Abstract
The underlying cause of neutropenia may be difficult to determine due to similar clinical presentation in many neutropenic conditions. The neutrophil protein hCAP-18 (pro-LL-37) is a major component of neutrophil secondary granules and in this prospective study we assessed the use of hCAP-18 levels in blood plasma for differential diagnosis of neutropenic patients (n = 133) of various aetiologies. Plasma levels of hCAP-18 were determined using immunoblot and ELISA. Patients with severe congenital neutropenia (n = 23) presented with the lowest levels of plasma hCAP-18 and differential diagnostic accuracy revealed high sensitivity (100%) and specificity (98.8%) for hCAP-18 ELISA. The correlation coefficient of the hCAP-18 ELISA versus immunoblotting was (R = 0.831) and that of the peptide LL-37 ELISA versus immunoblotting was (R = 0.405) (P < 0.001). Plasma hCAP-18 levels thus displayed high diagnostic value in differential diagnosis of chronic neutropenia. Neutropenic patients with Shwachman-Diamond syndrome, Barth syndrome, Cohen syndrome, acute myeloid leukaemia and specific granule deficiency presented with reduced plasma hCAP-18 levels as well. The blood plasma level of hCAP-18 was thus low in conditions in which the neutrophil antibacterial propeptide hCAP-18 is deficient, i.e. severe congenital neutropenia and neutrophil-specific granule deficiency, and in conditions in which bone marrow myelopoiesis is negatively affected.
Highlights
Neutrophils are innate immune cells of the first line of defence and constitute two thirds of blood leukocytes
We have previously demonstrated that the secondary granules in neutrophils of patients with severe congenital neutropenia (SCN) are deficient in hCAP-18, which is the proprotein of the antimicrobial peptide LL-3714
In the present prospective study, which encompasses 133 patients with neutropenia lasting more than two months, we assessed the value of using the plasma protein hCAP-18, which is the proprotein of the antibacterial peptide LL-3718, as a marker to discriminate neutropenia of various aetiologies
Summary
Neutrophils are innate immune cells of the first line of defence and constitute two thirds of blood leukocytes. Neutropenia may arise in a number of conditions[2] It may be caused by severe forms of bone-marrow failure or malignant disease[3,4] or emerge as a manifestation of illness secondary to other diseases. The inherited bone–marrow failure disorder severe congenital neutropenia (SCN) is characterised by circulating neutrophil levels below 0.5 × 109/L, severe recurrent infections and poor prognosis[7,8] Neutropenia in these patients is a consequence of premature apoptosis of neutrophil precursors in the bone-marrow leading to an absence of more mature stages of neutrophil development[9,10]. We have previously demonstrated that the secondary granules in neutrophils of patients with SCN are deficient in hCAP-18 (pro-LL-37, cathelin-LL-37), which is the proprotein of the antimicrobial peptide LL-3714. Our findings demonstrate that plasma hCAP-18 levels, but not the peptide LL-37 levels, can be used to discriminate the benign conditions of chronic neutropenia from chronic neutropenia caused by severe disease, including severe conditions involving impaired myelopoiesis
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