A variety of inherited immunodeficiency disorders have been associated with a genetic predisposition to EBV-associated complications. Patients with dysfunctional cytotoxic T-cell function are particularly susceptible to EBV-related lymphoproliferation and subsequent lymphoma due to inability to “prune” EBV+ B cells. The clinical syndromes driven by EBV are heterogeneous and include non-malignant B-cell hyperplasia, CAEBV infection, hemophagocytic lymphohistiocytosis (HLH), and overt lymphomas. X-linked lymphoproliferative disease (XLP) was historically the classic immunodeficiency disorder associated with vulnerability to life-threatening complications of EBV infection, but since the turn of the century a number of novel immunodeficiency disorders have been identified through technological advances in genetic testing and the enhanced capacity to identify clinically relevant gene mutations. XLP is notable in that patients are specifically susceptible to EBV and typically are unaffected by other microorganisms. Other immunodeficiency disorders (e.g., X-MEN disease, ITK, coronin 1 A, CD27, CD16, CD70, and MCM4 deficiencies) are characterized by susceptibility to viral infections in general, and patients frequently experience severe complications from EBV. EBV-related complications can also occur in immunodeficiency disorders in which patients are generally susceptible to both viral and nonviral infections (e.g., activated PI3Kδ syndrome, Chédiak Higashi syndrome, and deficiencies of STK4, ZAP70, CTPS1, and GATA2). Another group of immunodeficiency disorders notable for predisposition to EBV-associated complications is characterized specifically by susceptibility to developing lymphoma (e.g., Wiskott Aldrich syndrome, ataxia telangiectasia, and autoimmune lymphoproliferative syndrome). This section will highlight XLP1 and XLP2 and discuss the ever-expanding range of uncommon and even rare immune deficiency disorders that have been associated with lymphoproliferative complications of EBV infection (Table 1).
Table1. Primary Immunodeficiencies Associated With Lymphoproliferative Complications of Epstein-Barr Virus Infection
X-Linked Lymphoproliferative Diseases
X-Linked Lymphoproliferative Disease 1
Mutations or deletions in SH2D1A (Src homology 2 domain protein 1A) result in X-linked lymphoproliferative disease 1 (XLP1; Duncan disease), an immunodeficiency characterized by potentially fatal IM meeting the diagnostic criteria for HLH, agammaglobulinemia, or B-cell lymphoma. SH2D1A interacts with SLAM (signaling lymphocyte activation molecule), which plays a central role in the stimulation of B and T cells. SH2D1A controls several distinct key T-cell signaling pathways, and mutant SH2D1A does not bind SLAM, suggesting that it is a natural SLAM inhibitor. SAP association with SLAM receptors is crucial for development of normal natural killer (NK)/T cells, formation of normal GCs, and NK- and T-cell killing of EBV infected B cells. T cells from patients with XLP1 are also resistant to apoptosis by radiation-induced cell death. Immune hyperactivation induced by primary EBV infection may be due to specific defects in NK and CD8+ T-cell cytotoxicity rather than from decreased or absent cytotoxic proteins. Resistance to apoptosis may exacerbate the inflammatory response due to persistence of ineffective activated NK and T cells.
Following infection with EBV, patients with XLP1 mount a vigorous, uncontrolled polyclonal expansion of T and B cells. Infiltrating T cells cause extensive tissue destruction of the liver and bone mar row, resulting in death in 50% of XLP1 patients during primary EBV infection. Approximately 30% of patients have acquired hypogammaglobulinemia, and 25% of patients develop malignant B-cell lymphomas that are often extranodal, involving the intestinal ileocecal region. It is important to realize that some patients with SH2D1A mutations may present with only hypogammaglobulinemia, mimicking common variable immunodeficiency, and a diagnosis of XLP1 should be considered when more than one male patient with hypo gammaglobulinemia is encountered in the same family. Patients with fulminant immunologic responses to primary EBV infection may be treated with HLH treatment strategies (glucocorticoids and etoposide) and/or rituximab. However, the only curative therapy for immune dysregulation associated with dysfunctional XLP1 is allogeneic HSCT.
X-Linked Lymphoproliferative Disease 2
A second X-linked immune deficiency characterized by recurrent HLH (with or without EBV infection) is XLP2, caused by BIRC4 mutations and XIAP deficiency.31 Unlike patients with XLP1, those with XLP2 have less pleotropic clinical manifestations. It rarely results in lymphoproliferation or lymphoma and may be more accurately characterized as “X-linked familial HLH.” XIAP is a ubiquitously expressed member of a family of proteins defined by baculovirus IAP repeat (BIR) domains that inhibit apoptosis through inhibition of caspases. The mechanism of XIAP-induced HLH remains uncertain. Paradoxically, unlike in cases of XLP1, in which lymphocytes are resistant to apoptosis, XIAP deficiency in XLP2 confers increased sensitivity to radiation-induced cell death. The clinical manifestations of HLH in XLP2 patients with primary EBV infections appear less severe than in patients with XLP1. However, data remain insufficient to make specific therapy recommendations for XLP1 versus XLP2 or other forms of familial HLH.
Other Inherited Immunodeficiency Disorders Associated with Epstein-Barr Virus Disease
Most individuals recover from the acute phase of primary EBV infection with no long-term sequelae, including some patients with primary immunodeficiency disorders. However, a minority of patients with intrinsic defects in immune function may be vulnerable to severe complications from primary EBV infection (see Table1). Impairment of T/NK-cell cytotoxicity primarily is associated with risk for potentially lethal uncontrolled pathologic inflammation driven by EBV infection, manifest by fever and multisystem organ failure, typically meeting diagnostic criteria for HLH. Others, with immune deficiencies derived from defective T/NK-cell development, proliferation, differentiation, and signaling pathways may develop CAEBV or even EBV-associated LPD or malignancies. In addition to primary immunodeficiencies that result in failure to control EBV infection, there is an increasing list of gene defects associated with complex immune dysfunction that predispose to complications of EBV infection.
Immune regulation of EBV in primary immune deficiency (PID) or regulation syndromes depends on the particular cellular defect. Table 1 categorizes immune deficiency syndromes associated with lymphoproliferative complications of EBV infection based on type of immune defect. For example, similar to XLP1 and XLP2, there are numerous other disorders characterized by impairment of T/NK-cell cytotoxicity are associated with EBV-driven HLH. Primary T-cell deficiencies with defective T-, NK-, and/or B-cell development, such as severe combined immunodeficiency (SCID) lead to absence of T cells which render patients vulnerable to not only EBV, but a broad array of infectious diseases.32 Immune disorders characterized by improper T-cell differentiation, antigen-induced expansion, and signaling also leave patients not only susceptible to EBV, but a broad range of herpesviral diseases. Lastly, impaired T-cell immune regulation and poor B-cell control of EBV are associated with a risk of EBV-driven lymphoma in combined immunodeficiencies such as Wiskott-Aldrich syndrome, ataxia telangiectasia, as well as other DNA repair defects including Nijmegen breakage syndrome. Ultimately, although many of these immune deficiency syndromes are extremely rare, it is critical to evaluate patients with EBV-driven lymphoproliferation for potential underlying genetic alterations; identification of inherited predisposition not only sheds light on the disease etiology but has important implications in future therapeutic strategies. Such patients typically require restoration of immune function to provide curative intervention, be it through novel immunotherapeutic strategies or allogeneic HSCT.
