Mechanisms of granulocytosis in the absence of CD18.
Genetic deficiency in CD18 leads to disease characterized by myeloid hyperplasia, including profound granulocytosis and splenomegaly. Myeloid hyperplasia could directly result from the disruption of CD18 functions essential to granulopoiesis or basal leukocyte trafficking. Alternatively, myeloid hyperplasia could be reactive in nature, due to disruption of essential roles of CD18 in leukocyte responses to microbial challenge. To distinguish between 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. Granulocytosis and splenomegaly developed in mice that received CD18-deficient fetal liver cells. Splenomegaly was prevented and granulocytosis was inhibited by more than 95% in mice that had received both CD18-deficient and WT fetal liver cells, suggesting that myeloid hyperplasia was largely reactive in nature. Consistent with this postulate, the circulating life spans in the blood and the fraction of neutrophils that incorporated BrdU in the bone marrow were not increased for CD18-deficient neutrophils compared with the WT. However, these animals did develop mild granulocytosis compared with mice reconstituted with WT cells alone, and a higher percentage of CD18-deficient leukocytes were neutrophils compared with the WT leukocytes. These observations suggest that the granulocytosis observed in the absence of CD18 occurs through at least 2 mechanisms: one that is dramatically improved by 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.
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. bhorwitz@rics.bwh.harvard.edu
B H
BH
Horwitz
J P
JP
Mizgerd
M L
ML
Scott
C M
CM
Doerschuk
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D018821:CD18 Antigens / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D017690:Cell Transplantation / Q000534:rehabilitation; D004195:Disease Models, Animal; D006410:Hematopoiesis / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D014916:Whole-Body Irradiation
D018821:CD18 Antigens