DOMINANT HLA-MEDIATED PROTECTION FROM THE RISK OF AUTOIMMUNE RENAL DISEASE IS CONFERRED BY ANTIGEN-SPECIFIC REGULATORY CELLS

OOI JD1, PETERSEN J2, TAN YH2, HUYNH M1, WILLETT ZJ1, RAMARATHINAM SH2, EGGENHUIZEN PJ1, LOH KL2, WATSON KA3, GAN PY1, ALIKHAN MA1, DUDEK NL2, HANDEL A4, HUDSON BG5, FUGGER L6, POWER DA7, HOLT SG8, COATES PT9, GREGERSEN JW10, PURCELL AW2, HOLDSWORTH SR1,11, LA GRUTA NL2,3, REID HH2, ROSSJOHN J2, KITCHING AR1,11

1Monash University Centre for Inflammatory Diseases, Clayton, VIC, 2 Monash University Biomedicine Discovery Institute, Clayton, VIC, 3 Dept. of Microbiology and Immunology, Melbourne University, Melbourne, VIC, 4 University of Georgia, GA, USA, 5 Vanderbilt University, TN, USA, 6 University of Oxford, Oxford, UK, 7 Dept. of Nephrology, Austin Health, Heidelberg, VIC, 8 Dept. of Nephrology, Melbourne Health, Parkville, VIC, 9 Royal Adelaide Hospital, Adelaide, SA, 10 Dept. of Medicine, Viborg Regional Hospital, Viborg, Denmark, 11 Dept. of Nephrology, Monash Health, Clayton, VIC.

Aim: To use Goodpasture’s disease (GPD), a classical form of HLA-linked autoimmunity, to define the mechanism of HLA-mediated risk, and dominant protection from risk of disease.

Background: The mechanisms underpinning HLA-mediated susceptibility to, and protection from autoimmune diseases are unknown. GPD is HLA-linked and characterised by an immunodominant CD4+ self-epitope derived from the a3 chain of Type IV collagen (a3135-145).

Methods: HLA-DR transgenic mice, cells from HLA-typed healthy humans and from patients with GPD were used, with HLA-DR-a3135-145 tetramers, X-ray crystallography, and in vivo/in vitro models of autoimmunity.

Results: Autoreactive a3135-145-specific T cells clonally expanded in GPD patients. In a3135-145-immunised HLA-DR15 transgenic mice with GPD, a3135-145-specific T cells infiltrated the kidney. Structurally, HLA-DR15 and HLA-DR1 presented a3135-145 in different binding registers, resulting in differential T cell receptor (TCR) usage. HLA-DR15-a3135-145 tetramer+ CD4+ T cells in disease susceptible HLA-DR15 transgenic mice exhibited a conventional phenotype (Tconv), secreting pro-inflammatory cytokines. In contrast, HLA-DR1-a3135-145 tetramer+ cells in disease resistant HLA-DR1 and HLA-DR15/DR1 transgenic mice were largely CD4+Foxp3+ regulatory T cells (Tregs) expressing tolerogenic cytokines. In HLA-DR15/DR1 transgenic mice, HLA-DR1-a3135-145 specific Tregs conferred protection to a3135-145-specific autoimmunity and protected from GPD (a3135-145-immunised, Treg intact vs Treg depleted: segmental necrosis 0±0 vs 50±13% P<0.01, serum urea 9±1 vs 31±10 P<0.001). HLA-DR15+ and HLA-DR1+ healthy human donors displayed altered a3135-145-specific TCRs, with HLA-DR15-a3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-a3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes (a3135-145 tetramer+ Treg:Tconv ratios: DR15 0.04±0.00, DR1 9.61±1.79, P<0.001).

Conclusions: These studies define, for the first time in an autoimmune disease, a mechanism for the dominantly protective effect of HLA, where HLA polymorphisms determine the abundance of self-epitope specific Tregs, leading to protection or causation of autoimmunity.

About ANZSN

The ASM is hosted by Australian and New Zealand Society of Nephrology.

The aims of the Society are to promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology in Australia and New Zealand.

Conference Managers

Please contact the team at Conference Design with any questions regarding the conference.
/wp-content/uploads/2017/08/Conference-Design-400x400.png
© 2015 - 2016 Conference Design Pty Ltd