Blood, 1 April 2003, Vol. 101, No. 7, pp. 2898-2898
CORRESPONDENCE
To the editor:
Low levels of serum elastase are not associated with mutations
in ELA-2 elastase encoding gene in chronic idiopathic neutropenia
Chronic idiopathic neutropenia (CIN) has been described as
a persistent, unexplained reduction in the number of circulating neutrophils, below the lower limit of the normal distribution for a
given ethnic population.1 The diagnostic criteria of the
disorder have been presented elsewhere.2 The condition is
characterized by low incidence of infections, usually benign outcome,
female predominance, and an HLA class II genetic
predisposition.3 In a recent study we showed that CIN
patients display impaired granulocytopoiesis due to increased apoptosis
of bone marrow (BM) CD34+/CD33+ granulocyte
progenitor cells.4 Accelerated apoptosis of BM granulocyte
progenitors also has been reported in patients with severe congenital
neutropenia (Kostmann syndrome) and cyclic neutropenia. Recent
evidence suggests that mutations in the ELA-2 elastase encoding gene
may be involved in the pathogenesis of neutropenia in these neutropenic
states.5,6 No related studies have been reported in CIN.
To test the hypothesis that abnormalities in neutrophil elastase
might be implicated in the pathophysiology of CIN, we have studied
neutrophil elastase in 39 white CIN patients (5 men and 34 women) aged
27 to 74 years (median, 52 years) and 16 age-matched and sex-matched
healthy subjects. Specifically, we have measured serum neutrophil
elastase levels by means of an enzyme-linked immunosorbent assay
(ELISA) (HyCult Biotechnology, Uden, The Netherlands), and we also have
looked for mutations in the ELA-2 elastase coding gene by performing
genomic sequencing of polymerase chain reaction (PCR)-amplified exons
and exon/intron junctions of DNA extracts from EDTA
(ethylenediaminetetraacetic acid)-anticoagulated whole peripheral
blood using an ABI/PE Biosystems PRISM Big Dye terminator chemistry on
an ABI/PE Biosystems 310 Analyser (Applied Biosystems, Foster City,
CA). Informed consent according to the Helsinki protocol was obtained
from all subjects studied. Neutrophil counts ranged from 412 to 1795 (mean, 1475 ± 366 [SD]) per µL of blood in the patients and from
2747 to 6410 (mean, 4223 ± 1061 [SD]) per µL of blood in the
controls. We found that CIN patients displayed significantly lower
serum neutrophil elastase levels (mean, 757 ± 527 [SD]
ng/mL; median, 711 ng/mL; range, 101 to 2276 ng/mL) compared to healthy
subjects (mean, 3644 ± 3073 [SD] ng/mL; median, 2122 ng/mL; range,
1323 to 9325 ng/mL) (P < .0001, Mann-Whitney test).
Individual serum neutrophil elastase values strongly correlated to the
number of circulating neutrophils (r = 0.7158,
P < .0001; Spearman test) (Figure
1). No mutations in the critical regions of ELA-2 elastase coding gene
were identified.
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| Figure 1.
Strong correlation between the levels of
serum neutrophil elastase and the number of circulating neutrophils in
the entire group of subjects studied. The regression line is shown as a
solid line, and the 95% confidence limits are shown as dotted lines.
The equation, coefficient of correlation (r), and degree of
significance (P) are indicated. CIN patients ( ); healthy
controls ( ).
|
|
These data suggest that abnormalities in neutrophil elastase are
unlikely to be implicated in the pathogenesis of CIN. The observed low
concentration of the enzyme in patient sera probably reflects the low
number of circulating neutrophils.7 The finding is not
surprising, since potential elastase abnormalities are unlikely to have
a pathogenetic role in mediating apoptosis restricted to the
CD34+/CD33+ progenitor cell compartment. We
conclude that although increased apoptosis of BM granulocyte progenitor
cells may represent a common pathophysiologic mechanism underlying
neutropenia in both acquired and congenital cases, distinct
cellular and molecular defects are responsible for the increased
susceptibility of BM granulocyte progenitors to apoptosis in these
neutropenic states.
Helen A. Papadaki, Marshall Horwitz, Stavroula A. Coulocheri, Richard A. Person, Kathleen F. Benson, and George D. Eliopoulos
Correspondence: Helen A. Papadaki, University
Hospital of Heraklion, PO Box 1352, Heraklion, Crete,
Greece; e-mail:
epapadak{at}med.uoc.gr.
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