An IRCM Team Shows the Causal Effect of a Family of Protein in the Disease
Photo : Dr. Hua Gu and his team from left to right: Li Zhong, Xiaochen Zhang, Xin Li, and Weili Sun
A team directed by Dr. Hua Gu in the Molecular Immunology Research Unit at the Montreal Clinical Research Institute (IRCM) – also a Full Research Professor in the Department of Microbiology, Infectious Diseases and Immunology (Biomedical Sciences accreditation) at Université de Montréal and an Adjunct Professor at McGill University – recently unveiled an important discovery, bringing new light on the underlaying molecular mechanisms of human Systemic Lupus Erythematosus (SLE), a disease commonly known as Lupus.
Published in the highly prestigious scientific journal Immunity, this massive work is the first to identify a family of protein ubiquitin ligases (CBLs) as a common molecular trait causing Lupus in humans; a groundbreaking advance that could pave the way to future therapies in this field.
About Lupus (SLE)
Lupus is a chronic autoimmune disease that affects 1 in every 2000 Canadians of all ages, and 90 % of those affected are women. The disease causes the immune system to attack it own tissue, causing widespread inflammation which results in swelling, pain and other symptoms in most organs, with a severity ranging from mild to life threatening. Described for the first time in the mid-1800s, the disease remains without a cure to this day, and its causes remained little known.
In Dept
Previous studies revealed the increased presence of blood circulating Tfh cells (specialized among T-cells, a subcategory of immune cells) in lupus patients. Studies using mouse models have also established the role of Tfh cells in developing SLE-like disease. However, the molecular mechanism leading to the excessive Tfh cell development in SLE patients and whether it actually contributes to the manifestation of SLE remain elusive.
Dr. Hua Gu’s team found that SLE patients downregulated CBLs, a group of protein responsible for T-cell activation. The team and its collaborators compared the expression of blood circulating Tfh cells in both patients with active SLE and healthy donors. They were thus able to confirm, consistently with previous reports, that these SLE patients possessed more circulating Tfh cells than healthy individuals. Also, more than 80% of SLE patients in the study either lacked or downregulated both CBLs in T cells, confirming that this molecular alteration is a relative common defect in SLE patients. It was also noted that the degree of CBLs downregulation is strongly correlated to the severity of the disease in humans.
At a molecular level, using a mouse model, the team demonstrated that ablation of CBLs in T cells led to hyper Tfh cell responses and caused SLE in subjects, suggesting in CBLs deficient T cells preferentially leads to Tfh cell hyper responses, which is one primary cause for lupus development in mice and humans.
Interestingly, this study gave an important insight on Lupus’s pathogenesis, suggesting the pathologic downregulation of CBLs is more likely caused by epigenetic and environmental than genetic factors. This is because the data showed that the impaired expression of CBLs in Lupus patients occurred only at the post transcriptional level, among other things. This observation not only explains why previous genome-wide genetic and transcriptome analyses have failed to reveal this molecular defect but also provides a direction for future studies to uncover molecular risk traits contributing to SLE and other diseases.
“This work is highly promising because of the great potential it holds for future therapies. This new understanding of Lupus underlying mechanisms means we might have identified the first biomarker that will help detect the risks of developing, prevent or even cure Lupus is the future. Although more investigation is needed, this advance gives us great hope for the future”, explained Dr. Hua Gu.
The Next Steps
This new light on the molecular mechanism of Lupus opens a wide novel investigation field with a great potential for new lupus therapies.
“This is just the beginning, as many more questions are emerging from this work. For example, something that remains unclear is the molecular mechanism that leads to the downregulation of CBLs in T cells,” explained first author Dr. Xin Li, a former postdoctoral student at the IRCM, who is now a leading scientist at the Southern Medical University, in Guangdong, China.
Dr. Gu’s teams and his collaborators are already pushing forward, working on the next steps. Their goal is primarily 1) to further elucidate what causes this molecular alteration in Lupus patients, which may help to reveal the susceptible factors of SLE. 2) to determine whether Lupus can be treated by targeting this molecular pathway. 3) to establish a method based on their finding for the diagnosis and tracking the disease progression and predicting the prognosis during SLE treatments.
Acknowledgements
This work was made possible thanks to the Canadian Institutes of Health Research (CIHR). We also thank the IRCM core facilities for their support as well as our international collaborators.
