| Abstract |
Chronic benign neutropenia of infancy and childhood is a primary disorder of autoimmune origin considered to be the most common form of neutropenia in this age group. The cause of the immune mechanism as well as the potential regulatory role of G-CSF have not been elucidated. The aim of this study was to investigate the response of the bone marrow to peripheral cytopenia and to evaluate the role of G-CSF and the adhesion molecules ICAM-1 and E-selectin as markers of endothelial cell activation in the pathogenesis of chronic benign neutropenia and in the differentiation from secondary neutropenias of different origin. G-CSF regulates proliferation and differentiation of hemopoietic progenitor cells and enhances the functional integrity and survival of mature neutrophils. The adhesion molecules ICAM-1 and E-selectin are expressed on the vascular endothelial cells upon activation with IL-1β and TNF-α and enable rolling, firm adhesion, extravasation and migration of neutrophils into the tissues in sites of inflammation. Thirty-five children with primary benign neutropenia at diagnosis and 30 children of similar age with normal neutrophil count and without malignancy or infection used as controls were studied. The group of secondary neutropenia consisted of 25 children with acute leukemia in remission, 16 of which had developed neutropenia as a result of chemotherapy. The methods used included hemopoietic progenitor cells colony growth, replating of CFU-GM of the seventh day of the culture and ELISA for the detection of serum levels of G-CSF, ICAM-1, E-selectin, TNF-α and IL-1β. The replating capacity of CFU-GM is related to the ability of bone marrow to generate mature neutrophils and is estimated by the number and the distribution of secondary CFU-GM colonies. The results showed that in chronic benign neutropenia both the number (p=0.29) and the replating capacity of CFU-GM (p=0.12) were normal when all the cases were taken into account. The latter increased significantly in cases of severe neutropenias related to both normals (p=0.03) and the mild neutropenias (p=0.009). For the total of cases, replating capacity of CFU-GM did not correlate with the absolute neutrophil count (r = - 0.45, p = 0. 26), serum levels of G-CSF (r=0.24, p=0.5) or the age at the onset of disease (r = - 0.2, p=0.5). In secondary chemotherapy-associated neutropenia, the replating capacity of CFU-GM did not increase (p=0.2) and inversely correlated with the number of circulating neutrophils (r = - 0.64, p=0.02). In chronic benign neutropenia serum ICAM-1 and E-selectin levels positively correlated with each other (r=0.55, p=0.015) and inversely with the absolute neutrophil count (r= -0.64, p=0.003, r= -0.5, p= 0.04 for ICAM-1 and Ε-selectin respectively). In the group of acute leukemia in remission the onset of neutropenia did not influence serum ICAM-1 or E-selectin levels (p=0.3, p=0.14 respectively). In the group of secondary neutropenia serum ICAM-1 and E-selectin levels were significantly lower than the respective levels in the group of benign neutropenias (p<0.001 for both the adhesion molecules studied) and did not correlate with the number of neutrophils in the peripheral blood. Serum TNF-α and IL-1β levels in benign neutropenias were found increased as compared with normal levels (p=0.01, p=0.04 respectively) and the corresponding values in secondary neutropenias (p<0.001, p=0.5 respectively) and inversely correlated with the number of circulating neutrophils (r = -0.58, p=0.01 for TNF-α and r = -0.62, p=0.04 for IL-1β). Serum TNF-α levels positively correlated with ICAM-1 (r= 0.67, p<0.01) and G-CSF levels (r=0.65, p=0.01). Serum IL-1β levels positively correlated with E-selectin (r=0.67, p=0.04) and G-CSF levels (r=0.67, p=0.04). Endogenous serum G-CSF levels in children with benign neutropenia at diagnosis were widely distributed and the majority of them were within normal range. In mean values they did not differ from normal levels in a statistically significant manner (p=0.05). In cases of severe neutropenia serum G-CSF levels significantly increased (p=0.02) but in the total of cases they did not correlate with the number of white blood cells (r= - 0.27, p=0.3) or that of neutrophils in the peripheral blood (r= -0.2, p=0.4). Serum ICAM-1 levels (r= 0.53, p=0.01) and the number of peripheral monocytes (r=0.56, p=0.03) positively correlated with G-CSF levels. The mean serum G-CSF level in the group of patients with acute leukemia in remission irrespectively of neutropenia was low and did not differ from the corresponding normal mean level (p=0.26). In conclusion, in chronic benign neutropenia of childhood hematopoietic progenitor cells of granulocytic origin are normal in number and show increased self-proliferative capacity in the severe cases, related to their ability to generate mature neutrophils. The degree of neutropenia correlates with serum ICAM-1 and E-selectin levels markers indicative of an activated endothelium. Serum TNF-α and IL-1β levels that induce the activation of endothelial cells and G-CSF production are increased compared with normal levels and positively correlate with the degree of neutropenia. Serum G-CSF levels show a wide distribution of values and in the majority of cases are within normal levels and are not regulated upon the number of circulating neutrophils in the peripheral blood. G-CSF seems to act as an inducer of the activation of endothelium. The previous findings are indicative of the existence of a latent, low-grade inflammatory process in the cases of severe chronic benign neutropenia.
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Μελέτη αιμοποίησης σε νεογνά , βρέφη, παιδιά.Αξξιολόγηση δράσησς κυτταροκινών.Χρόνια καλοήθης ουδετεροπενία της βρεφικής και παιδικής ηλικίας.
