A Novel Primary Immunodeficiency with Specific Natural-Killer Cell Deficiency Maps to the Centromeric Region of Chromosome 8

Abstract

We describe four children with a novel primary immunodeficiency consisting of specific natural-killer (NK) cell deficiency and susceptibility to viral diseases. One child developed an Epstein-Barr virus-driven lymphoproliferative disorder; two others developed severe respiratory illnesses of probable viral etiology. The four patients are related and belong to a large inbred kindred of Irish nomadic descent, which suggests autosomal recessive inheritance of this defect. A genomewide scan identified a single 12-Mb region on chromosome 8p11.23-q11.21 that was linked to this immunodeficiency (maximum LOD score 4.51). The mapping of the disease-causing genomic region paves the way for the identification of a novel pathway governing NK cell differentiation in humans.

Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia

“…48 In this syndrome, the combined monocyte and NK-cell deficiency may be permissive for severe HPV disease. 19 The NK-cell deficiency in this disease may also account for the susceptibility to some herpesvirus infections 49,50 and to recurrent fetal losses in patients 1.II.5 and 4.II.1. 51 Viral etiologies have been clearly identified for certain human cancers: HPV with squamous carcinomas 52 ; EBV with nasopharyngeal carcinoma, leiomyosarcomas, and some lymphomas 53 ; and human herpesvirus 8 with Kaposi sarcoma and Castleman disease.…”

Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency

“…However, these cases were sporadic, and the defect in NK cells was documented after clinical viral diseases, raising lymphoproliferative disorder, and two others developed severe respiratory illnesses that were probably of viral origin. We mapped this immunodeficiency to a single 12-Mb region on the centromeric region of chromosome 8 (15) and then tried to decipher the molecular genetic basis of this new syndrome combining selective NK cell deficiency, growth retardation, adrenal insufficiency, and predisposition to viral infections and, possibly, cancer (18).…”

IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion

“…Their control relies on the integration of multiple signals received via inhibitory receptors mainly binding to MHC class I molecules and activating receptors recognizing ligands primarily expressed on infected or transformed cells. Studies on NK cell deficiencies in humans highlight their pivotal role in the control of herpesvirus infections including human cytomegalovirus (HCMV), herpes simplex virus (HSV), vesicular stomatitis virus (VSV), and EBV (1)(2)(3). A recent case report revealed that NK cells were able to control HCMV infection even in the absence of T cells (4).…”