Dr TOM LEA-HENRY1,2,3, Ms JEAN CAPPELLO1,2, Ms THUY NGUYEN HUYNH1, Ms SOMASUNDHARI SHANMUGANANDAM1,2, Ms ANANYA SANGEETHA NAGARJUNAN1, Ms NEVINKA PERERA1, ISABELLA BALES1, Associate Professor T DANIEL ANDREWS1, Dr AARON CHUAH1, Ms BRIDIE MOY4, Dr GILES WALTERS2,3, Associate Professor BRENDAN MCMORRAN1, Associate Professor AZURE HERMES4, Dr VICKI ATHANASOPOULOS1,2,5, Associate Professor SIMON JIANG1,2,3,5
1Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia, 2Centre for Personalised Medicine, Australian National University, Canberra, Australia, 3Department of Renal Medicine, The Canberra Hospital, Garran, Australia, 4National Centre for Indigenous Genomics, John Curtin School of Medical Research, Australian National University, Canberra, Australia, 5China Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Jiao Tong University, Shanghai, China
Biography:
Dr Tom Lea-Henry obtained his medical degree from the University of Queensland in 2010. He was admitted to fellowship of the RACP in 2017 after completing advanced training in nephrology at the Canberra and John Hunter Hospitals. Tom is a McCusker Postdoctoral Research Fellow in the Personalised Medicine and Autoimmunity group at the Australian National University and a Staff Specialist Nephrologist at the Canberra Hospital. His research programme investigates the genetic and molecular basis of autoimmunity and kidney disease with particular emphasis on Indigenous Australians. This research forms the basis for using precision medicine techniques to develop novel therapeutic interventions.
Aim:
To determine the role of A20 genetic variants in the development of chronic kidney disease (CKD) among Indigenous Australians
Background:
Kidney disease is the leading cause of death among the Indigenous Australian inhabitants of the Tiwi Islands, who have the highest reported rates of CKD worldwide. It is estimated that 65% of CKD risk on the islands is inheritable. A20 is a key regulator of Toll-like receptor (TLR)-mediated inflammatory responses and genetic variation in A20 is associated with CKD. We have discovered six genetic variants in the A20 gene that are globally extremely rare, yet occur in >90% of Tiwi Islanders.
Methods:
We conducted overexpression assays testing repression of TLR signalling. A mouse model reproducing the most deleterious of these variants (A20N102S) was developed using CRISPR-Cas9. To determine the impact of A20N102S-induced dysregulation of TLR-mediated autoimmune kidney disease, we crossed these mice to the Lyn-/- mouse model. Alterations to immune homeostasis and glomerulonephritis were analysed using flow cytometric immunophenotyping, ex vivo functional assays, autoantibody analysis, cytokine release assays, and necropsy.
Results:
We demonstrate that the A20N102S variant impairs repression of inflammatory TLR signalling. A20N102S/N102S mice have expansion of age-associated B cells and germinal centre B cells consistent with the reliance on TLR signalling in these immune cells. Lyn-/-.A20N102S/N102S mice have accelerated development of glomerulonephritis and increased production of IgG1 and IgG2 anti-DNA autoantibodies.
Conclusions:
Using the first mouse avatar designed to specifically study chronic diseases in Indigenous Australians, we demonstrate that genetic variants in A20 accelerate inflammatory kidney disease. This improves our understanding of the unique mechanisms of kidney disease among Indigenous Australians and identifies a novel therapeutic strategy targeting TLR signalling.