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Monogenic Autoimmune Disorders Display Gut Microbial Dysbiosis

T cells and autoimmunity

Image credit: NIAID, Flickr, licensed under CC BY 2.0

Autoimmune diseases are an outcome of a dysfunctional immune system. Most common autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are polygenic autoimmune disorders. However, several monogenic autoimmune disorders have been identified. These are generally rare diseases, for example, mutations in the transcription factor AIRE leads to autoimmune polyendocrinopathy-candidiases-ectodermal dystrophy (APECED) and mutations in Foxp3 leads to Treg-deficiency-induced multiorgan autoimmunity termed ‘scurfy’ in mice or immune dysregulation, polyendocrinopathy and enteropathy X-linked syndrome (IPEX) in humans.

Mechanistically, common autoimmune diseases require the innate-adGETaptive connection for their onset, during which microbes contribute to initiation or severity of autoimmunity. Microbes and microbial peptides activate antigen-presenting cells (APCs) through the interaction with innate receptor signalling presented on APCs, further inducing self-reactive T cells by antigen presentation and co-stimulation, and ultimately, destructing tissue target cells by self-reactive T cells or antibodies or cytokines produced by innate lymphoid cells (ILCs) and T cells.

The separation of monogenic autoimmune disorders from polygenic autoimmune disorders is in that the innate-adaptive connection is not critical for their onset. Monogenic autoimmunity is based on the loss of control over one of the principal mechanisms controlling adaptive immunity, such as inflammatory effector T cells (Th1/Th2) due to a deficiency of Foxp3+Tregs (IPEX).

A review article (1) summarised that monogenic diseases including IPEX (2) and APECED (3) are insensitive to commensal regulation because these diseases occur in germ-free (GF) animals, suggesting that autoimmune T cells are activated in the absence of the innate-adaptive connection. A study using GF mice compared with specific pathogen-free (SPF) mice to examine the critical role for Trg cell-mediated control of inflammation, demonstrated that Treg cell development and suppressive function showed little dependence on gut microbiota. However, in a Treg-depleted model (Foxp3-DTR), inflammation in the small intestine of SPF mice was more severe than in GF mice, as shown by significantly increased gut lymphocyte infiltration, decreased body weight, and increased % of IFN-γ-producing T helper cells, indicating that Treg cell deficiency-induced inflammation is related to gut microbiota (2).

More experiments provide evidence that single gene mutations affect gut microbiota. We observed that development of autoimmunity was accompanied by gut microbial dysbiosis over 22 days of life in Foxp3-deficient scurfy mice (4), demonstrating reduced bacterial diversity and altered bacterial composition. Furthermore, altered gut microbiota has been shown in immunodeficient mice lacking B cells only (Ighm-/-), T cells only (Cd3e-/-) or both B and T cells (Rag1-/-). Administration of Foxp3+Treg cells to T-cell-deficient mice restored bacterial diversity (5).

A detailed study compared Rag1+/+ and Rag1-/- mice of the same genetic background and eliminated the cage effect in order to determine the effect of Rag1 and adaptive immune system on gut microbiota. It demonstrated that Rag1 status is a source of variation in gut microbiota community structure (6).

Another study indicated that the composition of intestinal flora is altered in APECED patients (7), and the patients develop early and sustained responses to gut microbial Ags. Abnormal immune recognition of gut commensals is linked to gut-associated Treg, indicating that AIRE is an important regulator of intestinal homeostasis (8).

The evidence leads us to conclude that host adaptive immunity involved in single gene mutations alters gut microbiota. Therefore, it raises the potential therapeutic strategy by targeting the enteric microbiota for these monogenic autoimmune disorders.

We have demonstrated that the gut microbial dysbiosis due to Foxp3 Treg deficiency could be reprogrammed by probiotic Lactobacillus reuteri DSM 17938. Remodelling microbiota by Lactobacillus reuteri DSM 17938 inhibits Treg-deficiency-induced autoimmunity by restoring the levels of the purine metabolite inosine via adenosine A2A receptors (4).

Yuying Liu

 

Yuying Liu is an Associate Professor in the Department of Pediatrics at the University of Texas. Yuying will be presenting on combatting autoimmune diseases at the Probiotics Congress: USA.


Learn more about the upcoming probiotics meeting.

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