databases to examine patents (Google Scholar) and compensation (ProPublica's Dollars for Docs [PDD]). RESULTS: Authors were listed as inventors on 677 patents (maximum/author = 23), with three-quarters (74.9%) to HarPIM authors. Females were significantly underrepresented among patent holders. The PDD 2009-2013 database revealed receipt of US$13.2 million, the majority to (83.9%) to HarPIM. The maximum compensation per author was $869,413. The PDD 2014 database identified receipt of $6.8 million, with 50.4% of eligible authors receiving compensation. The maximum compensation received by a single author was $560,021. Cardiovascular authors were most likely to have a PDD entry and neurologic disorders authors were least likely. CONCLUSION: An appreciable subset of biomedical authors have patents and have received remuneration from medical product companies and this information is not disclosed to readers. These findings indicate that full transparency of financial pCoI should become a standard practice among the authors of biomedical educational materials.