J JAW1,2, M A ALIKHAN2, I S SCHUSTER3, S HOLDSWORTH1,2, M A DEGLI-ESPOSTI3, A R KITCHING1,2,4
1Department of Nephrology, Monash Health, 2Centre for Inflammatory Diseases, Department of Medicine, Monash University , 3Microbiology, Monash Biomedicine Discovery Institute, Infection and Immunity Discovery Program, Monash University , 4Department of Paediatric Nephrology, Monash Health
Aim: To investigate the effect of latent cytomegalovirus (CMV) infection on experimental anti-myeloperoxidase (MPO) autoimmunity and glomerulonephritis (GN).
Background: Autoimmunity to MPO results in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and GN. CMV is present, lifelong, in a latent state after primary infection. Latent CMV infection causes increased peripheral blood CD28- T cells that contribute to mortality in AAV, but this is mechanistically unclear.
Methods: Mice were infected with mouse CMV (K181delm157). Seven weeks later, when viral latency was established (by organ CMV plaque assay, including kidneys), mice were immunised with MPO and autoimmunity assessed 10- and 28-days after immunization. Anti-MPO GN was induced by immunising mice with MPO, GN was triggered by low dose anti-mouse basement membrane globulin, and disease assessed 4 days post trigger (day 21).
Results: Latent CMV infection induced heightened anti-MPO autoimmunity with increased lymph node MPO-stimulated IL-17A and IFNγ production (ELISPOT day 10, sustained at day 21 in anti-MPO GN). Latent CMV infection did not significantly increase MPO-ANCA titres, but autoreactive B cell numbers were increased. In mice with GN, latent infection resulted in increased intrarenal macrophages, CD4+and CD8+ T cells. Intrarenal CMV-specific CD8+ T cells were detected in CMV infected mice with GN by MHCI-peptide tetramer staining. CD28-CD4+and CD8+populations were expanded, while intrarenal CD4+ and CD8+ T cells in CMV infected mice with GN exhibited heightened TNF and IFNγ production as well as increased cytotoxic potential, measured by surface CD107a expression. CMV infected mice with GN developed increased proteinuria, though short-term histological glomerular injury was similar.
Conclusion: Experimentally, latent CMV infection results in heightened anti-MPO autoimmunity and renal inflammation; and may directly influence the course of MPO-AAV in humans.
Dr Juli Jaw is a Consultant Nephrologist at Monash Health and Teaching Associate at Monash University. She obtained her medical degree from The University of Melbourne in 2006 and completed her Nephrology training in 2016. She is currently undertaking a PhD at the Centre for Inflammatory Diseases in the Department of Medicine at Monash University under the supervision of Professor Richard Kitching, Dr Maliha Alikhan and Dr Joshua Ooi. Her PhD focuses on understanding the functional role of CD8+ T cells and latent cytomegalovirus infection in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.