Scientists show the importance of “putting the brakes on” cytokines to prevent autoantibodies and lupus

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A new study supported by Phenomics Australia has found that rare coding variants in a lupus risk gene could help understand how the immune system mistakenly targets the body’s own tissues.

This article was originally published on the ANU website.

The NCRIS supported Phenomics Australia infrastructure, including the Genome Engineering service at the Australian National University and the Australian Phenomics Facility played a long-term collaborative key role in this study. As well as our colleague NCRIS member, the National Computational Infrastructure.

“ The excellent services provided by Phenomics Australia were integral to the successful outputs of this study”, Dr Ellyard said.

Dr Julia Ellyard. Photo: Tracey Nearmy/ANU

A team led by Dr Julia Ellyard and Professor Carola Vinuesa at the Division of Immunology and Infectious Diseases of the John Curtin School of Medical Research (JCSMR) made this discovery in a study focused on understanding how genetics might contribute to the process of autoimmune disease development. The study was published in the Journal of Experimental Medicine.

Systemic lupus erythematosus (SLE) or Lupus is a complex disease that makes your immune system attack your own body, causing inflammation and damage to various organs. The causes of lupus are not well understood, and this limits treatment options for patients.

Two big factors in the development of lupus are production of autoantibodies and excessive cytokines or responses to cytokines. Cytokines are a group of proteins that function as chemical messengers in the immune system.

Professor Carola G Vinuesa. Photo: Jamie Kidston/ANU

“We found that 5% of lupus patients have changes in a gene, SH2B3, that is important for ‘putting the brakes on’ cytokine responses. This gene was already known to be a risk factor for lupus. Our study has demonstrated that these genetic changes mean the immune cells respond more to cytokines and this can promote autoimmune disease” said Dr Ellyard.

Dr Yaoyuan Zhang, lead author of the paper said, “B cells are a type of white blood cell that have the potential to make antibodies. Normally these cells are tightly controlled but in autoimmune diseases like lupus they go rogue and produce antibodies that attack our own tissues.  We found that because they can respond more to cytokines, these self-attacking B cells that would normally be destroyed are, in fact, able to survive. We think one reason is because they might be able to take up more of a molecule called BAFF that is known to help B cell survival”.

“Survival of self-attacking B cells is known as a break in immune tolerance and is an important step in the development of many autoimmune diseases, not just lupus” he added.

At present, a class of therapies called janus kinase inhibitors are being trialled in lupus patients and these therapies target the same pathway that this gene normally blocks.

“Importantly, our work suggests that SLE patients with these genetic changes may respond well to these therapies,” Dr Ellyard added.

“ The Australian Phenomics Facility (APF), which receives funding through Phenomics Australia, provided state-of-the-art facilities and high level of service to house and care for the mice carrying genetic variants orthologous to our patients. Resources and services from the Phenomics Translational Initiative and the full-body histopathology service supported by Phenomics Australia provided us with a comprehensive characterisation of the mouse models early on in the study”, Dr Zhang added.

Dr Yaoyuan Zhang. Photo: Annemarie Steiner

The Australian Phenomics Facility specialises in the development, characterising and archiving of mouse models of human disease. They have an experienced genomics and bioinformatics capability focussed on the identification of single nucleotide polymorphisms and the phenotyping capability to make the biological associations with probable human disease traits. Their goals are to first derive the underlying genetic mechanisms and then look to extend this across the population and better understand cohort differences and responses.

The facility was established in 2005 and receives funding from the Australian Government’s NCRIS, Super Science and CRIS programmes through the Phenomics Australia and contributions from the Australian National University.

They have an open access policy and support academic and corporate research programmes in Australia and internationally.

Phenomics Australia Histopathology and Digital Slide Service helps researchers across Australia in analysing histology images and data on genetically modified or treated experimental animals. This service offers the latest in high quality capabilities including: Quality controlled mouse necropsies and tissue preparation, pathological analysis  and scoring of tissues, digital slide scanner capable of producing high quality images, high resolution light microscopy with electronic image capture, specialised staining.

Staff providing this service have extensive histology, diagnostic and electronic imaging experience. Consultant Medical and Veterinary Pathologists are available to provide expert advice.

The Histopathology and Digital Slide Service is based at the Department of Anatomy and Physiology at the University of Melbourne.

With an established track record and reputation for excellence, Phenomics Australia Genome Engineering team uses techniques such as CRISPR-mediated mutagenesis, classical gene targeting, and transgenesis to create optimal tools for your research delivering a comprehensive service in genome modification.  To meet the high demand for this platform, Phenomics Australia offers genome editing services through four nodes across Australia, operating at MonashANUWEHI, and SAHMRI.

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