Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis

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. Impact This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome. The of monogenic PIDs is independent of microbiota; single-gene mutations such as AIRE or Foxp3 that affect central or peripheral immune tolerance produce monogenic diseases even in a GF environment. However, the and of PIDs are markedly impacted by the microbial composition. We suggest that future research for these conditions may focus on targeting the microbiome.

Automated summary

This study shows new evidence that the severity of monogenic autoimmune disorders may be linked to the microbial composition, suggesting that future research should focus on targeting the microbiome. Although the onset of monogenic PIDs is independent of microbiota, their severity is markedly impacted by the microbial composition.