Recent advances in chronic granulomatous disease

Abstract

Chronic granulomatous disease (CGD) is an inherited defect of phagocyte function due to defective NADPH oxidase. Patients with CGD are not able to effectively clear the infections because of the defect in the phagocyte production of oxygen free radicals and are prone to recurrent bacterial and fungal infections. Inflammatory complications are also noted in CGD such as colitis, non-infective granulomas causing gastrointestinal or urinary tract obstruction, hemophagocytic lymphohistiocytosis, and arthritis. Studies on toll-like receptor pathways and neutrophil extracellular traps in CGD have shed light on the role of NADPH oxidase in the innate immunity and pathogenesis of infections in CGD. Some reports also indicate a reduction of memory B cells and defective production of functional antibodies in CGD. Though the exact mechanisms for non-infective inflammatory complications in CGD are not yet clear, studies on efferocytosis and defective autophagy with inflammasome activation have made a substantial contribution to our understanding of the pathogenesis of inflammation in CGD. We also discuss the clinical and molecular features of p40^phox defects and a newer genetic defect, EROS. Clinical phenotypes of X-linked carriers of CYBB are also discussed.

Keywords: Chronic granulomatous disease; Colitis; EROS; Genetics; Infections; Inflammation; p40phox.

Figure 1

A representative figure depicting the units of NADPH oxidase complex. Membrane bound units include gp91^phox and p22^phox. Cytosolic components include p47^phox, p67^phox, p40^phox and Rac.

Figure 2

Dihydrorhodamine test by flow cytometry showing oxidative capacity of the PMA-stimulated neutrophils (green). (A) Control sample depicting normal shift of the activated neutrophils with the median fluorescence intensity (MFI) of 277.95 compared to 2.75 in the unstimulated neutrophils (red). (B) DHR of a patient with a defect in CYBB showing absent shift of the stimulated neutrophils (green) with MFI of 2.57 compared to 2.02 in the control (red). (C) DHR of an X-linked carrier of CYBB defect showing a bimodal population of the stimulated neutrophils (green).

Figure 3

Cytochrome b558 staining by flow cytometry. (A) Control sample showing normal staining and surface expression of b558. (B) Patient with a defect in CYBB showing absent surface staining for b558. (C) An X-linked carrier of CYBB defect showing mosaic pattern of expression of b558.