Virtually the entire population of sub-Saharan Africa, and some 70% of African Americans, carry a gene variant (allele) which results in a trait referred to as Duffy-negative. It has recognized that carriers of this version of the gene are fairly protected from some strains of malaria. In addition , the particular allele has recently been linked to benign neutropenia — the mild reduction in the numbers of neutrophilic granulocytes (neutrophils), a kind of white blood cells present in the circulation. Although neutrophils are known to play an important part in the innate defense defenses against pathogens, Duffy-negative individuals do not show any kind of obvious increase in susceptibility to infections. In a new research led by LMU’s Dr . Johan Duchê ne, Teacher Christian Weber and Professor Antal Rot (also in University of York), an international team of biomedical experts has now shown how the Duffy-negative variant affects the difference of white blood cells and why it results in a relative paucity of circulating neutrophils. The findings come in the current issue of the journal Nature Immunology .
All blood cellular types are generated in the bone marrow. In a procedure called hematopoiesis, so-called multipotent hematopoietic stem cells plus progenitor cells progressively give rise to the different types of cells present in the bloodstream. Among these are the neutrophils and the erythrocytes (aka red blood cells). Duffy-negative individuals lack a particular protein, the atypical chemokine receptor 1 (abbreviated ACKR1), normally found on the surface of the erythrocytes. ACKR1 is known to connect to signal molecules called chemokines that regulate immune reactions. However , some pathogens responsible for malaria use this receptor in order to dock onto and subsequently invade red blood cells. This describes why people who lack this receptor are more resistant to several types of malaria. “But how the lack of ACKR1 on blood alters the balance of white blood cell types has been entirely unknown up to now, ” Duchê ne says.
Using the mouse as an experimental model, Duchê eine and his colleagues have now shown that the link between ACKR1 and the white blood cell population lies at the amount of the differentiation of stem cells and precursor tissues during hematopoiesis. The authors discovered that progenitors of the erythrocytes form a specific “niche” in the bone marrow and assistance the differentiation of hematopoietic stem cells. Thus, amazingly the expression of ACKR1 on the surface of these erythrocyte progenitors determines the ultimate fates of the stem cells. “If the particular erythrocyte precursors do not express ACKR1, the stem tissue differentiate into neutrophilic granulocytes that differ both molecularly and functionally from those formed following contacts along with ACKR1, ” Duchê ne explains. “Our results reveal that these altered neutrophils readily leave the circulation plus migrate to the tissues, primarily into the spleen. ” The particular resulting decrease in the number of neutrophils in the bloodstream accounts for the particular characteristic neutropenia. Whether or not the neutrophils that migrate to the spleen organ survive there and contribute to immune responses remains ambiguous.
The researchers believe that the specific properties from the neutrophils produced by Duffy-negative individuals have a positive impact on natural immune responses against microbial pathogens, and that genetic version provides its carriers with a selective advantage. “But naturally , a stronger immune response can also be counterproductive, for example once the immune reaction gets out of hand, and leads to chronic irritation and autoimmune disease, ” Weber points out. Researchers right now want to obtain a better understanding of the effects of hematopoiesis in the lack of ACKR1 on the immune response in cancer, infectious, autoimmune and inflammatory diseases like atherosclerosis. “Our discovery is really a first step towards the understanding on why diseases might take different courses in people of African ancestry. Therefore possibly different medicines should be developed to treat common diseases for people of African ancestry” says Rot. Scientists hope that will their work should initiate further research and eventually open the way to novel, patient group targeted therapeutic techniques for Duffy-negative individuals.
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