Epigenetic reprogramming by BCG (Bacillus Calmette-Guérin) vaccination: A novel strategy to reverse immunodeficiency in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is associated with reflecting innate immune impairment. Chronic inflammation, oxidative stress, metabolic dysregulation, and prolonged uraemia are the primary causes of this condition. Monocytes, macrophages, and their progenitors may undergo drastic epigenetic changes in response to these systemic stresses. This has lowered the activation of histone marks, such as H3K4me3, and destabilised repressive marks, like H3K9me3. Critical immune response genes are silenced by chromatin closure. This epigenetic change exhausts the immune system and impairs its ability to clear pathogens. This causes ‘uraemic immunodeficiency’, a poor vaccination response, and increased susceptibility to infection. On the other hand, the Bacillus Calmette–Guérin (BCG) vaccination may produce trained immunity, a favourable innate immunological memory. BCG stimulates the NOD2 and Akt/mTOR pathways. This increases H3K4me3 near cytokine gene promoters and stabilises H3K9me3 in non-essential genomic areas. This progressive remodelling creates transcriptionally permissive chromatin that increases inflammatory reactivity. This increases the phagocytosis and antimicrobial activity of monocytes, macrophages, and neutrophils. BCG also reprogrammes hematopoietic stem and progenitor cells to create sustained myeloid cells. Comparing CKD-induced immunological paralysis to BCG-induced immune extension indicates that metabolic and environmental factors strongly influence the innate immune epigenome. BCG-induced trained immunity may represent a low-cost, host-directed strategy to reduce infection susceptibility and improve vaccine responsiveness in patients with CKD. This review shows that the BCG restores chromatin accessibility and transcriptional ability to treat CKD-induced immunological deficiencies. To restore immunological function in CKD patients, BCG-based therapies and epigenetic modulators should be studied.