Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases

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1 review Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases Nima Parvaneh, 1,2 Alexandra H. Filipovich 3 and Arndt Borkhardt 4 1 Paediatric Infectious Diseases Research Centre, Children s Medical Centre, Tehran University of Medical Sciences, 2 Division of Allergy and Clinical Immunology, Department of Paediatrics, Tehran University of Medical Sciences, Tehran, Iran, 3 Cincinnati Children s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA and 4 Department of Paediatric Oncology, Haematology and Clinical Immunology, Centre for Child and Adolescent Health, Heinrich-Heine University, Dusseldorf, Germany Summary Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, maintains lifelong subclinical persistent infections in humans. In the circulation, EBV primarily infects the B cells, and protective immunity is mediated by EBV-specific cytotoxic T cells (CTLs) and natural killer (NK) cells. However, EBV has been linked to several devastating diseases, such as haemophagocytic lymphohistiocytosis (HLH) and lymphoproliferative diseases in the immunocompromised host. Some types of primary immunodeficiencies (PIDs) are characterized by the development of EBV-associated complications as their predominant clinical feature. The study of such genetic diseases presents an ideal opportunity for a better understanding of the biology of the immune responses against EBV. Here, we summarize the range of PIDs that are predisposed to EBV-associated haematological diseases, describing their clinical picture and pathogenetic mechanisms. Keywords: Epstein-Barr virus, primary immunodeficiencies, haemophagocytic lymphohistiocytosis, x-linked lymphoproliferative disease, lymphoma. Epstein-Barr virus (EBV) is a latent c-herpesvirus that infects more than 95% of the adult population worldwide (Grose, 1985; Luzuriaga & Sullivan, 2010). Primary EBV infection in young children is often asymptomatic and infectious mononucleosis (IM) usually affects those who have primary EBV infection during or after the second decade of life (Luzuriaga & Sullivan, 2010). Epstein-Barr virus transmission occurs predominantly through exposure to infected saliva. Lytic infection of tonsilar crypt epithelial cells or B lymphocytes results in viral reproduction and high levels of salivary shedding during the early Correspondence: Nima Parvaneh, Paediatric Infectious Diseases Research Centre, Children s Medical Centre, 62 Gharib St, Tehran, Iran. nparvaneh@tums.ac.ir stages of infection (Balfour et al, 2005; Hadinoto et al, 2008). During primary infection, normal healthy individuals mount a vigorous immune response consisting of natural killer (NK) cells and EBV-specific cytotoxic CD8 + T lymphocytes (CTLs), which control both primary infection and the periodic reactivations that occur in all EBV-seropositive individuals (Callan et al, 1998; Strowig et al, 2008). After clearance of the primary infection, EBV persists in infected memory B cells, establishing latent infection characterized by the expression of only a limited set of EBV antigens (Fig 1; Hochberg et al, 2004). The vast majority of patients with primary EBV infection recover without apparent sequelae; however, in individuals who are immunocompromised, because of a primary or secondary immunodeficiency, primary EBV infections may result in life-threatening disease (Babcock et al, 1999; Williams & Crawford, 2006). Some types of primary immunodeficiencies (PIDs) are well known for developing EBV-associated diseases as the main feature (Borkhardt, 2012). They mainly consist of defects related to lymphocyte cytotoxic pathway or T-cell dysfunctions, including disruptive interactions between B cells and T cells. The consequences of these genetic defects include the development of the acute fulminant life-threatening condition known as haemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinaemia or chronic lymphoproliferative/ lymphoma disease after EBV infection. Here we describe new findings on the range of PIDs predisposed to uncontrolled EBV infection and portray their pathogenesis. Inherited defects of lymphocyte cytotoxic function CD8 + T lymphocytes and NK cells are essential for the elimination of virus-infected cells and surveillance against tumour cells. These cells exert their cytotoxic function through different means but retain the perforin-dependent pathway as a dominant component. The perforin-dependent pathway involves the polarized secretion of cytotoxic granules that contain perforin and granzymes. Perforin directs granzymes into the ª 2013 John Wiley & Sons Ltd First published online 11 June 2013 doi: /bjh.12422

2 Epithelium Lymphoid tissue Peripheral circulation Plasma cell EBV Germinal centre Naïve B cell Blast GC B cell Memory B cell Fig 1. Epstein-Barr virus (EBV) cycle and its interaction with host cells. During primary infection, EBV infects na ıve B cells resulting in the proliferation of blasting B cells. The activated B-cell blasts are rescued through entry into the pool of memory B cells when they receive signals from EBV-specific helper T cells (in the germinal centres). Circulating memory cells may differentiate into plasma cells, which circulate through the oropharynx and transfer the virus to epithelial cells, where it is replicated to infect new B cells as well as new hosts. CTLs recognize all types of infected B cells, with the exception of resting memory B cells. EBV, Epstein-Barr virus; CTL, cytotoxic T lymphocyte; GC, germinal centre; T FH, follicular helper T cell. target cell, triggering cell death (de Saint Basile et al, 2010). Defects in CTL and NK cell cytotoxic function through the granule-dependent pathway lead to uncontrolled but ineffective immune response, resulting in HLH (Menasche et al, 2005). This syndrome is often triggered by a viral infection, mainly of the herpes group, with EBV being the most common cause (Maakaroun et al, 2010). While EBV has a well-described tropism for B cells, the invasion of CD8 + T cell populations plays an important role in the pathogenesis of HLH (Kasahara & Yachie, 2002). Abnormal cytotoxic activity prevents efficient removal of infected cells leading to continuous antigenic stimulation of CTLs and NK cells. This condition precludes down-regulation of the elicited immune response resulting in persistent hyper-activation and proliferation of these effector cells (Arico et al, 1988; Schneider et al, 2002). Activated CTLs and NK cells produce large amounts of c interferon (IFN-c) and tumour necrosis factor-a (TNF-a), stimulating the macrophages, which infiltrate several organs and release damaging cytokines. Characteristic symptoms of HLH include unexplained fever, hepatosplenomegaly and cytopenias. Laboratory values include high ferritin, triglyceride, transaminases and scd25 (a -chain of the soluble interleukin-2 receptor), and decreased fibrinogen. Haemophagocytosis in the bone marrow is a characteristic morphological finding, however is initially absent in many of the patients (Janka, 2012). Untreated, PID-related HLH is a rapidly fatal disease; patients die from either infections or multiorgan failure. Chemotherapeutic and immunosuppressive interventions include dexamethasone, etoposide and ciclosporin A or even lymphocyte-specific antibodies that can control the hyper-inflammatory condition to some extent, maintaining the patient for haematopoietic stem cell transplantation (HSCT) as the definitive therapy (Horne et al, 2005; Ouachee-Chardin et al, 2006; Mahlaoui et al, 2007; Jordan et al, 2011; Marsh et al, 2011, 2013). Genetic defects of lymphocyte cytotoxic function can be divided into the familial HLHs (FHLs) and the HLH syndromes associated with albinism (Table I). Each involved gene encodes a protein that has been shown to mediate distinct steps of the process of cytotoxic granule exocytosis (Fig 2; de Saint Basile et al, 2010). Mutations in the genes PRF1, UNC13D (Munc13-4), STX11, and STXBP2 make up FHLs 2, 3, 4, and 5, respectively (Stepp et al, 1999; Feldmann et al, 2003; Zur Stadt et al, 2005, 2009; Cote et al, 2009). In addition to FHL, there are three other genetic conditions (associated with pigmentary dilution and/or platelet dysfunction) that can lead to HLH. These genetic disorders result from abnormal granule trafficking in different cell types. Chediak-Higashi syndrome, caused by mutations in LYST (Barbosa et al, 1996) is characterized by variable degrees of albinism, bleeding tendency, recurrent bacterial infections, and progressive neurological dysfunction, in addition to development of HLH (Introne et al, 1999). The LYST protein is involved in intracellular trafficking, and it is thought to participate in the sorting of lysosomal proteins to late endosomes (Tchernev et al, 2002; Williams & Urbe, 2007). Griscelli syndrome type 2 is a disorder characterized by pigmentary dilution and occurrence of HLH (Griscelli et al, 1978). The disease is caused by mutations in the RAB27A gene (Menasche et al, 2000; Mamishi et al, 2008), which encodes a small GTPase involved in terminal phases of cytotoxic granule/ melanosome exocytosis (Neeft et al, 2005; Ohbayashi et al, 2010). Hermansky-Pudlak syndrome type 2 (HPS2) is typified by partial albinism, bleeding tendency, increased susceptibility to infections due to congenital neutropenia and impaired cytotoxic activity (Badolato & Parolini, 2007). 574 ª 2013 John Wiley & Sons Ltd

3 Table I. Genetic disorders of lymphocyte cytotoxicity that present with HLH. Genetic disorder Inheritance Gene HLH Chronic EBV viraemia Lymphoma Dysgammaglobulinaemia Albinism FHL2 AR PRF1 + +/ + FHL3 AR UNC13D + +/ FHL4 AR STX11 + FHL5 AR STXBP Chediak Higashi syndrome AR LYST + + Griscelli syndrome type 2 AR RAB27A + + Hermansky Pudlak syndrome type 2 AR AP3B1 +/ + AR, autosomal recessive; EBV, Epstein-Barr virus; FHL, familial haemophagocytic lymphohistiocytosis; HLH, haemophagocytic lymphohistiocytosis, +, present; +/, infrequent;, not reported. Fig 2. Genetic defects of the lymphocyte cytotoxic function. Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the CTL/NK-target cell contact site where the immunological synapse forms. The genetic aberrations affect a precise step of the cytotoxic machinery, i.e. granule content, polarization, docking, priming or fusion. APC, antigen presenting cell; CHS, Chediak Higashi syndrome; CTL, cytotoxic T lymphocyte; FHL, familial haemophagocytic lymphohistiocytosis; GS2, Griscelli syndrome type 2; HPS2, Hermansky-Pudlak syndrome type 2; NK, natural killer. HPS2 results from mutations in AP3B1, which encodes the b-chain of the adaptor protein 3 (AP3) complex, leading to the disruption of the protein complex (Dell Angelica et al, 1997). AP3 is required for the transport of cargo proteins from the trans-golgi network to lysosome-related organelles (Dell Angelica et al, 1997). Affected patients may rarely develop HLH (Jessen et al, 2013). Collectively, these genetic defects preclude the maturation of an efficient immune response to control acute EBV infection, developing the devastating inflammatory reaction of HLH. However, chronic activation of EBV (Katano et al, 2004; Rudd et al, 2006; Pagel et al, 2012), and development of lymphoid malignancies (Clementi et al, 2005; Santoro et al, 2005; Cannella et al, 2007; El Abed et al, 2011) are occasionally reported only for some FHL genetic types. Overlapping symptoms with common variable immunodeficiency presenting with hypogammaglobulinaemia have been reported in patients with FHL5 and, less frequently, FHL3 (Rohr et al, 2010; Pagel et al, 2012), supporting a potential role for STXBP2 (Munc18-2) and UNC13D (Munc13-4) in B cell physiology (Feldmann et al, 2003; Zur Stadt et al, 2009). Moreover, recent studies documented that the expression of genes associated with B cell differentiation and function are down-regulated in patients with different forms of FHL (Sumegi et al, 2011). Inherited defects of T-cell signalling and T-cell/ B-cell interaction This group includes a heterogeneous complex of T-cell defects that predominantly preserve the CTL function but have genetic aberrations in intracellular T-cell signalling and/or T-B cell interaction (Fig 3). These disorders present with complications of EBV infection: HLH, chronic EBV activation or EBV-associated lymphomas (Table II), and also include or develop humoral defects in the course of disease. Some of these defects are recently described and thus include only a few cases, making it difficult to confidently predict the clinical phenotype (Borkhardt, 2012); however, each new disorder provides valuable insights into the pathways that direct host defence against EBV infection in the natural setting. ª 2013 John Wiley & Sons Ltd 575

4 Fig 3. T cell receptor (TCR) and associated co-stimulatory signals. Signalling pathways that organize T cell survival, proliferation, differentiation, homeostasis and migration. Mutant molecules in patients with EBV susceptibility are indicated in blue. BCL10, B-cell lymphoma/leukaemia 10; CARMA, CARD-containing MAGUK protein; DAG, diacylglycerol; ER, endoplasmic reticulum; FADD: Fas-associated protein with death domain; IKK, IkB kinase; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; LCK: lymphocyte-specific protein tyrosine kinase; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein; MAPK, mitogen-activated protein kinase; NCK, non-catalytic region of tyrosine kinase adaptor protein; NFAT, nuclear factor of activated T cells; NIK, nuclear factor (NF)-jB-inducing kinase; PIP2, phosphatidyl inositol bisphosphate; RASGRP, RAS guanyl nucleotide releasing protein; RHOH, Ras homolog gene family member H; RIP2, receptor-interacting serine/ threonine-protein kinase 2; SAP, SLAM, signalling lymphocyte activation molecule; SAP, SLAM-associated protein; XIAP, X-linked inhibitor of apoptosis protein; ITK, interleukin-2 inducible T cell kinase; MAGT1, magnesium transporter 1; STK4, serine/threonine protein kinase 4; SLP-76, SH2 domain containing leucocyte protein of 76 kda; STIM1, stromal interaction molecule 1; TAB 1, TAK1-binding protein; TRAF, TNF receptor associated factor; WASP, Wiskott-Aldrich syndrome protein; WIP, WASP-interacting protein; ZAP70, z-chain associated protein kinase of 70 kda. Signalling lymphocytic activation molecule (SLAM)- associated protein (SAP) deficiency X-linked lymphoproliferative disease (XLP), the prototypic PID with unique vulnerability to EBV infection (Purtilo et al, 1975), is caused by mutations in SH2D1A, which encodes the cytoplasmic adaptor protein, signalling lymphocyte activation molecule (SLAM)-associated protein (SAP; Coffey et al, 1998; Nichols et al, 1998; Sayos et al, 1998). Signalling lymphocytic activation molecule-associated protein is expressed in T/NK cells and participates in the signalling of several SLAM family receptors expressed on haematopoietic cells, including SLAM, Ly9, 2B4, CD84, and NTB-A (NK, T, and B cell antigen; Veillette, 2006; Ma et al, 2007; Schwartzberg et al, 2009; Veillette et al, 2009). SAP modulates SLAM signalling either by competitively blocking the binding of other SLAM receptor interacting proteins, such as Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2 (Sayos et al, 1998; Lewis et al, 2001) or by recruiting additional proteins, such as FynT, to the SLAM receptor (Chan et al, 2003; Latour et al, 2003). Signalling lymphocytic activation molecule-associated protein is also capable of binding intracellular protein kinases and serves as an initiator of multiple complex signalling pathways that modulate immune responses triggered by SLAM receptors (Sylla et al, 2000; Simarro et al, 2004; Gu et al, 2006; Li et al, 2009). XLP is associated with a diverse range of lymphocyte defects reflecting the involvement of SAP in multiple signalling pathways, however; it is unclear which of them underlies their unique susceptibility to EBV. Signalling lymphocytic activation molecule-associated protein-deficient NK cell and CD8 + T cell cytotoxicity is 576 ª 2013 John Wiley & Sons Ltd

5 Table II. T cell deficiencies predominantly presenting with EBV-associated diseases. Genetic disorder Inheritance Gene HLH Chronic EBV viraemia Lymphoma Dysgammaglobulinaemia inkt cell count SAP deficiency XL SH2D1A XIAP deficiency XL XIAP + + NL/ ITK deficiency AR ITK CD27 deficiency AR CD NL/ MAGT1 deficiency XL MAGT NL STK4 deficiency AR STK ? Coronin-1A deficiency AR CORO1A CAEBV?? ? EBV, Epstein-Barr virus; HLH, haemophagocytic lymphohistiocytosis; inkt, invariant natural killer T cell; SAP, SLAM (signalling lymphocyte activation molecule) associated protein; XIAP, X-linked inhibitor of apoptosis protein; ITK, interleukin-2 inducible T cell kinase; MAGT1, magnesium transporter 1; STK4, serine/threonine protein kinase 4; CAEBV, chronic active EBV disease; AR, autosomal recessive; XL, X-linked; +, present;, not reported;?, not studied or undefined; NL, normal. reduced when cells are stimulated via the SLAM receptors (Nakajima et al, 2000; Parolini et al, 2000; Tangye et al, 2000; Sharifi et al, 2004; Dupre et al, 2005; Hislop et al, 2010). The SAP-deficient cytotoxic CD8 + T cells are specifically not able to respond to B cell targets, while they could efficiently respond to viral antigens presented on other antigen presenting cells (Hislop et al, 2010; Palendira et al, 2011). This defect in cytotoxicity presumably contributes to HLH pathogenesis and it may contribute to the susceptibility to lymphoma due to compromised ability of NK cells and T cells to clear premalignant or malignant B cell populations (Marsh & Filipovich, 2011). SAP deficiency also leads to defective CD4 + T cell help for B cells, which is probably responsible for the dysgammaglobulinaemia observed in these patients (Cannons et al, 2006, 2010; Ma et al, 2007). Furthermore, T cells from patients with SAP deficiency are resistant to restimulation-induced cell death (RICD; Snow et al, 2010). The absence of SAP impairs T cell receptor (TCR)-induced up-regulation of Fas ligand (FasL, FASLG), B-cell lymphoma 2 interacting mediator of cell death (BIM, BCL2L11), and other pro-apoptotic mediators required for RICD (Nagy et al, 2009; Snow et al, 2009). This probably contributes to the accumulation of activated effector T cells during EBV infection, leading to HLH (Marsh & Filipovich, 2011). Absence of invariant natural killer T cell (inkt) cell populations has been reported in humans and mice with SAP deficiency, although its precise contribution to the manifestations of XLP is not well understood (Nichols et al, 2005; Pasquier et al, 2005). The most commonly recognized phenotypes of SAP deficiency are fulminant IM/HLH, hypogammaglobulinaemia and lymphoproliferative disorders including malignant lymphoma (Booth et al, 2011; Pachlopnik et al, 2011; Kanegane et al, 2012). Evidence of chronic EBV infection is lacking, and patients may develop clinical features also in the absence of EBV infection (Booth et al, 2011). Indeed, 10% of patients have immunological abnormalities before any evidence of EBV exposure (Gilmour et al, 2000; Sumegi et al, 2000). When the full clinical picture of HLH has already been developed, XLP has an extremely poor prognosis (Booth et al, 2011). Thus, we recommend allogeneic HSCT from an appropriate donor soon after confirming the diagnosis. X-linked inhibitor of apoptosis (XIAP) deficiency XIAP encodes for X-linked inhibitor of apoptosis (XIAP), an anti-apoptotic molecule that belongs to the IAP, and is composed of three baculovirus IAP repeat (BIR) domains and a C-terminal really interesting new gene (RING) domain with E3 ubiquitin ligase activity (Latour, 2007). It is ubiquitously expressed and functions as a suppressor of apoptosis through its direct interaction with caspases via its BIR domains (Fig 3; Hinds et al, 1999; Filipovich et al, 2010). XIAP is also involved in the activation of several signalling pathways, including Notch, c-jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor jb (NF-kB), however the functional implications of these activities remain unclear (Vaux & Silke, 2005; Galban & Duckett, 2010). Deficiency of XIAP was first described to present with a XLP phenotype (Rigaud et al, 2006). Since then, XIAP deficiency has also been observed in patients presenting with phenotypes more consistent with HLH (Marsh et al, 2010; Yang et al, 2012). Patients present with HLH, often in association with EBV and hypogammaglobulinaemia. Some patients with XIAP deficiency have a low inkt cell count (Rigaud et al, 2006), but the pathophysiology of HLH in XIAP-deficient patients is obscure at present. Interestingly, and in contrast to SAP deficiency, patients with XIAP deficiency do not develop lymphoma, although they often have chronic splenomegaly and are prone to developing severe colitis (Rigaud et al, 2006; Filipovich et al, 2010; Marsh et al, 2010; Yang et al, 2012). Compared to SAP deficiency, HLH is even more common in the XIAP-deficient patients who may experience repeated bouts of self-limited HLH. However, the development of neurological problems and fatal outcomes are less frequent in XIAP deficiency (Marsh et al, 2010; Pachlopnik et al, 2011; Yang et al, 2012). ª 2013 John Wiley & Sons Ltd 577

6 Interleukin-2-inducible T-cell kinase (ITK) deficiency The interleukin-2-inducible T-cell kinase gene (ITK) encodes a non-receptor tyrosine kinase expressed in T cells, which was originally described as an important component of proximal TCR signalling pathways (Gomez-Rodriguez et al, 2009; Grasis et al, 2010). In T cells, ITK modulates TCR complex signalling and affects the strength of activation signals by its requirement for normal TCR-induction of phospholipase Cc (PLCc) phosphorylation and subsequent calcium mobilization (Readinger et al, 2009). Moreover, ITK provides important signals for the terminal maturation, survival and cytokine production of inkt cells (Felices & Berg, 2008). The eight ITK deficient patients identified so far all presented primarily with massive EBV B-cell lymphoproliferation further progressing to full malignant Hodgkin lymphoma in some cases (Huck et al, 2009; Stepensky et al, 2011; Linka et al, 2012; Mansouri et al, 2012). Pulmonary involvement with large interstitial nodules was observed in the majority of patients. Further, EBV-related symptoms, such as hepatosplenomegaly, cytopenias or autoimmune phenomena, were observed in some of the patients. HSCT appears to be lifesaving. Common immunological features in ITK-deficient patients are a progressive hypogammaglobulinaemia and a progressive loss of CD4 + T cells with a declining proportion of naive cells. inkt cell counts were found to be low when measured. The occurrences of additional viral infections in some of the patients point to general T cell deficiency. In contrast to SAP- and XIAP-deficient patients, ITK-deficient patients showed very high EBV viral load in their peripheral blood (Linka et al, 2012). It is not clear whether ITK-deficient patients are inherently susceptible to develop lymphoma or dysgammaglobulinaemia also in the absence of EBV infection, as has been documented in SAP deficiency. CD27 deficiency In clinical practice, CD27 is recognized as a marker for memory B cells and is used to sub-classify patients with a variety of B cell immunodeficiencies (Wehr et al, 2008). After binding its natural ligand, CD70, CD27 regulates differentiation and cellular activity in subsets of T, B, and natural killer cells (Borst et al, 2005; Nolte et al, 2009). CD27 signalling is important to generate virus-specific memory CTL function and induce NK cell cytotoxicity (Yang et al, 1996; Yamada et al, 2002; van Gisbergen et al, 2011). Two independent reports have recently described a similar presentation of abnormal adaptive human immunity and persistent EBV viraemia attributed to CD27 deficiency (van Montfrans et al, 2012; Salzer et al, 2013). Ten patients from four independent families were confirmed to have homozygous mutations in the CD27 gene. The clinical picture varied from asymptomatic memory B cell deficiency to persistent symptomatic EBV viraemia and malignant lymphoma. Following EBV infection, hypogammaglobulinaemia developed in three of the affected individuals. T cell dependent B- cell responses were abnormal (van Montfrans et al, 2012) while anti-polysaccharide antibodies were detectable (Salzer et al, 2013). Moreover, CD8 + T-cell function was disturbed and inkt cell counts were diminished. Three patients died, two others underwent successful allogeneic HSCTs and two repeatedly received anti-cd20 therapy. CD27 deficiency predisposes to symptomatic and potentially fatal EBV infection and hypogammaglobulinaemia, a phenotype that is similar to XLP. Magnesium transporter 1 (MAGT1) deficiency A rapid transient Mg 2+ influx is induced by antigen receptor stimulation in normal T cells (Li et al, 2011). A recent study revealed an important role for MAGT1 (magnesium transporter 1) in human TCR signalling. Three male patients with chronic EBV infection and other recurrent infections exhibited low CD4 + T cell counts and a defect in T cell activation (Li et al, 2011). EBV-associated lymphoma was documented in one of the patients. Genetic analyses revealed deleterious mutations in the MAGT1, which resulted in the absence of detectable MAGT1 protein. MAGT1 is important for delivering Mg 2+ as a second messenger for PLCc1-dependent T cell receptor signalling. MAGT1 deficiency shares features with XLP but, so far, no cases of HLH have been described. However, the small number of reported cases makes it difficult to confidently predict the whole clinical phenotype. Serine-threonine kinase 4 (STK4) deficiency Serine-threonine kinase 4 (STK4) was originally identified as a ubiquitously expressed kinase with structural homology to yeast Ste20 (Creasy & Chernoff, 1995). It is the mammalian homolog of the Drosophila Hpo protein, controlling cell growth, apoptosis and tumourigenesis (Zhao et al, 2010). STK4 is necessary for activation of forkhead box protein O1 (FOXO1) and FOXO3, key transcription factors for T cell homeostasis and efficient CTL response to chronic viral infection (Kerdiles et al, 2009; Ouyang et al, 2009; Abdollahpour et al, 2012; Sullivan et al, 2012). Characterization of 8 patients from four unrelated families who had homozygous nonsense mutations in STK4, the gene encoding STK4, outlined its role as a critical regulator of T-cell homing and function (Abdollahpour et al, 2012; Crequer et al, 2012; Nehme et al, 2012). Clinically, the patients shared recurrent bacterial and candidal infections, lymphopenia, intermittent neutropenia, autoimmune cytopenias and subtle cardiac anomalies. Recurrent cutaneous viral infections with herpes simplex virus (HSV), varicella zoster virus (VZV), molluscum contagiosum virus (MCV) and human papillomavirus (HPV) were common. Persistent EBV viraemia and EBV-associated B cell lymphoproliferative disease was noted in 50% of reported cases. EBV-related diseases were transiently controlled with 578 ª 2013 John Wiley & Sons Ltd

7 anti-cd20. HSCT was curative in one patient and two patients died after transplant due to severe graft-versus-host disease (Nehme et al, 2012). STK4-deficient patients demonstrated hypergammaglobulinaemia and variable humoral responses. However, B-cell counts (especially memory B cells) were significantly reduced in one series (Abdollahpour et al, 2012). Peripheral T cells displayed markedly impaired survival/proliferation to mitogens and antigens, a response that worsened with time (Nehme et al, 2012). Moreover, the T cell compartment showed a restricted TCR repertoire, and a severe reduction of circulating naive (CD45RA + ) T-cells. Coronin-1A deficiency Coronin-1A is an actin regulator that is critical for the trafficking of na ıve T lymphocytes to secondary lymphoid organs (Foger et al, 2006). Coronin-1A also plays a key role for TCR-signalling and T-cell homeostasis (Mugnier et al, 2008; Mueller et al, 2011). CORO1A mutations have been reported in a patient with combined immunodeficiency characterized by T cell lymphopenia and severe predisposition to bacterial and viral infections (Shiow et al, 2008). However, recently 3 siblings from a consanguineous family presented with aggressive EBV-induced B-cell lymphoproliferation at infancy (Moshous et al, 2013). Immunological assessment revealed reduced numbers of na ıve T cells as well as inkt cells. The phenotype is reminiscent of ITK deficiency presenting defects in PLCc1 and MAPK signalling. Chronic active EBV disease (CAEBV) Chronic active EBV disease (CAEBV) is a life-threatening condition mostly reported from Japan. These patients have markedly elevated levels of EBV DNA in the blood and present with fever, splenomegaly, lymphadenopathy, hepatic dysfunction, and pancytopenia (Kimura et al, 2001). Based on the EBV-induced clonal expansion of different lymphocytes, the origin of CAEBV is classified as B, T, or NK cell (Cohen et al, 2009). Some patients have defective CTL and NK-cell cytotoxic activity against EBV-infected cells (Joncas et al, 1989; Fujieda et al, 1993; Sugaya et al, 2004). However, in the majority of the patients the aetiology of CAEBV remains to be elucidated. EBV-associated HLH is documented in about one-third of the patients and dysgammaglobulinaemia is also a common finding (Kimura et al, 2003; Sugaya et al, 2004; Cohen et al, 2011). Most patients have a poor prognosis. Antiviral therapy is useless; even though patients may show a transitory response to immunosuppressive and cytotoxic chemotherapies, these treatments are not curative; and most patients die. Allogenic HSCT is often therapeutic and should be considered early in the course of the disease (Sato et al, 2008; Cohen et al, 2011; Kawa et al, 2011). PIDs that occasionally present with EBVassociated complications A number of well-described T-cell disorders can occasionally develop HLH or acquire lymphoproliferative disease after EBV infection. Ataxia-telangiectasia (A-T) is one of the chromosomal breakage syndromes characterized by progressive neurological deterioration, susceptibility to infections and high incidence of malignancies. The affected protein, ATM (ataxia telangiectasia mutated), participates in the repair of DNA breakage and controls cell cycle and cellular apoptosis (Savitsky et al, 1995). EBV-positive malignancies and high EBV viral load have been reported in A-T (Saemundsen et al, 1981; Tran et al, 2008; Lankisch et al, 2013). Recent experiments propose a direct role for ATM in the control of herpesviral infection in mice, e.g., ATM knockout mice failed to mount a proper immune response against the murine herpesirus-68 (Kulinski et al, 2012). Interestingly, in vitro transformation of primary human B- cells by EBV is also markedly increased when the ATM/Chk2 DNA damage response pathway is pharmaceutically inhibited (Nikitin et al, 2010). Thus, it is reasonable to speculate that additional, yet unidentified loss-of function mutations in the DNA repair pathway genes may clinically present as EBV lymphoproliferation. Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immunodeficiency, eczema, and thrombocytopenia with small sized platelets (Ochs & Thrasher, 2006). EBV-associated HLH or lymphoproliferative disorders have been reported in WAS patients (Sasahara et al, 2001; Pasic et al, 2003; Sebire et al, 2003; Du et al, 2011). CTL and NK cell dysfunction contributes to the development of haematological malignancies in WAS patients (Gismondi et al, 2004; De Meester et al, 2010). Autoimmune lymphoproliferative syndrome (ALPS) is a PID associated with defective lymphocyte homeostasis caused by mutations in the components of Fas-mediated apoptotic pathway. Chronic non-malignant lymphoproliferation, autoimmune cytopenias and increased numbers of double negative TCR ab T cells in the circulation/lymph nodes are characteristic of this syndrome (Teachey et al, 2010). There is an increased likelihood of B-cell lymphoma development, regardless of EBV exposure (Straus et al, 2001). This increased susceptibility probably stems from a failure of B-cell homeostasis (Snow et al, 2010). However, chronic EBV infection associated with lymphoproliferation has sporadically been reported in ALPS (Nomura et al, 2011). The warts, hypogammaglobulinaemia, immunodeficiency and myelokathexis (WHIM) syndrome is a progressive immunodeficiency that results from mutation of CXC-chemokine receptor 4 (CXCR4), which prevents leucocytes from leaving the bone marrow (Hernandez et al, 2003). Excluding HPV and herpesviruses infection, systemic immunity to other viral ª 2013 John Wiley & Sons Ltd 579

8 pathogens is apparently robust (Balabanian et al, 2005; Tarzi et al, 2005). EBV-associated lymphoproliferative disease has been reported in 2 WHIM patients to date (Chae et al, 2001; Imashuku et al, 2002). The exact nature of EBV susceptibility of WHIM patients remains to be determined. Moreover, development of HLH or lymphoproliferation after EBV infection has been described in patients with other combined immunodeficiencies including, DNA ligase IV deficiency, cc deficiency, and DiGeorge syndrome (Ramos et al, 1999; Grunebaum et al, 2000; Toita et al, 2007; Itoh et al, 2011). Some cases of selective quantitative circulating human NK cell deficiencies with specific susceptibility to viral infections have been reported (Etzioni et al, 2005; Eidenschenk et al, 2006). Homozygous mutation in the MCM4 gene, encoding minichromosome maintenance complex component 4 (MCM4), in patients from the Irish traveller community has been reported as the cause of a developmental syndrome including NK cell deficiency (Gineau et al, 2012; Hughes et al, 2012). From an infectious point of view, the reported patients had susceptibility to infection with herpesviruses and experienced complications from EBV infection. Additionally, homozygous defects in Fcc receptor IIIA (FccRIIIA, CD16) are associated with severe herpesvirus infections with EBV-associated Castleman disease as a salient feature (De Vries et al, 1996; Jawahar et al, 1996; Grier et al, 2012). The affected patients show deficient spontaneous NK cell cytotoxicity as the underlying immune defect (Grier et al, 2012). Discussion Novel PIDs conferring predisposition to a single type of infection in otherwise healthy individuals are increasingly being recognized (Alcais et al, 2009; Parvaneh et al, 2013). The study of such disorders highlights the immune responses targeted against each infectious agent, and thus confers the opportunity to develop specific and effective therapies. Given its worldwide distribution, EBV serves as an indicator virus which challenges various components of the immune system quite considerably. Several lines of evidence show the importance of cellular immunity in EBV surveillance. EBV-associated post-transplant lymphoproliferative disease is successfully treated by adoptive T cell therapy (Bollard et al, 2012). Moreover, the importance of T cells in the control of EBV has become more obvious with the definition of PIDs with inherent defects in CTL function as well as T-cell intracellular signalling. Further investigations are needed to determine the preferential development of HLH in genetic defects of CTL function rather than predisposition to lymphoproliferation and chronic EBV viraemia in several T-cell signalling defects. The role of innate immune responses to control EBV infection is less clear. Reduced NK cell activity against EBVinfected B cells has been reported in patients with XLP (Ma et al, 2007). Additionally, the characterization of PIDs with isolated NK cell deficiency (e.g. MCM4 and CD16 deficiencies) that present the exceptional susceptibility to herpesviruses sheds light on the role played by NK cells to control EBV infection. The underlying immunodeficiency in several EBV prone PIDs is also confounded with inkt deficiency (Table II). inkt cells constitute a distinctive subpopulation of lymphocytes that are involved in innate immunity against viruses. They express invariant TCRs [TRAV24 (TCRVa24) and TRBV11 (TCRVb11)] that recognize glycosphingolipids presented by major histocompatibility complex (MHC) class I- like molecule CD1D (Bienemann et al, 2011). inkt function might take place at the first steps of EBV infection to contain transforming infection of na ıve B cells (Hislop et al, 2007). They also might contribute to the contraction of the pool of activated T cells that normally occurs once the virus particles are eliminated (Latour, 2007). Host defence against EBV is complex. Investigation of patients with EBV-associated haematological complications has increased our understanding of host-ebv interaction. Clinicians should always be on the alert to consider a severe underlying PID when patients suddenly fail to control the EBV or other herpesviruses without obvious iatrogenic reasons, e.g., immunosuppressive medications. Author contributions NP, AHF, and AB proposed the review and wrote the manuscript. 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