A new disease has been discovered that links disruptions of blood formation, the immune system, and inflammation
In the quest to find the origin of the puzzling symptoms in four children, researchers from St Anna Children’s Cancer Research Institute (St Anna CCRI), the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM ÖAW), and the Medical University of Vienna (MedUni Vienna) have discovered a completely new disease, linking disruptions of blood formation, the immune system, and inflammation.
This groundbreaking discovery provides the basis for a better understanding of similar diseases.
It is a milestone that the researchers have published in a prestigious international journal, the New England Journal of Medicine.
The newly identified defect in the DOCK11 gene leads to abnormalities in both white and red blood cells.
Kaan Boztug, senior author of the study and scientific director of St Anna CCRI, said: “Such rare and previously unknown diseases provide valuable insights into the fundamental principles of blood formation and the immune system.
“They allow us to better understand the dysregulated processes underlying these diseases.”
The gene defect was first identified in a young patient from Spain, where despite repeated tests, no explanation could be found for the severe inflammation affecting various organs such as the kidneys, intestines, and skin.
The treating physician then contacted the St Anna CCRI providing blood samples from the patient. And was successful.
The internationally leading centre for rare diseases of blood formation and the immune system found the cause.
Boztug, who is also a professor in the field of Paediatrics and Inflammation Research at MedUni Vienna and an adjunct principal investigator at CeMM ÖAW, added: “We work closely with international partner institutions to understand such diseases and help the patients.”
The patient’s genome sequencing revealed a severe defect in the DOCK11 gene, a gene that had not been previously associated with any human disease and is involved in cell communication.
Jana Block, first author of the publication and a PhD student in Boztug’s research group at St Anna CCRI and CeMM, explained: “Initially, we had only one patient and therefore did not know which symptoms were related to the gene defect and which were just additional accompanying manifestations. That was quite a challenge.”
Through their international collaborations, the researchers managed to find additional patients with similar DOCK11 mutations, which helped provide a clearer understanding of the disease.
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DOCK11 controls blood formation
One of the patients suffered from a significantly reduced number of red blood cells and required regular blood transfusions.
Block said: “Anaemia often occurs with immune deficiencies, and often, a person’s own red blood cells are destroyed by autoantibodies that target their own blood cells.
“In healthy people, however, this does not happen. However, in our investigations, we did not find such autoantibodies.”
The cause of the decreased number of red blood cells was clarified by the researchers using a zebrafish model.
The DOCK11 defect resulted in impaired blood cell formation, leading to a novel mechanism for anaemia, a deficiency of red blood cells.
The role of DOCK11 in humans was, until now, unexplored; previous studies had shown the importance of the protein for the development of B cells in mouse models.
The researchers have now shown that to a certain extent, B cells also do not develop properly in humans with DOCK11 deficiency, and at the same time, other immune cells, called T lymphocytes, are overactivated.
Block said: “The protein appears to play a role in keeping the activation of T cells within a certain range.”
This is important because overactivation can lead to damage to surrounding tissues and organs, especially in the absence of an actual pathogen.
A connection between T-cell defects and predisposition to tumour diseases is observed in other immune deficiencies and cannot be ruled out in the case of DOCK11 deficiency.
Boztug added: “We will certainly investigate this question further in our research.”
Although not all details of DOCK11’s function are yet understood, the researchers suspect that transplantation of blood-forming stem cells could cure the disease.
Boztug advised: “Of course, these questions need to be investigated in future studies.
“It is also conceivable that DOCK11 deficiency could be treated through gene therapy.”
The fact that there is now hope for the development of therapies has a very special significance for the scientists.
Block said: “Our work over the past five years is undoubtedly a significant milestone, but we are also aware that several of the patients have died from the disease.”
The researcher hopes that now other centres will become aware of this gene mutation and further advance the exploration of this disease.
Boztug concluded: “This disease is truly severe, so we see it as our mission not only to understand the biological processes but also to develop effective therapeutic strategies based on that.”
Image: Healthy T cells (left) and DOCK11-deficient T-cells (right) with visible nucleus (blue) and aktin-cytoskeleton (green). Credit: St Anna Children’s Cancer Research Institute.