LONG TERM BONE MARROW CULTURE IN CHEDIAK-HIGASHI SYNDROME (CHS)

Abstract

The granulocyte defects of CHS include neutropenia, giant lysosomal granule morphology, and abnormal cell motility. Findings of elevated levels of adenosine 3′, 5′ cyclic monophosphate nucleotide (cAMP) and of concanavalin A (Con A) capping have suggested a pathogenic role for these changes. In order to test which defects derive from the cells' genetic program and which from the host environment, we examined granulocytes produced by CHS long term bone marrow cultures. These cells exhibited the giant granule morphology and defective cell motility of CHS. However, they had normal cAMP contents and normal spontaneous capping of Con A despite elevated values in the patient's peripheral blood granulocytes. Granulopoiesis diminished dramatically after five weeks in culture, with accompanying autophagocytosis by mononuclear phagocytes, possibly corresponding to the in vivo neutropenia with intramedullary autophagia of CHS. In mixing experiments of CHS hematopoietic cell engrafted on normal stroma and vice versa, the phenotype of the resultant granulocytes corresponded to the genotype of the hematopoietic component of the culture rather than the stroma. These results indicate that the giant granule morphology and cell motility defect of CHS are expressions of the genetic program of the hematopoietic cells, but abnormalities in cAMP and microtubule regulation may be secondary manifestations of the disease.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account

Continue with Google

Continue with ORCiD