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#63 The oscillation in peripheral blood-I

The figure comes from the Fig. 2. of reference. CN = cyclic neutropenia; PV= polycythemia vera; AA = aplastic anemia; Neu = neutrophil; Pla = platelet; Ret = reticulocyte (the immature form of the red blood cells). The figure shows that all these 3 disease have oscillation of the number of cells in peripheral blood. Where do these oscillations come from? In these 3 serial episodes, we will first introduce some basic knowledge about cyclic neutropenia, we will then use MATLAB for simulation of the dynamics of cyclic neutropenia, and finally we will simplify our system into a 2D model to facilitate the discussion about its dynamics.
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The number of cells in peripheral blood greatly matters the well-being of the person. The white blood cells in our peripheral blood could be classified into at least 5 categories. They are neutrophils, lymphocytes, monocytes, eosinophils and basophils. Among these, neutrophils are the vanguard occurred in most infection and tissue necrosis, and their density is about 2500 ~ 7500/μL.  They could phagocytose bacteria and produce superoxide chemicals with NADPH oxidase. The nucleic acids released by dead neutrophils could even disrupt the spreading of pathogens. There are many deadly pathogens in our environment, such as Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, Aspergillus fumigatus and so on. Were it not for the neutrophils, most of us would die from infection caused by these pathogens.

However, patients with chronic granulomatous disease are not as lucky. Due to the mutation of gene encoding NADPH oxidase, their neutrophils are basically nonfunctional and they are therefore susceptible to the pathogens mentioned before. There are some other patients that usually look healthy but get serious infection every 2 to 3 weeks. The period varies from patient to patient but it is nearly a constant for the same patient. The most common period observed is about 21 days. Because of the cyclic pattern in the absolute neutrophil counts in their peripheral blood, the disease is called cyclic neutropenia. It’s a rare disease with prevalence about 1~9/million. How could the absolute neutrophil counts oscillate?

Let’s see how the neutrophils are produced. The hematopoietic stem cells (HSC) in bone marrow stimulated by G-CSF(granulocytes-colony stimulating factor) will differentiate toward neutrophils. HSCs would sequentially become myeloblasts, promelocytes, myelocytes, metamyelocytes and finally the neutrophils. All cells except metamyelocytes and neutrophils could proliferate by mitosis (cell divisions). Mature neutrophils are released steadily into the peripheral blood.

Nowadays we know that cyclic neutropenia is caused by the mutation of ELANE gene, which produces an enzyme called elastase. However, knowing this could tell nothing about “why” this mutation causes the cyclic variation in absolute neutrophil count in peripheral blood. In contrary, John Milton & Michael C Mackey successfully reproduced the dynamics of cyclic neutropenia and predicted the most possible mutation in 1989. How could they do that? Let’s talk about it next time.
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Haurie, C., Dale, D. C. and Mackey, M. C. (1998). Cyclical Neutropenia and Other Periodic Hematological Disorders: A Review of Mechanisms and Mathematical Models. Blood, 92(8): 2629-2640.