INVESTIGATING THE ROLE OF ACCELERATED IMMUNESENESCENCE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

• Advancing age is recognised as a major risk factor for autoimmune inflammatory conditions, such as Rheumatoid Arthritis (RA). Despite strong associations with older age we understand little of the role ageing processes play in disease pathogenesis in RA. The immune system undergoes a dramatic remodelling with age, termed immunesenescence, which contributes towards increased risk of autoimmunity1. Previous research in patients with established RA has shown certain features of immunesenescence, such as thymic atrophy and telomere shortening in T cells, at a younger age2,3.ObjectivesIn this study we aimed to determine if immunesenescence is seen in the very earliest stages of RA and therefore might be a contributor to RA pathogenesis rather than a result of the disease.MethodsWe have assessed aspects of the aged immune phenotype by immunostaining and flow cytometry4 in adults with arthralgia (n=25), undifferentiated arthritis (UA; n=41), confirmed RA of less than 3 months (n=25) and more than 3 months duration (n=78) and compared these to age and sex matched healthy controls (n=38). Nanostring methodology was used to determine gene expression changes associated with the development of RA.ResultsWe observed increased features of T and B cell immunesenescence in DMARD-naïve recently diagnosed RA patients driven by reduced naïve T cells (p<0.01) and B cells (p<0.01), increased senescent (CD28-ve, CD57+ve, KLRG1+ve) T cells (p<0.01), an increased Th17/Treg ratio (p<0.01) and increased frequency of age-associated B cells (p<0.01). With the exception of naïve T cell frequency, which was reduced in UA patients (p<0.05), these changes were not seen in the very early stages of RA, namely patients with arthralgia and UA. These data suggest that immunesenescence only occurs once disease is established. Furthermore, using nanostring we have identified several biological ageing processes (DNA damage, autophagy) associated with this state of immunesenescence in RA.ConclusionAccelerated immune ageing is an early feature of RA and biological ageing processes represent novel targets to modulate disease progression.References[1]Duggal NA, Upton JA, Phillips AC, Sapey E, Lord JM (2013) An age-related numerical and functional deficit in CD19+CD24hiCD38hi B cells is associated with an increase in systemic autoimmunity. Aging Cell 12:873-881.[2]Goronzy, J.J. and Weyand CM (2001). Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol. 22(5):251-5.[3]Steer SE, Williams FMK, Kato B, Gardner JP, Norman PJ, Hall MA, Kimra M, Vaughan R, Aviv A, Spector T (2007) Reduced telomere length in rheumatoid arthritis in independent of disease activity and duration. Ann Rheum Dis 66:476-480.[4]Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM (2018). Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17:e12750Disclosure of InterestsNone declared

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