Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression

Abstract

Patients with rheumatoid arthritis (RA) develop features of accelerated ageing, including immunosenescence. These changes include decreased thymic functionality, expansion of late-differentiated effector T cells, increased telomeric attrition, and excessive production of cytokines (senescence-associated secretory phenotype). The progression of RA has been associated with the early development of age-related co-morbidities, including osteoporosis, cardiovascular complications, and cognitive impairment. Here I review data supporting the hypothesis that immune-senescence contributes to the aggravation of both articular and extra-articular manifestations. Of note, poor cognitive functions in RA were associated with senescent CD28- T cells, inflammaging, and autoantibodies against brain antigens. The pathways of immune-to-brain communication are discussed and provide the rationale for the cognitive impairment reported in RA.

Keywords: Ageing; Cell senescence; Cognitive impairment; Immune ageing; Rheumatoid arthritis.

Fig. 1

The senescent T cells are associated with inflammaging and age-related morbidities in RA. The late-stage differentiated (senescent) T cells are defined by phenotypic changes including loss of CD28 expression, acquisition of inflammatory (SASP: senescence-associated secretory phenotype) and cytotoxic functions, as well as expression the chemokine receptor CX3CR1, which could underlie their ability to infiltrate peripheral inflammatory sites. These cells do not proliferate, because of shortened telomeres, but remain metabolic active. These cells have been found expanded in RA, of note during the clinical progression. They have been implicated with articular damage and osteoporosis, cardiovascular diseases and cognitive impairment

Fig. 2

Pathways involved in the immune-to-brain communication. Three pathways participate in the immune-to-brain communication: humoral, neural and cellular (leukocyte) routes. Tissue-resident macrophages get activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Both PAMPs (infections) and DAMPs (sterile injury) engage inflammatory signalling pathways, such as nuclear factor-κB (NF-κB). The pro-inflammatory cytokines in turn are promptly secreted and enter the bloodstream. The plasma cytokines can reach the brain through various mechanisms, including the i) active transport by crossing the brain-blood barrier (BBB) through leaky areas in the circumventricular organs (humoral route); or ii) through the activation of afferent neural pathways (e.g., the vagus nerve). The leukocytic route is another mechanism of immune-to-brain communication and is mediated by the migration of circulating leukocytes to the brain borders. Leukocytes are present in small numbers in brain circumventricular organs and choroid plexus. Under healthy conditions, these peripheral immune cells support neuronal function and scan the brain for pathogens or tissue damage