RESUMO
Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871*) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.
RESUMO
BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity. OBJECTIVE: To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of ß-glucan through the Dectin-1 pathway, which is required for defense against Candida species. METHODS: Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy. RESULTS: PBMCs from patients with APECED syndrome had reduced TNF-α responses after Dectin-1 ligation but in part used a Raf-1-mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-α release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain-containing protein 9 after receptor ligation and localized with Dectin-1 at the cell membrane. CONCLUSION: AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome.