Human natural killer cell deﬁcienciesJordan S. Orange Purpose of review Abbreviations Human natural killer cell deﬁciencies are a relevant clinical ANKD absolute natural killer cell deﬁciency entity that provides insight into the role of natural killer cells CMV cytomegalovirus CNKD classical natural killer cell deﬁciency in host defense, as well as the basic biology of natural killer EBV Epstein-Barr virus cells. Since previously reviewing these disorders, FHL familial hematophagocytic lymphohistiocytosis FNKD functional natural killer cell deﬁciency signiﬁcant developments warrant their reconsideration. HLH hematophagocytic lymphohistiocytosis Recent ﬁndings HSV herpes simplex virus NK natural killer Human natural killer cell deﬁciencies can occur as part of a NKT cell natural killer T cell more pervasive immunodeﬁciency syndrome or, rarely, in SCID severe combined immunodeﬁciency VZV varicella zoster virus isolation. The most informative examples of the former are in WAS Wiskott-Aldrich syndrome the context of a known genetic defect, because the WASp Wiskott-Aldrich syndrome protein deﬁciency of natural killer cell development or activity can be attributed to the speciﬁc gene function. Since last ß 2006 Lippincott Williams & Wilkins reviewed, there are ﬁve human gene mutations that are now 1528-4050 appreciated to affect natural killer cells, and additional new insights into natural killer cell biology have been obtained through seven others. Six new reports of isolated natural Introduction killer cell deﬁciencies, as well as a suggested classiﬁcation Natural killer (NK) cells are lymphocytes of the innate scheme, are also reviewed. immune system that are capable of a number of useful Summary and important functions (reviewed in ). They are Appreciation of human genetic syndromes that include considered to be part of innate immunity because they natural killer cell deﬁciencies, as well as new cases of do not rearrange their germline DNA to obtain speci- isolated natural killer cell deﬁciencies, continue to advance ﬁcity. As a result, they rely upon an array of receptors with the understanding of natural killer cell biology and solidify distinct speciﬁcities that can activate NK cells to generate the role of natural killer cells in defense against human function. These include receptors that can sense cell herpesviral infection. stress or pathogen-speciﬁc signatures. The function of Keywords these activation systems is restrained by inhibitory recep- cytotoxicity, herpesviruses, natural killer cell deﬁciency, tors that, in the majority, recognize alleles of class-I natural killer cells, natural killer T cells, primary MHC. The coexistence of these two systems creates a immunodeﬁciency balance where NK cells can be readily activated by cells that become distinguished from normal for a large num-Curr Opin Allergy Clin Immunol 6:399–409. ß 2006 Lippincott Williams & Wilkins. ber of reasons.Department of Pediatrics, University of Pennsylvania School of Medicine, After a NK cell is activated by contact with a susceptiblePhiladelphia, USA target cell, it is capable of several distinct functions.Correspondence to Jordan S. Orange, The Joseph Stokes Jr Research Institute of Cytotoxicity is the best known, but cytokine productionthe Children’s Hospital of Philadelphia, Division of Allergy and Immunology,Department of Pediatrics, University of Pennsylvania School of Medicine, 3615 and costimulation of other immune cells are also import-Civic Center Blvd, ARC-1216F, Philadelphia, PA 19104, USA ant. The last two activities can be readily elicited by theTel: +1 267 426 2836; e-mail: firstname.lastname@example.org exposure to appropriate soluble signals in addition to cellCurrent Opinion in Allergy and Clinical Immunology 2006, 6:399–409 contact. NK cell functions have been demonstrated to be essential in the control of numerous infections and dis- ease states, using animal models [2–4]. Their role in human diseases is not as well established although there is very strong supporting evidence in a number of con- ditions. One critical demonstration of how NK cells defend against disease and participate in human host defense is derived from rare deﬁciencies of NK cells that have been described. These include deﬁciencies of NK cells that are part of a larger immunological syndrome, but also isolated deﬁciencies of NK cells. A recurring 399
400 Primary immune deficiency diseasetheme of the human deﬁciencies of NK cells, which is Autoimmune lymphoproliferative syndrome withalso substantiated through in-vitro and animal-based immunodeﬁciency (caspase 8 deﬁciency)experimental systems, is an important role for NK cells Caspase 8 deﬁciency results in a form of autoimmunein defense against infectious disease caused by the her- lymphoproliferative syndrome (ALPS) that is associatedpesvirus family of viruses. with a combined immunodeﬁciency affecting numerous cell types. The ALPS phenotype in caspase 8 deﬁciencySince initially reviewing the human NK cell deﬁciencies results from an upstream requirement for caspase 8 in thein 2002 , substantial progress has been made in the activation of caspase 3, which in turn is required forrecognition of additional patients affected by isolated NK apoptosis . The immunodeﬁciency phenotype resultscell deﬁciencies. Additionally, progress has been made in from a requirement for caspase 8 in immunoreceptor-understanding the impact of novel as well as previously induced NF-kB activation. Speciﬁcally, caspase 8 linksappreciated genetic immunodeﬁciencies upon NK cells. the complex consisting of CARMA1, BCL10 andThrough each of these efforts, further insight has been MALT1 to the inhibitor of NF-kB kinase complexgained into the role of NK cells in protection against (IKK) . NK cells derived from patients deﬁcient inhuman disease, as well as the basic biology of human NK caspase 8 have impaired activation receptor-inducedcells. This review does not comprehensively cover the stimulation and NF-kB nuclear translocation. Theimpact of genetic immunodeﬁciencies upon NK cells, as requirement for the IKK complex for NK cell functionthe majority of what was previously reviewed is has been previously demonstrated through studies ofunchanged and still valid. Instead, focus in this area will human IKK-g deﬁciency (NEMO deﬁciency) [8,9]. Cas-be directed to data reported since the last review. In the pase 8-deﬁcient patients are susceptible to infectiouscase of the isolated NK cell deﬁciencies, a more com- disease indicative of their combined T cell and B cellprehensive review is presented in light of several recently deﬁciency, such as upper respiratory bacterial infectiondescribed cases. and even bronchiectasis . These patients also experi- ence mucocutaneous herpesviral disease, thus suggestingNew associations between genetic disease a potentially relevant NK cell deﬁcit.and natural killer cell deﬁciencyAs the molecular understanding of deﬁciencies of host Familial erythrophagocytic lymphohistiocytosis type 3susceptibility has increased, a number of previously (Munc 13-4 deﬁciency) and type 4 (syntaxin-11unappreciated genetic etiologies have been discovered deﬁciency)since the human NK cell deﬁciencies were last reviewed. Familial erythrophagocytic lymphohistiocytosis, alsoIn some cases, these gene mutations have been directly referred to as familial hematophagocytic lymphohistio-linked to deﬁciencies of NK cells among other com- cytosis (FHL), represents a subset of patients with hema-ponents of immunity. In other cases, some previously tophagocytic lymphohistiocytosis (HLH). HLH is aappreciated genetic disorders of the immune system have phenotype that results from extraordinary immune acti-only recently been linked to NK cell defects. These new vation typically following herpesviral infection, and it isconnections are summarized in Table 1 and are reviewed reviewed elsewhere . In essence, an inability to medi-here. This category represents an extension of the ate cytotoxic activity after infection prevents down-‘known gene mutation in a disease that includes a NK modulation of immunity and/or eradication of infectioncell deﬁciency’ category from the previous review . leading to a systemic inﬂammatory response syndrome.Table 1 New associations between genetic defects and human natural killer cell deﬁciency Gene Affected Natural killerDisease mutated protein Infections cell defect Other defects ReferenceAutoimmune CASP8 Caspase 8 Sinopulmonary Activation T cell, B cell [6,7] lymphoproliferative bacterial receptor- activation defects. syndrome with mucocutaneous induced TLR signaling immunodeﬁciency herpesviruses stimulation defectsFamilial erythrophagocytic UNC13D Unc-13 homolog Herpesviruses Cytotoxicity CTL defect [18,19] lymphohistiocytosis-type 3 D (Munc13-4)Familial erythrophagocytic STX11 Syntaxin-11 Herpesviruses Cytotoxicity CTL defect [16,17] lymphohistiocytosis-type 4Hermansky-Pudlak syndrome AP3B1 Adaptor-related Sinopulmonary Cytotoxicity CTL and neutrophil [21,22] protein complex, bacterial defects b1 subunit (AP-3) herpesvirusesPapillon-Lefevre syndrome CTSC Cathepsin C Periodontitis Cytotoxicity Neutrophil defects  (herpesvirus)
Human natural killer cell deficiencies Orange 401This phenotype is very similar to that found during the Munc13-4-deﬁcient (and likely syntaxin-11-deﬁcient)herpesviral-induced accelerated phase of several other NK cells in that the lytic granules will fuse with thewell deﬁned disorders of cytotoxicity, including Chekiak- cell membrane in the former. This can be measuredHigashi syndrome due to LYST mutation, Griscelli syn- experimentally by ﬂow cytometry for CD107a, alsodrome due to RAB27A mutation, and even X-linked known as LAMP-1 . CD107a is contained in thelymphoproliferative syndrome due to SH2D1A mutation lytic granules, but instead of being secreted is retained(all reviewed previously ). As a group, these molecu- in the cell membrane after granule fusion. Thus, FHL2lar diseases have helped to better deﬁne the cytolytic NK cells have normal expression of CD107a after acti-process in human NK cells, which involves the vation, but FHL3 NK cells do not, as Munc13-4 isintracellular trafﬁc of lytic granules (a form of secretory required for the fusion process. Presumably, thislysosome) containing the pore-forming molecule per- approach will also work for patients having mutationsforin, as well as granzymes and granulysins, to the of LYST and RAB27A, but these patients can also beimmunological synapse formed with a susceptible target distinguished by the albinism phenotype characteristiccell . The extrusion of these organelles through the of these mutations.immunological synapse onto the target cell allows for itscontrolled destruction. Hermansky-Pudlak syndrome (AP-3 deﬁciency) Hermansky-Pudlak syndrome is closely related to Che-There are currently three molecular defects that can kiak-Higashi and Griscelli syndrome in that patients alsoresult in familial causes of HLH. The ﬁrst, FHL2, was have oculocutaneous albinism. They are distinguished indeﬁned in 1999 and results from mutation of the PFP1 that they have a bleeding diathesis, ceroid accumulationgene encoding the pore-forming molecule perforin . and, in some cases, immunodeﬁciency. There are twoThe second (FHL3) and third (FHL4) are more recently known genes that cause Hermansky-Pudlak syndromedeﬁned. FHL3 is due to mutation of the UNC13 gene and the one that has been consistently associated withencoding the Unc-13 homolog D protein, more com- immunodeﬁciency is caused by mutation of the ADTB3Amonly referred to as Munc13-4 , and FHL4 is due gene, encoding the b chain of the adaptor protein-3 (AP-to mutation of the STX11 gene encoding the syntaxin-11 3) complex. This form of Hermansky-Pudlak is referredprotein [16,17]. Unlike some of the gene mutations that to as HPS2 and was initially appreciated as impairingimpair cytotoxicity to result in the HLH phenotype, cytotoxic T-cell lytic function. Speciﬁcally, AP-3-Munc13-4 and syntaxin-11 play very late roles in the deﬁciency results in enlarged lytic granules that fail tocytolytic process. In fact, the lytic granules in Munc13- move along microtubules to the immunological synapse4-deﬁcient cytotoxic cells trafﬁc to the cell membrane and . More recent studies have deﬁned a similar defect indock, but fail to fuse . Thus, Munc13-4 is essential in NK cells . Interestingly, the NK cell cytolyticpriming the lytic granule for membrane fusion and, sub- defect persisted even after IL-2 stimulation, and wassequently, exocytosis. Although detailed studies have not associated with a decreased cellular perforin content.been performed in syntaxin-11-deﬁcient human NK cells, As evidence of the signiﬁcance of this defect and linkagethe deﬁcit is likely to be very similar to that found in to other albinism/immunodeﬁciency overlap syndromes,Munc13-4 deﬁciency. This is because syntaxin-11 is a an HPS2 patient having defective NK cell and cytotoxicSNARE (soluble N-ethylmaleimide sensitive factor T-cell cytolytic activity has been reported to have HLHattachment protein receptor) protein that functions to . AP-3, therefore, can be viewed as a critical step infacilitate lytic granule adherence to the inside surface of initiating granule trafﬁc in human NK cells.the NK cell membrane. There may ultimately prove to beimportant differences, however, as clinical distinctions Papillon-Lefevre syndrome (cathepsin C deﬁciency)have been described in FHL4 patients, including a later Papillon-Lefevre syndrome is characterized by hyperker-age of disease onset and a relatively high incidence of atosis of the palms and soles and early onset periodontitis,secondary hematologic malignancy . which is in some cases believed to be viral in origin. The disease is caused by mutations in the CTSC gene, whichInterestingly, NK cells in Munc13-4 are deﬁcient in encodes cathepsin C (also known as dipeptidyl peptidase I).their cytotoxic activity, but not uniformly so . This Cathepsin C is a cysteine protease that acts in lyticmay be a feature of speciﬁc hypomorphic mutations or granules and other lysosomal organs to activate serineredundancy in the granule-priming process, but is not proteases such as granzymes A and B. Deﬁciency ofconsistent enough to discern FHL2 from FHL3, especi- cathepsin C was initially not found to lead to a cytolytically because there are also genotype–phenotype defect in cultured NK cells , but it was later discoveredcorrelations among perforin mutations. Although that a defect was present in NK cells that had not beenspeciﬁc data are not available, residual NK cell cytotox- activated in vitro . Speciﬁcally, ex-vivo patient NKicity has also been referred to in FHL4 patients . cells contained reduced active granzyme B and increasedPerforin-deﬁcient NK cells can be distinguished from amounts of pro-granzyme B. Incubation of patient NK cells
402 Primary immune deficiency diseasewith IL-2 restored their ability to process granzyme B and has not been previously associated with NEMOmediate cytotoxicity. Thus, cathepsin C is a required deﬁciency. Similar to other NEMO-deﬁcient patients,component in readying the cytolytic effector molecules however, this patient had a defect in cytokine production,required for NK cell activity. These observations also thus highlighting the speciﬁc contribution of deﬁcienthighlight the powerful effects of IL-2 upon human NK cytotoxicity in the development of HLH. Unfortunately,cells, as well as the need to study NK cells directly from the the exact role that NEMO plays in NK cell cytotoxicity ispatient without additional manipulation to fully appreciate still unknown, but is under investigation .their attri-butes. Familial erythrophagocytic lymphohistiocytosis type 2New insights from additional study of (perforin deﬁciency)diseases, which have been previously linked Increasing numbers of patients with HLH due to PFP1to natural killer cell deﬁciencies gene mutations encoding the perforin protein have alsoThere have been several new important developments been recognized. Although the vast majority of thesefor diseases whose link between a particular gene result in complete deﬁciency of the protein and a severemutation and NK cell deﬁciency has been previously clinical phenotype, there are some missense mutationsreviewed . These new connections are highlighted in that lead to only partial reductions in cytotoxicity, and/Table 2. Continued study of NK cells from patients with or presence of perforin protein [18,27,28,29]. Interest-this category of diseases will provide deepening mechan- ingly, patients with these mutations tend to have HLHistic insights into how human NK cells function. later in life and may have a milder clinical course. The exact reasons why these altered perforin proteins lead toNEMO deﬁciency less severe disease will likely provide insight into theA number of patients with NEMO deﬁciency due to role of perforin in NK cell function, and the mechanismmutation of the IKBKG gene have now been described as by which it facilitates target cell destruction. Presently,having deﬁcient NK cell cytotoxicity, as well as some it is appreciated that individual missense mutations canclinical consequences that may be attributable to NK cell lead to incorrect perforin proteosomal processing,defects [8,9]. A patient with this phenotype who also had increased degradation and/or incomplete maturationHLH at 2 months of age has been reported . This . In addition, some missense mutations of theparticular child also had cytomegalovirus (CMV) retinitis perforin gene have also been identiﬁed in patients withat 4 months of age. His NK cells possessed adequate hematologic malignancies [30,31], as well as in an adultlevels of perforin, but had cytotoxic activity that was with chronic active Epstein-Barr virus (EBV) infectioninitially absent and persistently less than control. This . These associations may point more speciﬁcally to acase is especially informative in that the HLH phenotype requirement for NK cell cytotoxicity in hematologicTable 2 New insights into natural killer cell biology and function from additional study of genetic diseases known to affect naturalkiller cellsDisease Gene mutated Affected protein New insight ReferenceNF-kB essential modulator IKBKG NEMO HLH phenotype [8,9] deﬁciencyFamilial erythrophagocytic PFP1 Perforin 1. Missense mutations can result in milder [18,27,28,29] lymphohistiocytosis-type 2 phenotype; 2. missense mutations can lead to aberrant perforin processing; 3. mutations can be present in patients with hematologic cancers without HLHSevere combined IL2RG, JAK3 IL-2r gc, Janus Dispensability of IL-2, IL-4 and IL-7, but not [34–37] immunodeﬁciency kinase 3 IL-15 signaling for natural killer cell developmentBare lymphocyte syndrome TAP2 Transporter 1. CECAM can function as an alternative and [38,39,41] associated with potent natural killer cell inhibitory receptor; antigen processing 2 2. increased CCR2 function results in abnormal natural killer cell accumulationsWiskott-Aldrich syndrome WASP WASp 1. WASp-directed actin reorganization is [44–46] required for integrin clustering at the natural killer cell immunological synapse; 2. WASp is required for cytotoxicity mediated by ex-vivo natural killer cells; 3. IL-2 increases cytotoxicity in WASp-deﬁcient natural killer cells; 4. WASp can facilitate natural killer cell activation by linking to NF-kB and NFAT activation
Human natural killer cell deficiencies Orange 403tumor cell surveillance, and they are supported by syndrome resulting from deﬁciency of the transportertransplantation data that deﬁne NK cells as possessing associated with antigen processing 2 (TAP-2). It has beenpowerful graft-antitumor effects . difﬁcult to understand why NK cells from TAP-2- deﬁcient patients fail to lyse bystander host cells, as theySevere combined immunodeﬁciency will have diminished MHC class I expression, thus pre-Studies of the lymphocyte composition of patients with sumably making them highly susceptible to NK cellsevere combined immunodeﬁciency (SCID) have pro- cytotoxicity. Although earlier studies have helpedvided valuable insight into the requirements for human explain this phenomenon, a new line of evidence demon-NK cell development. In particular, NK and T-cell strates that this does not occur due to increased expres-negative SCID resulting from mutations of either the sion and function of the MHC class I-independentIL2RG gene encoding the common gamma chain (gc) or inhibitory receptor carcinoembryonic antigen-related cellthe JAK3 gene encoding the Janus kinase 3 (JAK3) have adhesion molecule (CEACAM1) . This increasedillustrated the need for cytokines using this signaling function correlated with decreased soluble levels ofpathway to generate NK cells. As both of these proteins CEACAM1, serving to augment the inhibitory effectare required for the function of IL-2, 4, 7, 9, 15, and 21, mediated by cell surface CEACAM1 . Another poten-discerning exact cytokine requirements for NK cell tial explanation might derive from the recently appreci-development has not been possible. Rare patients with ated phenomenon of NK cell licensing discovered inSCID due to atypical IL2RG or JAK3 mutations, however, mice, wherein exposure to an MHC molecule is requiredhave been described as having NK cells. These to enable cytolytic potential in NK cells . Evenmutations allow for selective cytokine signaling and thus though this does not translate perfectly, as TAP-2-demonstrate speciﬁc NK cell developmental require- deﬁcient NK cells can still mediate lysis of selectedments. The ﬁrst of these patients had an A156V substi- target cells, it is likely a contributing factor. In this light,tution of gc and was unable to generate signals in impaired expression and function of the NK cell cyto-response to IL-4 or IL-7, but maintained intact IL-2 toxicity receptor NKp46 on TAP-2-deﬁcient patientand IL-15 function . The second patient had an cells point to a potential developmental defect .IL2RG 468 þ3AC splice site mutation in intron 3 Further studies of TAP-2-deﬁcient NK cells, however,resulting in three distinct mRNA species . These will provide additional human context for the NK cellwere the insertion of a stop codon, a twenty amino acid licensing hypothesis.extracellular domain insertion due to the presence of acryptic splice site, and wild-type due to ‘leakiness’ of the Finally, a comprehensive proteomic analysis of NK cellsmutation. The patient had normal numbers of NK cells from TAP-2-deﬁcient patients has helped to elucidate anthat could mediate cytotoxicity, but failed to proliferate unusual feature of the disease, which is the progressivein response to IL-2. Although the exact mechanism was accumulation of NK cells in the skin and respiratory tractnot deﬁned in this case, the results suggested the dis- . This work demonstrated that patient NK cells hadpensability of IL-2 signaling relative to IL-15 signaling in increased expression and function of the CC chemokinehuman NK cell development. A similar conclusion can be receptor 2 (CCR2), as well as increased serum andderived from a patient having SCID due to predicted bronchoalveolar lavage ﬂuid levels of CCR2 ligands.G589S alteration in JAK3, who had a normal number of Although the mechanistic link between TAP-2NK cells that could mediate some cytotoxicity against deﬁciency in promoting this abnormality is unclear, theK562 target cells . As IL-2 was unable to induce ﬁndings do explain the clinical phenotype and may high-STAT5 phosphorylation in cells from this patient, the light an adverse consequence resulting from inappropri-relative dispensability of IL-2 signaling for NK cell ate NK cell licensing.development is highlighted and the importance of IL-15 suggested. It is also worth mentioning a SCID patient Wiskott-Aldrich syndromewho did not have an identiﬁable mutation, but had very Finally, signiﬁcant advances have been made in under-low T-cell counts and absent NK cells . This case standing how the Wiskott-Aldrich syndrome (WAS)occurred in a young boy and was especially interesting in protein (WASp) contributes to NK cell functionsthat he had a speciﬁc deﬁcit in expression and function of through additional study of NK cells from patients withthe IL-2/IL15Rb chain. Although the IL2RB gene and its the disease. The combined immunodeﬁciency WAS1.1KB promotor regions had a normal sequence, the case results from mutations in the WASP gene that encodesdoes further highlight an absolute requirement for IL-15 WASp, which is a cytoskeletal adaptor protein capable ofin human NK cell development. facilitating the branching of actin ﬁlaments. As WASp can interact with at least 22 distinct proteins, its role inBare lymphocyte syndrome (TAP-2 deﬁciency) immunological function is likely to be complex .Signiﬁcant new understanding has also been gained into Furthermore, WASp is only one member in a family ofthe NK cells found in patients with bare lymphocyte related proteins that can act to rearrange actin, and thus
404 Primary immune deficiency diseaseis likely to be redundant in some respects. In ex-vivo NK non-NK cell-dependent immune components shouldcells that have been prepared directly from peripheral be largely normal. The ﬁrst classiﬁcation is Absoluteblood without any additional stimulation or activation, NK Cell Deﬁciency (ANKD) and it is deﬁned by thedefective NK-cell function was appreciated . This complete lack of NK cells and NKT cells. The inclusionﬁnding has been extended to a large cohort of WAS of both cell types in the ANKD diagnosis results from thepatients and correlates to some degree with the severity use of CD56, which is common to both NK cells andof the particular disease-causing mutation . Further- NKT cells, by ﬂow cytometry to deﬁne NK cells. ANKDmore, the defect in cytotoxicity includes both natural is not deﬁned as simply the absence of CD56, as NK cellscytotoxicity and antibody-dependent cellular cytotox- and their functions must truly be absent from all tissuesicity (ADCC) . These ﬁndings point to a critical role evaluated. The second classiﬁcation is Classical NK Cellfor WASp in NK cell cytolytic functions. This is in large Deﬁciency (CNKD), which is the same as ANKD exceptpart due to inappropriate accumulation of ﬁlamentous that NKT cells are present. This includes invariant NKTactin at the contact formed between the NK cell and cells (iNKT), which express CD3, CD56 and a limitedtarget cell (also known as the NK cell immunological repertoire of T-cell receptor genes, typically includingsynapse) in WASp-deﬁcient NK cells . The WASp- Va24 and Vb11, that enable them to recognize glycolipiddirected F-actin reorganization was additionally shown antigen in the context of the non-classical MHC mol-to be required for CD2 and integrin clustering at, and ecule CD1d. The third classiﬁcation is Functional NKpolarization of perforin-containing lytic granules to the Cell Deﬁciency (FNKD), characterized by the presenceimmunological synapse . Furthermore, an initial of NK cells that have some signiﬁcant and static abnormaldescription  and subsequent in-depth investigation activity. This is most typically a defect in cytotoxicity, demonstrated that exposure of NK cells to IL-2 in but can include any combination of other functionsculture was able to overcome the functional NK cell such as speciﬁc activation receptor-induced cytotoxicity,defect resulting from WASp deﬁciency. Given that a e.g. ADCC, cytokine production, target cell recognitionmajor susceptibility of WAS patients is to herpesviruses, range, adhesion, chemotaxis, and/or costimulationIL-2 therefore may have therapeutic potential in WAS. capacity.Culture-activated WAS NK cells are not entirely normal,however. Even though many functions are returned, One controversy that exists in this group of disorders isthere is still a defect in the activation of NF-kB and whether they are inborn or acquired. Even though, to beNFAT , demonstrating that WASp has important considered, the defect must be consistent over time, it isfunctions other than just actin remodeling in NK cells. possible that some cases are the result of acquired but immutable defects in NK cells. There is, however, oneAdvances in the understanding of isolated identiﬁed gene defect that results in FNKD, and alsonatural killer cell deﬁciencies several familial cases of ANKD have been reported. As aAlthough the genetic defects affecting immunity are result, NK cell deﬁciency is now listed in the Onlineuseful in addressing questions of NK cell biology, the Mendelian Inheritance in Man database (entry 609981).most important illustrations of the role of NK cells inhuman host defense remain the rare isolated deﬁciencies Table 3 Classiﬁcation of the isolated natural killer cellof NK cells. These cases are essential in that they truly deﬁciencieshighlight the speciﬁc contributions that NK cells make in Diagnosisa Natural killer Natural killer Natural killer cell functionb T cellsc cellsddefense against disease and in the maintenance of health.Determination of genetic lesions resulting in these phe- ANKD Absent Absent Absentnotypes will also provide great insight into the speciﬁc CNKD Absent Present Absentrequirements for NK cell development, survival and FNKD Deﬁcient Present Presentefunction in a human context. Since last reviewed, therehas been important progress made regarding patients ANKD, absolute natural killer cell deﬁciency; CNKD, classical natural killer cell deﬁciency; FNKD, functional natural killer cell deﬁciency.with this diagnosis and illustrative new cases have been a In natural killer cell deﬁciency, the observed defect must be consistentreported. Unfortunately, speciﬁc new genes resulting in over time and non-natural killer cell immune components or non-naturalthese phenotypes have still not been identiﬁed. Here, killer cell-dependent immune components should be normal. b Natural killer cell function as typically deﬁned by cytotoxicity, but cannew cases of isolated NK cell deﬁciency are reviewed and include any function that can be attributed to natural killer cells. As manyconsidered in the context of previously reported cases. of these functions are also performed by other cells, it is important that the deﬁcit be speciﬁcally attributed to the natural killer cell. c Natural killer T cells as deﬁned by the presence of CD3þ, CD56þ cells.As proposed and described previously [1,5,12,47], the This includes the iNKT cell population expressing the Va24 and Vb11classiﬁcation of the isolated NK cell deﬁciencies can combination of TCR genes.be facilitated by the division of these disorders into three d Natural killer cells as deﬁned by, but not limited to CD3À, CD56þ cells. e Although natural killer cells by deﬁnition are present in FNKD, there maycategories (Table 3). In each of these, immunological be phenotypic abnormalities or absence of particular natural killer cellassessments of non-NK cell immune components or subsets.
Human natural killer cell deficiencies Orange 405The issue of immutability of the NK cell defect over time reports of this deﬁciency (Table 4). Two cases of ANKDis an important aspect of the isolated NK cell were highlighted in the previous review of NK celldeﬁciencies. This is especially relevant as many of the deﬁciencies . One of these was the often-cited caseevaluations of NK cells performed to raise the suspicion of an adolescent female who had disseminated life-threa-of a diagnosis are functional assays, and exogenous factors tening VZV followed by CMV pneumonitis and herpescan reduce the number of NK cells in peripheral blood, simplex virus (HSV) . This patient’s herpesviralthe function of NK cells in peripheral blood, or both. infections occurred over several years and requiredThese factors include a number of pharmaceutical agents life-long prophylaxis. She persistently lacked CD56þand psychosocial stress [48,49]. It is now also appreciated NK cells and NK cell cytotoxicity over an observationthat in some patients who have experienced severe period of over 6 years. The second older case was in anvaricella zoster virus (VZV) infection, a transient adolescent boy who had disseminated mycobacteriumdeﬁciency of NK cells can also be observed . This avium and then died of disseminated VZV infectionlast report presents speciﬁc diagnostic challenges as VZV . He lacked NK cells and NK cell function, but alsohas been a signiﬁcant factor in several patients who have had a number of other immunologic features that mighthad consistent and not transient NK cell deﬁciencies. suggest a broader immunologic syndrome. His infectiousThe reported transient deﬁciency, however, was very susceptibility, however, at least partially overlapped withtransient as NK cell function reappeared in all patients that of the initial patient and thus is useful.by 4–6 weeks after initial appearance of the viralexanthem. Overall, these ﬁndings highlight a need to Since the previous review, there have been four additionalperform repeated assessments of an individual patient’s reports that are important to discuss. It is not clear in allNK cells and to consider exogenous factors. cases that NKT cells were also affected as they were not speciﬁcally evaluated, but they are discussed collectivelyFurthermore, the distinction between ANKD and in this section, as opposed to the next section, to allowCNKD is an important one. In particular, the expanding comparison. The ﬁrst was reported in two sisters, the oldestnumber of functions attributed to NKT cells makes this of whom died at 18 months of age from disseminated CMVessential. As an example, an isolated human deﬁciency of infection . The younger sister has not experiencedNKT cells has been reported and has an impressive severe infectious disease, but has not been infected withphenotype . This child had disseminated vaccine herpesviruses. The older sister did not have CD2þ/CD3Àstrain VZV despite having normal NK cell cytotoxicity lymphocytes and was assumed not to have NK cells. Theand an intact VZV-speciﬁc CD8þT cell response. younger sister did not have CD56þ/CD3À NK cells at birthAlthough this highlights a potential and important role to 3 years of age and had negligible percentages of NKTof NKT cells in defense against VZV, it underscores the cells. NK cell cytotoxicity was unmeasurable amongimportance of deﬁning the relative contributions of NK PBMC preparations. Both girls did have low CD8þ T cellscells versus NKT cells to host defense. Thus, as the role at birth, as well as persistent neutropenia. The remainderand importance of NKT cells have expanded signiﬁ- of their immunity, however, appeared intact. Interestingly,cantly it is very important to consider NKT cells and to by age 5, the surviving child’s NK cell percentages haddistinguish ANKD from CNKD. risen, approaching the 5th percentile for age, but with an unusual preponderance of CD56þ/CD16À NK cells.Absolute natural killer cell deﬁciency These sisters also had intrauterine growth retardation,ANKD is deﬁned as the complete absence of NK and facial abnormalities and eczema, suggestive of an over-NKT cells and there have been at least six separate arching genetic syndrome. Some mechanistic insight intoTable 4 Reports of isolated absolute natural killer cell deﬁciencyAuthor Infection Outcome Associated abnormalities ReferenceBiron VZV, CMV, HSV Died, bone marrow transplantation Low absolute lymphocyte counts  age 21 yearsWendland VZV, M. avium Died M. avium age 19 years Low absolute lymphocyte and  neutrophil counts. Decreased antigen presenting cell functionBernard A. CMV; B. none A. Died CMV age 18 months; B. living Low absolute neutrophil and  CD8þ T cell countsEtzioni VZV Died VZV age 29 months None Notarangelo VZV Successful HSCT age 4.5 years Neutropenia, lymphopenia Eidenschenk A. None; B. viral A. Alive; B. alive; None  pneumonia; C. EBV; C. lymphoproliferation; D. alive D. viral pneumonia
406 Primary immune deficiency diseasethe defect in this family has been reported in subsequent maximum LOD score of 4.51. This region contains 59studies by the authors. Using T cells from the surviving genes, including the PRKDC gene encoding proteinpatient, they have found impaired responses to IL-2 or IL- kinase, DNA-activated, catalytic polypeptide, which15, as well as excessive spontaneous apoptosis, suggesting does give rise to an immunologic phenotype whenthat IL-15-dependent NK cell survival may be speciﬁcally deleted in mice. Other interesting proteins encoded bydefective in this particular disorder . genes in this region include the CAAT enhancer binding protein delta, which is an important transcriptional reg-The second new case of ANKD occurred in a 23-month- ulator and can be mutated in certain cancer cells. Furtherold girl born to consanguineous parents, who had dis- studies of this family will likely provide a genetic etiologyseminated VZV infection with encephalitis . She of ANKD, as well as valuable information regarding NKhad a recurrence of the VZV infection 6 months later, cell development and function.which proved fatal. She did generate VZV-speciﬁc IgG,had quantitatively normal T cell populations, and normal Classical natural killer cell deﬁciencyproliferative responses to T cell and B cell mitogens CNKD is deﬁned as the absence of NK cells, but not(including IL-15), but had drastically reduced numbers NKT cells. There have been no new cases reported sinceof NK cells. She also had essentially absent NK cell the last review, but as mentioned, this could be affectedcytotoxicity, which could not be induced with IL-2. by the fact that NKT cells were not characterized in someAlthough substantial longitudinal evaluations were not cases of ANKD. Two patients with CNKD have beenperformed, this case is important in that the remainder of previously reported (Table 5); one had severe and recur-her immunity was intact. Also, the consanguinity in the rent infection with Human Papilloma virus (HPV), andfamily raised the possibility of a recessive genetic lesion. the other with fungi. Continued attention should be paid to this category as studies of these patients have theThe third new report was associated with a more signiﬁ- potential to provide great insight into the speciﬁc role ofcant overall immunological phenotype, but described a NK cells in host defense, as well as factors speciﬁc to NKgirl with total absence of CD16þ lymphocytes and NK cell development, survival, or both.cell cytotoxicity who had disseminated VZV infection atage 4.8 years . She also had leukopenia, low B cells, Functional natural killer cell deﬁciencyand poor lymphocyte proliferative responses, and was FNKD is deﬁned as the presence of normal numbers ofsuccessfully treated with hematopoietic stem cell trans- NK cells that have some deﬁciency in their function inplantation. Although her relatively late age at presen- the absence of other substantial immunologic abnormal-tation distinguishes her from children with SCID, she ities. Due to the fact that NK cells are present in thesedoes appear to have some similarity to the NK cell patients, as determined using standard clinical ﬂow cyto-predominant SCID described in the section on SCID metric analyses, the diagnoses are difﬁcult and require a. high degree of suspicion. Despite this challenge, there are a number of important examples of patients withThe ﬁnal new report of ANKD described four children abnormal host defense and isolated functional defects infrom three sets of consanguineous parents all from the NK cells. This diagnostic category is also most likely tosame family of Irish nomadic descent . One child grow as subtleties of host defense are increasinglyhad an EBV-related lymphoproliferation and two others related back to immunological phenotypes. The FNKDhad recurrent respiratory tract infections presumed to be category is also very valuable for understanding theof viral origin. Each of these children (three male, one relative importance of speciﬁc NK cell attributes andfemale) had low NK cell numbers. NK cell cytotoxic characteristics.function, as well as IL-2-induced cytotoxicity, was absentin the one patient tested. The speciﬁc phenotypic evalu- Previously, several reports of FNKD were reviewed ation of iNKT cells in two of the children also demon- and there have been two new reports worthy of mentionstrated very low numbers of these cells. It is important to since that time (Table 6). The previously reviewedpoint out that NK cells were low but not completelyabsent from the affected members of this family. Table 5 Reports of isolated classical natural killer cellAlthough, when tested, the function of the NK cells deﬁciencywas absent among total PBMC, it is unclear how the Associatedfew existing NK cells functioned. It is also unclear if the Author Infection Outcome abnormalities Referencephenotype of the few existing NK cells was normal. To Ballas HPV Died early 30s of HPV- None take advantage of the size and genetic similarity of this associated malignancy.kindred, a genomic scan of the family was performed and Sister died of leukemia in childhooddeﬁned a 12 megabase linkage region on chromosome 8(8p11.23-q11.21) that linked to the phenotype with a Akiba Fungi Fungal dissemination Lupus 
Human natural killer cell deficiencies Orange 407Table 6 Reports of isolated functional natural killer cell deﬁciencyAuthor Infection Outcome Associated abnormalities ReferenceFleisher (A) EBV, progressive (A) Acutely fatal None  (B) EBV, progressive (B) Died bronchiectasis age 38 (C) EBV, progressive (C) Alive with recurrent respiratory infectionKomiyama (A) Respiratory viruses Lymphoma None [62,71] (B) Respiratory virusesAoukaty EBV ? Decreased LAIR-1 expression Gazit CMV, VZV Alive Uniform KIR2DL1 expression  and absolute inhibitionDe Vries EBV, HSV, VZV, ? FCGR3A 48H/H  respiratory virusesJawahar HSV, respiratory viruses Alive FCGR3A 48H/H reports include the single known genetic cause of FNKD, overlap with the unusual occurrence of direct NK cellwhich results from a homozygous mutation in FCGR3A infection with EBV and subsequent lymphoproliferationgene, which encodes FcgRIIIA (or CD16) [59,60]. . Individuals affected by this latter condition areAlthough this gene is polymorphic, this rare variant described to have hypersensitivity to mosquitoes and areresults in a NK cell cytotoxicity defect and is associated more commonly Japanese, and the mechanism under-with severe herpesvirus infections. Fortunately, the lying the disorder is unclear. Both of these diagnoses areresulting CD16 variant molecule can be distinguished distinct from ‘chronic fatigue syndrome’, which hasfrom wild-type receptor using two different commercially been associated with EBV infection by some authors,available monoclonal anti-CD16 antibodies B73.1 and and can perhaps be associated with transient and mild3G8, the variant receptor not being recognized by the effects upon the NK cell population [65,66].former. No new cases of this variety of FNKD have beenreported since initially reviewed. The second case is that of a 7-year-old child with severe disseminated CMV and CMV pneumonitis, who later hadAdditional work has also been performed in one of the severe VZV infection. The patient was assessed as havingother previously reviewed cases of FNKD  and has intact immunity, including NK cell cytotoxicity. NK celldemonstrated a functional defect that has persisted for phenotype was also normal with the exception of uniformover 20 years (LaRosa and Orange, in preparation). Inter- high-level expression of the inhibitory receptor KIR2DL1estingly, this patient had an abnormal hardwired NK cell . This was of functional signiﬁcance as the patient’sphenotype, suggesting there was an inherent defect in NK cells were completely inhibited by target cells expres-NK cell activation or development. Since this functional sing HLA-Cw4 (a cognate ligand for KIR2DL1). Thedefect occurred in three of four siblings within a single factors governing this unusual expression of a singlefamily (two of whom died prematurely – one from EBV KIR gene are uncertain, but the resulting potential forand the other from repeated respiratory tract infections), broader inhibition of NK cells through consistentit is likely to have been genetic in origin. The other KIR2DL1 function may provide a selective advantagepreviously reviewed case also occurred in siblings, further to pathogens whose control typically depends upon NKhighlighting a potentially genetic etiology . cell mediated defense. Since linking speciﬁc KIR haplo- types to disease phenotypes has proven highly relevantThe two cases reported since the last review both , this case suggests that considering the speciﬁc expres-involve phenotypic aberrations of NK cells that may sion levels of individual KIR is also important.have functional consequences. The ﬁrst was describedin a patient with severe EBV infection described as Conclusionchronic and active . This patient had decreased There are an increasing number of deﬁcits in human NKNK cell cytotoxicity among culture propagated NK cells cells that have either been attributed to a mechanismbut, interestingly, had very low expression of leukocyte- underlying a broader immunological syndrome, or thatassociated immunoglobulin-like receptor 1 (LAIR1). represent isolated deﬁciencies within the NK cell popu-The signiﬁcance of this association is unclear, but is lation itself. The former group has continued to provideinteresting given the role of inhibitory receptor signaling insight into the speciﬁc functional and genetic require-in NK cell licensing. In this light, it is worth mentioning ments of human NK cells. The latter group has furtherthe literature referring to chronic and active infections highlighted the role of NK cells in human host defense.with EBV. This diagnostic entity is difﬁcult and may Additional studies of both groups of NK cell deﬁciencies
408 Primary immune deficiency disease 20 Clark RH, Stinchcombe JC, Day A, et al. Adaptor protein 3-dependentwill provide important insights into NK cell biology and microtubule-mediated movement of lytic granules to the immunologicaltheir role in human health and disease. synapse. Nat Immunol 2003; 4:1111–1120. 21 Fontana S, Parolini S, Vermi W, et al. Innate immunity defects in Hermansky-Acknowledgements Pudlak type 2 syndrome. Blood 2006; 107:4857–4864. Demonstration that AP-3 is required for the normal formation and trafﬁc of lyticThis work was supported by NIH grant AI055602, a subcontract from granules in NK cells.the US immunodeﬁciency network, and a faculty development awardfrom the Education Research Trust of the American Academy of Allergy 22 Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistio- cytosis in Hermansky-Pudlak syndrome type II. Blood 2006; 108:81–87.and Immunology. 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