How does age determine the development of human immune-mediated arthritis?

Abstract

Does age substantially affect the emergence of human immune-mediated arthritis? Children do not usually develop immune-mediated articular inflammation during their first year of life. In patients with juvenile idiopathic arthritis, this apparent 'immune privilege' disintegrates, and chronic inflammation is associated with variable autoantibody signatures and patterns of disease that resemble adult arthritis phenotypes. Numerous mechanisms might be involved in this shift, including genetic and epigenetic predisposing factors, maturation of the immune system with a progressive modulation of putative tolerogenic controls, parallel development of microbial dysbiosis, accumulation of a pro-inflammatory burden driven by environmental exposures (the exposome) and comorbidity-related drivers. By exploring these mechanisms, we expand the discussion of three (not mutually exclusive) hypotheses on how these factors can contribute to the differences and similarities between the loss of immune tolerance in children and the development of established immune-mediated arthritis in adults. These three hypotheses relate to a critical window in genetics and epigenetics, immune maturation, and the accumulation of burden. The varied manifestation of the underlying mechanisms among individuals is only beginning to be clarified, but the establishment of a framework can facilitate the development of an integrated understanding of the pathogenesis of arthritis across all ages.

Fig. 1. Model of age-related arthritis emergence.

Emergence of arthritis is a multifactorial phenomenon. Given the striking differences observed between paediatric-onset and adult-onset arthritis, age-specific mechanisms are likely to be present. How these mechanisms articulate in individuals is still only beginning to be clarified. We propose an age-related model of arthritis emergence, based on three hypotheses that are not mutually exclusive, and that are potentially even interconnected. The ‘critical window’ hypothesis relates to pro-arthritogenic factors that might define a set point for arthritis emergence. As such, genetic predisposition, epigenetic status and associated comorbidities represent relevant components for this critical window. The immune-maturation hypothesis relates to the fact that the first year of life is usually free of arthritis, suggesting an immune ‘privilege’. Currently available data suggest a low propensity at this age to autoimmune inflammatory responses that is related to regulatory controls such as the presence of a naive immune repertoire, with tolerogenic T lymphocytes, naive dendritic cells and a diverse regulatory T (T_reg) cell repertoire. Early microbiota composition, built from fetal stages onwards, may also contribute to this ‘tolerogenic’ environment. However, aberrant priming of the immune system, especially resulting from infection with pro-arthritogenic pathogens (and other unknown mechanisms) could also affect the emergence of arthritis. Finally, the accumulation of a pro-inflammatory burden resulting from acquired influences such as adiposity, smoking, microbiome dysbiosis, immunosenescence and inflammageing, and more widely by the exposome, represent additive hits upon regulatory control, leading to breach of tolerance, and inflammation.

Fig. 2. Factors influencing immune-system maturation and arthritis development.

The adaptive immune system of the fetus and the child gradually acquires the ability to respond to specific antigenic challenges. By nature, the naive immune system harbours tolerogenic cells, including naive dendritic cells and regulatory T (T_reg) cells. Priming of the immune system reshapes the immune response and the predisposition to later inflammatory arthropathies. This influence starts in utero with exposure to maternal microbiota, and continues with breastfeeding and with environmental exposures. Altogether, these factors are responsible for large modifications of the microbiota during growth, especially in the gut, and for the subsequent activation of the immune system, potentially triggering the emergence of arthritis in children.

Fig. 3. Influence of prior joint priming on arthritis fate.

Proposed (age-dependent) factors determining arthritis ‘heterogeneity’, depending on the baseline status of the joint (‘naive’ versus ‘primed’). In naive and in primed joints, some factors are presumed to have a dampening influence on joint inflammation, and similarly, in naive and in primed joints, other factors are thought to have a perpetuating influence on inflammation. T_(RM) cells, tissue-resident memory T cells.