title: 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.
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, James H. Quillen VA Medical Center, Johnson City, P.O. Box 70622, TN 37614-0622, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Watkins
authors.forename: Hana
authors.initials: H
authors.lastname: Saleh
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Song
authors.forename: Gayatri Bala
authors.initials: GB
authors.lastname: Jaishankar
authors.forename: David S
authors.initials: DS
authors.lastname: Chi
authors.forename: Niva
authors.initials: N
authors.lastname: Misran
authors.forename: Emma
authors.initials: E
authors.lastname: Peiris
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Altrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Barklow
authors.forename: Guha
authors.initials: G
authors.lastname: Krishnaswamy
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007113:Immunity, Innate; D008163:Luminescent Measurements; D008297:Male; D037601:Mannose-Binding Lectin / Q000172:deficiency / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D037601:Mannose-Binding Lectin; D008562:Membrane Glycoproteins; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases