The Age-Old Question of ANCA-Associated Vasculitis

Abstract

Anti-Neutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitis (AAV) is a group of systemic autoimmune disorders characterised by severe inflammation of the small blood vessels. Unusually for an autoimmune disease, AAV primarily affects older individuals, however the reasons behind this later-in-life development remains unknown. Although chronological age is widely accepted as an important factor in AAV development, biological ageing, a concept defined by ageing-specific cellular and molecular biomarkers as opposed to chronological time, has received little attention in this disease. With various measurement techniques now available, biological age has been shown to correlate closely with both lifespan and healthspan, making it an interesting approach for the risk assessment of age-associated diseases. Despite biological age measures being a superior method of capturing how the ageing body can lead to disease, biological age has not been assessed in AAV.

Accelerated ageing, which can be determined using these measures of biological age, is often associated with a chronic, low-grade inflammation, a process known as "inflammageing". A key early step in AAV development is the reaction of autoantibodies, known as ANCAs, with innate immune cells leading to their activation and subsequent inflammatory response. The effect that age has on these cells in the context of AAV remains unclear.

Additionally, recent evidence indirectly links AAV pathology and type I interferon (IFN) proteins, a family of innate immune cytokines. The inflammation seen in certain autoimmune conditions, termed type I interferonopathies, is largely due to an overproduction of these type I IFNs and their responses. Our lab has also noted a dysregulation of type I IFN regulated genes with age, possibly indicating a role for these cytokines in the process of inflammageing. However, to our knowledge this protein family are yet to be comprehensively assessed in AAV.

Therefore, during this PhD project we aimed to investigate the relationship between ageing and AAV activity. Our work has demonstrated that AAV patients experience age acceleration compared to healthy controls, using a DNA-methylation based measure of biological age. We have shown that chronological ageing can affect certain immune functions specific to particular immune cell types in response to ANCA stimulation. Finally, we demonstrated that type I IFN signalling is not systemically dysregulated in AAV and therefore AAV should not be considered a type I interferonopathy. Overall, our work indicates important roles for the biological mechanisms associated with ageing in the pathogenesis of AAV.