Illuminating the path towards new lupus treatments

Publication date
Tuesday, 14 Dec 2021

In 2016, the China-Australia Centre for Personalised Immunology (CACPI) was established to benefit patients with immune diseases.

Connecting the Centre for Personalised Immunology at The John Curtin School for Medical Research, The Australian National University and the Renji Hospital at Shanghai Jiao Tong University School of Medicine, CACPI seeks to use the joint expertise of both institutes to understand the genetic causes of immune diseases, improve diagnosis, and develop more specific and effective treatments.

Now, at the five-year mark since its inception, CACPI published results of their latest research that could stimulate new treatments for lupus.

Lupus is a chronic autoimmune disease in which a patient's immune system attacks the healthy tissues in their own body, causing inflammation and pain. The disease affects over five million people across the globe, but its causes remain poorly understood and its cure absent.

To shed light on the genetic contribution to lupus development, CACPI researchers teamed up with Jason Cyster's lab at the University of California, San Francisco and looked into the genomes of people with lupus or lupus-related antiphospholipid syndrome.

By sequencing the protein-coding regions in genomes of the patients and their families, the researchers identified three rare mutations in the gene P2RY8, including a new mutation in a child with severe lupus nephritis (inflammation of the kidneys).

These rare variants allowed the international team to uncover the role of P2RY8 in immune tolerance, a critical state in preventing the immune system from being overreactive.

All three identified mutations led to a decreased expression of the P2RY8 protein—a phenomenon seen even in many lupus patients not carrying the mutations.

Low P2RY8 also correlated with lupus nephritis and increased self-targeting immune cells, suggesting that compromised functioning of the P2RY8 pathway may contribute to the development of lupus.

"It was exciting to see a correlation between low P2RY8 in disease-causing B cells and kidney damage," said Dr Yuke He, the co-lead author of the study.

In China, lupus patients are likely to have more severe kidney damage and higher mortality risk.

The discovery of a link between P2RY8 deficiency and kidney damage, as CACPI Co-director Professor Nan Shen believes, could light up the way of developing pathway-specific therapeutics against this debilitating disease. Professor Shen is a corresponding author of the study.

"Our findings raise the possibility that augmenting signalling via the P2RY8 pathway may have therapeutic potential in prevention or treatment of systemic autoimmune disease," the researchers wrote in their paper published in the Journal of Experimental Medicine.

"The authors perform a detailed immune and genetic phenotyping to characterise new genetic variants of P2RY8 occurring in SLE patients," commented Dr Maud Tusseau and Professor Alexandre Belot from Claude Bernard University Lyon 1, "And they demonstrate the critical role of P2RY8 in preventing systemic autoimmunity." Tusseau and Belot are not involved in the study.

Behind the success story of this new insight into lupus development and treatment is a paradigm for international cooperation in immunology research that CACPI established over the past half-decade.

"This study highlights the importance of international partnerships and carrying out genetic studies in ethnically diverse populations," said Professor Carola Vinuesa, CACPI Co-director and one of the corresponding authors of the study.

Future studies in lupus models may help further characterise the mechanism of how P2RY8 limits autoimmunity.