Concomitant Gene Mutations of MBL and CYBB in Chronic Granulomatous Disease: Implications for Host Defense

Abstract

Chronic granulomatous disease (CGD) is associated with defective function of the NADPH-oxidase system in conjunction with phagocytic defects which leads to granuloma formation and serious infectious complications. This is often associated with significant morbidity and mortality. The association of defective phagocyte function with other coincidental immune defects is unknown. Defects in innate pathways seen with CGD, including complement systems, and toll-like and dectin receptor pathways, have not been described before. We present the case of a 2-year old male patient hospitalized with recurrent pneumonia, a non-healing skin ulcer, necrotizing lung granulomas, and epididymo-orchitis. Defective neutrophil chemiluminescence was detected by dihydrorhodamine (DHR) testing. Further evaluation demonstrated characteristic molecular mutations of CYBB consistent with CGD. Immune evaluation demonstrated polyclonal hyperglobulinemia, but a greatly reduced mannose binding lectin (MBL) level. Six biallelic polymorphisms in MBL gene and its promoter were analyzed using Light CyclerTM Real-time PCR assay. The LXPA/LYPB haplotype of MBL was detected in our patient; the latter is the defective haplotype associated with low MBL levels. Due to the implications for innate immunity and the protection against bacterial, viral, and fungal infections provided by MBL, a deficiency of this protein may have disastrous consequences on the long term outcomes of CGD. MBL deficiency can also complicate other disorders affecting the immune system, significantly increasing the risk of infection in such patients. Further studies looking at the frequency and implications of MBL deficiency in CGD are needed.

Mannose-binding lectin protein and its association to clinical outcomes in COPD: a longitudinal study

“…It has been reported earlier that MBL deficiency showed no association to COPD severity [ 33 ]. Studies have shown that MBL deficiency may have detrimental consequences on the long-term outcomes in chronic granulomatous disease (CGD) [ 34 ] and those with variant forms of MBL have a high risk of developing autoimmune disorders [ 35 ].…”

Genetical Analysis of All Danish Patients Diagnosed with Chronic Granulomatous Disease

“…Our data suggest that other factors also may influence the severity of the disease as the seven patients with the common del75_76 GT in NCF1 have very different disease courses ranging from a patient with a very severe and fatal course to a patient newly diagnosed at the age of 38 years. It has been shown that the risk of developing chronic gastrointestinal complications and/or autoimmunity/rheumatologic disorders is dependent on the genotype of several proteins involved in the innate immune system .…”