Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis.

Spinelli Spinelli,Di Franco Di Franco,Guzzo Guzzo,Lucchino Lucchino,Iannuccelli Iannuccelli,Conti Conti

doi:10.3390/cells8070700

Spinelli Spinelli, Di Franco Di Franco

Open Access

https://doi.org/10.3390/cells8070700

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Journal: Cells	Publication Date: Jul 10, 2019
Citations: 34	License type: CC BY 4.0

Affiliation: Sapienza University of Rome

Abstract

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA—namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa–environment interaction.

Highlights

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting mainly the joints
Several studies, performed on sample collected before the onset of RA, showed that anti-citrullinated peptides antibodies (ACPAs) and rheumatoid factor (RF) are present up to 13 years before the clinical onset of the disease [3]
A series of pathogenic events may outline a possible model of systemic autoimmune response development, in which oral and lung mucosa, under the stimuli of environmental factors, represent sites of ACPA production while gut dysbiosis increases the inflammatory state though increased Th17 polarization and IL-23/IL-17 axis activation (Figure 2)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting mainly the joints. Several studies, performed on sample collected before the onset of RA, showed that anti-citrullinated peptides antibodies (ACPAs) and rheumatoid factor (RF) are present up to 13 years before the clinical onset of the disease [3]. The evidence of several immune abnormalities in subjects at risk for RA without any joint involvement suggests that the pathogenic events leading to the disease may occur outside the joints [12]. All the mucosal sites are equipped with barrier mechanisms, both physical and immunological, to protect the host from potentially harmful pathogens or toxins present in the environment. The purpose of this review is to explore the link between the immune abnormalities present in subjects at risk for RA and the possible influences of environmental factors at the mucosal level

A Multistep Model of RA Development and Genetic Predisposition

The Lung as a Site of ACPA Production

Periodontal and Gut Dysbiosis in the Humoral Autoimmunity

Secretory Immunoglobulins and Aberrant Glycosylation

Abnormal T Cell Polarization and T Cell Phenotypes

Innate Lymphoid Cells May Link Microbiota Changes with T Cell Activation

NETosis in Mucosal Inflammation and Citrullinated Antigen Generation

Findings

Conclusions