Inflammation and repeated infections in CGD: two sides of a coin

Abstract

Chronic granulomatous disease (CGD) is an uncommon congenital immunodeficiency seen approximately in 1 of 250,000 individuals. It is caused by a profound defect in a burst of oxygen consumption that normally accompanies phagocytosis in all myeloid cells (neutrophils, eosinophils, monocytes, and macrophages). This "respiratory burst" involves the catalytic conversion of molecular oxygen to the oxygen free-radical superoxide, which in turn gives rise to hydrogen peroxide, hypochlorous acid, and hydroxyl radicals. These oxygen derivatives play a critical role in the killing of pathogenic bacteria and fungi. As a result of the failure to activate the respiratory burst in their phagocytes, the majority of CGD patients suffer from severe recurrent infections and rather unexplained prolonged inflammatory reactions that may result in granulomatous lesions. Both may cause severe organ dysfunction depending on the tissues involved. Preventive measures as well as rapid (invasive) diagnostic procedures are required to successfully treat CGD. Hematopoietic stem cell transplantation may be a serious option in some of the patients.

Fig. 1

NADPH oxidase enzyme complex in neutrophils. Upon cellular activation, an active enzyme complex of proteins is formed, consisting of the membrane-associated cytochrome b558 and the cytosolic components p40^phox, p47^phox, p67^phox. The enzymatic activity of this protein complex—and only as a complex—is able to generate large amounts of superoxide

Fig. 2

Interferon-induced tryptophan catabolism via IDO. Interferon-γ is a major inducer of IDO expression and possibly of other enzymes involved in the catabolism of tryptophan, the kynurenine pathway. IDO is the rate-limiting enzyme in the kynurenine pathway; hence, regulating IDO-dependent counter-inflammatory homeostatic responses in potentially harmful inflammation, and requires superoxide for its activity. Tryptophan catabolism leads to tryptophan starvation and the production of immunoregulatory kynurenine metabolites, the combined effects of which result in an arrest of lymphocyte proliferation, induction of apoptosis and reversible impairment of T cell activity, as well as in the induction of various mediators, such as IL-6, IL-8, and IL-10

Fig. 3

Triple staining of CGD granuloma in lung tissue. a (left): neutrophils (MPO; red), IDO (blue), activated caspase 3 (apoptosis, green); b (middle) as in A for macrophages (CD68; red), c (right) as in a for T cells (CD3; in red)