Heartbreaking Rare Disease: Study Reveals New Insights into XLP-2 Immunodeficiency
Reviewed by Megan Craig, M.Sc. – August 3, 2023
A recent study conducted by a research team led by the University of Ottawa has shed light on the mechanisms behind X-linked lymphoproliferative type 2 (XLP-2) immunodeficiency, a devastating rare disease that primarily affects boys. The findings, published in the peer-reviewed medical journal PLOS Pathogens, offer new hope for understanding and potentially treating this condition.
XLP-2 is a genetic disease that was first identified in 2006. It is characterized by severe complications in individuals who contract the Epstein-Barr virus (EBV), a common virus that usually causes no harm in the general population. However, in XLP-2 patients, the Epstein-Barr virus can lead to immunodeficiency, an impairment of the immune system that often proves fatal.
The researchers set out to investigate how the inactivation of a specific protein-coding gene called XIAP contributes to this immunodeficiency. Dr. Subash Sad, the senior author of the study and a cellular immunologist at the University of Ottawa’s Faculty of Medicine, explained, We aimed to examine how the inactivation of XIAP triggers this immunodeficiency. It was previously believed that the inactivation directly affected T cells, but our work has shown that this is not entirely true. Inactivation of XIAP impacts the survival of T cells through both direct and indirect effects, resulting in a state of immunodeficiency.
To understand the impact of XIAP inactivation, the researchers conducted experiments using recombinant bacteria and T cell transgenic cells. The majority of the experiments were performed on a mouse model, with additional mechanistic studies conducted on various immune system cells.
The study revealed two key underlying mechanisms. First, inactivation of XIAP leads to reduced expression of Interleukin-6 (IL-6), a protein crucial for the proliferation of activated T cells. Second, XIAP inactivation compromises the ability of activated T cells to survive long-term. Consequently, memory T cells, which are responsible for monitoring the body and are typically induced during previous infections or vaccinations, struggle to survive in the presence of XIAP inactivation. This discovery helps elucidate why XLP-2 patients experience immunodeficiency.
One of the project reviewers described the research as a series of very elegant studies and praised the findings as novel and well substantiated by the data. The rigorous research undertaken by the team has taken four years to reach this publication, thanks in part to funding from the NSERC and CIHR, as well as the expertise of the University of Ottawa’s Flow cytometry core facility.
Looking ahead, the research team plans to further investigate downstream mechanisms and pathways that could be targeted for therapy. They are also keen to collaborate with XLP-2 patient families and encourage them to reach out to the Children’s Hospital of Eastern Ontario (CHEO), an institutional partner of the University of Ottawa’s Faculty of Medicine.
This groundbreaking study opens up avenues for future research and potential treatments for XLP-2 immunodeficiency. By deepening our understanding of the underlying mechanisms, scientists can develop novel therapeutic approaches to combat this devastating disease. The study’s findings offer hope for improving the lives of individuals affected by XLP-2 and their families, as well as paving the way for advancements in the treatment of other immunodeficiencies.
Journal Reference:
Thakker, P., et al. (2023) XIAP promotes the expansion and limits the contraction of CD8 T cell response through cell extrinsic and intrinsic mechanisms respectively. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011455.
