M ALIKHAN 1, J JAW 1,2, L SHOCHET 1,2, K ROBSON 1,2, J OOI 1, S HOLDSWORTH 1,3, A KITCHING 1,2,4
1Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Australia, 2Department of Nephrology, Monash Health, Clayton, Australia, 3Department of Clinical Immunology, Monash Health, Clayton, Australia, 4Department of Paediatric Nephrology, Monash Health, Clayton, Australia
Aim: To investigate the contribution of age to the development of anti-myeloperoxidase (MPO) autoimmunity and glomerulonephritis in murine models.
Background: Autoimmunity to the neutrophil protein MPO results in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) commonly causing glomerulonephritis. The incidence of AAV increases with age often resulting in worse prognosis and increased mortality. Previous work in aged mice using a passive transfer model of anti-MPO IgG induced glomerulonephritis has implicated innate effectors. However, the role of ageing on active anti-MPO autoimmunity and effector responses is unclear
Methods: Young (2-3 months) and aged (15-22 months) mice were immunised with whole proteins or peptides from ovalbumin (a model foreign antigen) or MPO and autoimmunity assessed 10‐ and 35‐days later. Anti‐MPO glomerulonephritis was induced by immunising mice with MPO and glomerulonephritis was triggered by low dose anti‐mouse basement membrane globulin. Disease was assessed 4 days later (day 21).
Results: While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to MPO and its immunodominant CD4+ and CD8+ epitopes was increased after immunisation with either whole MPO protein or peptides, assessed by peptide and antigen specific production of the pro-inflammatory cytokines interferon-γ and interleukin-17A. Both OVA- and MPO-ANCA titres were decreased in aged mice compared with young mice 35 days after immunisation. Aged mice with anti-MPO glomerulonephritis developed more glomerular segmental lesions (young:30.2±4.9, aged:56.3±6.4% P<0.004) and cell mediated injury (including IFN-γ and TNF producing T cells), 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 AAV in older people.
Maliha Alikhan is a Research Fellow in the Centre for Inflammatory Diseases, Department of Medicine at Monash University. Maliha completed her PhD at Monash University in 2012 under the supervision of Professor Sharon Ricardo, investigating the role of reparative macrophages in acute kidney injury. She joined the Autoimmune Kidney Disease and Vasculitis Research Group under the supervision of Professor Richard Kitching in 2013. Her main research area is investigating adaptive immune responses in experimental models of autoimmune anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis to better understand the pathogenesis of T cell mediated kidney disease and identify potential therapeutic targets.