While CD16 function is required to mediate ADCC, strikingly the patients with CD16 L66H mutation have normal ADCC-mediated cellular cytotoxicity, yet impaired natural cytotoxicity

While CD16 function is required to mediate ADCC, strikingly the patients with CD16 L66H mutation have normal ADCC-mediated cellular cytotoxicity, yet impaired natural cytotoxicity. subset generation, as well as their importance in immune homeostasis. The presence of inherently abnormally developed or functionally impaired NK cells, in particular, appears to be problematic in the way of interfering with normal human host defense and may be more impactful than low numbers of NK cells alone. Here, we review the known genetic causes of NKD and the insight that is derived by these into the requirements for human subset generation and, by extension, for NK cell-mediated immunity. mutations. Furthermore, ITGA7 is also the only gene associated with NKD that is autosomal dominant (haploinsufficiency) and the only for which spontaneous cases have been reported (35, 36), thus supporting the statement of commonality from a genetic standpoint as well. GATA2 deficiency is complex as it can be a multi-syndromic disease affecting multiple organs and presenting in multiple different ways. Blonanserin Patients can be susceptible to atypical Blonanserin mycobacterial infections, fungal infections, and severe and recalcitrant viral infections. Interestingly, there is a seemingly progressive nature of the Blonanserin disease, with many patients presenting in young adulthood and some even later in life. The range of clinical presentations and natural history has been well described elsewhere (39). Interestingly, one of the earliest clinical features to appear is a susceptibility to HPV disease, which could point to a role for NK cell-mediated defenses. In addition to immune deficiency, GATA2 deficiency is a cause of familial bone marrow failure (40), and a recent study of over 400 children and adolescents revealed GATA2 mutation to be the most common germline mutation leading to myelodysplastic syndrome in children and young adults (41). While this group did not specifically examine NKD in their cohort, they report half of their patients to have immunodeficiency, suggesting that the high rates of NK cell cytopenias reported by Spinner et al. (39) are likely present in this group. However, there are some notable aspects of GATA2 deficiency with regards to NK cell biology. While other NK cell deficiencies have been reported as affecting the frequency of subset distribution (particularly MCM4, described below), the loss of the CD56bright NK cell subset is as near to absolute as has been described. The mechanism by which GATA2 regulates the development or maintenance of the CD56bright NK cell pool is not understood. GATA2 is a zinc finger transcription factor that is required for embryonic hematopoiesis, and maintenance of the stem cell pool in adults (42, 43) and GATA2 haploinsufficiency can also lead to loss of dendritic cell subsets and B cell cytopenias. Therefore, given its important role in stem cell maintenance and hematopoiesis, GATA2 deficiency may affect multiple immune cell lineages, which are again highly variable from patient to patient. differentiation of NK cells from patient hematopoietic stem cells leads to aberrant NK cell development, suggesting that NKD is cell intrinsic in these patients (33). However, given the interdependence on particularly NK and DC cross Blonanserin talk, it is likely that loss of other subsets affects NK cell numbers and functions in these patients, although this has not been explicitly studied. Immune manifestations include susceptibility to mycobacterial disease, frequently and differentiation experiments demonstrate an NK cell intrinsic role for GATA2 through the phenocopying of the CD56bright NK cell subset loss in NK cells derived from patient CD34+ HSC (33). Whether GATA2 is required for the generation or homeostasis of CD56bright NK cells, or whether the defect arises earlier in lineage commitment, remains to be determined. GATA2 is highly expressed not only in CD34+ HSC, but also across a range of lineages including monocytes, monocyte-derived dendritic cells, B cells, and mature NK cells, as well as the common myeloid precursor (44C46). Conditional deletion of in mice has recently demonstrated its requirement for DC differentiation from lineage negative precursors (47). Interestingly, this is at least partially through repression of genes that control T cell and ILC lineages, including mutation affecting Mcm4 have genomic instability reminiscent of that found in MCM4 patients (58). Careful analysis of the patients fibroblasts showed normal MCM2C7 complex formation and DNA-binding but impaired DNA replication and, subsequently, cell cycle arrest (53). Genomic instability frequently accompanies impaired replication, and this is also the case in MCM4 patient fibroblasts, which had increased rates of chromosomal breakage (53). Interestingly, accompanying the decrease in NK cell number and specific decrease in frequency of CD56dim NK cells, patient NK cells had impaired proliferation in response to cytokine stimulation and increased rates of apoptosis (53)..