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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1578-1583
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Mechanisms of granulocytosis in the absence of CD18
Bruce H. Horwitz,
Joseph P. Mizgerd,
Martin L. Scott, and
Claire M. Doerschuk
From the Department of Pathology, Brigham and Women's
Hospital; the Division of Emergency Medicine, Children's Hospital; and
the Physiology Program, Harvard School of Public Health, Boston, MA;
and Biogen, Cambridge, MA.
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.
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