The ablity of phagocytic leukocytes to kill ingested microorganisms arises from two general mechanisms. One of these depends on the phagocyte's ablity to assemble and activate a multicomponent oxidase system that generates superoxide anion (O^-₂) by oxidizing its substrate, NADPH. The resultant superoxide anions are converted to other reactive oxygen derivatives (RODs), whose precise chemical nature is influenced by the biochemical composition of the phagocyte. In normal human neutrophils (PMN), these secondary RODs include H₂O₂, hydroxyl radical, hypochlorous acid and chloramines, all of which are considerably more microbicidal than superoxide itself.
In addition to undergoing an oxidative attack by RODs, ingested microbes are exposed to antimicrobial constituents normally contained within the phagocyte's cytoplasmic granules. Among these antimicrobial factors are cathepsin G and “defensins”. The microbicidal activity of cathepsin G against bacteria and Candida species occurs independently of its neutral protease activity. Defensins are a recently-defined family of antimicrobial peptides whose members appear to be important effectors of ROD-independent antimicrobial activity by PMN and certain macrophages. The activity spectrum of human and rabbit defensins encompasses both gram-positive and gram-negative bacteria, many fungi, certain viruses and even tumor cells. Defensins constitute 30-50% of the total protein in azurophil granules and account for approximately 6% of the total protein in human PMNs. They exert potent activity against C. albicans, an important agent of opportunistic fungal infection. Human defensins permeabilize microbial membranes, but only the bioenergized membranes of metabolically active microbial targets appear to be susceptible to these effects.
Although the clinical syndromes associated with deficiencies of myeloperoxidase and NADPH oxidase activity have been recognized for several years, abnormalities of leukocyte defensins and cathepsin G have been detected only recently. Neutrophils from patients with “specific granule deficiency” lack defensins, whereas PMN in Chediak-Higashi syndrome are deficient in neutral proteases, including cathepsin G.

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