Ageing enhances cellular immunity to myeloperoxidase and experimental anti-myeloperoxidase glomerulonephritis

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disease characterised by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase, an autoantigen responsible for ANCA-associated vasculitis, increases with age, anti-myeloperoxidase autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity. METHODS: Young (8 weeks) and aged (either 15 or 22 month) mice were immunised with whole proteins or peptides from ovalbumin, as a model foreign antigen, or myeloperoxidase protein or peptides. Mice were subjected to a model of active anti-myeloperoxidase glomerulonephritis. Cellular and humoral immune responses and tissue inflammation were assessed. RESULTS: While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to myeloperoxidase and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen specific production of the pro-inflammatory cytokines interferon-γ and interleukin-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys. CONCLUSION: Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of ANCA-associated vasculitis in older people