Gene, Environment, Microbiome and Mucosal Immune Tolerance in Rheumatoid Arthritis

Anca I. Catrina; Kevin D. Deane; Jose U. Scher

Disclosures

Rheumatology. 2016;55(3):391-402. 

In This Article

Development of the Mucosal Immune System: Relationship With the Microbiome

Although humans undergo embryogenesis under sterile conditions, immediately postpartum the newborn's body is populated by a range of microbes originating in the surrounding environment. Thereafter, and for life, this vast and dynamic community of microorganisms coexists with us in a complex but mutually beneficial relationship. Initially, however, a period of floral instability is the norm, particularly in the gastrointestinal tract.[40] Slowly, and during the first year of life, both the taxonomic richness and diversity of bacterial species increase. When solid foods are introduced, the gut microbiota expands, becomes more stable and begins to mimic the characteristics of the adult communities.[41] The neonatal period is critical in the establishment of the microbiome and its relationship with the host. Microbial colonization of the intestinal lumen and other sites has a profound effect on the development and function of the immune system. Animals kept under germ-free conditions have impaired development of the mucosal immune system, including lymphoid tissue genesis and organization of Peyer's patches and lymphoid follicles, secretion of antimicrobial and bactericidal peptides by epithelial cells and mucosal accumulation of immune cells. Immunoglobulins (sIgA) delivered by breastfeeding prevent the translocation of aerobic bacteria from the neonatal gut into draining lymph nodes and results in a protective pattern of intestinal epithelial cell gene expression in adult mice.[42] Throughout adult life, the microbiota continues to affect the host immune system utilizing multiple signal mechanisms, including microbial components and their metabolites. In turn, the immune system is capable of recognizing these factors by activating innate immune receptors. The armamentarium used to prevent tissue damage and antigen translocation includes cellular repairing factors, antimicrobial proteins and secretory sIgA.[43–45]

Mucosal microbiota influences innate immune recognition and leads to the development of a diverse and specific mucosal lymphocyte repertoire.[46] Recent paradigm-shifting studies using gnotobiotic experiments have demonstrated how individual components of the microbiota can induce specific populations of immune cells and alter the balance between pro-inflammatory and Tregs at mucosal sites and in the periphery. This has challenged the assumption that microbes and/or their components are only able to activate the innate immune system. The gut commensal segmented filamentous bacterium (SFB), for example, is sufficient to activate Th17 cells in the lamina propria[47] and eventually trigger autoimmunity and inflammatory arthritis[48] (see section Environmental and genetic factors contributing to the generation of autoimmunity at mucosal sites below). One plausible explanation derives from a recent study showing that the TCR repertoire of intestinal Th17 cells in SFB-colonized mice is highly specific and that most Th17 cells, but not other T cells, recognize antigens encoded by SFB. This explains potential mechanisms of Th17 cell induction by microbiota and how gut-induced Th17 cells can contribute to distal organ-specific autoimmunity.[49] For their part, Bacteroides species and their molecule polysaccharide A are unique in that they appear to be specific inducers of Tregs in the mucosa[50] and provide protection against the development of IBD[51] and multiple sclerosis in an animal model.[52]

In humans, microbiota composition is influenced by diet, antibiotic use, infections and possibly the host genome. When this fine equilibrium is altered in an unfavourable way, a state of dysbiosis ensues, typically characterized by an overgrowth of potentially pathogenic bacteria (termed pathobionts) and/or a decrease in the number of beneficial bacteria.[53,54] A growing body of evidence has shown a correlation between dysbiosis, autoimmunity and systemic inflammation. This is true for both animal models and human studies and has been reported in various conditions, including not only IBD,[55,56] but also systemic autoimmune diseases such as type 1 diabetes,[57] encephalomyelitis[58] and RA.[48,59,60] The following section provides detailed evidence for the implication of the microbiome in local and systemic autoimmune processes.

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