Effect of platelet calpain on normal T-lymphocyte CD43: hypothesis of
events in the Wiskott-Aldrich syndrome
E Remold-O'Donnell, J Van Brocklyn and DM Kenney
Center for Blood Research, Boston, MA 02115.
The Wiskott-Aldrich syndrome (WAS) is an inherited disease involving
defects of platelets (small size, severe thrombocytopenia due to
accelerated destruction) and T lymphocytes (progressive immunodeficiency,
lymphopenia). The best-characterized molecular defect is the deficiency
and, in some cases, abnormal forms of the T- lymphocyte surface mucin
molecule CD43; deficiency of the platelet surface mucin GPIb was observed
previously in two of four patients. Neither of these defects is primary,
since CD43 and GPIb are encoded by autosomal genes and the disease is
X-linked. This study uses cellular biological approaches to explore the
possibility that destruction of structurally defective WAS platelets,
mimicked experimentally by sonication of normal platelets, plays a role by
releasing protease and generating other cellular defects. We show that a
protease of normal platelets, identified as Ca(2+)-dependent neutral
protease (calpain), which is known to cleave platelet GPIb, also
specifically cleaves CD43 on the surface of neighboring desialylated T
lymphocytes. The identification of the CD43 cleaving protease was based on
its requirement for Ca2+ and inhibition by leupeptin, but not by
diisopropylfluorophosphate (DFP). The approximate site of CD43 cleavage was
identified by the use of a rabbit antibody. Sensitivity of GPIb to calpain
is shown to be sialylation-independent and that of CD43 to be
sialylation-dependent, and these findings are explained in terms of
molecular structures. These and previous findings are incorporated into a
putative mechanism, which explains most of the defects in the WAS. The
mechanism suggests that the primary defective molecule in the WAS is
unlikely to be a surface glycoprotein, but rather a cytoplasmic molecule
with a function in cytoskeletal interactions and/or calcium ion regulation
and calpain activation.
Volume 79,
Issue 7,
pp. 1754-1762,
04/01/1992
Copyright © 1992 by The American Society of Hematology
