Over the past 50 years, the rate of autoimmune diseases, including type 1 diabetes (T1D) has increased significantly in many developed countries around the world. Canadians are at the top of the list, having the third highest rate of type 1 diabetes in the world.
Previously known as juvenile diabetes, the onset of T1D usually occurs during childhood or adolescence and has been occurring at younger age in the recent decades. The disease results from the immune system attacking insulin-producing cells in the pancreas. As a result T1D patients are prescribed insulin injections for the rest of their lives. But why does the immune system attack these insulin-producing cell? Variants in the human leukocyte antigen (HLA) genes are known determinants of disease risk. However, since human genes change slowly over time, genetic changes cannot explain the recent increase in T1D rates. Instead, data suggests that changes in our modern environment have increased the risk for autoimmune diseases including T1D.
Recent studies looking for a link between the gut microbiome composition and T1D onset have found patients with T1D have less microbe diversity compared to healthy controls. However, no link has been found between specific bacteria and future disease risk.
To investigate further, researchers at The Hospital for Sick Children (SickKids) looked at the immune responses beyond the gut microbiome. A team led by Dr. Jayne Danska, Senior Scientist and Associate Chief, Faculty Development at SickKids, together with Dr. Alexandra Paun, Research Fellow, Genetics and Genome Biology at SickKids and Christopher Yau, Ph.D. student at SickKids and The University of Toronto investigated patterns of antibody responses detected in the blood from children with recent onset T1D or pre-diabetic children with genetic risk factors for the disease.
They found that the patterns of antibody responses to gut bacteria in children who were recently diagnosed with T1D differed from those without T1D. They also looked at anti-bacterial antibody responses in children with genetic risk factors for T1D, collected months before half the kids went on to develop and the other half of the kids did not develop T1D. The antibody response patterns they observed were strongly associated with a future disease diagnosis. In addition, these antibody response patterns were strongly associated with variants in the HLA genes which are the most impactful genetic risk factor for this disease.
This research, published in the February 2019 issue of Science Immunology, is the first to clearly connect immune responses to gut microbes with the future development of T1D in children.
“Our results suggest that the influence of gut microbes on type 1 diabetes is controlled by immune recognition,” says Dr. Danska. “This recognition depends on HLA genes that are the foundation of the immune system’s ability to respond to diverse proteins of both microbial and human origin. The next step will be to determine if any of these anti-bacterial antibodies cross-react with human molecules that may underlie autoimmune responses.”
The analysis platform Danska’s group developed may be useful for predicting T1D risk before the disease appears, and for monitoring responses to drugs that seek to balance the immune system, which are the focus of clinical trials being done to prevent and treat autoimmune diseases.
This study was supported by the Canadian Institutes of Health Research, the Juvenile Diabetes Foundation, the SickKids Foundation and the Anne and Max Tanenbaum Chair, University of Toronto. This is an example of how SickKids is making Ontario healthier, wealthier and smarter (www.healthierwealthiersmarter.com).
The Hospital for Sick Children (SickKids)