Researchers and clinicians at VIB, KU Leuven and University Hospitals Leuven have identified a genetic mutation that causes a rare form of the autoimmune disease lupus. They discovered the mutation in one Belgian family’s DNA.
Lupus is an autoimmune disorder, meaning that the body’s immune system mistakenly attacks its own tissues. Lupus can affect multiple organs.
Its cause, however, is often not clear. In most cases, a combination of genetic and environmental factors is at play.
One Belgian family’s DNA
Researchers have now discovered a novel genetic mutation in a patient who, at the age of 12, presented with both lupus and problems in the ability of the immune system to fight common infections. This unusual combination of symptoms was quite puzzling.
By analysing the patient’s DNA and that of the parents, the scientists could trace the problem back to a specific mutation in the gene encoding the Ikaros protein. The protein binds DNA to regulate the expression of other proteins.
Hyperactive immune system
Erika Van Nieuwenhove, clinician and scientist at VIB-KU Leuven, explains how the mutation caused the patient’s immune system to be hyperactive: "Because of the mutation, Ikaros can no longer bind its target DNA properly. We also observed that certain immune cells of the patients were hyperactive, even in the absence of stimulation."
"The link between both observations is CD22, a protein that normally dampens the immune response. In normal conditions, Ikaros stimulates the expression of this inhibitor, but that was not the case in this patient."
Very rare form of lupus
About 5 million people worldwide have lupus, but a causative mutation in Ikaros is very rare.
Leuven scientists in Lupus breakthrough https://t.co/VVSqfFTE5y
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"Small changes in Ikaros are associated with susceptibility to adult-onset lupus, but because the effects are weak it is hard to work out what Ikaros is doing to the immune system," explains Professor Adrian Liston (VIB-KU Leuven), the lead author of this study and head of the Translational Immunology lab.
"In this particular family, however, a mutation created a large change in Ikaros, causing early-onset lupus. The mutation was strong enough to allow us to work out how changes in Ikaros cause lupus and immune deficiency."
Mapping the disease mechanism
Although the patient in this study has a very rare form of lupus, the discovery nevertheless helps to map the overall disease mechanisms, says Professor Carine Wouters, a paediatric rheumatologist at University Hospitals Leuven and the co-lead author of the study.
"The mechanism we uncovered in this patient could also be meaningful in a different context with other patients. Now that we understand what goes wrong in this particular case, it could help us think of better treatments for others as well."
The study "A kindred with mutant Ikaros and autoimmunity" was published in the Journal of Allergy and Clinical Immunology ( doi: 10.1016/j.jaci.2018.04.008 ).