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. IMPACT: This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome. The onset 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 severity and outcome of PIDs are markedly impacted by the microbial composition. We suggest that future research for these conditions may focus on targeting the microbiome.

Figure 1.

Clinical autoimmune manifestations of representative monogenic autoimmune diseases. A-B. Immunodysregulation, polyendocrinopathy, and enteropathy syndrome with X-linked inheritance (IPEX syndrome) (30); C-F. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (34), G. Omenn syndrome (OS) (35), and H-I. Wiskott-Aldrich syndrome (WAS) (32).

Figure 2.. Two main groups of autoimmune diseases as defined by innate-adaptive immunity and microbial environment.

Group I diseases follow the rules of innate-adaptive immunity activation. They can be affected by microbial environment, and/or may result from genetic alterations to PRR sensing and signaling, co-stimulation, or cytokine production. Innate PRR expressed on APC recognizes pathogenic antigens and presents to naïve T cells, activating naïve T cells by several pairs of ligand-receptor interactions to differentiate T cell subsets. This results in more inflammatory Teffs and self-reactive T cells than Tregs, and damage to self-tissues. Group II diseases are caused by genetic alterations in lymphocyte development or regulation. An example shown is a Foxp3 gene mutation in Foxp3⁺Treg cells in thymus, which results in defects in peripheral tolerance due to Treg-deficiency/dysfunction that cannot inhibit inflammatory Teffs, yielding high levels of proinflammatory cytokines. Group II diseases are independent of innate-adaptive immune activation, and their onset is less affected by microbiota. Ags: antigens; PRR: pattern recognition receptor; PAMPs: pathogen-associated molecular patterns; APC: antigen presenting cell; nTreg: natural regulatory T cell; Teff: effector T cell; Tem: effector/memory T cell.

Figure 3.

The mechanism of probiotic Lactobacillus reuteri DSM 17938 (L. reuteri)-associated protection against Treg-deficiency autoimmunity in SF mice. A. In WT mice, Tregs generate adenosine from ATP/AMP by CD39/CD73 signaling expressed on Treg cells. Adenosine interacts with A_2A expressed on inflammatory Teffs to control Teff s and reduce inflammation. B. In SF mice, inflammatory Teffs lose their control by Tregs through loss of the adenosine mechanism, resulting in severe inflammation and autoimmunity. C. Gavage feeding of L. reuteri to SF mice modulates gut microbiota, generates the adenosine metabolite inosine, an A_2A agonist, which interacts with A_2A to inhibit Teff cell differentiation and reduce multiorgan inflammation. D. The therapeutic effect of L. reuteri and inosine was blocked by genetically knocking out receptor A_2A in SF mice, indicating that A_2A plays a key role in L. reuteri protection. ATP: adenosine triphosphate; AMP: adenosine monophosphate; A_2A: adenosine receptor 2A; TCR: T cell receptor; SF mice: scurfy mice; Th1: T helper cell; Treg: regulatory T cell; Teff: effector T cell.