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

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


Rheumatology. 2016;55(3):391-402. 

In This Article

Mucosal Structure and Function

There are a variety of mucosal sites in humans, including the eye, respiratory tract, gastrointestinal tract and genitourinary tract, as well as mammary glands and serosal sites such as the pleural and peritoneal cavities.[14–16] In addition, there are multiple subsites with unique immunological characteristics. As examples, the oral cavity has salivary glands as well as subgingival spaces; the respiratory tract can be divided into the nasopharynx (and even the middle ear), the airways (including the trachea and bronchi) and the aveolar spaces.[17]

In general, the mucosa consists of epithelial cells that form a surface barrier, with hair (in some areas) and a coating of mucus contributing to that barrier (Fig. 1). In some sites, such as the larger airways in the lung, these epithelial cells have cilia that contribute to the removal of foreign material. On the luminal surface there is a variety of components of the immune system, including immunoglobulins, complement and cells that include neutrophils, macrophages, dendritic cells and T and B cells.[15,18–23] Intermixed with the mucosal epithelial cells are cells that produce mucus (e.g. goblet cells), cells with endocrine function (e.g. enteroendocrine cells in the intestine), cells that participate in a non-specific fashion in host defence (e.g. Paneth cells in the gut) and cells that participate in antigen recognition and presentation, including dendritic cells and M cells. In addition, there are intra-epithelial lymphocytes that serve to maintain mucosal homeostasis and are similar to T cells.[24] Underlying the epithelial cell layer in the lamina propria are blood vessels and lymphatics as well as cells that include neutrophils, mast cells, macrophages, dendritic cells, T cells (including effector T cells producing IL-17, Th17 cells and Tregs), B cells, as well as NK cells.[25]

Figure 1.

Overview of the immune response in the tonsil and regional lymph node as an example of the mechanisms of immunity at mucosal sites
Tonsils, adenoid tissue and the intestine contain M cells that mediate antigen uptake into the tissue rich with lymphoid follicles (A) in which the primary expansion of naive B cells occurs (dendritic cells can also uptake antigen at mucosal sites through processes that extend into the lumen). Antigen presentation is followed by the subsequent generation of memory B cells that populate other lymphoid tissues, especially regional lymph nodes. Dark and light zones containing centroblasts and centrocytes and the mantle zone, in which dendritic cells, B cells and T cells collaborate for B cell activation, are shown in the upper right of (B). A similar expansion of memory (and naive) B cells can occur with secondary exposure in the lymph nodes that are draining the airways as well as other mucosal sites. FDC: follicular dendritic cells; HEV: high endothelial venule. Figure reprinted from Kato A et al., B-lymphocyte lineage cells and the respiratory system. J Allergy and Clinical Immunol 2013;131:933-57,[ 17] with permission from Elsevier.

The mucosal surfaces sit at the interface between the environment and the host and have multiple means that involve both innate and adaptive factors to manage not only potential threats from the environment, such as toxins and pathogens, but also factors that may be beneficial to the organism, such as commensal bacteria. Among the innate factors, lysozyme, lactoferrin, complement, immunoglobulin and cellular elements such as neutrophils and macrophages play important roles. In addition, areas of submucosal organized lymphatic tissue called mucosa-associated lymphoid tissue (MALT)[20,26] are present in most mucosal surfaces. In the gut, MALT and in particular Peyer's patches form in utero and with influence from endogenous factors;[14] in contrast, MALT tissue in the nasopharynx begins development only after the tissue is exposed to exogenous flora.[27] In well-developed MALT, cells such as M cells, dendritic cells and macrophages can sample antigens and lead to immune responses. In the lung, an ectopic lymphatic tissue called bronchus-associated lymphatic tissue can form, with local production of antibodies and class switching that can aid in clearance of local insults, apparently only in the presence of inflammation or as a consequence of microbial pathogens.[28–30] Immune responses generated in MALT and ectopic lymphoid structures can then traffic first to regional lymphatics, then systemically and finally back through the circulation to mucosal sites (such as the gut lamina propria) where they can perform effector functions.[17,19] In particular, several molecules including α4β7 integrin are known to facilitate effector cell homing to the gut mucosa.[31] However, little is known about the specific factors that may induce effector cell homing in other tissues, although these factors likely exist.[31]

Immunoglobulins are central players in mucosal immunity. All of the immunoglobulin isotypes (IgA, IgD, IgE, IgG and IgM) may be present at mucosal surfaces;[19] however, the hallmark of mucosal immune responses is the presence of IgA, which is typically in its secretory form (sIgA). IgG is also present at mucosal sites, and can arrive by active transport typically through the neonatal Fc receptor, diffusion from the circulation or local production.[17] IgM is also present at mucosal surfaces, typically in its secretory form. IgD may also play an important role in mucosal responses, including a role in basophil activation and cytokine secretion (IL-4, IL-13) and in particular is present in secretions from the upper airway and nares and in human breast milk.[17]

Overall, mucosal immunological structure and function allow for protection against invasion of harmful factors through both mechanical barriers and immune responses. In addition, the mucosa contributes to the generation of beneficial immune responses of protective immunity to many natural infections, allowing the use of oral vaccines, enteric viruses and pathogens and of a nasal vaccine against influenza.[32] However, immune responses that initiate at mucosal surfaces can also lead to harm and in the next sections we discuss in detail how the mucosa balances defence with homeostasis and cooperation with common environmental factors, including the microbiome, and how these relationships may go awry and lead to autoimmunity.