Human natural killer cell deficiencies and susceptibility to infection

Microbes and Infection 4 (2002) 1545–1558 www.elsevier.com/locate/micinf

Forum in Immunology

Human natural killer cell deficiencies and susceptibility to infection Jordan S. Orange * Division of Immunology, Children’s Hospital and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA

Abstract There are a surprisingly large number of human natural killer (NK) cell deficiency states that provide insight into the role of NK cells in defense against human infectious disease. Many disorders associated with NK cell defects are caused by single gene mutations and, thus, give additional understanding concerning the function of specific molecules in NK cell development and activities. A resounding theme of NK cell deficiencies is susceptibility to herpesviruses, suggesting that unexplained severe herpesviral infection should raise the possibility of an NK cell deficit. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: NK cells; Primary immunodeficiency; Herpesviruses; NK cell deficiency

1. Introduction One way to elucidate the importance of a particular aspect of the immune system is to study its specific absence. Murine models of targeted immune deficiency have proven invaluable in the pursuit of knowledge from gene to phenotype. The study of human immunodeficiency presents the opportunity to investigate the converse, linking phenotypes to immunologic functions and, ultimately, genotypes. In addition, evaluation of immunodeficient humans with known genetic abnormalities can help elucidate pathways involved in human immune development and function. Natural killer (NK) cells lack surface expression of T cell receptors and immunoglobulin and comprise 5–15% of human peripheral blood lymphocytes. They are poised to be either activated or inhibited by a variety of germline-encoded receptors. Although the specificities of the majority of NK cell-activating receptors remain enigmatic, some are capable of recognizing microbial pathogens [1,2]. Physiologic ligation of NK cell-activating receptors can result in both cytotoxicity and cytokine production. One particular activating receptor, CD16 or FCcRIIIa, can bind immunoglobulin, resulting in antibody-dependent cellular cytotoxicity (ADCC). ADCC and cytotoxicity mediated through other NK cellactivating receptors (known as NK cell cytotoxicity, natural cytotoxicity, or spontaneous cytotoxicity) differ in the intra-

* Corresponding author E-mail address: [email protected] (J. Orange) © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. PII: S 1 2 8 6 - 4 5 7 9 ( 0 2 ) 0 0 0 3 8 - 2

cellular signaling pathways they utilize [3]. NK cell proliferation, trafficking, and cytotoxicity can also be induced by cytokines. With these various activation mechanisms, it is not surprising that induction of and alterations in peripheral blood NK cell populations can be induced by numerous infectious pathogens. NK cell activation during and contribution to defense against infectious disease has been the subject of other review articles [4] and is discussed by other authors in this issue. Literature describing defective NK cell activities and resultant infectious vulnerabilities has not been comprehensively examined. In this review, I will specifically focus on human NK cell deficiencies and associated infectious susceptibilities in order to help comprehend the role of NK cells in host defense. The rarity of NK cell deficiencies signifies the essential nature of NK cells in host defense. Studying NK cell deficiencies, however rare, thus provides information useful for understanding the role of these cells in antimicrobial defense. NK cell deficiencies can be due to absence of NK cells or absence of NK cell activity. For the purpose of this review, an NK cell deficiency is defined as a consistent and significant reduction in NK cell numbers, cytolytic activity, cytokine responsiveness, or cytokine production. Using these criteria, human NK cell deficiencies are divisible into four broad categories (see Table 1): (1) isolated NK cell deficiency associated with an identified gene defect; (2) isolated NK cell deficiency without a known gene defect, not associated with a known disease; (3) NK cell deficiency associated with a disease due to a known gene defect that also causes another

Disease

1546

Table 1 Summary of human NK cell deficiency states Gene mutation Affected protein

NK cell numbers b

NK cell phenotype c

NK cytotoxicity

ADCC

Cytokine References d response

Aberrant CD16

Normal/decreased

Normal

Absent

[6,7,10]

Absent Absent

Absent

Absent Absent

[11,12] [13,15]

Absent

[16–18]

Normal Partial Normal Normal

[19,27,29] [19,28,30] [19,25,26] [34,35] [36,37] [32,33] [39–41]

Known gene mutation and isolated NK cell defect NK cell deficiency due to CD16 impairment FCGR3A

CD16 (FCcRIIIa)

HSV, VZV, EBV

Normal

Unknown gene mutation and isolated NK cell defect Absolute NK cell deficiency Classical NK cell deficiency

Unknown Unknown

Unknown Unknown

CMV, VZV, HSV, B, Mb HPV, Trichophyton

Absent Absent

Functional NK cell deficiency

Unknown

Unknown

EBV, HSV

Normal

IL2RG JAK3 ADA BLM FANCA-G XPAG TAP1, TAP2

Multiple Multiple Multiple Fungi, B Multiple B

Absent/decreased Absent/decreased Absent/decreased Normal Normal Normal Normal

PFP1

Common c chain Janus kinase 3 Adenosine deaminase Bloom helicase FA proteins DNA repair enzymes Transporter associated with antigen processing Perforin

EBV, CMV, VZV, HSV

LYST

Lysosome trafficking regulator Myosin-Va, RAB27A

X-linked lymphoproliferative syndrome Leukocyte adhesion deficiency

MYO5A, RAB27A SH2D1A ITGB2

X-linked hyper-IgM-I

TNFSF5

CD154 (CD40 ligand)

Paroxysmal nocturnal hemoglobinuria

PIG-A

Phosphatidylinositol glycan class A Multiple

Decreased

von Hippel–Lindau syndrome Wiskott–Aldrich syndrome

NKTR WASP

NK-tumor recognition molecule Wiskott–Aldrich syndrome protein

B, viruses

IL-12 receptor deficiency

IL12RB1

IL-12Rb

X-linked agammaglobulinemia

BTK

Ectodermal dysplasia with immunodeficiency

Known gene mutation in a disease that includes an NK cell deficiency X-linked SCID Autosomal recessive SCID Metabolic SCID Bloom syndrome Fanconi’s anemia Xeroderma pigmentosum Bare lymphocyte syndrome (MHC-I deficiency) Familial erythrophagocytic lymphohistiocytosis Chediak–Higashi syndrome

CD56+ T cells present Normal

Decreased

Normal Normal Normal Normal

Usually absent Usually absent Usually absent Decreased Decreased Decreased Absent

Normal

Normal

Normal

Absent

Absent

EBV, B, Candida, Aspergillus B, EBV, HSV

Normal

Normal

Absent

Absent

Normal

Normal

Absent

EBV Bacteria, picornavirus, HSV PCP, enteroviruses, B

Normal Increased

Normal Absent LFA-1/MAC-1 Absent CD154

Absent Absent

Normal Absent

Absent/decreased Absent

Normal Increased

Absent GPI-linked CDs Absent pNKR Normal

Mb, Salmonella

Normal

Absent IL-12Rb Normal

Bruton’s tyrosine kinase

B, enteroviruses

Normal

IKBKG

NFjB essential modifier (NEMO)

CMV, HSV, Mb, B

Normal

Decreased CD8, Decreased CD16 Normal Decreased

Normal/ Normal decreased Normal Absent or partial Normal Partial Normal/ decreased Absent IL-12 Decreased

Unknown gene mutation in a disease that includes an NK cell defect Chronic fatigue syndrome

Unknown

Unknown

EBV, B, Candida

Normal

Common variable immunodeficiency

Unknown

Unknown

B, Candida

Chronic mucocutaneous candidiasis

Unknown

Unknown

Candida

Griscelli syndrome

a

SLAM-associated protein CD18

Absent/normal

Absent Decreased

Normal/decreased

Decreased

Normal to variable Normal

Decreased

Normal

Decreased

Normal/decreased

Variable Normal

Absent or [45–48,52,54] partial Partial [55–62] Normal

[67–69]

Normal Partial

[72,74–78] [82–86,89] [22,23,90] [94–97,99] [101] [17,26,105–108] [112,113] [22,23,26,114,115]

Normal/ Partial decreased

[120]

Normal/ Normal decreased Normal/ Normal decreased

[123,124] [22,23,25,114,115,125] [128–130]

Abbreviations: HSV—herpes simplex virus, VZV—varicella zoster virus, EBV—Epstein–Barr virus, CMV—cytomegalovirus, B—non-mycobacterial bacteria, Mb—mycobacteria, HPV—human papilloma virus, PCP—Pneumocystis carinii. b CD56+/CD3– or equivalent if this value has not been reported. d For complete list of relevant references see corresponding section of the text. c Determination was usually based on incomplete NK cell subset analyses.

J. Orange / Microbes and Infection 4 (2002) 1545–1558

Infectious susceptibility a

J. Orange / Microbes and Infection 4 (2002) 1545–1558

immune deficiency; and (4) NK cell deficiency associated with a known disease without a known genetic etiology. Each of these categories will be addressed separately.

2. Known gene mutation and isolated NK cell deficiency The most informative group of disorders involves an isolated human NK cell deficiency that can be associated with a specific gene mutation. Because only NK cells are affected, these diseases can ascribe defective NK cell activities to infectious susceptibilities and can link gene expression to NK cell function. Although improved molecular technologies may allow for the expansion of this category, there is only one known human gene alteration resulting in isolated NK cell deficiency. CD16 is an IgG Fc receptor (FccRIIIa) that is expressed on NK cells as well as phagocytes. The primary known function of CD16 in NK cells is activation induced by IgG binding, although an IgG-independent role in activation has been demonstrated [5]. Extracellular domains of CD16 have been characterized, in part, by specific monoclonal antibodies that bind to distinct regions of the molecule. There are known CD16 polymorphisms, one of which disrupts the epitope recognized by mAb B73.1 and is caused by T → A substitution at position 230 resulting in L48 → H. Individuals homozygous for this allele have NK cells that are phenotypically normal, but cannot be recognized by mAb B73.1 [6,7]. A different CD16-specific mAb, such as clone 3G8, however, demonstrates normal expression of the molecule. Several patients having the homozygous 48H phenotype have been reported. A 5-year-old girl had frequent upper respiratory infections, recurrent herpes simplex virus (HSV) stomatitis, and recurrent herpetic whitlow [7]. This child was deficient in NK cell cytotoxicity against K562 target cells, but had normal ADCC. Brothers homozygous for the 48H phenotype had recurrent upper respiratory infections, and the older boy also had invasive Calmette–Guérin bacillus infection, as well as progressive Epstein–Barr virus (EBV) and varicella infections [6]. Unlike the 5-year-old girl, these boys had normal K562 killing and ADCC. Importantly, all three patients had evidence of normal adaptive immunity with protective pathogen-specific antibody titers. A fourth 48H homozygous patient with severe and prolonged varicella infection was also described [6]. Although NK cell IL-2 responsiveness was found to be intact in the first patient [7], NK cell cytokine production was not evaluated in any of the four patients. The 48H phenotype implies a particularly important function of the epitope recognized by mAb B73.1 in resistance to viral infection, as individuals with other mutations or polymorphisms in the CD16 gene have autoimmune disorders, but do not have recurrent infections [8,9]. Subsequent investigation of CD16 polymorphisms demonstrated presence of the 48H allele in approximately 8% of a Scandinavian Caucasian population. This would result in

1547

greater than 6/1000 homozygous individuals [10]. This large predicted number of 48H homozygotes may be population specific, but suggests that other factors may be required for infectious susceptibility in these individuals. Alternatively, 48H homozygous patients with troublesome herpesviral infections may be undiagnosed. It will be informative to determine the frequency of the 48H allele in other populations and whether there is a relationship of the homozygous phenotype to unexplained severe herpesviral disease in otherwise healthy individuals.

3. Unknown gene mutation and isolated NK cell deficiency An extremely important group of disorders involve isolated NK cell deficiencies in individuals who do not have known diseases affecting the immune system and who do not demonstrate evidence of other non-NK cell immune deficiency. Surprisingly, several patients fit this description. They can be divided into three categories: (1) absolute NK cell deficiency (ANKD), with no detectable CD56+ cells or NK cell activity; (2) classical NK cell deficiency (CNKD), with no detectable CD56+/CD3– “classical” NK cells; and (3) functional NK cell deficiency (FNKD), with detectable NK cells but one or more absent NK cell functions. The lack of molecular etiologies for these conditions implies that several pathways critical for human NK cell function and development are still an enigma. These disorders, however, present a valuable opportunity to understand the role of NK cells in human health and disease. The best known human NK cell deficiency is that of a female adolescent presenting with disseminated, lifethreatening varicella infection [11]. This patient subsequently developed cytomegalovirus (CMV) pneumonitis and cutaneous HSV. She had evidence of intact adaptive immunity with normal varicella-induced lymphocyte proliferation and varicella-specific antibody titers. In repeated evaluations, she was found to have ANKD as determined by a lack of lymphocytes expressing CD56 or CD16, as well as a lack of demonstrable NK cell cytotoxicity or ADCC. In addition, incubation of her lymphocytes with IFN-a or IL-2 failed to induce cytotoxic activity. Since publication of the original report, the patient developed aplastic anemia and died from complications related to bone marrow transplantation. Postmortem attempts to uncover a genetic etiology for her syndrome were unsuccessful and included normal sequence evaluation of her IL-15 receptor genes (J.L. Sullivan, personal communication). Despite the lack of a molecular etiology, this well-conceived evaluation definitively demonstrated susceptibility to herpesviruses in an individual lacking NK cells who was without other marked immunologic impairment. Since the initial description of ANKD, one other unrelated male patient has been described [12]. This patient had Salmonella enteritis at age 17 and subsequently developed

1548

J. Orange / Microbes and Infection 4 (2002) 1545–1558

disseminated M. avium infection and died at age 19 from disseminated varicella. He had low percentages of B cells, and he lacked CD56+ cells and NK cytotoxicity. He was mildly hypogammaglobulinemic, but had evidence of normal specific antibody production as well as antigen-induced lymphocyte proliferation and M. avium-specific cytotoxic activity. Intact IL-12 and IFN-c production, as well as IL-12 responsiveness, was also demonstrated, distinguishing him from other individuals genetically susceptible to mycobacteria due to deficiencies in these pathways (discussed in Section 4.3.3). Thus, two individuals with isolated deficiencies of NK cells had severe susceptibility to herpesviruses, which strongly suggests the importance of NK cells in defense against human herpesvirus infections. CNKD is also important in understanding the role of NK cells and could prove particularly useful in separating their in vivo function from that of CD56+ T cells. Individuals with CNKD have isolated deficiency of CD56+/CD3– “classical” NK cells but normal or increased populations of CD56+/CD3+ cells. The most definitive report of CNKD is that of a 23-year-old woman with severe and recurrent human papilloma virus (HPV)-induced condolomatous disease [13]. She had evidence of normal adaptive immunity, as demonstrated by protective pathogen-specific antibody titers and lymphocyte proliferation. She lacked NK cell cytotoxic activity against K562 as well as NK cell cytotoxicity induced by IFN-a and IL-2. Although she had a large population of CD56+/CD3+ cells (18%) in her peripheral blood, she lacked lymphocytes expressing CD16 and was nearly deficient in CD56+/CD3– cells. Her depressed NK cell activity was probably not due to HPV infection alone, as severe HPV disease has been shown not to affect NK cell numbers or lytic activity against K562 target cells [14]. A second patient probably having CNKD was recently reported [15]. He had invasive Trichophyton infection, with evidence of normal T and B cell populations as well as normal Trichophyton-induced lymphocyte proliferation. He lacked detectable NK cell cytotoxicity and had only 0.2% CD16+/CD56+ lymphocytes. CD56, however, was found on approximately 4% of his total lymphocytes, suggesting the existence of CD56+/CD3+ cells. His presentation was complicated by pre-existing lupus, and thus, CNKD as an independent diagnosis is uncertain. Whether individuals with CNKD have a developmental block in lymphoid development causing the deletion of classical NK cells or decreased survival of mature NK cells is unknown, but further study of this condition will prove informative. Regardless, CNKD is associated with unusual infectious susceptibilities and suggests a role for NK cells in defense against HPV and Trichophyton. A more difficult, but equally useful, diagnosis is FNKD, in which NK cells are present as a normal percentage of peripheral blood lymphocytes, but are deficient in activity. Although many diseases and exposures affect NK cell activity, patients with FNKD have an isolated, presumably permanent, deficiency of NK cell activity without evidence of other immunologic disease or immune dysfunction. Several re-

ported groups of patients fulfill these criteria and have infectious susceptibilities to pathogens, including EBV and HSV. The earliest study described four siblings (three male and one female) with disseminated EBV infections and absent NK cell cytotoxicity [16]. Although their NK cell phenotypes were not evaluated, one sibling had normal induction of K562 target cell killing when PBMCs were IFN-stimulated, suggesting the presence of NK cells in this family. These children did not have the X-linked lymphoproliferative syndrome (XLP), as there was no evidence of lymphoproliferation and one affected child was female. A subsequent report described four patients with widespread or invasive HSV disease, all with low NK cell cytotoxicity and absent or low NK cell cytotoxic activity against HSV-infected fibroblasts [17]. Finally, two brothers with recurrent upper respiratory infections were found to have phenotypically normal NK cells that did not mediate cytotoxic activity or respond to IFN-a or IL-2 [18]. Although one of the boys had Hodgkin’s disease, he was successfully treated, and his NK cell deficiency persisted 6 years after his cure. Although it is possible that all of these individuals with FNKD might have diseases with known gene mutations affecting NK cell activity (discussed below), they lack characteristics of those conditions. Overall, greater vigilance for diagnosing patients with isolated NK cell deficiencies will likely provide fundamental data regarding the role of NK cells in defense against infectious disease. Furthermore, the subsequent search for molecular etiologies of these conditions holds promise in understanding pathways relevant to NK cell function and development.

4. Known gene mutation in a disease that includes an NK cell defect Although isolated NK cell deficiencies present the opportunity to understand NK cell-specific genes and NK cell roles in human antimicrobial defense, a variety of other diseases have NK cell deficiency as a component. Many of these diseases are caused by known gene mutations and provide insight concerning molecular pathways important in NK cell function, but common to other cell types. Certain infectious susceptibilities are poorly explained by other immunologic activities affected by these gene defects and suggest roles for NK cells. Many of the diseases described in this section were defined prior to the discovery of their genetic etiology, and thus, NK cell characteristics are discussed in patients who carried only the clinical diagnosis as well as those who have the molecular diagnosis. 4.1. Mutations affecting NK cell development and survival One of the most informative immunodeficiencies in terms of lymphocyte development is severe combined immunodeficiency (SCID). The majority of gene mutations in children with SCID are rare and do not interfere with NK cell devel-

J. Orange / Microbes and Infection 4 (2002) 1545–1558

opment, revealing that these genes are dispensable for NK cell maturation. The most common genetic causes of SCID, however, are associated with aborted NK cell development or deletion of NK cells and are caused by mutations in genes coding for the cytokine receptor common-c chain (cc), Janus kinase 3 (JAK-3), or adenosine deaminase (ADA). Although there are notable exceptions, these children do not have NK cells and do not have NK cell cytotoxic activity [19]. Similarities between the clinical presentation of SCID caused by a variety of gene mutations make it difficult to pair historical reports of NK cell activity and phenotype to particular mutations. Thus, early reports described significant variability regarding NK cell activity, some patients having no NK cell cytotoxicity and ADCC and others having activity that was quite high [20–27]. It is now clear that SCID patients with mutations not affecting NK cell lineages can have high NK cell cytotoxicity because of relative NK cell enrichment resulting from depletion of other lymphocytes. In some historical cases, a molecular diagnosis can be conferred, including ADA-SCID, which has been understood biochemically for some time, and obvious X-linked SCID, presumably due to cc mutation. Several of these reports demonstrate that infants with X-linked SCID and ADA-SCID lack NK cells and/or NK cell cytotoxicity [25–27]. More recent studies show that patients with cc or JAK-3 mutations generally do not have NK cells [19,28]. A minority of these patients, however, have circulating NK cells, which survive due to selective mutations incompletely impairing gene function [28–30]. One child, in particular, lacked T cells, but not NK cells, and was found to have an unusual cc mutation resulting in partial receptor function. He had impaired responses to IL-4 and IL-7, but normal IL-2 and IL-15 signaling [29]. This implies that distinct signals are required for NK cell development and provides clues with which to investigate enigmatic NK cell deficiencies. In contrast, SCID due to ADA mutation presumably results in toxic destruction of NK cells or NK cell precursors due to accumulation of dATP, which inhibits ribonucleotide reductase. Children with SCID are susceptible to a wide variety of infections, most of which are largely due to the absence of T and B cell subsets. Many viral infections affect SCID patients, including those of the herpesvirus family. In fact, one of the few cases of disseminated vaccine strain varicella was found in a patient with ADA-SCID [31]. Although it is likely that lack of NK cells is involved in the viral susceptibility of SCID patients, the severity of T cell defects precludes further conclusion. Specific comparison of viral disease in SCID with and without NK cells would be informative, but is not presently available. Similar to metabolic SCID, DNA repair disorders, such as xeroderma pigmentosum caused by errors in XPA genes, Bloom’s syndrome caused by mutation in BLM, and Fanconi’s anemia due to defects in FANCA-G genes, probably affect the stability of immune cells, including NK cells. Although NK cells have not been comprehensively evaluated in these diseases, studies suggest that NK cells are present,

1549

but with impaired activity [32–37]. In both xeroderma pigmentosum and Bloom’s syndrome, NK cells respond normally to IL-2 [33,34], whereas in Fanconi’s anemia, cytokine responses are more variable [36,37]. Although the main vulnerability in patients with these disorders is to malignancy, a variety of infectious susceptibilities are also known. Individuals with these syndromes and documented NK cell deficiencies have suffered from consequences of fungi, respiratory bacteria, and HPV infections [35,36]. However, another disorder of DNA repair, ataxia telangiectasia, caused by mutation of the ATM gene, has normal NK cell function [38]. Thus, it is unclear whether NK cell functions are particularly dependent upon effective DNA repair or specifically on XPA, BLM, and FANC genes. An additional group of gene mutations affecting NK cell development and, ultimately, NK cell function are those causing the bare lymphocyte syndrome (BLS). BLS is caused by a mutation in the gene coding for either of the two subunits of the transporter associated with antigen processing (TAP). NK cells of patients with TAP-1 or TAP-2 deficiency have a normal immunophenotype but fail to lyse MHC-I-deficient target cells [39–41]. This is consistent with the fact that NK cells from BLS patients fail to mediate widespread lysis of autologous MHC-I-deficient cells in vivo. Interestingly, patient NK cells can mediate lysis in response to stimulatory cytokines [39,41] and express a normal array of activating receptors that function adequately [40]. This suggests that there is a developmental alteration of NK cells in BLS, or high expression of an unknown inhibitory receptor on NK cells that recognizes a molecule other than TAP-generated MHC-I. In light of the absence of MHC-I and decreased activity of NK cells, it is surprising that patients with BLS suffer from only bacterial infections and do not experience severe viral disease. Thus, virusspecific lytic activity of NK cells might be intact in BLS, and virus-specific NK cell-activating receptor function may be an important feature of immune defense in TAP-deficient individuals. Diseases affecting NK cell development and survival highlight requirements for the existence of functional NK cells. They also suggest that impaired NK cell defenses might contribute to particular infectious susceptibilities. Furthermore, NK cells present in some of these disorders can help to better understand the contribution of NK cells in defense against infection. 4.2. Mutations affecting NK cell cytolytic effector mechanisms Three primary immunodeficiencies result from known aberrations in cytotoxic effector mechanisms. They are familial erythrophagocytic lymphohistiocytosis (FELH), the Chediak–Higashi syndrome (CHS), and the Griscelli syndrome (GS). These are distinct from diseases affecting cytotoxic cell activation, as they are specifically due to defective molecules or production of molecules from activated cyto-

1550

J. Orange / Microbes and Infection 4 (2002) 1545–1558

toxic cells responsible for target cell destruction. These syndromes do not result in isolated deficiencies of NK cell activities, as they have effects on cytotoxic function in other cell types as well. FELH is an autosomal recessive syndrome characterized by immunologic hyperactivation and cytokine overproduction after infection with one of several herpesviruses. Many cases of this disease are not overtly familial but appear similar immunologically and are known as hematophagocytic lymphohistiocytosis (HLH). These disorders are associated with a variety of immunologic abnormalities, including defective T cell and NK cell activities. In contrast to other immunodeficiencies involving NK cells, the herpesviral infection in FELH/HLH is not disseminated, but appears to trigger an overwhelming immune response that requires potent chemotherapeutic immunosuppression to curtail. In many cases, the best therapeutic option is bone marrow transplantation. A defect in NK cell cytotoxicity has long been recognized as a consistent immunologic finding in FELH and in many cases of HLH [42,43]. NK cells are usually present in normal numbers, but are deficient in cytotoxic activity [42,44–48], and deficient activity persists after disease remission [44,45]. Furthermore, family members of patients can also have absent or decreased NK cell cytotoxicity [45,48]. Other patient NK cell functions, including ADCC and IL-2- or IFN-ainduced cytotoxicity, are deficient as well [42,45]. Despite low cytotoxic activity, there is no obvious defect in NK cell cytokine production. There are actually extraordinarily high serum levels of cytokines during active disease, including IL-12 and IFN-c, as well as increased IFN-c production by CD2+ cells [49–51]. This characteristic may help explain the ability to control herpesviral infection at the cost of overwhelming and often fatal immune response. Approximately 20% of patients with FELH have a mutation in the gene coding for the pore-forming molecule perforin [52,53]. These mutations prevent expression of perforin but do not affect levels of other NK cell gene products, such as granzyme B [52]. Absence of perforin in FELH can be readily detected in patient NK cells by intracellular flow cytometry [54]. Lack of perforin would prevent NK cellproduced cytolytic molecules from entering the target cell and causing apoptosis. Because aberrant perforin is only responsible for a subset of FELH, it is likely that mutations affecting other cytolytic effector molecules also cause FELH/HLH. Thus, NK cell deficiency in FELH results in the inability to downregulate an immune response, suggesting a regulatory role for cytotoxic lymphocytes in herpesviral infection. Another distinct autosomal recessive syndrome with pathogenesis similar to FELH is CHS. Individuals with CHS have oculocutaneous albinism and recurrent respiratory bacterial infections, as well as susceptibility to Candida and Aspergillus. Patients have neutropenia, granulocytes with giant granules, and deficient NK cell activity. NK cells in CHS have been well characterized and are defective in spon-

taneous cytotoxicity [55,56]. In addition, they have abnormal morphology, with giant granules, and are also defective in ADCC [57–59]. Despite these abnormalities, CHS NK cells are present in normal numbers and bind target cells effectively [59–61]. They also retain an ability to mediate target cell lysis after activation by IFN-a/b [56,60,62]. Cytokine production in CHS is presumably intact, as most patients will eventually succumb to an “accelerated phase”. The accelerated phase of CHS is a state of immune hyperactivation and cytokine overproduction very similar to the lymphohistiocytosis seen in FELH and is associated with EBV infection [63,64]. The molecular pathogenesis of CHS was established, in part due to a naturally occurring murine model of the disease. Both humans with CHS and beige mutant mice have been shown to have mutations in the LYST gene [65]. It is believed that LYST, or lysosome trafficking regulator, functions in vesicle attachment to microtubules, and thus, vesicular transport is defective in CHS due to LYST mutation. Granules in CHS coalesce around the nucleus due to defective sorting of late lysosomes, which affects a variety of cell types [66]. The defect in NK cells, however, is probably more central to disease morbidity due to the association of cytotoxicity and virus-induced accelerated phase (as determined in FELH). A third disorder of NK cell effector mechanisms very similar to CHS is GS. As with CHS, patients with GS also have oculocutaneous albinism and increased infections and often enter a virus-associated accelerated phase as seen in FELH and CHS [67]. Individuals with GS have a variable immune deficiency that typically includes a marked reduction in NK cell cytotoxic activity [67–69]. Unlike CHS and FELH, however, NK cell cytotoxicity can be induced in vitro by IFN-a or IL-2 stimulation [67,69]. Despite the responsiveness of NK cells, infectious susceptibility includes EBV and HSV, and the accelerated phase is believed to be initiated by EBV [67]. GS has recently been associated with a mutation in one of two different genes involved in granule trafficking. Two GS patients were found to have a mutation of MYO5A, which encodes the myosin-Va motor protein, an unconventional myosin motor [70]. More recently, a series of GS patients were found to have a mutation in RAB27A, which encodes one of the GTP-binding RAB family member proteins important in intracellular protein traffic [71]. The variable immunologic deficit present in GS, however, makes it unclear as to which mutation causes a more significant NK cell phenotype and greater infectious susceptibility. Taken together, these three disorders demonstrate the importance of granule contents and granule mobility in NK cell function and suggest a role for NK cells in the infectious susceptibility found in these diseases. Furthermore, they suggest a contribution of NK cell cytolytic activity in regulation of herpesvirus-induced lymphoproliferation and immune dysregulation. Finally, these diseases are distinct from conditions in which NK cells and other cytokine-producing lymphocytes are absent in that susceptibility to herpesviruses

J. Orange / Microbes and Infection 4 (2002) 1545–1558

is not associated with disseminated infection. This suggests distinct roles for NK cell cytolytic and cytokine functions. 4.3. Mutations affecting NK cell activation There are a relatively large number of human gene mutations or gene deletions associated with diseases that include defective NK cell activation. They are roughly divisible into the following categories: (1) defective activating receptor/coreceptor function; (2) impaired activation-induced cytoskeletal alteration; (3) defective cytokine responsiveness; and (4) aberrant intracellular signaling. Although these diseases affect many immune functions, they provide insight into genes and signals specifically required for induction of NK cell activity. Careful analysis of these disorders is also suggestive of specific roles for NK cells in defense against infection. 4.3.1. Mutations affecting NK cell-activating receptors or co-receptors A prototypic disorder impairing NK cell-activating receptor function is XLP. The majority of individuals with XLP live without major complications until they encounter EBV infection. As in patients with diseases affecting NK cell effector mechanisms, EBV infection in XLP is not disseminated, but results in lymphohistiocytosis and malignant lymphoproliferation. Individuals affected by XLP as well as their male siblings predisposed to developing disease have deficient NK cell cytotoxic activity [72–77]. In contrast, ADCC and IFN-a/b-induced NK cell activity are present [72,73,75]. Failure to lyse EBV+ target cells, however, is a consistent feature, regardless of the NK cell activation state [74,78]. Subsequent studies identified mutations in signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in individuals affected by XLP [79]. SAP is required for the function of several lymphocyte receptors, including SLAM and 2B4 (CD244), the latter of which is of greater interest regarding NK cells. Ligation of 2B4 induces NK cell cytotoxicity, and this activity is defective in XLP patients with SAP mutation [76,77]. Interestingly, 2B4 mediates an inhibitory, as opposed to an activating, signal in NK cells from XLP patients [78]. The natural ligand of 2B4 is CD48, which is upregulated on EBV-infected cells [80]. Transfection of resistant target cells with CD48 has shown that NK cell activation via a specific 2B4–CD48 interaction is impaired in XLP [77]. As in the case of FELH, cytokine production in XLP is presumably intact and results in control of viral spread at the cost of lymphohistiocytosis. Thus, XLP caused by SAP mutation results in defective receptor-mediated cell activation, leading to NK cells with a specific inability to lyse EBV-infected host cells. Another disorder affecting essential NK cell receptor systems is leukocyte adhesion deficiency (LAD). Patients with LAD have elevated peripheral blood leukocyte numbers and experience severe mucocutaneous bacterial infections without pus formation [81]. Although the majority of infectious susceptibilities involve bacteria, some patients have had sig-

1551

nificant viral disease, including one with recurrent HSV and another who died from picornaviral infection [81,82]. There are multiple immunologic abnormalities in LAD, which include defective NK cell activity. NK cells in LAD are present in normal percentages, but in increased numbers due to extraordinarily high leukocyte counts [82]. On a per lymphocyte basis, their ability to mediate NK cell cytotoxicity or ADCC or kill HSV-infected target cells is severely deficient [82–86]. Activity after in vitro activation is also defective [87]. Adoptive transfer of PBMCs from LAD patients into HSV-infected neonatal mice demonstrated that patient cells failed to provide protection, and this was not corrected by IFN-a [85]. Single cell cytotoxicity assays have proved most informative and demonstrate that NK cells from LAD patients largely fail to bind target cells [83]. This is intriguing, given the absent ADCC in these patients, and suggests that adhesion or co-stimulation in addition to antibody binding is required for this activity. LAD is caused by a variety of mutations in the b2 integrin, CD18 [88]. These result in inappropriate expression of several key adhesion complexes, including LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18), both of which are highly expressed on NK cells. LFA-1 also serves an important signaling function in NK cells through association with an immunoglobulin-like activating receptor, DNAM-1 [89]. DNAM-1 signaling activity is deficient in NK cells from LAD patients and can be restored by introduction of functional CD18, allowing interaction between LFA1 and DNAM-1. Thus, LAD results in a deficiency of NK cell adhesion as well as a deficiency of certain NK cell-activating signals and is associated with a broad spectrum of infectious susceptibilities, a minority of which might imply deficient NK cell function. An immunodeficiency with a more variable impairment of NK cells is X-linked hyper-IgM syndrome (XHM). The major defect in XHM is B cell antibody production, and there is a general absence of isotype switching. Although a variety of viral infections have been reported in XHM, there is particular susceptibility to Pneumocystis, enteroviruses, parvovirus, and respiratory bacteria. A limited number of studies have documented NK cell deficiency in XHM. The most pronounced is that of a boy with complete absence of CD56+ or CD16+ lymphocytes as well as NK cell cytotoxicity [90]. Interestingly, NK cells and NK cell activity could be induced after a 5-d culture of his PBMCs in IL-2. Other patients with XHM have been found to have decreased NK cell cytotoxicity [22,23], but normal ADCC [23]. Therefore, the NK celldeficient patient probably represents an extreme case. XHM results from mutation in the TNFSF5 gene, which codes for CD154 (CD40L). Although CD154 is an important costimulatory molecule in T cell interactions, there is also evidence that CD154 functions in NK cell activation by dendritic cells [91]. CD154 is expressed on activated NK cells and can participate in the induction of NK cell cytotoxicity [92]. Thus, CD154 is a probable contributor to NK cell

1552

J. Orange / Microbes and Infection 4 (2002) 1545–1558

function, and a deficiency of and role for NK cells in XHM may be under appreciated. A disorder that presumably affects a variety of NK cellactivating receptors is paroxysmal nocturnal hemoglobinuria (PNH). PNH is caused by an acquired gene mutation in a proportion of hematopoietic stem cells and results in aplastic anemia as well as susceptibility to a wide range of infections [93]. Although the frequency of NK cells is usually decreased in patients with PNH [94,95], there is a nearly complete absence of NK cell cytotoxicity, and IFN fails to significantly induce activity [94,96,97]. PNH results from stem cell mutations in the phosphatidylinositol glycan class A gene, which causes all cell progeny to lack glycosylphosphatidylinositol (GPI)-anchored proteins [98]. This affects NK cells, as defective GPI linking is found in NK cells from PNH patients [99]. Interestingly, ADCC is normal in NK cells from PNH patients, as the FcRcIIIa is not GPI-linked like its monocyte counterpart FcRcIIIb [100]. Several GPIlinked proteins are probably important to NK cells and NK cell activities. One candidate is CD48, which, as previously discussed, is the ligand for the NK cell-activating receptor 2B4. Thus, it is likely that although individuals with PNH presumably express 2B4, they may lose 2B4 function due to the absence of CD48. Not all NK cell-activating receptor mutations that result in defective in vitro lysis of tumor-derived target cells are associated with infectious susceptibility. One example is found in a subset of patients with von Hippel–Lindau (VHL) disease. VHL is a familial cancer syndrome resulting from aberration of the VHL tumor suppressor gene on chromosome 3p. Absence of the VHL gene causes dysregulation of the hypoxiainducible transcription factor (HIF) and results in increased extracellular matrix deposition and angiogenesis. A subset of patients with VHL also has other closely linked chromosome 3 genes affected [101]. One such affected gene in VHL can be the NK tumor recognition molecule (NK-TR) [102,103]. These individuals have normal NK cell populations but lack expression of NK-TR. PBMCs from such patients are defective in NK cell cytotoxicity and IL-2-induced NK cell cytotoxicity, but have normal ADCC [101]. The defect is presumably specific to patients with affected NK-TR, as VHL patients with intact NK-TR have normal NK cell activities. Thus, in vitro deficiency of NK cell tumor lysis may specifically correlate with an increased incidence of malignancy in vivo but does not necessarily imply infectious susceptibility. As a group, these disorders demonstrate that NK cell receptor and co-receptor specificities and function are critical to NK cell activities and are likely to play particular roles in defense against infectious disease. 4.3.2. Mutations affecting activation-induced cytoskeletal alteration Activation-induced cytoskeletal rearrangement is a critical process in the formation of supramolecular activation clusters and effective molecular congregations allowing productive cell signaling. The Wiskott–Aldrich syndrome

(WAS) is a disorder of activation-induced actin polymerization in which there is defective molecular clustering in cellactivating interactions. Children with WAS suffer from a combined immunodeficiency and are susceptible to a wide variety of infections, including severe viral infections and disseminated varicella [104,105]. Although there is a welldefined T cell deficiency in WAS, historical reports of NK cell activity in WAS have been equivocal. PBMC populations from WAS patients demonstrate variable deficits in K562 and HSV-infected target cell lysis as well as ADCC [17,26,105–107]. More recent studies demonstrate that NK cell populations are increased in WAS and may account for observed variability in NK cell cytotoxicity [108]. When fresh NK cells from WAS patients are enriched, they are consistently defective in cytolytic activity on a per cell basis. WAS is caused by mutations in the WASP gene leading to defective WAS protein (WASp). Upon specific activation, WASp normally functions to create and extend actin branches by catalyzing the interaction of actin monomers and the actin-related protein 2/3 complex. WASp is expressed in NK cells and accumulates along with filamentous actin at contact points with susceptible target cells. In NK cells from patients with WASP mutations, however, filamentous actin fails to accumulate in contact zones with target cells [108]. Thus, NK cells utilize WASp-mediated cytoskeletal rearrangements, and WAS demonstrates the importance of the cytoskeleton in NK cell function. 4.3.3. Mutations affecting NK cell cytokine responsiveness A subset of hereditary mycobacterial susceptibility syndromes is due to aberrant type I cytokine pathways and has presumably normal-appearing NK cells. These are in contrast to SCID due to cc or JAK-3 mutations, in which defective cytokine signaling interferes with NK cell development (discussed in Section 4.1). Individuals with type I cytokine defects due to mutations in the genes coding for IL-12 p40, IL-12Rb, IFN-cR1, and IFN-cR2 have susceptibility to both typical and atypical mycobacteria as well as Salmonella. Interestingly, patients with IFN-cR deficiencies can have severe viral infections, including disseminated varicella, HSV, and CMV [109]. Presumably, there are deficiencies of NK cell function in all type I cytokine defects. As NK cells contribute to IFN-c production during viral infection, it is likely that this aspect of NK function is impaired in individuals with an inappropriate IFN-c response due to IFN-cR mutation. Likewise, individuals with IL-12 p40 mutations fail to produce IFN-c from PBMC populations in response to physiologic stimuli, suggesting that NK cells are unable to produce IFN-c effectively [110,111]. Despite these presumed NK cell defects, NK cell studies have only been reported in IL-12Rb deficiency. Patients with this mutation have normal numbers of NK cells [112,113] as well as normal NK cell cytotoxicity [112]. As expected, however, IL-12 failed to further induce NK cell cytotoxicity, and IFN-c production from patient NK cells was severely impaired [112]. Thus, specific defects in type I

J. Orange / Microbes and Infection 4 (2002) 1545–1558

cytokine responsiveness and production result in aberrant NK cell function, which likely contributes to infectious susceptibility in these individuals. Further study of NK cells in these disorders will most certainly be informative and will help to better understand co-ordination of human NK cell defenses. 4.3.4. Mutations affecting NK cell intracellular signaling Although a number of the aforementioned disorders ultimately affect NK cell intracellular signaling, two conditions caused by mutation of intracellular signaling molecules are associated with NK cell defects. The first is X-linked agammaglobulinemia (XLA), characterized by absent B cells and immunoglobulin. Patients with XLA are susceptible to bacterial infections and a variety of viral infections, including those caused by enteroviruses. NK cells are present in normal numbers in XLA patients, but there is a relative deficiency of CD16+ and CD8– NK cells [114]. It is not known whether this is a developmental or activation-related phenomenon. In terms of function, several patients with XLA have mild deficiencies of NK cell cytotoxicity and ADCC [22,23,26,115]. Normal cytotoxic activity was also documented in patients from each of these studies. Studies of NK cell function, however, have not been reported in patients with a documented molecular defect causing XLA. XLA is caused by mutation in the Src family kinase Btk. Although Btk expression is assumed to be specific to B cells, it is possible that Btk may be expressed in and function in NK cells under certain conditions. Indeed, expression of the Btk-associated linker molecule (BLNK) has been demonstrated in NK cells, suggesting viability of this pathway in NK cell activity [116]. Thus, NK cell observations in XLA are alluring, and additional study is required to further elucidate the role of Btk in NK cell function. The second condition affecting intracellular signaling associated with an NK cell deficiency is ectodermal dysplasia with immunodeficiency (EDID). EDID is an X-linked syndrome of aberrant ectodermal development associated with a deficit in immunoglobulin as well as IL-12 and IFN-c production [117–119]. Like patients with type 1 cytokine deficiencies, patients with EDID are primarily susceptible to mycobacterial infections. Interestingly, there have been several patients with reported susceptibility to herpesviruses [118,120]. One boy, in particular, had recurrent, invasive episodes of CMV despite protective levels of CMV-specific IgG. This patient and several others were found to have deficient NK cell cytotoxicity, but normal ADCC and normal percentages of NK cells [120]. In vitro stimulation with IL-2 induced NK cell cytotoxicity in PBMCs from multiple patients. Likewise, in vivo administration of IL-2 to the patient with recurrent CMV disease induced NK cell activity, and long-term treatment was associated with absence of CMV disease. It is probable, therefore, that the NK cell deficiency in this individual contributed to his susceptibility to CMV. Normal ADCC with deficient NK cell cytotoxicity is particularly interesting in light of the molecular defect causing

1553

EDID. EDID is caused by mutation of the NFjB essential modifier (NEMO) gene [117]. NEMO is part of the IjB kinase complex that phosphorylates IjB, freeing cytoplasmic NFjB so that it may be translocated to the nucleus to activate transcription. Individuals with EDID due to NEMO mutation have evidence of impaired NFjB activation. Although there are no independent evaluations of NEMO function in NK cells, NFjB activity has been reported to be essential to NK cell cytotoxicity [121]. There are several avenues to potentially activate NFjB in NK cell cytotoxicity that may not be as heavily utilized in ADCC, including signaling via Pyk-2 and PI3K [3]. Thus, the deficit in EDID adds additional evidence for the role of NK cells in defense against CMV and provides insight into intracellular divergence among NK cell activities.

5. Unknown gene mutation in a disease that includes an NK cell defect The most difficult data to interpret involve diseases that include an NK cell defect but are not caused by known gene mutations. Although several diseases or disease states are associated with NK cell impairment, this discussion is limited to presumably genetic disorders with immunodeficiency and non-transient defects of NK cell activities. These conditions are markedly heterogeneous and probably represent a variety of genetic mechanisms. One disease that only loosely fits this description, but has a rich literature regarding NK cell deficiency, is chronic fatigue syndrome. Although there is variability in diagnosis, a subgroup of chronic fatigue patients may have susceptibility to EBV infection and transient or long-term NK cell deficiencies. The NK cell-specific data in this disease have been previously reviewed [122]. More recently, a family has been described with multiple members having chronic fatigue syndrome and normal NK cell populations but persistently decreased NK cell cytotoxicity [123]. The majority of unaffected family members had normal NK cell lytic activity. These types of data raise the possibility that a subset of individuals with chronic fatigue have a genetic defect affecting NK cell activity. Susceptibility to severe or prolonged EBV infection in these patients may exist and imply a role for NK cell function, but additional study is required. Common variable immunodeficiency (CVID) is another diagnosis that describes a fairly heterogeneous group of individuals. Unlike those with chronic fatigue, however, all patients with CVID have a stringently documented humoral immune deficiency as characterized by hypogammaglobulinemia and lack of specific antibody production. CVID is also associated with a number of other immunologic deficits, including decreased or absent NK cell cytotoxicity and ADCC in some patients [22,23,26,115,124]. This variability probably reflects distinct genetic lesions giving rise to the CVID phenotype. NK cells are present in CVID but are typically in decreased numbers and percentages [114]. Re-

1554

J. Orange / Microbes and Infection 4 (2002) 1545–1558

cently, 12 patients with CVID were shown to have an increased number of monocytes containing IL-12, which correlated with an increased number of T cells containing IFN-c [125]. Interestingly, there was a decrease in number of NK cells containing IFN-c, suggesting an NK cell-specific defect in CVID. Individuals with CVID are susceptible to bacterial and candidal infections, and a single patient with a particularly severe NK cell defect had invasive CMV infection [124]. The contribution of NK cell deficiency to genetic infectious susceptibility in CVID is unclear, but greater understanding of the molecular etiology of this disorder may provide insight into NK cell function. Many of the previously described immunodeficiencies involve susceptibility to candidiasis. Although NK cells are activated in animal models of Candida exposure [126], the role they play in human candidal disease is unclear. Human NK cells have anticandidal activity, suggesting that there may be an in vivo role for NK cells in defense against candidiasis [127]. Chronic mucocutaneous candidiasis (CMCC) is an immunodeficiency associated with specific susceptibility to Candida and characterized by variable inheritance and immunologic defects. There is typically a loss of delayed type hypersensitivity to Candida and decreased IL-12 and IFN-c formation but increased IL-10 production. CMCC probably arises from a variety of molecular etiologies, and a subset of CMCC patients with polyendocrinopathies has been found to have a mutation in the autoimmune regulator gene, AIRE. Two series of CMCC patients without endocrinopathies reported NK cell deficiencies. In one group of 23 patients, 18 of the affected had decreased NK cell populations [128]. A second series of five patients had decreased NK cell cytotoxicity [129]. An isolated case was also reported of an individual with both decreased NK cell numbers and cytolytic activity [130]. Although it is possible that candidal infection or anticandidal drugs may be affecting NK cells, these patients suggest a contribution of NK cell defense in candidiasis. Furthermore, better genetic understanding of CMCC without endocrinopathy stands to shed light on NK cell anticandidal mechanisms.

6. Summary

Based upon data derived from the various NK cell deficiencies, evaluation of a patient with a suspected defect should be relatively thorough. Analysis of NK cell populations by flow cytometry using the standard clinical laboratory reagents alone will overlook the majority of NK cell deficiency states. Assessment of NK cell cytotoxicity, ADCC, cytokine responsiveness, NK cell subset phenotype, and, preferably, cytokine production will provide a more complete understanding of a patient’s NK cell status. Although clinically certified laboratories perform many of these evaluations, some are, unfortunately, still performed only as research protocols. Further study of NK cells in infectious susceptibility syndromes may present opportunity for therapeutic intervention. As NK cells in many of the disorders reviewed are responsive to immunostimulatory cytokines, in vivo cytokine administration might be useful when conventional options fail. Finally, the study of NK cells in human disease can provide valuable information regarding molecular pathways and cellular processes important in NK cell function. Some observations will certainly recapitulate predictions made using rodent models, while others will likely uncover novel contributions to NK cell biology.

Acknowledgements The author thanks J.L. Sullivan for sharing unpublished data, as well as J.E. Boyson and M.S. Fassett for constructive discussion. J.S.O. is supported by NIH grant AI-07512.

References [1]

[2]

[3] [4]

NK cell deficiency states are associated with a wide range of diseases and infectious susceptibilities (Table 1). Evaluation of the isolated human NK cell defects and common themes of the diseases that include NK cell deficiencies suggests that human NK cell activity is especially important in defense against herpesviral infection. The presence of severe herpesviral disease in the absence of a wellcharacterized lymphocyte immunodeficiency should prompt evaluation of NK cell activities. In addition, other unexplained infections, including those caused by fungi, mycobacteria, and papilloma viruses, should also raise the possibility of an NK cell defect or a disorder that is associated with an NK cell defect.

[5]

[6]

[7]

H. Arase, E.S. Mocarski, A.E. Campbell, A.B. Hill, L.L. Lanier, Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors, Science 296 (2002) 1323–1326. O. Mandelboim, N. Lieberman, M. Lev, L. Paul, T.I. Arnon, Y. Bushkin, D.M. Davis, J.L. Strominger, J.W. Yewdell, A. Porgador, Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells, Nature 409 (2001) 1055–1060. B. Perussia, Signaling for cytotoxicity, Nat. Immunol. 1 (2000) 372–374. C.A. Biron, K.B. Nguyen, G.C. Pien, L.P. Cousens, T.P. SalazarMather, Natural killer cells in antiviral defense: function and regulation by innate cytokines, Annu. Rev. Immunol. 17 (1999) 189–220. O. Mandelboim, P. Malik, D.M. Davis, C.H. Jo, J.E. Boyson, J.L. Strominger, Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity, Proc. Natl. Acad. Sci. USA 96 (1999) 5640–5644. E. de Vries, H.R. Koene, J.M. Vossen, J.W. Gratama, A.E.G.K. von dem Borne, J.L.M. Waaijer, A. Haraldsson, M. de Haas, M.J.D. van Tol, Identification of an unusual Fc c receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections, Blood. 88 (1996) 3022–3027. S. Jawahar, C. Moody, M. Chan, R. Finberg, R. Geha, T. Chatila, Natural killer (NK) cell deficiency associated with an epitopedeficient Fc receptor type IIIA (CD16-II), Clin. Exp. Immunol. 103 (1996) 408–413.

J. Orange / Microbes and Infection 4 (2002) 1545–1558 [8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22] [23]

[24]

T. Takeuchi, T. Nakagawa, T. Ikemoto, M. Sasaki, S. Makino, A. Shimizu, N. Ohsawa, A novel mutation in the FccRIIIA gene (CD16) results in active natural killer cells lacking CD16, Autoimmunity 31 (1999) 265–271. J. Wu, J.C. Edberg, P.B. Redecha, V. Bansal, P.M. Guyre, K. Coleman, J.E. Salmon, R.P. Kimberly, A novel polymorphism of FccRIIIa (CD16) alters receptor function and predisposes to autoimmune disease, J. Clin. Invest. 100 (1997) 1059–1070. M. de Haas, H.R. Koene, M. Kleijer, E. de Vries, S. Simsek, M.J. van Tol, D. Roos, A.E. von dem Borne, A triallelic Fc c receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc c RIIIa, J. Immunol. 156 (1996) 3948–3955. C.A. Biron, K.S. Byron, J.L. Sullivan, Severe herpesvirus infections in an adolescent without natural killer cells, N. Engl. J. Med. 320 (1989) 1731–1735. T. Wendland, S. Herren, N. Yawalkar, A. Cerny, W.J. Pichler, Strong ab and cd TCR response in a patient with disseminated Mycobacterium avium infection and lack of NK cells and monocytopenia, Immunol. Lett. 72 (2000) 75–82. Z.K. Ballas, J.M. Turner, D.A. Turner, E.A. Goetzman, J.D. Kemp, A patient with simultaneous absence of “classical” natural killer cells (CD3–, CD16+, and NKH1+) and expansion of CD3+, CD4–, CD8–, NKH1+ subset, J. Allergy Clin. Immunol. 85 (1990) 453–459. J. Malejczyk, M. Malejczyk, S. Majewski, G. Orth, S. Jablonska, NK-cell activity in patients with HPV16-associated anogenital tumors: defective recognition of HPV16-harboring keratinocytes and restricted unresponsiveness to immunostimulatory cytokines, Int. J. Cancer 54 (1993) 917–921. H. Akiba, Y. Motoki, M. Satoh, K. Iwatsuki, F. Kaneko, Recalcitrant trichophytic granuloma associated with NK-cell deficiency in a SLE patient treated with corticosteroid, Eur. J. Dermatol. 11 (2001) 58–62. G. Fleisher, S. Starr, N. Koven, H. Kamiya, S.D. Douglas, W. Henle, A non-X-linked syndrome with susceptibility to severe Epstein–Barr virus infections, J. Pediatr. 100 (1982) 727–730. C. Lopez, D. Kirkpatrick, S.E. Read, P.A. Fitzgerald, J. Pitt, S. Pahwa, C.Y. Ching, E.M. Smithwick, Correlation between low natural killing of fibroblasts infected with herpes simplex virus type 1 and susceptibility to herpesvirus infections, J. Infect. Dis. 147 (1983) 1030–1035. A. Komiyama, H. Kawai, A. Yabuhara, Y. Mitsuhiko, Y. Miyagawa, M. Ota, H. Hasekura, T. Akabane, Natural killer cell immunodeficiency in siblings: defective killing in the absence of natural killer cytotoxic factor activity in natural killer and lymphokine-activated killer cytotoxicities, Pediatrics 85 (1990) 323–330. R.H. Buckley, R.I. Schiff, S.E. Schiff, M.L. Markert, L.W. Williams, T.O. Harville, J.L. Roberts, J.M. Puck, Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants, J. Pediatr. 130 (1997) 378–387. G.F. Pierce, S.H. Polmar, B.Z. Schacter, C. Brovall, D.L. Hornick, R.U. Sorensen, Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing, Hum. Immunol. 15 (1986) 85–96. C. Lopez, D. Kirkpatrick, P.A. Fitzgerald, C.Y. Ching, R.N. Pahwa, R.A. Good, E.M. Smithwick, Studies of the cell lineage of the effector cells that spontaneously lyse HSV-1 infected fibroblasts (NK(HSV1)), J. Immunol. 129 (1982) 824–828. H.S. Koren, D.B. Amos, R.H. Buckley, Natural killing in immunodeficient patients, J. Immunol. 120 (1978) 796–799. S.O. Sanal, R.H. Buckley, Antibody-dependent cellular cytotoxicity in primary immunodeficiency diseases and with normal leukocyte subpopulations. Importance of the type of target, J. Clin. Invest. 61 (1978) 1–10. N. Flomenberg, K. Welte, R. Mertelsmann, R. O’Reilly, B. Dupont, Interleukin 2-dependent natural killer (NK) cell lines from patients with primary T cell immunodeficiencies, J. Immunol. 130 (1983) 2635–2643.

1555

[25] M.C. Sirianni, L. Businco, R. Seminara, F. Aiuti, Severe combined immunodeficiencies, primary T-cell defects and DiGeorge syndrome in humans: characterization by monoclonal antibodies and natural killer cell activity, Clin. Immunol. Immunopathol. 28 (1983) 361–370. [26] M. Lipinski, J.L. Virelizier, T. Tursz, C. Griscelli, Natural killer and killer cell activities in patients with primary immunodeficiencies or defects in immune interferon production, Eur. J. Immunol. 10 (1980) 246–249. [27] H.H. Peter, W. Friedrich, R. Dopfer, W. Muller, C. Kortmann, W.J. Pichler, F. Heinz, C.H. Rieger, NK cell function in severe combined immunodeficiency (SCID): evidence of a common T and NK cell defect in some but not all SCID patients, J. Immunol. 131 (1983) 2332–2339. [28] F. Candotti, S.A. Oakes, J.A. Johnston, S. Giliani, R.F. Schumacher, P. Mella, M. Fiorini, A.G. Ugazio, R. Badolato, L.D. Notarangelo, F. Bozzi, P. Macchi, D. Strina, P. Vezzoni, R.M. Blaese, J.J. O’Shea, A. Villa, Structural and functional basis for JAK3-deficient severe combined immunodeficiency, Blood. 90 (1997) 3996–4003. [29] S. Kumaki, N. Ishii, M. Minegishi, S. Tsuchiya, D. Cosman, K. Sugamura, T. Konno, Functional role of interleukin-4 (IL-4) and IL-7 in the development of X-linked severe combined immunodeficiency, Blood. 93 (1999) 607–612. [30] L.D. Notarangelo, S. Giliani, C. Mazza, P. Mella, G. Savoldi, C. Rodriguez-Perez, E. Mazzolari, M. Fiorini, M. Duse, A. Plebani, A.G. Ugazio, M. Vihinen, F. Candotti, R.F. Schumacher, Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model, Immunol. Rev. 178 (2000) 39–48. [31] F. Ghaffar, K. Carrick, B.B. Rogers, L.R. Margraf, K. Krisher, O. Ramilo, Disseminated infection with varicella-zoster virus vaccine strain presenting as hepatitis in a child with adenosine deaminase deficiency, Pediatr. Infect. Dis. J. 19 (2000) 764–766. [32] P.G. Norris, G.A. Limb, A.S. Hamblin, J.L. Hawk, Impairment of natural-killer-cell activity in xeroderma pigmentosum, N. Engl. J. Med. 319 (1988) 1668–1669. [33] P.G. Norris, G.A. Limb, A.S. Hamblin, A.R. Lehmann, C.F. Arlett, J. Cole, A.P. Waugh, J.L. Hawk, Immune function, mutant frequency, and cancer risk in the DNA repair defective genodermatoses xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy, J. Invest. Dermatol. 94 (1990) 94–100. [34] Y. Ueno, T. Miyawaki, H. Seki, K. Hara, T. Sato, N. Taniguchi, H. Takahashi, N. Kondo, Impaired natural killer cell activity in Bloom’s syndrome could be restored by human recombinant IL-2 in vitro, Clin. Immunol. Immunopathol. 35 (1985) 226–233. [35] A. Etzioni, N. Lahat, A. Benderly, R. Katz, S. Pollack, Humoral and cellular immune dysfunction in a patient with Bloom’s syndrome and recurrent infections, J. Clin. Lab. Immunol. 28 (1989) 151–154. [36] P. Hersey, A. Edwards, R. Lewis, A. Kemp, J. McInnes, Deficient natural killer cell activity in a patient with Fanconi’s anaemia and squamous cell carcinoma. Association with defect in interferon release, Clin. Exp. Immunol. 48 (1982) 205–212. [37] P. Froom, E. Aghai, J.B. Dobinsky, M. Quitt, N. Lahat, Reduced natural killer activity in patients with Fanconi’s anemia and in family members, Leukoc. Res. 11 (1987) 197–199. [38] I. Tsuge, H. Matsuoka, S. Torii, J. Okada, T. Mizuno, M. Matsuoka, Y. Kodera, T. Takahashi, Preservation of natural killer and interleukin-2 activated killer cell activity in ataxia-telangiectasia with T cell deficiency, J. Clin. Lab. Immunol. 23 (1987) 7–13. [39] J. Zimmer, L. Donato, D. Hanau, J.P. Cazenave, M.M. Tongio, A. Moretta, H. de la Salle, Activity and phenotype of natural killer cells in peptide transporter (TAP)-deficient patients (type I bare lymphocyte syndrome), J. Exp. Med. 187 (1998) 117–122.

1556

J. Orange / Microbes and Infection 4 (2002) 1545–1558

[40] M. Vitale, J. Zimmer, R. Castriconi, D. Hanau, L. Donato, C. Bottino, L. Moretta, H. de la Salle, A. Moretta, Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells, Blood. 99 (2002) 1723–1729. [41] H. Furukawa, T. Yabe, K. Watanabe, R. Miyamoto, A. Miki, T. Akaza, K. Tadokoro, S. Tohma, T. Inoue, K. Yamamoto, T. Juji, Tolerance of NK and LAK activity for HLA class I-deficient targets in a TAP1deficient patient (bare lymphocyte syndrome type I), Hum. Immunol. 60 (1999) 32–40. [42] N. Perez, J.L. Virelizier, F. Arenzana-Sieisdedos, A. Fischer, C. Griscelli, Impaired natural killer activity in lymphohistiocytosis syndrome, J. Pediatr. 104 (1984) 569–573. [43] S. Imashuku, H. Shigeyoshi, S. Todo, Hemophagocytic lymphohistiocytosis in infancy and childhood, J. Pediatr. 130 (1997) 352–357. [44] B. Stark, I.J. Cohen, M. Pecht, T. Umiel, R.N. Apte, E. Friedman, S. Levin, R. Vogel, M. Schlesinger, R. Zaizov, Immunologic dysregulation in a patient with familial hemophagocytic lymphohistiocytosis, Cancer 60 (1987) 2629–2636. [45] M. Arico, L. Nespoli, R. Maccario, D. Montagna, F. Bonetti, D. Caselli, G.R. Burgio, Natural cytotoxicity impairment in familial haemophagocytic lymphohistiocytosis, Arch. Dis. Child 63 (1988) 292–296. [46] R. Eife, G.E. Janka, B.H. Belohradsky, H. Holtmann, Natural killer cell function and interferon production in familial hemophagocytic lymphohistiocytosis, Pediatr. Hematol. Oncol. 6 (1989) 265–272. [47] Y. Kataoka, S. Todo, Y. Morioka, K. Sugie, Y. Nakamura, J. Yodoi, S. Imashuku, Impaired natural killer activity and expression of interleukin-2 receptor antigen in familial erythrophagocytic lymphohistiocytosis, Cancer 65 (1990) 1937–1941. [48] K.E. Sullivan, C.A. DeLaat, S.D. Douglas, A.H. Filipovich, Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and first degree relatives, Pediatr. Res. 44 (1998) 465–468. [49] Y. Osugi, J. Hara, S. Tagawa, K. Takai, G. Hosoi, Y. Matsuda, H. Ohta, H. Fujisaki, M. Kobayashi, N. Sakata, K. Kawa-Ha, O. Shintaro, A. Tawa, Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis, Blood. 89 (1997) 4100–4103. [50] J.I. Henter, G. Elinder, O. Soder, M. Hansson, B. Andersson, U. Andersson, Hypercytokinemia in familial hemophagocytic lymphohistiocytosis, Blood. 78 (1991) 2918–2922. [51] K. Akashi, S. Hayashi, H. Gondo, S.I. Mizuno, M. Harada, K. Tamura, K. Yamasaki, T. Shibuya, N. Uike, T. Okamura, T. Miyamoto, Y. Niho, Involvement of interferon-c and macrophage colony-stimulating factor in pathogenesis of haemophagocytic lymphohistiocytosis in adults, Br. J. Haematol. 87 (1994) 243–250. [52] S.E. Stepp, R. Dufourcq-Lagelouse, F. Le Deist, S. Bhawan, S. Certain, P.A. Mathew, J.I. Henter, M. Bennett, A. Fischer, G. de Saint Basile, V. Kumar, Perforin gene defects in familial hemophagocytic lymphohistiocytosis, Science 286 (1999) 1957–1959. [53] K. Goransdotter Ericson, B. Fadeel, S. Nilsson-Ardnor, C. Soderhall, A. Samuelsson, G. Janka, M. Schneider, A. Gurgey, N. Yalman, T. Revesz, R. Egeler, K. Jahnukainen, I. Storm-Mathiesen, A. Haraldsson, J. Poole, G. de Saint Basile, M. Nordenskjold, J. Henter, Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis, Am. J. Hum. Genet. 68 (2001) 590–597. [54] K. Kogawa, S.M. Lee, J. Villanueva, D. Marmer, J. Sumegi, A.H. Filipovich, Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members, Blood. 99 (2002) 61–66. [55] J.C. Roder, T. Haliotis, M. Klein, S. Korec, J.R. Jett, J. Ortaldo, R.B. Heberman, P. Katz, A.S. Fauci, A new immunodeficiency disorder in humans involving NK cells, Nature 284 (1980) 553–555.

[56] T. Haliotis, J. Roder, M. Klein, J. Ortaldo, A.S. Fauci, R.B. Herberman, Chediak–Higashi gene in humans I. Impairment of natural-killer function, J. Exp. Med. 151 (1980) 1039–1048. [57] M. Klein, J. Roder, T. Haliotis, S. Korec, J.R. Jett, R.B. Herberman, P. Katz, A.S. Fauci, Chediak–Higashi gene in humans. II. The selectivity of the defect in natural-killer and antibody-dependent cellmediated cytotoxicity function, J. Exp. Med. 151 (1980) 1049–1058. [58] J.C. Roder, T. Haliotis, L. Laing, D. Kozbor, P. Rubin, H. Pross, L.A. Boxer, J.G. White, A.S. Fauci, H. Mostowski, D.S. Matheson, Further studies of natural killer cell function in Chediak–Higashi patients, Immunology 46 (1982) 555–560. [59] T. Abo, J.C. Roder, W. Abo, M.D. Cooper, C.M. Balch, Natural killer (HNK-1+) cells in Chediak–Higashi patients are present in normal numbers but are abnormal in function and morphology, J. Clin. Invest. 70 (1982) 193–197. [60] P. Katz, A.M. Zaytoun, A.S. Fauci, Deficiency of active natural killer cells in the Chediak–Higashi syndrome. Localization of the defect using a single cell cytotoxicity assay, J. Clin. Invest. 69 (1982) 1231–1238. [61] Z. Brahmi, Nature of natural killer cell hyporesponsiveness in the Chediak-Higashi syndrome, Hum. Immunol. 6 (1983) 45–52. [62] S.R. Targan, R. Oseas, The “lazy” NK cells of Chediak-Higashi syndrome, J. Immunol. 130 (1983) 2671–2674. [63] C.M. Rubin, B.A. Burke, R.W. McKenna, K.L. McClain, J.G. White, M.E.J. Nesbit, A.H. Filipovich, The accelerated phase of ChediakHigashi Syndrome, Cancer 56 (1985) 524–530. [64] M. Bejaoui, F. Veber, D. Girault, C. Gaud, S. Blanche, C. Griscelli, A. Fischer, Phase accélérée de la maladie de Chediak–Higashi, Arch. Fr. Pediatr. 46 (1989) 733–736. [65] M.D. Barbosa, Q.A. Nguyen, V.T. Tchernev, J.A. Ashley, J.C. Detter, S.M. Blaydes, S.J. Brandt, D. Chotai, C. Hodgman, R.C. Solari, M. Lovett, S.F. Kingsmore, Identification of the homologous beige and Chediak–Higashi syndrome genes, Nature 382 (1996) 262–265. [66] J.K. Burkhardt, F.A. Wiebel, S. Hester, Y. Argon, The giant organelles in beige and Chediak–Higashi fibroblasts are derived from late endosomes and mature lysosomes, J. Exp. Med. 178 (1993) 1845–1856. [67] C. Klein, N. Philippe, F. Le Deist, S. Fraitag, C. Prost, A. Durandy, A. Fischer, C. Griscelli, Partial albinism with immunodeficiency (Griscelli syndrome), J. Pediatr. 125 (1994) 886–895. [68] A.J. Mancini, L.S. Chan, A.S. Paller, Partial albinism with immunodeficiency: Griscelli syndrome: report of a case and review of the literature, J. Am. Acad. Dermatol. 38 (1998) 295–300. [69] A. Plebani, B. Ciravegna, M. Ponte, M.C. Mingari, L. Moretta, Interleukin-2 mediated restoration of natural killer cell function in a patient with Griscelli syndrome, Eur. J. Pediatr. 159 (2000) 713–714. [70] E. Pastural, F.J. Barrat, R. Dufourcq-Lagelouse, S. Certain, O. Sanal, N. Jabado, R. Seger, C. Griscelli, A. Fischer, G. de Saint Basile, Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene, Nat. Genet. 16 (1997) 289–292. [71] G. Menasche, E. Pastural, J. Feldmann, S. Certain, F. Ersoy, S. Dupuis, N. Wulffraat, D. Bianchi, A. Fischer, F. Le Deist, G. de Saint Basile, Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome, Nat. Genet. 25 (2000) 173–176. [72] J.L. Sullivan, K.S. Byron, F.E. Brewster, D.T. Purtilo, Deficient natural killer cell activity in X-linked lymphoproliferative syndrome, Science 210 (1980) 543–545. [73] T. Lindsten, J.K. Seeley, M. Ballow, K. Sakamoto, S. St Onge, J. Yetz, P. Aman, D.T. Purtilo, Immune deficiency in the X-linked lymphoproliferative syndrome. II. Immunoregulatory T cell defects, J. Immunol. 129 (1982) 2536–2540. [74] S. Harada, T. Bechtold, J.K. Seeley, D.T. Purtilo, Cell-mediated immunity to Epstein–Barr virus (EBV) and natural killer (NK)-cell activity in the X-linked lymphoproliferative syndrome, Int. J. Cancer 30 (1982) 739–744.

J. Orange / Microbes and Infection 4 (2002) 1545–1558 [75] S. Argov, D.R. Johnson, M. Collins, H.S. Koren, H. Lipscomb, D.T. Purtilo, Defective natural killing activity but retention of lymphocyte-mediated antibody-dependent cellular cytotoxicity in patients with the X-linked lymphoproliferative syndrome, Cell. Immunol. 100 (1986) 1–9. [76] L. Benoit, X. Wang, H.F. Pabst, J. Dutz, R. Tan, Defective NK cell activation in X-linked lymphoproliferative disease, J. Immunol. 165 (2000) 3549–3553. [77] S.G. Tangye, J.H. Phillips, L.L. Lanier, K.E. Nichols, Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome, J. Immunol. 165 (2000) 2932–2936. [78] S. Parolini, C. Bottino, M. Falco, R. Augugliaro, S. Giliani, R. Franceschini, H.D. Ochs, H. Wolf, J.Y. Bonnefoy, R. Biassoni, L. Moretta, L.D. Notarangelo, A. Moretta, X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill EpsteinBarr virus-infected cells, J. Exp. Med. 192 (2000) 337–346. [79] J. Sayos, C. Wu, M. Morra, N. Wang, X. Zhang, D. Allen, S. van Schaik, L. Notarangelo, R. Geha, M.G. Roncarolo, H. Oettgen, J.E. De Vries, G. Aversa, C. Terhorst, The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM, Nature 395 (1998) 462–469. [80] H. Nakajima, M. Cella, H. Langen, A. Friedlein, M. Colonna, Activating interactions in human NK cell recognition: the role of 2B4-CD48, Eur. J. Immunol. 29 (1999) 1676–1683. [81] D.C. Anderson, F.C. Schmalsteig, M.J. Finegold, B.J. Hughes, R. Rothlein, L.J. Miller, S. Kohl, M.F. Tosi, R.L. Jacobs, T.C. Waldrop, et al., The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features, J. Infect. Dis. 152 (1985) 668–689. [82] Y.L. Lau, L.C. Low, B.M. Jones, J.W. Lawton, Defective neutrophil and lymphocyte function in leucocyte adhesion deficiency, Clin. Exp. Immunol. 85 (1991) 202–208. [83] S. Kohl, T.A. Springer, F.C. Schmalstieg, L.S. Loo, D.C. Anderson, Defective natural killer cytotoxicity and polymorphonuclear leukocyte antibody-dependent cellular cytotoxicity in patients with LFA1/OKM-1 deficiency, J. Immunol. 133 (1984) 2972–2978. [84] D.C. Anderson, F.C. Schmalstieg, W. Shearer, K. Becker-Freeman, S. Kohl, C.W. Smith, M.F. Tosi, T. Springer, Leukocyte LFA-1, OKM1, p150, 95 deficiency syndrome: functional and biosynthetic studies of three kindreds, Fed. Proc. 44 (1985) 2671–2677. [85] S. Kohl, L.S. Loo, F.S. Schmalstieg, D.C. Anderson, The genetic deficiency of leukocyte surface glycoprotein Mac-1, LFA-1, p150, 95 in humans is associated with defective antibody-dependent cellular cytotoxicity in vitro and defective protection against herpes simplex virus infection in vivo, J. Immunol. 137 (1986) 1688–1694. [86] G.D. Ross, R.A. Thompson, M.J. Walport, T.A. Springer, J.V. Watson, R.H. Ward, J. Lida, S.L. Newman, R.A. Harrison, P.J. Lachmann, Characterization of patients with an increased susceptibility to bacterial infections and a genetic deficiency of leukocyte membrane complement receptor type 3 and the related membrane antigen LFA-1, Blood. 66 (1985) 882–890. [87] A.M. Krensky, S.J. Mentzer, C. Clayberger, D.C. Anderson, F.C. Schmalstieg, S.J. Burakoff, T.A. Springer, Heritable lymphocyte function-associated antigen-1 deficiency: abnormalities of cytotoxicity and proliferation associated with abnormal expression of LFA-1, J. Immunol. 135 (1985) 3102–3108. [88] T.K. Kishimoto, N. Hollander, T.M. Roberts, D.C. Anderson, T.A. Springer, Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150, 95 glycoproteins cause leukocyte adhesion deficiency, Cell 50 (1987) 193–202. [89] K. Shibuya, L.L. Lanier, J.H. Phillips, H.D. Ochs, K. Shimizu, E. Nakayama, H. Nakauchi, A. Shibuya, Physical and functional association of LFA-1 with DNAM-1 adhesion molecule, Immunity 11 (1999) 615–623.

1557

[90] B. Ostenstad, S. Giliani, O.J. Mellbye, B.R. Nilsen, T. Abrahamsen, A boy with X-linked hyper-IgM syndrome and natural killer cell deficiency, Clin. Exp. Immunol. 107 (1997) 230–234. [91] Y. Amakata, Y. Fujiyama, A. Andoh, K. Hodohara, T. Bamba, Mechanism of NK cell activation induced by coculture with dendritic cells derived from peripheral blood monocytes, Clin. Exp. Immunol. 124 (2001) 214–222. [92] E. Carbone, G. Ruggiero, G. Terrazzano, C. Palomba, C. Manzo, S. Fontana, H. Spits, K. Karre, S. Zappacosta, A new mechanism of NK cell cytotoxicity activation: the CD40–CD40 ligand interaction, J. Exp. Med. 185 (1997) 2053–2060. [93] R.E. Ware, S.E. Hall, W.F. Rosse, Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence, N. Engl. J. Med. 325 (1991) 991–996. [94] Y. Yoda, T. Abe, Deficient natural killer (NK) cells in paroxysmal nocturnal haemoglobinuria (PNH): studies of lymphoid cells fractionated by discontinuous density gradient centrifugation, Br. J. Haematol. 60 (1985) 669–675. [95] S.J. Richards, D.R. Norfolk, D.M. Swirsky, P. Hillmen, Lymphocyte subset analysis and glycosylphosphatidylinositol phenotype in patients with paroxysmal nocturnal hemoglobinuria, Blood. 92 (1998) 1799–1806. [96] Y. Yoda, T. Abe, K. Mitamura, K. Saito, K. Kawada, Y. Onozawa, Y. Adachi, T. Nomura, Deficient natural killer (NK) cell activity in paroxysmal nocturnal haemoglobinuria (PNH), Br. J. Haematol. 52 (1982) 559–562. [97] M.H. De Souza, A.R. Pires, H.R. Diamond, Study of lymphocyte populations and natural killer activity in severe aplastic anaemia, J. Clin. Lab. Immunol. 30 (1989) 111–116. [98] J. Takeda, T. Miyata, K. Kawagoe, Y. Iida, Y. Endo, T. Fujita, M. Takahashi, T. Kitani, T. Kinoshita, Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria, Cell 73 (1993) 703–711. [99] J. Schubert, R.E. Schmidt, M.E. Medof, Regulation of glycoinositol phospholipid anchor assembly in human lymphocytes. Absent mannolipid synthesis in affected T and natural killer cell lines from paroxysmal nocturnal hemoglobinuria patients, J. Biol. Chem. 268 (1993) 6281–6287. [100] R.J. Klaassen, W.H. Ouwehand, T.W. Huizinga, C.P. Engelfriet, A.E. von dem Borne, The Fc-receptor III of cultured human monocytes. Structural similarity with FcRIII of natural killer cells and role in the extracellular lysis of sensitized erythrocytes, J. Immunol. 144 (1990) 599–606. [101] J.R. Ortaldo, G.M. Glenn, H.A. Young, J.L. Frey, Natural killer (NK) cell lytic dysfunction and putative NK cell receptor expression abnormality in members of a family with chromosome 3p-linked von Hippel–Lindau disease, J. Natl. Cancer. Inst. 84 (1992) 1897–1903. [102] S.K. Anderson, S. Gallinger, J. Roder, J. Frey, H.A. Young, J.R. Ortaldo, A cyclophilin-related protein involved in the function of natural killer cells, Proc. Natl. Acad. Sci. USA 90 (1993) 542–546. [103] J.L. Frey, T. Bino, R.R. Kantor, D.M. Segal, S.L. Giardina, J. Roder, S. Anderson, J.R. Ortaldo, Mechanism of target cell recognition by natural killer cells: characterization of a novel triggering molecule restricted to CD3– large granular lymphocytes, J. Exp. Med. 174 (1991) 1527–1536. [104] N.A. Wade, M.L. Lepow, J. Veazey, H.J. Meuwissen, Progressive varicella in three patients with Wiskott–Aldrich syndrome: treatment with adenine arabinoside, Pediatrics 75 (1985) 672–675. [105] K.E. Sullivan, C.A. Mullen, R.M. Blaese, J.A. Winkelstein, A multiinstitutional survey of the Wiskott–Aldrich syndrome, J. Pediatr. 125 (1994) 876–885. [106] C. Messina, D. Kirkpatrick, P.A. Fitzgerald, R.J. O’Reilly, F.P. Siegal, C. Cunningham-Rundles, M. Blaese, J. Oleske, S. Pahwa, C. Lopez, Natural killer cell function and interferon generation in patients with primary immunodeficiencies, Clin. Immunol. Immunopathol. 39 (1986) 394–404.

1558

J. Orange / Microbes and Infection 4 (2002) 1545–1558

[107] A. Plebani, P. Airo, D. Brugnoni, M. Lebowitz, R. Cattaneo, V. Monafo, A. Meini, L.D. Notarangelo, M. Duse, A.G. Ugazio, Expansion of large granular lymphocyte subsets in Wiskott–Aldrich syndrome, Haematologica 80 (1995) 521–525. [108] J.S. Orange, N. Ramesh, E. Remold-O’Donnell,Y. Sasahara, L. Koopman, M. Byrne, F.A. Bonilla, F.S. Rosen, R.S. Geha, J.L. Strominger, Wiskott-Aldrich Syndrome protein is required for NK cell cytotoxicity and localizes to NK cell activating immunologic synapses, Proc. Natl. Acad. Sci. USA 99 (2002) 11351–11356. [109] S.E. Dorman, G. Uzel, J. Roesler, J.S. Bradley, J. Bastian, G. Billman, S. King, A. Filie, J. Schermerhorn, S.M. Holland, Viral infections in interferon-c receptor deficiency, J. Pediatr. 135 (1999) 640–643. [110] F. Altare, D. Lammas, P. Revy, E. Jouanguy, R. Doffinger, S. Lamhamedi, P. Drysdale, D. Scheel-Toellner, J. Girdlestone, P. Darbyshire, M. Wadhwa, H. Dockrell, M. Salmon, A. Fischer, A. Durandy, J.L. Casanova, D.S. Kumararatne, Inherited interleukin 12 deficiency in a child with bacille Calmette–Guérin and Salmonella enteritidis disseminated infection, J. Clin. Invest. 102 (1998) 2035–2040. [111] S.E. Dorman, S.M. Holland, Mutation in the signal-transducing chain of the interferon-c receptor and susceptibility to mycobacterial infection, J. Clin. Invest. 101 (1998) 2364–2369. [112] F. Altare, A. Durandy, D. Lammas, J.F. Emile, S. Lamhamedi, F. Le Deist, P. Drysdale, E. Jouanguy, R. Doffinger, F. Bernaudin, O. Jeppsson, J.A. Gollob, E. Meinl, A.W. Segal, A. Fischer, D. Kumararatne, J.L. Casanova, Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency, Science 280 (1998) 1432–1435. [113] R. de Jong, F. Altare, I.A. Haagen, D.G. Elferink, T. Boer, P.J. van Breda Vriesman, P.J. Kabel, J.M. Draaisma, J.T. van Dissel, F.P. Kroon, J.L. Casanova, T.H. Ottenhoff, Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients, Science 280 (1998) 1435–1438. [114] R.M. Aspalter, W.A. Sewell, K. Dolman, J. Farrant, A.D. Webster, Deficiency in circulating natural killer (NK) cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia, Clin. Exp. Immunol. 121 (2000) 506–514. [115] H.F. Pross, S. Gupta, R.A. Good, M.G. Baines, Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. VII. The effect of immunodeficiency disease, Cell. Immunol. 43 (1979) 160–175. [116] Y.M. Vyas, K.M. Mehta, M. Morgan, H. Maniar, L. Butros, S. Jung, J.K. Burkhardt, B. Dupont, Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions, J. Immunol. 167 (2001) 4358–4367. [117] J. Zonana, M.E. Elder, L.C. Schneider, S.J. Orlow, C. Moss, M. Golabi, S.K. Shapira, P.A. Farndon, D.W. Wara, S.A. Emmal, B.M. Ferguson, A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-c (NEMO), Am. J. Hum. Genet. 67 (2000) 1555–1562.

[118] R. Doffinger, A. Smahi, C. Bessia, F. Geissmann, J. Feinberg, A. Durandy, C. Bodemer, S. Kenwrick, S. Dupuis-Girod, S. Blanche, P. Wood, S.H. Rabia, D.J. Headon, P.A. Overbeek, F. Le Deist, S.M. Holland, K. Belani, D.S. Kumararatne, A. Fischer, R. Shapiro, M.E. Conley, E. Reimund, H. Kalhoff, M. Abinun, A. Munnich, A. Israel, G. Courtois, J.L. Casanova, X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-jB signaling, Nat. Genet. 27 (2001) 277–285. [119] A. Jain, C.A. Ma, S. Liu, M. Brown, J. Cohen, W. Strober, Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia, Nat. Immunol. 2 (2001) 223–228. [120] J.S. Orange, S.R. Brodeur, A. Jain, F.A. Bonilla, L.C. Schneider, R. Kretschmer, S. Nurko, W.L. Rasmussen, J.R. Kohler, S.E. Gellis, B.M. Ferguson, J.L. Strominger, J. Zonana, N. Ramesh, Z.K. Ballas, R. Geha, Deficient natural killer cell cytotoxicity in patients with IKK-c/NEMO mutations, J. Clin. Invest. 109 (2002) 1501–1509. [121] M. Valle Blazquez, I. Luque, E. Collantes, E. Aranda, R. Solana, J. Pena, E. Munoz, Cellular redox status influences both cytotoxic and NF-j B activation in natural killer cells, Immunology 90 (1997) 455–460. [122] T.L. Whiteside, D. Friberg, Natural killer cells and natural killer cell activity in chronic fatigue syndrome, Am. J. Med. 105 (1998) 27S–34S. [123] P.H. Levine, T.L. Whiteside, D. Friberg, J. Bryant, G. Colclough, R.B. Herberman, Dysfunction of natural killer activity in a family with chronic fatigue syndrome, Clin. Immunol. Immunopathol. 88 (1998) 96–104. [124] T. Witte, S. Werwitzke, R.E. Schmidt, CMV complications in common variable immunodeficiency, Immunobiology 202 (2000) 194–198. [125] R. Cambronero, W.A. Sewell, M.E. North, A.D. Webster, J. Farrant, Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency, J. Immunol. 164 (2000) 488–494. [126] L. Scaringi, E. Rosati, P. Cornacchione, K. Fettucciari, R. Sabatini, R. Biondi, L. Mezzasoma, M. Valiani, P. D’Errico, P. Marconi, Local and systemic immune response to inactivated Candida albicans in mice, Nat. Immun. 14 (1995) 234–249. [127] Z. Gulay, T. Imir, Anti-candidial activity of natural killer (NK) and lymphokine activated killer (LAK) lymphocytes in vitro, Immunobiology 195 (1996) 220–230. [128] A.G. Palma-Carlos, M.L. Palma-Carlos, Chronic mucocutaneous candidiasis revisited, Allerg. Immunol. (Paris) 33 (2001) 229–232. [129] S. Guduri, Z.K. Ballas, Deficient NK-cell function in adult patients with recurrent non-invasive mucosal candidiasis, J. Allergy Clin. Immunol. 109 (2002) S186. [130] T. Segura, Z.K. Ballas, Natural Killer (NK) cell deficiency in a patient with chronic mucocutaneous candidiasis, J. Allergy Clin. Immunol. 101 (1998) 313.