Chronic granulomatous disease: a review of the infectious and inflammatory complications

Abstract

Chronic Granulomatous Disease is the most commonly encountered immunodeficiency involving the phagocyte, and is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas in tissue. The disease is the result of a disorder of the NADPH oxidase system, culminating in an inability of the phagocyte to generate superoxide, leading to the defective killing of pathogenic organisms. This can lead to infections with Staphylococcus aureus, Psedomonas species, Nocardia species, and fungi (such as Aspergillus species and Candida albicans). Involvement of vital or large organs can contribute to morbidity and/or mortality in the affected patients. Major advances have occurred in the diagnosis and treatment of this disease, with the potential for gene therapy or stem cell transplantation looming on the horizon.

Figure 1

Distribution of Common Immunodeficiencies. Primary immune deficiencies can involve either the adaptive (T- and B-lymphocyte deficiencies) or the innate (phagocyte, complement or other defects) immune response (Figure 1). Of these, defects in phagocyte function constitute only about 18%, with the larger portion of the defects seen in the B cell/antibody and/or T cell components of immunity.

Figure 2

Defects Leading to Immunodeficiency Disease. The various defects are summarized in Figure 2, which describe the potential sequence of events, starting from T- and B cell interactions and antibody synthesis to the involvement of phagocyte and complement components of the innate immune response. Explanation for the various aspects of the immune response is provided at the bottom of the figure (components 1-8); Components 5 and 6 deal with phagocytic/neutrophil defects.

Figure 3

Role of Macrophages in Host Defenses. Macrophages are generated from bone marrow precursor cells in the presence of stem cell hematopoietic factors (such as granulocyte-macrophage colony stimulating factor/GM-CSF and macrophage colony stimulating factor/M-CSF). The activation of macrophages (in the presence of specific receptors and T lymphocytes as shown in the figure- CD40/CD40L, CD28/B7, interleukin-interleukin receptor etc) results in functional consequences such as microbicidal activity directed especially towards intracellular pathogens and aided by the expression of peroxides and superoxide radicals. These processes are defective in CGD (see text). Other secretory effects of macrophages result in the production of a plethora of mediators that assist in immunity (these are shown in the figure and include complement, enzymes, interleukins, interferons and growth factors).

Figure 4

The NADPH Oxidase System. The assembly of the various subunits of NADPH oxidase is shown in the figure, while the molecular genetics, rough prevalence, inheritance pattern and chromosomal localization of CGD subtypes are shown in the bottom of the figure. There are several components of NADPH oxidase: of these the cytochrome-b₅₅₈ heterodimer is located in the membrane and consists of the gp91^phox and p22^phox units, while three cytosolic components exist- including the p67^phox , p47^phox and a p40^phox. Following cellular activation, the soluble cytosolic components, p67^phox , p47^phox , and a p40^phox , move to the membrane and bind to components of the cytochrome-b₅₅₈ heterodimer. This is also accompanied by the binding of the GTPase protein, Rac, culminating by unclear mechanisms in flavocytochrome activation. This catalyzes the transfer of electrons from NADPH to oxygen, resulting in the formation of superoxide in the extracellular compartment (phagolysosome). Subsequent reactions via superoxide dismutase (SOD), catalase or myeloperoxidase (MPO), occurring in the phagolysome, can result in formation of H₂O₂, H₂O or HOCl^- respectively.