Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis

Abstract

Primary immunodeficiency diseases (PIDs) caused by a single-gene defect generally are referred to as monogenic autoimmune disorders. For example, mutations in the transcription factor autoimmune regulator (AIRE) result in a condition called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; while mutations in forkhead box P3 lead to regulatory T cell (Treg)deficiency-induced multiorgan inflammation, which in humans is called "immune dysregulation, polyendocrinopathy, enteropathy with X-linked inheritance" (or IPEX syndrome). Previous studies concluded that monogenic diseases are insensitive to commensal microbial regulation because they develop even in germ-free (GF) animals, a conclusion that has limited the number of studies determining the role of microbiota in monogenic PIDs. However, emerging evidence shows that although the onset of the disease is independent of the microbiota, several monogenic PIDs vary in severity in association with the microbiome. In this review, we focus on monogenic PIDs associated with Treg deficiency/dysfunction, summarizing the gut microbial dysbiosis that has been shown to be linked to these diseases. From limited studies, we have gleaned several mechanistic insights that may prove to be of therapeutic importance in the early stages of life.

Probiotic-educated Tregs are more potent than naïve Tregs for immune tolerance in stressed new-born mice

“…Tregs suppress innate and adaptive immune responses and are critical for intestinal immune homeostasis (Liu et al, 2022a;Scheinecker et al, 2020). The generation and maintenance of Tregs require the expression of Foxp3 transcriptional factor in Tregs (Tran et al, 2007).…”

Nutraceuticals in the Modulation of the Intestinal Microbiota: Current Status and Future Directions

“…Autoimmune Diseases (ADs) are disorders characterized by an immune response directed against self-antigenic proteins, which causes damage and loss of function of involved tissues. They are mainly classified as polygenic disorders (rheumatoid arthritis, systemic lupus erythematosus, type I diabetes) when several genes are involved in their pathogenesis, or monogenic disorders, when a single gene is associated with their onset (Liu et al, 2021). Although the presence of a genetic background predisposing to monogenic or polygenic ADs has been discovered, it is widely accepted that gut microbes and their metabolites may play a pivotal role in their onset and maintenance since they may affect intestinal permeability, with bacterial proteins translocating in the bloodstream, which in some cases mimic autoantigens and could interfere in the Th17/Treg cell balance (Atarashi et al, 2011).…”

Inborn errors of immunity and related microbiome

“…Single-gene IEIs generally refer to monogenic autoimmune disorders, such as immune dysregulation, polyendocrinopathy, and enteropathy with X-linked inheritance (or IPEX syndrome) caused by mutations in the forkhead box P3 (Foxp3), and APECED caused by mutations in the autoimmune regulatory transcription factor (AIRE) ( 71 ). Previous studies concluded that single-gene IEIs were not influenced by commensal microbial regulation since they developed even in germ-free (GF) mice ( 72 , 73 ).…”

“…Previous studies concluded that single-gene IEIs were not influenced by commensal microbial regulation since they developed even in germ-free (GF) mice ( 72 , 73 ). However, new evidence reveals that while microbiota has no impact on the disease onset; the severity of many single-gene IEIs varies with the microbiome ( 71 ).…”

“…Liu et al. showed that in the mouse model of IPEX syndrome, gut microbial dysbiosis could be corrected using the human probiotic Lactobacillus reuteri DSM 17938, which is a human-derived probiotic that has been used in the treatment of infantile colic and acute infectious diarrhea ( 71 ). Similarly, He et al.…”