Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: The Year in Immunology

Primary immunodeficiencies and the control of Epstein–Barr virus infection

Umaimainthan Palendira1,2 and Alan B. Rickinson3 1Centenary Institute, Newtown, New South Wales, Australia. 2Discipline of Medicine, Sydney Medical School, University of Sydney, NSW, Australia. 3Cancer Sciences and Centre for Human Virology, University of Birmingham, Birmingham, United Kingdom

Address for correspondence: Umaimainthan Palendira, Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. [email protected]

Human primary immunodeficiency (PID) states, where mutations in single immune system genes predispose indi- viduals to certain infectious agents and not others, are experiments of nature that hold important lessons for the immunologist. The number of genetically defined PIDs is rising rapidly, as is the opportunity to learn from them. Epstein–Barr virus (EBV), a human herpesvirus, has long been of interest because of its complex interaction with the immune system. Thus, it causes both infectious mononucleosis (IM), an immunopathologic disease associated with exaggerated host responses, and at least one malignancy, EBV-positive lymphoproliferative disease, when those responses are impaired. Here, we describe the full range of PIDs currently linked with an increased risk of EBV- associated disease. These provide examples where IM-like immunopathology is fatally exaggerated, and others where responses impaired at the stage of induction, expansion, or effector function predispose to malignancy. Current evidence from this rapidly moving field supports the view that lesions in both natural killer cell and T cell function can lead to EBV pathology.

Keywords: primary immunodeficiencies; Epstein–Barr virus; genetic defects; cell-mediated immunity

Introduction our species and its antecedents over millions of years, have arrived at a virus–host balance that is The multiplicity of hematopoietic cell types and critically dependent upon host control. Most of effector pathways constituting the human immune these agents are widespread in the population, often system bears witness to the multiple challenges being acquired silently or with mild symptoms in that infectious agents have posed throughout the childhood and then carried for life as asymptomatic evolution of our species and its antecedents. Any latent infections. PID patients are therefore likely one type of pathogen is likely to alert several to be exposed to these viruses relatively early in life response pathways, and so understanding the and will have to deal with them both as a primary relative importance of those pathways to overall infection and as a persistent challenge. Here, we control of that infection is a complex task. In this focus on one particular herpesvirus, Epstein–Barr regard, the study of patients with primary immun- virus (EBV), which largely conforms to the above- odeficiencies (PIDs) can be hugely instructive.1–3 mentioned pattern of asymptomatic infection in Such individuals, carrying mutations in single the immunocompetent host, yet is etiologically immune system genes, have to deal with the vast linked to a range of nonmalignant and malignant range of naturally acquired infections but will diseases.4,5 How the human immune system nor- present in the clinic only with those against which mallycontrolsEBVandtowhatextentaberrantcon- their defenses are especially compromised. trols contribute to disease pathogenesis remain to be The human herpesviruses are particularly inter- fully determined.6,7 A brief survey of the biology and esting litmus tests of immune competence. All are immunology of EBV infection, as currently inferred potentially pathogenic but, having coevolved with

doi: 10.1111/nyas.12937

22 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus from studies in the immunocompetent host and in expansion seen in acute IM blood appears to be virus immunosuppressed patients, is given below as a pre- specific and mainly directed against immediate lude to the evidence emerging from PID states. early and some early proteins of the lytic cycle, with smaller responses against the latent proteins.6,16 EBV infection in the immunocompetent Coincident with the resolution of symptoms, these host responses contract to smaller virus-specific mem- EBV is a gamma-1 herpesvirus, a genus whose ory populations that persist for life, at levels not members are distinguished by their restriction to obviously different from those found in long-term primate hosts, their persistence in the B lymphoid viruscarrierswithnohistoryofIM.16,17 Thereisalso + system, and their ability to drive B cell growth a parallel, but much smaller, CD4 Tcellresponse through coordinate expression of a unique set of to both lytic and latent cycle antigens in IM, from + latent cycle genes.4,8–10 As illustrated in Figure 1, which CD4 T cell memory populations are likewise the virus is acquired orally and replicates as a lytic derived.18,19 In addition, recent work has shown infection within the oropharynx, leading to high that while total natural killer (NK) cell numbers are levels of infectious virus shedding in throat wash- not obviously increased in the blood in acute phase, ings. Little is known about these very early events; this masks a significant expansion of activated NK however, lytic replication is thought to occur in cells with a phenotype intermediate between the less oropharyngeal epithelium and possibly also locally mature CD56bright,KIR– subset normally dominant infiltrating B cells. Thereafter, from the evidence in lymphoid tissues, and the more mature CD56dim, + of tonsillar tissues from infectious mononucleosis KIR subset normally dominant in blood.20 (IM) patients undergoing primary EBV infection,11 IM is increasingly considered to be an the virus appears to spread into the B cell system by immunopathologic disease whose febrile symp- transient activation of a latent growth-transforming toms and malaise are caused by proinflammatory infection. Many of these expanding cells express cytokines released from hyperactivated T cells. It is the full panel of virus latent proteins and, by not clear whether the immune responses seen in IM implication, resemble the lymphoblastoid cell lines simply exaggerate those occurring during asymp- (LCLs) that arise when the virus transforms normal tomatic primary infection, or if the two situations Bcellsin vitro. However, in at least some cells, the are also qualitatively distinct. Recent data, albeit in growth-transforming program is suppressed and a humanized mouse model, suggest that in asymp- those cells, now carrying the virus genome as a tomatic primary infection, NK cells act to limit truly latent (antigen-negative) infection, enter the the initial replication of the virus, thereby reducing recirculating memory B cell pool (see Fig. 1 legend the peak antigen load and avoiding antigen-driven + for details and Refs. 12–14). This pool then appears overexpansion of the CD8 T cell response that to be stably maintained for life, with occasional drives the disease process.21 Such a role for NK cells cells reactivating from latency into lytic infection would accord to earlier in vitro work demonstrating at oropharyngeal sites, thereby initiating new that an infected cell’s entry into the lytic cycle is B cell–transforming infections as well as seeding accompanied by increased sensitivity to NK cell secondary foci of virus replication at oropharyngeal recognition.22 Furthermore, other innate effectors surfaces that lead to low-level virus shedding.4,6,9 may also be involved at such early times. In that Beneath this broad framework, the detailed context, although there have been no studies of virological and immunological events involved in invariant natural killer T (iNKT) cell activation in asymptomatic infection are still poorly understood. acute IM, there is evidence that iNKT cells are able Much is inferred from studies on patients, mainly to recognize and kill B cells immediately after EBV young adults, in whom an atypically delayed infection in vitro23 and, when adoptively transferred primary infection is clinically manifest as IM; even in humanized mouse models in vivo,cancontrol in these circumstances, the characteristic disease the outgrowth of EBV-positive tumor cell lines.24–26 symptoms (fever, lymphadenopathy, and CD8+ Multiple arms of the cell-mediated response could T lymphocytosis) only develop some 4–6 weeks therefore be employed at one point or another in after virus acquisition,15 and little is known about the control of EBV, and the relationship between this long prodromal phase. Much of the CD8+ Tcell them remains to be determined.

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 23 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson

Primary infection (IM) Persistent infection

Oropharynx Tonsil Tonsil Oropharynx

B cell B cell L3 L3 B cell

CD8 Lyt B cell B cell CD4 CD8 B cell B cell L3 Lyt Lyt L3 Latent responses B cell Lyt L3 Lyt B cell B cell Reactivation signal Lyt Virus L0 reservoir Epithelial Epithelial CD8 CD4 cells NK CD8 B cell B cell cells CD8 CD4 CD8 L0 L0 NK CD8 CD8 CD8 CD4 CD8 CD8

Lytic responses Latent responses Lytic responses

B cell B cell NK CD8 CD8 CD8 CD4 CD4 L0 L0 CD8 CD4 NK CD8 CD4 CD8 CD8 CD8 CD8 CD4 CD8 CD8 Blood CD8 Blood

Lytic primary Latent primary Latent memory Lytic memory responses responses responses responses Figure 1. A schematic diagram to illustrate the main features of EBV infection in the immunocompetent host, as currently understood. Orally acquired EBV replicates locally as a lytic infection (Lyt), probably in oral epithelial cells (and possibly locally infiltrating B cells), leading to high levels of viral shedding detectable in throat washings. On the basis of studies of tonsillar tissues from IM patients, the virus then spreads through initiating a latent growth-transforming infection (Latency III, L3) of B cells that expand through clonal proliferation; this appears to involve the expression of the full array of EBV latent proteins, just as when EBV infects B cells in vitro to produce EBV-transformed LCLs. Thereafter, in at least some cells, the virus downregulates the expression of the latent proteins; the cells move out of cycle and then carry the virus genome as a true antigen-negative latent infection (Latency 0, L0). Such cells are found exclusively within a memory B cell reservoir that preferentially recirculates between the peripheral blood and oropharyngeal lymphoid tissues. How the virus selectively populates the memory (but not naive) B cell pool in vivo is not clear, though various models have been proposed, including the possibility that virus-infected naive B cells are driven through a germinal center reaction, thus exploiting the physiologic route into memory.4,9,12–14 Thereafter, during long-term virus carriage, some latently infected B cells will reactivate into the lytic cycle (possibly as a result of cognate antigen-driven differentiation into plasma cells) and produce infectious virions. These may either initiate new growth-transforming infections in neighboring B cells or seed secondary foci of lytic replication at oropharyngeal sites, thereby leading to low-level virus shedding in throat washings. Host immune responses have the potential to interfere with these events at many points. During primary infection (as seen in IM), NK cells are activated, and there is a rapid expansion of CD8+ T cells against the lytic cycle and to some extent latent cycle antigens (both of which are more apparent in the blood than the tonsil), while there is a much smaller expansion of latent and lytic antigen-specific CD4+ T cells. As the primary infection resolves, both virus load in the blood and (eventually) virus shedding in the throat fall to much lower levels; similarly, virus-specific T cell responses contract to smaller long-term populations that persist for life both in the blood and, at higher frequencies, in tonsillar tissues. During virus persistence, latent antigen-specific memory T cells may control new B cell transforming infections, while lytic antigen-specific memory T cells may control new foci of virus replication in the oropharynx. Black arrows on the diagram represent movement of infected cells, dotted arrows represent movement of virus particles, and red arrows represent the targeting of NK and T cell responses.

EBV infection in the immunosuppressed first-year posttransplant when the immunosup- host pressive regime is most intense, such patients show increased latent viral loads in the blood and are at Further evidence that cell-mediated surveillance is risk of EBV-driven B lymphoproliferative disease important in maintaining the EBV–host balance (B-LPD). This disease can present initially as an comes from the study of immunosuppressed solid IM-like lymphadenopathy but develops into oligo- organ and stem cell transplant recipients. In the clonal or monoclonal foci of B lymphoproliferation.

24 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus

Here, as in in vitro transformed LCLs, most cells like EBV-driven B-LPD, an EBV-positive smooth express the full spectrum of latent cycle proteins, muscle cell tumor (leiomyosarcoma) has only while a few are switching from the transformed state been observed in highly immunocompromised into the lytic cycle.27,28 Essentially, the same disease transplant and late-stage AIDS patients.35 Three was also often seen in human immunodeficiency other tumors, Burkitt lymphoma (BL), Hodgkin virus (HIV)-infected patients who, before the era lymphoma (HL), and diffuse large B cell lymphoma of highly active retroviral therapy, progressed to (DLBCL) (the latter often recorded as non-Hodgkin late-stage acquired immune deficiency syndrome lymphoma), can occur in either EBV-positive or (AIDS) with profound CD4+ T cell lymphopenia EBV-negative forms and are not as directly linked to and associated CD8+ T cell exhaustion.29 In both profound immune impairment. However, all three the posttransplant and late-stage AIDS contexts, occur at increased incidence in AIDS patients, as do it is tempting to attribute the appearance of EBV- the Hodgkin and diffuse large B cell lymphomas in driven B-LPD entirely to a loss of effective T cell two further groups: solid-organ transplant patients surveillance. Certainly, the LPD lesions themselves on long-term immune suppression, and elderly can be effectively targeted by adoptive transfer of patients in the general population who may suffer human leukocyte antigen (HLA)-matched T cell age-related immune senescence.8,29,36 preparations enriched for EBV-specific (mainly CD8) reactivities by LCL stimulation in vitro.30,31 Primary immune deficiency states However, the circumstances that precede B-LPD and EBV-associated disease development, that is, the tipping of the virus–host balance toward the high virus loads, may not be The explosion in human genome sequencing means entirely a consequence of impaired T cell controls. that there are now over 200 genetically defined PIDs Thus, there is evidence that T cell–suppressive affecting one or other aspect of hematopoietic cell drugs, such as cyclosporine, and also uncontrolled development and/or immune effector function.37 HIV infection can both impair some aspects of NK Here, we focus on those with evidence of EBV- cell function.32–34 associated disease. To give structure to the review, As fully described elsewhere, EBV is etiologically we have arranged those conditions into four groups, linked to a number of other malignancies.4,5,29 based upon their overall susceptibility to infectious For the purposes of this review, we mention only agents and/or lymphoma; we would emphasize that those tumors where there is either clear evidence or the boundaries between these groups are not set reasonable suspicion that tumor risk is elevated by in stone, and may indeed change in the future. As immune impairment, that is, tumors whose appear- each group is introduced in the coming text, the ance might therefore be taken as a sign of impaired essential characteristics of the constituent PIDs will EBV control in specific PID settings. In that context, be summarized in Tables 1–4.

Table 1. PIDs selectively susceptible to EBV

Disorder Affected gene Other pathogenic Inheritance Associated immune defects EBV-associated disease infections

XLP NK Impaired lysis, B cell targets Most with severe IM, fatal HLH None SH2D1A iNKT Absent X-linked T Impaired B cell recognition B Hypogamma

XIAP NK Normal Some with severe IM, HLH None BIRC4 iNKT Reduced numbers X-linked T Apoptosis prone B Hypogamma in some cases

HLH, hemophagocytic lymphohistiocytosis.

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 25 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson

Immunocompetent XLP

sis Lysis ed ly Lysis Lysis SAP pair CD8 ImpairedIm lysis SHP-1 CD8 NTBA NTBA + pMHC-TCR NTBA pMHC-TCR NTBA SHP-1 SAP 2B4 SHP-1 Non- 2B4 Non- CD48 CD48 B cell B cell B cell B cell target NTBA target target NTBA target NTBA NTBA

CD48 SAPSAP CD48 Activatory receptors SHIP-1 Activatory receptors 2B4 + ImpairedIm lysis2B4 p Lysis air SHIP-1 SAPSAP ed NK Lysis ly NK Lysis sis

SHIP-1

Figure 2. A schematic diagram of the molecular pathogenesis of XLP. In immunocompetent hosts, the CD8+ T cell or NK cell interaction with B cell targets relies on positive signals delivered through the signaling lymphocyte activation molecule family of receptors (SLAMFRs). In this regard, NTBA–NTBA interactions and 2B4–CD48 interactions deliver a positive signal to T cells or NK cells via the adaptor protein SAP.The presence of SAP also prevents the binding of negative regulators, such as SHP-1 or SHIP-1, to SLAMFR. The ensuing positive signals activate CD8+ T cells and NK cells to lyse B cell targets. By contrast, CD8+ TcellorNK cell recognition of non-B cell targets, such as dendritic cells and epithelial cells, is independent of the SLAMFR interaction. In XLP patients, when CD8+ T cells and NK cells attempt to engage B cell targets, the absence of SAP allows the recruitment of negative regulators such as SHP-1 (CD8+ T cells) and SHIP-1 (NK cells) to the SLAMFRs, resulting in impaired target lysis.159 However, the effector functions of SAP-deficient CD8+ T cells and NK cells against non-B cell targets remain unaffected.

Group 1: PIDs selectively susceptible molecule (SLAM)-associated protein (SAP), which to EBV is expressed in T cells, NK cells, and iNKT cells. SAP binds to the cytoplasmic tails of the SLAM family of X-linked lymphoproliferative syndrome receptors, namely, SLAM (CD150), 2B4 (CD244), X-linked lymphoproliferative syndrome (XLP) is a NTBA, CD229, CD84, and CRACC. These recep- rare X-linked immune deficiency first recognized tors are expressed on a variety of hematopoietic through young boys presenting with an extreme, cells and, with one exception (2B4), mediate often fatal, form of IM following primary EBV infec- cell–cell communication through homodimeric tion (Fig. 2).38–41 The acute disease was charac- interactions; 2B4 has a heterologous ligand, CD48, terized by massive sustained expansions of EBV- + that is highly expressed on EBV-infected B cells. infected B cells, CD8 T cells, and NK cells in blood Loss-of-function mutations in SAP lead to the and tissues, and a resultant cytokine storm that led complex immunodeficient phenotype seen in XLP. on to macrophage activation and hemophagocytic Affected boys lack iNKT cells, have specific defects lymphohistiocytosis (HLH). Surprisingly, other in NK and T cell function, and cannot generate virus infections appeared to be handled normally, classical T cell–dependent B cell memory.42 While making XLP the paradigmatic example of genetic the absence of iNKT cells has fueled speculation susceptibility to a single infectious agent. However, of a role for these cells in EBV control, greater not all boys with the XLP trait presented in this way; insight came with the findings that NK cells,43,44 others had a history of hypogammaglobulinemia + and subsequently EBV-specific CD8 T cells,45,46 or B cell lymphoma that was independent of, and from XLP patients failed to form immune synapses often preceded, EBV infection.38 Reconciling these with B lymphocytes; in contrast, recognition of disparate presentations only became possible once other target cell types was unaffected. As illustrated the genetic basis of XLP was discovered. in Figure 2 and described in the legend, B cell The affected gene SH2D1A encodes an adaptor recognition by NK cells and T cells requires positive protein, the signaling lymphocyte activation

26 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus signaling through two SLAM receptors, 2B4 and encodes the X-linked inhibitor of apoptosis (IAP) NTBA; in the absence of SAP, the 2B4–CD48 and protein, XIAP. Indeed, the trait was first identified NTBA–NTBA interactions still occur but now by screening 15 families in which boys presented appear to deliver a negative signal. with XLP-like symptoms; three of these families These functional defects in NK–B cell and T– were found to have a BIRC4 rather than SH2D1A B cell communication help to explain several aspects gene mutation, with seven of 12 affected boys hav- of the XLP patients’ varied clinical presentation, in ing recurrent HLH possibly linked to EBV infection. particular their unique susceptibility to EBV. Thus, However, subsequent surveys of HLH in genetically the virus colonizes its host specifically via B cell identified XIAP patients have not found such a infection, a cell type that in XLP patients neither NK strong link with EBV, and it is likely that the initial cells nor virus-specific CD8+ T cells can efficiently focus on XLP-like patients may have contributed recognize. These effectors therefore cannot contain to a high degree of EBV penetrance in the original the infection nor, in the case of CD8+ T cells, report. Clearly, XIAP and XLP share important can they receive the restimulation-induced cell clinical features, notably presentation either as HLH death signals through which highly expanded T cell and hypogammaglobulinemia, but are different in responses are normally curtailed.47 In the absence other respects; in particular, XIAP patients some- of this autoregulatory route, lymphoproliferation times present with chronic colitis but not with B cell is further amplified, generating the cytokine storm lymphoma. The relationship between the two con- that presages HLH. ditions therefore remains a subject of debate.49–52 Nevertheless, some XLP patients survive the How loss of XIAP protein function leads to initial onslaught of EBV infection and go on to the clinical phenotype is unclear. The protein maintain a stable EBV viral load in the blood. is one of eight members of the IAP family and Remarkably, several such patients showed evidence acts mainly as a potent inhibitor of caspases 3, 7, of somatic reversion to SAP positivity in a small and 9; however, it is also involved in a variety of fraction of circulating lymphocytes, almost exclu- other signaling pathways, including nuclear factor- sively in the CD8+ T cell compartment. These kappaB(NF-␬B) and c-Jun N-terminal kinase reverted cells had not only regained effective B cell activation.53 Interestingly, the reduced iNKT cell recognition but also many appeared to be EBV numbers first noticed in XIAP51 appear to be specific, suggesting that selective pressure from restricted to EBV-positive patients,54 implying that EBV infection had expanded a rare population of EBV infection itself may drive activation-induced spontaneous revertants to detectable levels.48 iNKT cell death. By contrast, NK cell numbers Clearer evidence that the CD8+ Tcellresponse and 2B4-dependent effector function appear to be to EBV is primarily driven by virus infection in normal in XIAP patients, as are circulating T cell the B cell compartment, and not, for example, numbers despite the fact that T cells are more sensi- by replication in oropharyngeal epithelial cells, tive to apoptosis-inducing signals in vitro.Arecent came from a study of XLP carrier mothers. In such study of one XIAP kindred (albeit one also carrying individuals, random X-chromosome inactivation a rare CD40 ligand polymorphism) has identified means that 50% of T cells are SAP positive, and 50% individuals with persistent CD8 lymphocytosis, and SAP negative. While T cell memory to two non-B– unusually large expansion of EBV-specific CD4+ tropic viruses (influenza and the cytomegalovirus and CD8+ T cells, in the blood many years after (CMV)) was present in both subsets, EBV-specific symptomatic primary EBV infection.55 This is at CD8+ T cells against both lytic and latent cycle least consistent with the idea that hyperexpansion antigens were almost all found in the SAP-positive of the EBV-induced T cell response could underlie population.45 at least some cases of XIAP-associated HLH. Group 2: PIDs with broader virus X-linked inhibitor of apoptosis protein susceptibility but frequent EBV disease deficiency A second immunodeficiency sharing some char- CD27 deficiency acteristicswithXLPstemsfrommutationofan CD27 deficiency, a PID arising in almost all adjacent gene on chromosome Xq25, BIRC4, which cases from homozygous CD27 mutation, was

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 27 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson

Table 2. PIDs with broader virus susceptibility but frequent EBV disease

Disorder Affected gene Other pathogenic Inheritance Associated immune defects EBV-associated disease infections

CD27 def NK Normal 12/17 with severe IM or chronic Influenza, VZV, CMV + CD27 iNKT Low-normal EBV; 9/17 with EBV tumors: Autosomal recessive T Normal B-LPD, HL, DLBCL B Hypogamma in some cases

XMEN NK Impaired lysis 4/7 with EBV+ tumors: B-LPD, BL, Viral pneumonia, HL, NHL M. contagiosum, MAGT1 iNKT ? VZV, HSV X-Linked T Impaired lysis BNormal

ITK def NK Normal 8/9 with EBV+ tumors: B-LPD, HL VZV, CMV ITK iNKT Reduced numbers Autosomal recessive T Progressive CD4 lymphopenia B Progressive hypogamma

Coronin 1A def NK Normal 4/6 with EBV+ tumors: B-LPD, HL, HSV, HPV CORO1A iNKT Near absent DLBCL Autosomal recessive T T lymphopenia B Hypogamma

CD16 def NK Impaired lysis 1/3 with severe IM, 1/3 with EBV+ HPV, VZV FCGR3A iNKT Normal tumor: B-LPD Autosomal recessive T Normal BNormal

MCM4 def NK Impaired maturation 1/13 with EBV+ tumor: B-LPD HSV, VZV MCM4 iNKT Normal Autosomal recessive T Normal BNormal

VZV, varicella-zoster virus; CMV, cytomegalovirus; NHL, non-Hodgkin lymphoma; HSV, herpes simplex virus. recently recognized through its unexpectedly high with influenza virus or with herpesviruses such as incidence of EBV-associated pathology. Among varicella-zoster virus (VZV) or CMV.56–58 17 affected individuals identified to date, 12 had CD27, a costimulatory molecule belonging to either suffered symptomatic primary EBV infec- the tumor necrosis factor receptor (TNFR) family, tion/lymphadenopathy early in life or had presented is constitutively expressed as a transmembrane with chronic EBV viremia. Importantly, nine of the homodimer on all memory B cells, on all T cells above 17 (not always those individuals with prior except for a terminally differentiated (CD57+) EBV problems) eventually developed malignancy, subset, and on CD56bright NK cells. Its ligand, CD70, six involving EBV-positive LPD/lymphomas, and is transiently expressed on activated dendritic cells three Hodgkin lymphomas that seem likely to have (DCs), as well as on B cells and T cells following been EBV positive though their virus status was antigen receptor signaling.59 In CD8+ T cells, not recorded. Clearly, however, CD27 deficiency is signaling through CD27 has been shown to induce not entirely EBV selective in its effects since some expression of IL-2 and the prosurvival protein patients also had a history of severe infections Bcl-XL, consistent with its importance for the

28 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus survival of virus-specific CD8+ T cells in mouse and neoplasia (XMEN). Of the seven patients models.60 In addition, mouse models have also reported, all had high EBV genome loads in the shown that in CD4+ T cells, CD27–CD70 signaling blood and four had developed one of the follow- suppresses Th17 differentiation and promotes an ing EBV-positive lymphomas: classical B-LPD, IFN-␥–secreting Th1 phenotype.61 Burkitt lymphoma, Hodgkin lymphoma, and non- Perhaps surprisingly, CD27-deficient patients Hodgkin lymphoma. Again, the immunodeficiency showed very little disturbance of lymphocyte is not selective for EBV. These patients also have populations in the blood, with normal numbers a history of recurrent respiratory infections, viral and normal distribution of most B and T cell pneumonia, and severe poxvirus (molluscum subsets (though CD8+ effector memory T cells are contagiosum) or herpesvirus (VZV and HSV) sometimes expanded), and normal numbers of NK infections.64–66 This implies a wider impairment cells, iNKT cells, and ␥␦T cells. Studies to date on of viral immune surveillance, which subsequent immune functions have shown, at most, only subtle studies have addressed with interesting results. impairments.56–58 NK cell cytotoxicity was reduced MAGT1, one of 20 mammalian Mg2+ trans- in some but not all patients,57 while one report porters, is expressed in many cell lineages but speaks about hypogammaglobulinemia along its immunological importance was only realized with reduced T cell–dependent B cell responses with discovery of the XMEN syndrome. In T cells, in vitro.56 However, since no EBV-seronegative MAGT1 mediates the Mg2+ influx induced by T cell individuals have yet been identified so far, it is receptor (TCR) stimulation and, through down- unclear whether these are mild primary features of stream Mg2+ pathway signaling, also optimizes CD27 deficiency per se or secondary effects of Ca2+ influx. MAGT1-deficient patients have low EBV infection. Importantly, the two patients CD4+ T cell numbers, likely due to poor thymic analyzed for EBV-specific T cell responses to date output, whereas NK cell and CD8+ T cell (including both had normal levels of EBV-specific CD8+ EBV-specific CD8+ T cell) numbers appear normal. T cells and these cells appeared to be functional in However, both NK and CD8+ T cell cytotoxicity cytokine- and degranulation-based assays.57 Why was partly impaired. As illustrated in Figure 3, this CD27-deficient patients have such preferential led to the finding that free Mg ions regulate these susceptibility to EBV is as yet unclear. Some cells’ expression of NKG2D, a membrane protein subtle impairment of T cell, or CD56bright NK cell, that engages its ligand, NKG2DL, on the target function remains a possibility. It is worth noting cell surface. As the name implies, NKG2D was first that, in vitro, EBV infection upregulates the CD27 identified as an NK activating receptor but it also ligand CD70 to high levels on the B cell surface.62 now appears to be required for optimal cytotoxicity Thus, CD27–CD70 interactions may be particularly by NKG2D-expressing CD8+ T cells. Thus, the important in determining their susceptibility to cytotoxic function of NK- and EBV-specific T cells virus-specific T cell or NK cell surveillance. This from XMEN patients in vitro could be fully restored latter possibility is interesting given that another by Mg2+ supplementation of the medium, coin- PID, affecting a different TNFR family member cident with upregulation of NKG2D expression. OX40, was identified through the patient’s unusual Furthermore, an Mg2+-supplemented diet was also susceptibility to the Kaposi sarcoma-associated able to reduce EBV genome loads in vivo,strongly herpesvirus (KSHV). That susceptibility may reflect suggesting a role for one or both of these effectors the importance of OX40–OX40 ligand interactions in maintaining the EBV–host balance.66 It is likely in KSHV surveillance since the ligand is highly that NK and/or T cell control of other viruses is upregulated on virus-infected endothelial cells.63 similarly impaired.

MAGT-1 deficiency ITK deficiency A second PID recently identified through its Homozygous mutations in the interleukin-2– impairment of EBV control is caused by loss of inducible T cell kinase gene (ITK) underpin the X-chromosome–encoded Mg2+ ion transporter another PID, again first recognized through its MAGT-1, hence its definition as X-linked immun- high prevalence of EBV-associated disease but not odeficiency with Mg2+ defect, EBV infection, strictly EBV specific in its effects. ITK is one of the

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 29 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson

Immunocompetent XMEN disease

CD8 sis Lysis d ly CD8 ire pa ImpairedIm lysis NKG2D

NKG2DL

NKG2DL MAGT1

+ + EBV EBV pMHC-TCR 2+ Reduced Mg B cell B cell Mg2+ target target uptake

MAGT1 NKG2DL Activatory receptor NKG2DL

NKG2D ImpairedIm lysis p air Lysis ed NK NK ly sis

Figure 3. A schematic illustration of the molecular pathogenesis of XMEN disease. In mammalian cells, there are several different Mg2+ transporters involved in the regulation of Mg2+ influx. One such transporter, MAGT1 is an important regulator of intracellular free Mg2+ in immune cells. In T cells, optimal activation following TCR stimulation depends on Mg2+ influx. In addition, the expression of the activatory receptor NKG2D on T cells and NK cells is also dependent on free Mg2+. In immunocompetent individuals, a functional MAGT1 receptor therefore facilitates optimal T cell and NK cell activation upon recognition of virally infected targets. In patients with XMEN disease, the defective MAGT1 receptor results in reduced Mg2+ uptake in T and NK cells, leading to reduced NKG2D expression and impaired target cell lysis.

five members of the Tec family that function as non- of EBV disease in two ITK-deficient sisters,70 by receptor protein tyrosine kinases.67 Its expression is screening for ITK mutations in patients who had a restricted to T cells, NK cells, iNKT cells, and mast history of EBV-associated tumors; hence, the seem- cells. In T cells, it is induced upon TCR activation or ingly very high penetrance of EBV disease in ITK IL-2 stimulation and is thought to play a critical role deficiency may be an overestimate. Nevertheless, the in downstream signaling. Altogether nine patients recently identified EBV-naive patient subsequently from six kindred have been identified to date, with acquired EBV and developed a smooth muscle cell inactivating mutations affecting different domains tumor.71 Several instances of severe VZV and CMV of the protein. The condition is characterized by a infections were also recorded among the above- progressive loss of CD4+ T cells, particularly naive mentioned patients and so the overall picture of viral CD4+ T cells, and a progressive hypogammaglob- susceptibility associated with ITK mutation remains ulinemia. Most of the patients have normal levels unclear. The incidence of EBV-associated disease is of CD8+ T cells and NK cells, whereas circulating nevertheless interesting and further work is needed iNKT cell numbers are heavily reduced.68–70 The to determine to what extent iNKT deficiency and/or recent identification of an EBV-naive patient has impaired T or NK cell function is responsible. confirmed that these features are primary conse- quences of ITK deficiency and not EBV induced.71 Coronin 1A deficiency Remarkably, the first eight reported ITK-deficient Recent work has identified three kindred with a patients from five unrelated kindred had all devel- combined immune deficiency linked to homozy- oped EBV-positive malignancies, either B-LPD or gous or heterozygous mutations in the gene Hodgkin lymphoma.72 Note that several of these encoding the coronin family member coronin 1A. cases were discovered, following the initial report This protein, widely expressed in hematopoietic

30 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus

Immunocompetent CD16 mutation

Activatory receptors Activatory receptors EBV+ EBV+ NK target target NK CD16 CD2 cell cell CD2 X mCD16 Lysis ImpairedImpaired llysisysis

Figure 4. A schematic view of the immune defect associated with CD16 deficiency. In immunocompetent individuals, NK cell lysis of target cells depends upon a favorable balance between activatory and inhibitory receptors. CD16 is one such activatory receptor that can deliver activating signals to NK cells when it engages its ligand, CD2, expressed on target cells. Missense mutations in FCGR3A, leading to expression of a mutant CD16 (mCD16), abrogate the CD16–CD2 interaction and impair spontaneous NK cell lysis of virally infected targets cells. cells, directly binds filamentous (F) actin and viruses (HPVs), and/or Mycobacterium leprae in regulates actin polymerization through interaction their first decade before, in one case, developing with the actin-related protein (ARP) 2/3 complex.73 Hodgkin lymphoma and then a diffuse large B cell Murine studies first showed that coronin 1A lymphoma, both tumors being confirmed as EBV deletion caused peripheral T lymphopenia, perhaps positive.78 by affecting thymic emigration74 or TCR signaling in naive T cells,73 and led to impaired T-dependent CD16 impairment antibody responses; by contrast, NK cell and naive Homozygous missense mutations in FCGR3A, the B cell development were unaffected. Subsequent gene encoding the Fc receptor CD16 expressed screening of patients with a T-deficient, B- and on NK cells, have been identified in at least three NK-sufficient phenotype indeed identified indi- patients from unrelated families.79–81 Importantly, viduals with coronin 1A mutations; where studied, these patients have normal numbers of NK iNKT cell numbers were also grossly reduced in cells, T cells, and B cells but, while T and B cell these patients.75 functions appear unaffected, and key aspects of All six affected individuals identified to date NK cell function are impaired. Normally, NK showed a general predisposition to various infec- cells recognize target cells for destruction when tions but with a high penetrance of EBV-associated signals received through their activatory recep- disease. A first case, with heterozygous gene muta- tors outweigh those received through inhibitory tions and no detectable coronin 1A protein, had a receptors. One such activatory receptor is CD16 history of respiratory infections, oral thrush, and expressed by mature NK cells; its best known inability to control a live attenuated VZV vaccine function is to engage the immunoglobulin G (IgG) before stem cell transplantation at 4 years of age.76 Fc domain of IgG-opsonized target cells and induce In another kindred, where a homozygous missense antibody-dependent cellular cytotoxicity (ADCC). coronin 1A mutation led to barely detectable However, CD16 can also promote conventional NK protein expression, three affected siblings again had lysis through a coactivating interaction with CD2 a history of recurrent respiratory infections but on the target cell surface. Interestingly, the FCGR3A interestingly all three later developed EBV-positive mutations described above leave ADCC function LPD.77 Finally, in a third kindred, two siblings intact but, as illustrated in Figure 4, abrogate with heterozygous mutations suffered multiple the CD16–CD2 interaction and impair sponta- cutaneous infections with HSV, human papilloma neous NK cell cytotoxicity. This NK-selective PID

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 31 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson therefore offers the clearest litmus test of the Group 3: PIDs generally susceptible importance of NK cell–mediated killing in viral to viral and nonviral infections defense. Activating mutations of the PI3K pathway All three patients suffered from a number of Recent work has identified a new class of PIDs, viral infections, including HPV and VZV; once marked by recurrent bacterial and viral infec- again, however, there was a significant incidence tions and caused by hyperactivation of the of EBV-associated disease. One patient suffered phosphatidylinositol-3-OH kinase (PI3K) pathway. a prolonged IM-like illness that lasted nearly The class I PI3Ks, responsible for phosphoryla- 10 months, while another developed recurrent tion of the inositol ring of phosphatidylinositol EBV-associated B-LPD.

Table 3. PIDs generally susceptible to viral and nonviral infections

Disorder Affected gene Other pathogenic Inheritance Associated immune defects EBV-associated disease infections

Hyperactive PI3K NK Normal numbers 2/30 with EBV+ Respiratory bacteria, P110␦/p85a iNKT ? tumors: HL, DLBCL VZV, HSV, CMV Dominant active T CD4 lymphopenia, CD8 exhaustion B Hypogamma in some cases

STK4 def NK Normal numbers 3/8 with EBV+ Bacterial, fungal, HPV, STK4/MST1 iNKT ? tumors: B-LPD, HL VZV, CMV Autosomal recessive T Naive T cell deficiency B Low-normal numbers

ZAP70 def NK Normal numbers 1/19 with EBV+ Bacterial, fungal, HSV, ZAP-70 iNKT Normal numbers tumor: DLBCL HPV, M. contagiosum Autosomal recessive T CD4 reduced BNormalnumbers

CTPS1 def NK Normal numbers 8/8 with recurrent IM, Bacterial, HPV, VZV, and 3/8 with EBV+ tumor: other viruses CTPS1 iNKT Absent B-LPD Autosomal recessive T CD4 lymphopenia B Reduced memory

NHEJ def NK Low-normal (1) 2/6 with EBV+ Bacterial, viral 1. Artemis iNKT ? tumors: B-LPD 2. DNA Lig IV (2) 2/17 with EBV+ Hypomorphic T Reducednumbers tumors: DLBCL BReducednumbers

Gata 2 def NK Near absent 2/57 with EBV+ tumors: Bacterial, VZV, CMV, GATA2 iNKT Normal smooth muscle, HSV, HPV Autosomal dominant T CD4 lymphopenia in some mesenchymal cases B Near absent

Chediak-Higashi NK Impaired lysis Some cases of accelerated Respiratory bacteria LYST iNKT ? disease/HLH? Autosomal recessive T Normal (?) BNormal

32 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus membrane lipids, consist of a catalytic subunit rylate members of the FOXO transcription factor (p110␣, p110␤, or p110␦) and a regulatory subunit family can have multiple downstream effects. For (p85␣,p85␤,orp55␥).82 The p110␦/p85␣ het- example, in T cells, FOXO1 regulates the expression erodimer in particular plays a key role in both TCR of the IL-7 receptor and of the lymphoid homing and B-cell receptor (BCR) signaling, and mutations molecules CCR7 and CD62L. Loss of STK4 has all affecting both subunits have been described. Thus, the hallmarks of a severe T cell deficiency. The main two studies have reported a combined total of 26 immune defects include a progressive loss of naive PID patients from 14 kindred with p110␦ muta- T cells, restricted TCR diversity, and CD4+ Tcell tion; all cases had gain-of-function mutations that lymphopenia. CD8+ T cell and B cell numbers are resulted in hyperactivation of the PI3K–Akt–mTOR normal in some cases but low in others, whereas pathway.83,84 Similar hyperactivation can also result NK cell numbers are normal. from heterozygous splice site mutations leading To date, eight STK4-deficient patients have been to a truncated p85␣ subunit that has lost regula- identified from four kindred. All suffered recurrent tory function.85–87 In each case, the main immune infections in early life with bacteria, fungi, and defects were a progressive loss of CD4+ (particularly virusessuchasHPV,HSV,VZV,andEBV.Specif- naive CD4+) T cells, defective T cell–dependent ically, three of four children from two unrelated antibody responses, a reduction in class-switched families had high EBV loads in blood and, of these, memory B cells, and accumulation of immature one went on to develop EBV-positive Hodgkin transitional B cells. NK cell numbers were normal in lymphoma.90 In two further reports, one of three most cases but, from evidence in mouse models,88 affected siblings and a single child in another family their function may be compromised. both developed EBV-positive LPD.89–91 All patients with PI3K mutations suffered recur- ZAP70 deficiency rent respiratory bacterial infections and increased Another severe T cell deficiency is caused by susceptibility to several viral infections; details mutations affecting ZAP70, a nonreceptor tyrosine varied between reports, to some extent reflecting kinase that is a key component of the TCR signal the depth of analysis. In one study, five of the transduction pathway. Upon TCR stimulation, 17 patients with p110␦ mutations had a history of ZAP70 is recruited to the CD3␨ chain where, severe herpesvirus infections,83 whereas two of nine after its phosphorylation by Lck, it phosphorylates patients in a parallel study developed EBV-positive a number of downstream targets to initiate the tumors, one a classical Hodgkin lymphoma and the signaling cascade. ZAP70 mutation is characterized other a diffuse large B cell lymphoma; furthermore, by a profound T cell deficiency with near absence all nine had high EBV viral loads, and some also of CD8+ T cells and impaired TCR signaling in the high CMV loads, in the blood.84 Also one of remaining CD4+ T cells, whereas the B cell and NK the four patients with p85 mutation had high cell compartments seem unaffected.92 EBV and CMV viral loads in the blood.87 When So far, at least 19 ZAP70-deficient patients have analyzed, most patients were able to generate large + been identified. Although their clinical presen- numbers of EBV-specific CD8 T cells. However, tations have been heterogeneous, generally, they like the CD8 population as a whole, these cells were show increased susceptibility to recurrent bacterial, skewed toward terminally differentiated phenotype, fungal, or viral infections in the first 2 years of life possibly indicative of chronic antigen challenge and a failure to thrive. Of the viral infections, HSV, and/or functional impairment.84 molluscum contagiosum, and HPV are the most pathogenic. The EBV status of many patients was STK4 deficiency often not determined. However, one infant with A similar broad susceptibility to infections is + normal numbers of B cells and CD4 T cells, but a seen in another recently defined PID caused by + near absence of CD8 T cells, developed an aggres- homozygous mutations in the gene encoding the sive EBV-positive diffuse large B cell lymphoma.93 ubiquitously expressed serine–threonine kinase 4 (STK4), which is also known as mammalian sterile CTPS1 deficiency 20-like protein (MST1).89,90 SKT4’s role in immune A recent study has identified homozygous muta- cells is poorly defined, but its ability to phospho- tions in the gene encoding cytidine 5 triphosphate

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 33 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson synthase 1 (CTPS1) as responsible for another of hypomorphic DNA ligase IV mutation have combined deficiency of adaptive immunity. CTPS1 been identified,99–107 again with multiple recurrent is strongly and specifically activated in T cells infections. Three of these cases developed an following TCR engagement and appears to be the EBV-positive diffuse large B cell lymphoma.99,107 In main source of cytidine 5 triphosphate support- one instance, the disease arose in one of two sisters, ing deoxyribonucleic acid (DNA) synthesis for both heterozygous for a null and a hypomorphic TCR-induced proliferation. Thus, T cells from DNA ligase IV (LIG4) allele and showing reduced CTSP1-deficient patients retained the immediate T cells, almost absent B cells, but normal NK cell signaling events after TCR triggering in vitro but numbers and an expanded ␥␦T cell population.99 could not sustain the subsequent proliferative burst. B cell proliferation following BCR stimulation in GATA2 deficiency vitro was also impaired, whereas IL-2–induced NK The hematopoietic transcription factor GATA2 cell responses were much less affected. Some, but is a member of a family of zinc finger transcrip- not all affected individuals had T cell, B cell, and, to tion factors that regulate gene expression during some extent, NK cell lymphopenia, most obviously hemopoiesis.108 It appears to be more important for during active infections, while further analysis in non-T cell lineages and indeed is highly expressed one case failed to detect any iNKT cells.94 in CD56bright NK cells.109 Heterozygous mutations Eight CTSP1-deficient patients in this first report of GATA2 are now recognized to underlie a complex suffered recurrent encapsulated bacterial infections range of immune-deficient phenotypes, typically as well as multiple viral infections, with EBV and characterized by marked reductions in NK cell, VZV particularly prominent. Thus, four of the monocyte, B cell, and DC numbers in blood; half of eight patients studied had a history of a severe those surveyed to date also had reduced CD4+ Tcell IM-like syndrome within the first year of life, numbers. With respect to NK cells, the CD56bright while another three developed EBV-positive B-LPD subset is particularly affected but, in some patients, lesions in the central nervous system, a classic site CD56dim cells are also low and their function is for uncontrolled EBV transforming events.94 The impaired.109,110 Interestingly, what is now recog- susceptibility to herpesvirus, especially EBV, infec- nized as the index case of GATA2 deficiency was tions would accord with failure of the virus-induced originally reported as an NK cell defect linked to primary T cell burst. severe VZV, CMV, and HSV infections.111 However, a recent survey of 57 patients found generalized sus- Nonhomologous DNA end-joining deficiencies ceptibility to multiple viruses, also including HPV, The process of nonhomologous DNA end joining as well as to mycobacterial and fungal infections. (NHEJ) is generally important for DNA double- Interestingly, only a small minority of patients had strand break repair in mammalian cells, but high EBV viral load in the blood, but two individuals also crucial for the generation of BCR and TCR developed unusual EBV-positive malignancies: one diversity in lymphocytes through V(D)J recom- was a smooth muscle cell tumor and the other an bination. Genetic defects in several components uncharacterized tumor of mesenchymal origin.110 of the NHEJ machinery cause severe combined Given the complexity of the GATA2-deficient immunodeficiency in humans, abrogating all B and phenotype, it is difficult to interpret these findings T lymphopoiesis and necessitating hematopoietic in terms of EBV control. The relative rarity of high stem cell transplantation (HSCT).95 However, EBV blood loads, and the absence of EBV-positive hypomorphic mutations in two of these compo- LPD, may simply reflect the paucity of mature nents, the Artemis protein and DNA ligase IV, have B cells; indeed, the frequency of EBV infection in beenfoundallowinglimitedBandTlymphocyte these patients is still poorly documented. A limited development. All six reported cases of hypomorphic B cell reservoir may reduce the chance of EBV Artemis gene (DCLRE1C) mutation were suscep- establishing its conventional latency; however, in tible to multiple infectious agents early in life.96–98 these circumstances, the absence of effective NK However, two of four affected individuals in the cell control over replicative infection may allow the original report eventually died of an EBV-positive virus to access atypical cell lineages, such as smooth LPD, one of which developed spontaneously and muscle cells, in which it cannot replicate but is the other as a post-HSCT lesion.96 At least 17 cases potentially oncogenic.

34 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus

Hypomorphic MCM4 mutation ence in T cell cytotoxicity between CHS patients and Hypomorphic mutations leading to reduced controls;119 however, some more recent papers have levels of the minichromosome maintenance-4 shown defects in some, but not all patients.118,120 (MCM4) protein have been identified in 14 patients Patients suffer recurrent life-threatening bacterial from at least five kindred of a nomadic Irish and viral infections. Furthermore, without HSCT, community.112,113 MCM4, a helicase component almost 85% of affected children will progress to of the DNA replication system, is widely expressed an accelerated disease with lymphoproliferative in many cell types. Accordingly, MCM4 deficiency infiltration of major organs and HLH.121 What is characterized by several developmental defects, causes this accelerated phase is largely unknown, including adrenal failure and growth retardation. but an exaggerated T cell response to viral infections However, immunological abnormalities appear has been suggested.115 Although there has been no to be restricted to the final stages of NK cell detailed analysis, EBV infection has been postulated maturation. Normal numbers of CD56bright NK as a trigger.122 In one early report, six of nine cells are found in the near absence of the mature unrelated patients were EBV seropositive, and three CD56dim NK subset. This likely reflects a specific of these were reported to have signs of chronic role for MCM4 in maintaining chromosomal active EBV infection post-IM.123 Another more integrity during cell proliferation involved in the recent report, although only in one patient, has CD56bright to CD56dim NK cell transition. shown a more clear association between primary Of four affected siblings in the original report, EBV infection and CHS acceleration.124 at least three had a history of recurrent respiratory tract/pulmonary infections in early childhood. Group 4: PIDs with an inherent One went on to develop EBV-positive B-LPD, susceptibility to lymphoma whereas the other siblings all carried the virus There are at least three conditions, all formally asymptomatically.114 Subsequently, two more classifiedasPIDsbutwithdifferentdegreesof affected family members were identified, one of immune impairment, which are also associated whom had a history of recurrent HSV and VZV with increased cancer incidence, in particular, infections.113 An independent study, describing lymphoma. In each case, it is not clear whether eight more patients, focused on the other develop- immune impairment and cancer risk are separate mental consequences of MCM4 insufficiency and consequences of the genetic defect or are interre- information on infections was limited.112 Further lated. However, the involvement of EBV in some studies are needed to determine the susceptibility (but not all) of these tumors implies that the of such patients to infectious diseases in general disturbance of immune function has increased the and to EBV-associated pathology in particular. chances of virus-associated malignancies arising. Chediak–Higashi syndrome Wiskott–Aldrich syndrome Chediak–Higashi syndrome (CHS) has long been Wiskott–Aldrich syndrome (WAS) is an X-linked recognized as an autosomal recessive disorder, immunodeficiency caused by mutations in the gene though it is still relatively rare with <500 cases encoding the WAS protein. This protein, expressed reported worldwide.115 The affected gene, LYST, exclusively in hematopoietic cells, is a key regulator encodes a regulator of lysosomal trafficking. of actin polymerization and plays an important role Mutations affect the size, structure, and function of both in lymphoid development and in the matu- lysosomes and other secretory granules, resulting ration and function of myeloid monocytic cells.125 in abnormally large organelles in virtually all More than 300 mutations have been identified with granulated cells.116 The most important features different effects on WAS expression or function.126 of the immunodeficiency are neutropenia and NK However, the classical syndrome, associated with cell dysfunction. Several studies, including the complete absence of WAS protein, is characterized mouse models, have shown clear defects in NK cell by small platelets, thrombocytopenia, and increased activity.117,118 To what extent cytotoxic T cell func- susceptibility to bacterial, viral, and fungal infec- tion is affected by the secretory granule impairment tions. Among several immune defects are a pro- remains controversial. Early reports found no differ- gressive T cell lymphopenia, near absent iNKT cell

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 35 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson

Table 4. PIDs with an inherent susceptibility to lymphoma

Disorder Affected gene Other pathogenic Inheritance Associated immune defects EBV-associated disease infections

Wiskott–Aldrich NK Impaired lysis 15/154 with lymphoma, Bacterial, fungal, viral WAS iNKT Near absent some EBV+ X-linked T Progressive T lymphopenia, impaired lysis BNormal

Ataxia telangiectasia NK Normal numbers 50/279 with B-lymphoma. Bacterial, fungal, HPV, ATM iNKT ? 12/12 HL EBV+, 19/38 VZV, CMV Autosomal recessive T CD4 lymphopenia in some NHL EBV+ cases BReducednumbers

ALPS NK ? 16/150 with B-lymphoma, TNFRSF6 iNKT ? some EBV+ Autosomal dominant T Increased numbers of CD4–CD8– Tcells B Increased numbers of CD5+ B cells, hypergamma numbers, and impaired NK and T cell effector func- present as mild impairment of both humoral and tion due to defective immune synapse formation. cell-mediated immunity. Low levels of serum anti- Interestingly, some 13% of WAS patients go on bodies and reduced numbers of B cells are common to develop malignancies, mainly B cell lymphomas, features, whereas NK cell numbers appear normal. with an average age of onset of 9.5 years.127 The CD4+ T cell lymphopenia has been reported in link between WAS deficiency, its immunologic some patients but T cell function remains broadly consequences, and tumor incidence is still not intact. Patients are particularly susceptible to fully understood. However, EBV infection appears bacterial sinopulmonary infections early in life and to increase the lymphoma risk. Thus, there are many develop chronic lung disease.136 several case reports of WAS patients developing Early studies of malignancy risk highlighted acute EBV-positive diffuse large B cell lymphoma,128–131 lymphoblastic leukemia and T-prolymphocytic Hodgkin lymphoma,132 and an unusual laryn- leukemia in AT cohorts. However, later studies geal B cell lymphoma133 as well as another rare have revealed even more cases of B cell lymphoma EBV-positive lesion, cutaneous lymphomatoid and some carcinomas of various origins.137 A granulomatosis.134 recent survey found that 69/279 AT patients had developed malignancies; intriguingly, 12 were Ataxia telangiectasia Hodgkin lymphomas and all were EBV associated, Ataxia telangiectasia (AT) is caused by autosomal while 38 non-Hodgkin lymphomas, of which half recessive mutations in the gene-encoding AT were also EBV associated.138 mutated (ATM) protein. The most obvious clinical features are progressive cerebellar ataxia and ocular Autoimmune lymphoproliferative syndrome telangiectasia; additional features are hypersensi- Autoimmune lymphoproliferative syndrome tivity to ionizing radiation, a degree of immune (ALPS) is caused by mutations that impair lym- deficiency, and increased risk of malignancies. phocyte responses to apoptosis triggered by the These reflect ATM’s multiple roles as a widely Fas pathway. Normally, upon stimulation by Fas expressed STK involved in DNA damage repair, ligand, Fas receptors recruit an adaptor protein Fas- cell cycle checkpoint control, and apoptosis.135 associated death domain (FADD) and caspases 8 and Immune defects vary between patients, but typically 10 to their intracellular death domain. This leads to

36 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus caspase activation and triggers a signaling cascade where mutation of the Bruton’s tyrosine kinase that results in cell death. Fas-mediated apoptosis is gene blocks all mature B cell development. On the important for general lymphocyte homeostasis and basis of a single study, XLA patients appear not to is also crucial for negative selection of potentially acquire EBV, at least not as a long-term persistent autoimmune B cells arising within germinal center infection.143 More attention should be given to the reactions. Most ALPS cases stem from heterozy- EBV status of patients with XLA, or other PIDs gous mutations of the Fas (CD95)-encoding gene affecting the pre-BCR/BCR pathway, to determine TNFRSF6, resulting either in Fas proteins with dom- whether the virus can ever be stably acquired via inant interfering function or less frequently in low- non-B cell infection. By contrast, a number of other level protein expression and haplo insufficiency.139 PIDs selectively affecting IgG and/or IgA antibody Other ALPS patients carry mutations in genes responses are B cell proficient, and therefore encoding downstream mediators of the Fas path- presumably infectable, yet have not been linked to way such as Fas ligand, FADD, or caspase 10. The EBV-associated disease. One such condition, CD21 condition presents in childhood as nonmalignant deficiency, is of special interest because CD21 (the lymphadenopathy/splenomegaly and a characteris- complement receptor CR2) is the main receptor- tic expansion of mature CD4/CD8 double-negative mediating B cell infection by EBV; however, such T cells. Autoimmune reactions appear to be respon- patients still acquire the virus because a second sible for the subsequent development of peripheral complement receptor on the B cell surface, CD35, anemia, thrombocytopenia, or neutropenia. can substitute for CD21.144 OtherPIDswithdefec- ALPS patients, particularly those with dominant tive IgG and IgA responses arise from lesions in the interfering TNFRSF6 mutation, are also at increased genes encoding the CD40 or CD40 ligand proteins risk of B cell lymphoma, with 10 cases of Hodgkin required for T/B interactions, isotype switching, and six of non-Hodgkin lymphoma seen in a and memory B cell production. Even in the absence prospective cohort of 150 patients.139,140 Estimates of classical memory B cells, such patients become of the fraction of ALPS lymphomas that are EBV- stably infected and appear to carry the virus in associated vary from 15% to 40% in independent the B cell system without ill effect.145,146 Overall, surveys.139–141 How deficiency in the Fas-mediated therefore, the evidence from such PIDs implies apoptosis pathway could increase the risk of EBV- a relatively minor role for humoral immunity, associated lymphomas is unknown. However, one certainly for isotype-switched antibody responses, possibility is that during long-term virus carriage, in controlling the virus. one of the immune controls governing EBV in the A second set of significant negatives with respect B cell system involves Fas-mediated cell killing. to EBV-associated disease involves PIDs affecting expression of the HLA class I or II proteins that, PIDs and susceptibility to EBV: significant + + respectively, present antigen to CD8 and CD4 negative associations T cells. Thus, mutations in the transporter associ- From the ever-increasing number of genetically ated with antigen presentation (TAP) genes, TAP1 defined PIDs, the above text has highlighted those or TAP2, abrogate the main pathway of peptide that show a clear disposition to EBV-induced loading onto nascent HLA class I molecules and disease. However, there are a number of other thereby reduce surface HLA class I expression, often PIDs where problems with EBV infection might up to 100-fold, on the surface of target cells. At least have been anticipated but, to date, have not been 19 such cases of HLA class I deficiency have been observed; these significant negative associations identified. Of the 10 patients surveyed in one report, may also help us to understand the biology of the all suffered from severe respiratory infections yet virus and its host control. appeared to carry herpesviruses such as EBV, First, there is a range of conditions where the CMV, and VZV asymptomatically.147–149 Affected + primary lesion directly targets components either of individuals had reduced ␣␤ CD8 Tcellnumbers, the BCR complex itself or of the BCR signaling path- particularly where TAP mutation had the strongest way, and thereby impairs the production of some or effect on HLA class I levels, though the TCR reper- all immunoglobulin isotypes.142 The most extreme toire was still polyclonal; by contrast, NK and ␥␦ example is X-linked aggammaglobulinemia (XLA), T cell populations were expanded. One possibility

Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences 37 published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Primary immunodeficiencies and Epstein–Barr virus Palendira & Rickinson is that viral surveillance in TAP-deficient patients genes whose mutations affect multiple cell lineages depends on these latter cell types, particularly on and lead to complex phenotypes. Indeed, for several NK cells since low HLA class I levels on target of the more recently identified conditions, little cellswillfavorNKcellactivation.Note,however, or nothing is yet known about their effects on that large herpesviruses, including EBV, are also potentially important players such as iNKT cells, a rich source of TAP-independent target epitopes ␥␦ T cells, and mucosal-associated invariant T that are selectively presented to CD8+ Tcells (MAIT) cells. Second, given the nascent state of the in a TAP-negative context, and such responses field, current evidence on disease penetrance within may also contribute to virus surveillance.150–152 A a particular PID often comes from just a small num- separate HLA class II deficiency (bare lymphocyte ber of affected individuals and may be influenced by syndrome) arises from homozygous mutation of screening bias. Third, in the specific context of EBV, genes encoding regulatory factors controlling HLA disease incidence may be low if affected individuals class II expression, and principally affects CD4+ do not survive long enough to acquire the virus or if T cell numbers and T cell–dependent antibody the PID itself is a bar to EBV infection. Fourth, EBV responses. These patients are broadly susceptible infections have a unique pathology. Thus, in the to both bacterial and viral infections from early in absence of host control, herpesviruses such as HSV, life; however, the largest study of 35 North African VZV, and CMV can be acutely life-threatening patients noted cases of CMV- and HSV- but no through lytic infections in multiple cell types, EBV-related disease.153 It would again be of interest requiring urgent treatment with acyclovir-based to know if such patients ever become EBV-infected drugs capable of inhibiting herpesvirus replication; since HLA class II acts as an essential coreceptor for by contrast, uncontrolled lytic EBV infection leads both CD21- and CD35-mediated viral entry into only to restricted oral leukoplakia lesions that will B cells.144,154 often go unnoticed clinically.157 The threat from Finally, a range of mutations affecting either EBV comes instead from growth-transforming IFN-␥ receptor chains, the p40 subunit of IL-12 infections of the B cell system; these can be insid- and IL-23, the IL-12 receptor chain ␤1, or the signal ious in onset, often beginning with febrile IM-like transducer and activator of transcription factor 1 symptoms, but can then evolve into potentially (STAT1) all influence IFN-␥–mediated immunity. fatal LPDs or other B cell malignancies. These were discovered through their enhanced With these caveats in mind, what lessons can be susceptibility to mycobacterial infections, although drawn from the current evidence linking PID states a significant number of patients also have a history and susceptibility to EBV-associated disease? of VZV or CMV disease. It is therefore interesting First, the limited data available suggest that to note that among 150 IFN-␥R–deficient and 141 complete B cell deficiency abrogates EBV infection, IL-12R␤–deficient patients,155,156 there was only or at least stable virus acquisition, and so such one EBV-associated pathology, an EBV-positive patients can tell us nothing about the importance non-Hodgkin lymphoma in a patient with com- of humoral immunity in controlling the virus. By plete IFN-␥R deficiency.155 This suggests that contrast, the issue of EBV infection in PIDs with IFN-␥–dependent effector pathways are not major defects in memory B cell development is potentially players in the control of EBV infection and, by more interesting since these patients will not only inference, that T cell– and/or NK cell–mediated fail to make virus-specific IgG and/or IgA antibody controls are more likely to be exercised through cell responses but also lack the B cell subsets in which killing than through cytokine release. the virus naturally persists. It seems that such patients do nevertheless acquire the virus,145 and Conclusions so the absence of reported EBV disease in these The ever-increasing number of genetically defined cohorts suggests that isotype-switched antibody PIDs is a potentially rich source of new information responses play only a minor role in containing about the immune control of important pathogens both primary and persistent infections. The major such as EBV. However, there are reasons for caution containing role therefore falls to cell-mediated when attempting to draw conclusions from the evi- immune responses, with potential contributions dence as it currently stands. First, many PIDs involve from iNKT cells, NK cells, and T cells.

38 Ann. N.Y. Acad. Sci. 1356 (2015) 22–44 C 2015 The Authors Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Palendira & Rickinson Primary immunodeficiencies and Epstein–Barr virus

Although there are model systems in which the T cell defect occurs in the absence of any NK or, iNKT cells have shown activity, to date the evi- where studied, iNKT cell defect. Note that in many dence that iNKT cells play an important role of the T-lymphopenic PIDs, the defect is progressive in controlling EBV infection in the natural host and principally involves the CD4+ T cell subset. In remains circumstantial. It rests on the complete that context, laboratory studies have highlighted the absence of the iNKT subset in XLP patients, on the ability of EBV-specific CD4+ T cells to recognize apparently severe depletion of iNKT cell numbers and kill their target cells. However, interpreting the in ITK-, coronin 1A-, CTSP1-, and WAS-deficient current PID findings as evidence of direct EBV con- individuals, and on the recent suggestion that in trol by CD4+ effectors is complicated by the fact that XIAP patients, such depletion is actually driven by CD4 impairment can also affect the maintenance EBV infection. However, XLP and WAS deficiency and/or quality of CD8+ Tcellmemory.158 also involve defects in both NK and T cell func- The balance of evidence to date from PID states tions, while the other PIDs have associated T cell therefore supports a combined role for NK cells impairments. The degree to which defective iNKT and T cells in controlling EBV infection. Currently, responses contribute to the EBV disease phenotype however, we do not fully understand how these in these conditions therefore remains conjectural. two lineages cooperate, or at which points the By comparison, a much stronger case can be made different subsets of NK and T cells are involved. If linking NK cell deficiency with EBV-associated forced to a rank order, then the strong (but still not disease. Thus, in two PIDs with a high penetrance absolute) correlation between T cell impairment of disease, XLP and MAGT1 deficiency, there are and EBV disease tempts us to identify T cells as different but defined defects in NK cell–mediated the more important of the two. As to which T cell cytotoxicity; however, in both cases, interpretation subset, the apparently benign EBV carrier state is complicated by the fact that the same defects seen in TAP-deficient individuals cautions against have also been shown in EBV-specific CD8+ Tcell assigning primacy to CD8+ over CD4+ T cells as the preparations from these patients. More convincing effector subset. At the moment, all such conclusions is the evidence from CD16 deficiency, where need to be seen as provisional because each can be impairment of NK cell killing occurs in the absence challenged by anomalies; indeed, it is through study- of any detectable effect on T cells; all three patients ing such anomalies that real progress will be made. reported so far were generally susceptible to severe Thus, what are the compensatory responses keeping herpesvirus infections, but these included one case EBV at bay in TAP-deficient patients? Likewise, why with a prolonged IM-like illness and one with EBV- does the EBV-specific T cell response not adequately positive LPD. Also, intriguing in this context are the compensate for a particular NK cell defect in CD16- occasional EBV-positive solid tumors reported in deficient patients? Finally, consider the fascinating GATA2 deficiency, a complex PID affecting various example of high EBV disease penetrance in the PID hematopoietic lineages including NK cells and in associated with CD27 deficiency, where there is some cases B cells, but apparently not T cells. no marked disturbance of lymphocyte subsets and An important role for T cells in EBV control is where the inability to control EBV infection remains implicit in the data from XLP patients where a func- unexplained. This emphasizes how much there is tionally defective CD8+ Tcellresponsenotonlyfails still to learn and how many surprises are still in to control the virus but also actively contributes to store. disease pathogenesis through hyperexpansion and Conflicts of interest cytokine release. Several other PIDs with significant EBV disease penetrance are characterized by other The authors declare no conflicts of interest. types of T cell impairment, involving either T cell lymphopenia (the PIDs affecting ITK, coronin 1A, References PI3K, STK4, ZAP70, and NHEJ function), poor T cell proliferative capacity (CTSP1 deficiency), or 1. Fischer, A. 2007. Human primary immunodeficiency dis- poor effector function (MAGT1 deficiency). Fur- eases. Immunity 27: 835–845. 2. Casanova, J.-L. & L. Abel. 2004. The human model: a thermore, in at least some of these conditions (those genetic dissection of immunity to infection in natural con- affecting PI3K, STK4, ZAP70, and NHEJ function), ditions. Nat. Rev. Immunol. 4: 55–66.

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