Causal risk and protective factors in rheumatoid arthritis: A genetic update

Abstract

The characterization of risk and protective factors in complex diseases such as rheumatoid arthritis (RA) has evolved from epidemiological studies, which test association, to the use of Mendelian randomization approaches, which test direct relationships. Indeed, direct associations with the mucosal origin of RA are retrieved with periodontal disease (Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans predominantly), interstitial lung involvement, tobacco smoking and air pollutants. Next, factors directly associated with an acquired immune response include genetic factors (HLA DRB1, PTPN22), capacity to produce anti-modified protein antibodies (AMPA), and relatives with a history of autoimmune diseases. Finally, factors can be also classified according to their direct capacity to interfere with the IL-6/CRP/sIL-IL6R proinflammatory pathway as risk factor (body fat, cardiometabolic factors, type 2 diabetes, depressive syndrome) or either as protective factors by controlling of sIL-6R levels (higher education level, and intelligence). Although some co-founders have been characterized (e.g. vitamin D, physical activity, cancer) the direct association with sex-discrepancy, pregnancy, and infections among other factors remains to be better explored.

Keywords: Inflammation; Mendelian's randomization; Rheumatoid arthritis; Risk factors; Soluble IL-6 receptor.

Fig. 1

RA development presents four immune-related stages. First the mucosa stage with an intake by antigen-presenting cells (APC) of neo-epitopes corresponding to peptides post-transcriptionally modified at arginine by citrullinisation or at lysine by carbamylation or acetylation in the mouth and/or lung. Second the immunization stage, following APC migration to the secondary lymphoid organs, that involves T and B cells and leading to the production of anti-modified protein autoantibodies targeting mucosal neo-antigens. This step can be completed by the production of anti-peptidylarginine deiminase (PAD) antibodies, antibody targeting bacteria involved in the neo-antigen process, and rheumatoid factors (RF), an anti-immunoglobulin G autoantibody. Third and joint step corresponding to an autoimmune arthritis with a synovial inflammation, which starts following joint leukocyte recruitment, synovial fibrin citrullinisation and fibroblast-like synoviocyte (FLS) proliferation. Finally in the fourth step a chronic and systemic inflammation takes place involving the pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and a dysregulation of the IL-6 signaling pathway to produce joint damage, cartilage destruction, bone erosion and extra-articular manifestations. Abbreviations: HLA: human leukocyte antigen; ACPA: anti-citrullinated antibodies; aCarP: anti-carbamylated antibodies; aPgA: anti-Porphyromonas gingivalis antibodies; AaLtxA: anti-Aggregatibacter actinomycetemcomitans leukotoxin A antibodies; PMN = polymorphonuclear granulocyte cells; MLS: macrophage-like synoviocyte; APC: antigen presenting cells.

Fig. 2

Direct associations between rheumatoid arthritis (RA) development stages and RA-associated risk and protective factors according to Mendelian randomization results. Abbreviations: PD: periodontal disease (Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans); ILD: interstitial lung disease; HLA-DRB1: human leukocyte antigen human leukocyte antigen DR antigen beta 1 chain; SE: shared epitope at HLA-DRB1; Val11: valine 11 at HLA-DRB1; PTPN22: missense R620W polymorphism at non-receptor type 22 gene; BMI: body mass index; CAD: coronary artery disease; CRP: C-reactive protein; sIL-6R: soluble interleukin-6 receptor.

Fig. 3

Interleukin-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor also known as the cluster of differentiation CD126) and gp130 both present in membrane-bound forms or in soluble forms. In the IL-6 classic-signaling pathway (left), IL-6 binds to mIL-6R that recruits gp130 to form a high-affinity functional receptor as observed in lymphocytes and hepatocytes. In the IL-6 trans-signaling pathway (middle), the soluble form of IL-6R (sIL-6R) can bind IL-6 and form in non-immune cells a complex with gp130. Soluble (s)-gp130 (right) is the natural inhibitor of the IL-6/sIL-6R trans-signaling pathway.