Chronic granulomatous disease

Abstract

Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, the liver, the brain and the bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia, Serratia marcescens and Salmonella species.

Sources of data: CGD is a rare (∼1:250 000 individuals) disease caused by mutations in any one of the five components of the NADPH oxidase in phagocytic leucocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.

Areas of agreement: CGD patients suffer not only from life-threatening infections, but also from excessive inflammatory reactions.

Areas of controversy: Neither the cause of these inflammatory reactions nor the way to treat them is clear.

Areas timely for developing research: Patient selection for and timing of bone marrow transplantation along with gene therapy.

Keywords: IL-1β; NADPH oxidase; autophagy; autoreactive T cells; chronic granulomatous disease; hyperinflammation.

Fig. 1

Phagocytosis and killing of microorganisms by phagocytic leukocytes. Top: A micro-organism, opsonized with antibodies and complement fragments, binds to receptors on the leukocyte surface, such as Fc-gamma receptors and CR3 (CD11b/CD18). This starts the uptake (phagocytosis) of the micro-organism by the phagocyte: pseudopods of the phagocyte fold around the micro-organism and engulf it in a vacuole: the phagosome. At the same time, TLR receptors bind to various microbial ligands (sensing). Subsequently, the NADPH oxidase enzyme complex is assembled from flavocytochrome b₅₅₈ (in the membrane of specific granules) and the cytosolic components p40^phox, p47^phox and p67^phox. This enzyme then starts to produce various forms of ROS in the phagosome. At the same time, azurophil granules, with their content of proteases (such as elastase) and myeloperoxidase (MPO), fuse with the phagosome and deliver these enzymes in the neighborhood of the microorganisms. The phagosome closes during these last steps and killing of the microbes is completed.

Fig. 2

The first steps of autophagy. The autophagy pathway proceeds through a series of stages, including nucleation of the autophagic vesicle, elongation and closure of the autophagosome membrane to envelop cytoplasmic constituents, docking of the autophagosome with lysosomes and degradation of the material inside the autophagosome. For details, see Ref. . This picture shows an essential step in the process of elongation, i.e. lipidation of Atg8-like proteins, such as LC3, and targeting of these lipidated proteins to the autophagosomal membrane. The delipidation of these proteins, also by Atg4, is inhibited by ROS, the source of which can vary with the cell involved and the cause of autophagy induction. In case of disturbed ROS production, as in CGD macrophages, the delipidation will be increased and autophagosome formation will be decreased.

Fig. 3

Reciprocal effects of autophagy on inflammasome activity. During phagocytosis and when microbes have escaped into the cytoplasm, binding of their constituents to TLR receptors will induce inflammasome formation. This leads to IL-1β formation from pro-IL-1β. IL-1β is excreted from the cells but can bind to the IL-1β receptor and in this way accelerates the production of IL-1β. This binding to the IL-1β receptor is inhibited by anakinra, which thus limits IL-1β production. Since anakinra also limits LC3 lipidation, IL-1β supposedly limits autophagy. On the other hand, inflammasome formation also triggers activation of the small G protein RalB, which promotes autophagosome formation. Moreover, autophagosome formation is connected with destruction of ubiquitinated inflammasomes and their contents by binding of the autophagic adaptor p62, which then binds LC3, followed by destruction in autophagosomes. Autophagy also limits IL-1β production by enhancing the degradation of pro-IL-1β in proteasomes.