Mechanisms of granulocytosis in the absence of CD18

Genetic deficiency in CD18 leads to disease characterized by myeloid hyperp lasia, including profound granulocytosis and splenomegaly, Myeloid hyperpla sia could directly result from the disruption of CD18 functions essential t o granulopoiesis or basal leukocyte trafficking. Alternatively, myeloid hyp erplasia could be reactive in nature, due to disruption of essential roles of CD18 in leukocyte responses to microbial challenge. To distinguish betwe en these mechanisms, the hematopoietic systems of lethally irradiated wild- type (WT) mice were reconstituted with either WT fetal liver cells or CD18- deficient fetal liver cells, or an equal mixture of both types of cells. Gr anulocytosis and splenomegaly developed in mice that received CD18-deficien t fetal liver cells. Splenomegaly was prevented and granulocytosis was inhi bited by more than 95% in mice that had received both CD18-deficient and WT fetal liver cells, suggesting that myeloid hyperplasia was largely reactiv e in nature. Consistent with this postulate, the circulating life spans in the blood and the fraction of neutrophils that incorporated BrdU in the bon e marrow were not increased for CD18-deficient neutrophils compared with th e WT. However, these animals did develop mild granulocytosis compared with mice re-constituted with WT cells alone, and a higher percentage of CD18-de ficient leukocytes were neutrophils compared with the WT leukocytes. These observations suggest that the granulocytosis observed in the absence of CD1 8 occurs through at least 2 mechanisms: one that is dramatically improved b y the presence of WT cells, likely reactive in nature, and a second that is independent of the WT hematopoietic cells, involving an alteration in the lineage distribution of blood leukocytes. (Blood, 2001;97:1578-1583) (C) 20 01 by The American Society of Hematology.