The Use of Interferon-Gamma Therapy in Chronic Granulomatous Disease

Paolo   R.   Errante; Josias   B.   Frazao; Antonio      Condino-Neto

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by early onset of recurrent and severe infections. The molecular defects causing CGD are heterogeneous and lead to absence, low expression, or malfunctioning of one of the phagocyte NADPH oxidase components. It is known that mutations leading to CGD reside within the genes encoding four essential components of the oxidase designated as gp91-phox (phagocyte oxidase), p22- phox, p47-phox and p67-phox. gp91- together with p22-phox form the membrane cytochrome b558 and play an essential role in the transfer of electrons following assembly of the active oxidase with the cytoplasmic p47- and p67-phox components. In hematopoietic cells, CYBB expression (the gene encoding gp91-phox) is limited to the granulocyte and monocyte/macrophage lineages during the process of terminal differentiation. CYBB is responsive to a number of inflammatory cytokines, especially interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). Cytokines have been also studied for activation of phagocytes respiratory burst. IFN-γ stimulates superoxide release and is a prophylactic agent for CGD. It has been shown in vitro and in vivo to correct at least in part alterations of the oxidative metabolism, and to improve their microbicidal function. It has demonstrated clinical benefit in the majority of patients with CGD, reducing the relative risk of severe infections in 70%. In this study, we review mechanisms showing that IFN-γ improves the splicing efficiency of CYBB gene transcripts in a particular group of CGD patients. The present article is an informative review of recent patents related to the use of interferon gamma therapy in chronic granulomatous disease.

Keywords: Interferon-gamma, chronic granulomatous disease, human primary immunodeficiency, cytochrome b558, gp91- phox, granulocyte, macrophage, NADPH oxidase, phagocyte oxidase