Common variable immunodeficiency (CVID) is a disease of the immune system caused by inborn errors. These errors result in a dysfunctional immune system that is unable to protect us against the microbes that surround us. Patients with CVID acquire infections more often or develop more severe disease. The immune system can also become ‘overactive’ and induce responses to innocuous antigens or self-antigens. This immunological dysregulation can ultimately result in auto-immune disease and is an important cause of death. More study is required to develop tools to diagnose and treat this aspect of CVID.
The gene IKZF1 encodes for the transcriptional regulator IKAROS and mutations in this gene give rise to CVID. The spectrum of disease caused by IKZF1 mutations is broad; some patients develop recurring infections whereas others mainly autoimmune diseases. Genetic analysis often reveals that healthy family members also carry the mutation in IKAROS.
We hypothesize that the level of gene function disruption by the distinct IKZF1 mutations is an important determinant of disease. To study the molecular and phenotypical consequences of IKZF1 mutations, we will combine powerful technologies such as single cell RNA sequencing with a large cohort of patients. With this study, we aim to understand the variable clinical presentation associated with CVID caused by IKZF1 mutations. These insights could lead to novel diagnostic and therapeutic opportunities.