Immunoglobulin class and subclass deficiencies prior to Epstein‐Barr virus infection in males with X‐linked lymphoproliferative disease

Abstract

Patients with X-linked lymphoproliferative (XLP) disease are characterized by extreme vulnerability to Epstein-Barr virus (EBV). Following infection with EBV, affected males develop fatal infectious mononucleosis (IM), hypogammaglobulinemia (H), or non-Hodgkin's lymphoma (NHL). In addition, hyper IgM, red cell aplasia, necrotizing lymphoid vasculitis (NLV), and aplastic anemia occur rarely. The recent use of DNA restriction fragment length polymorphism (RFLP) probes in linkage with the XLP gene now permit detection of affected males prior to primary EBV infection. We have measured immunoglobulin class and subclass levels in sera from EBV-negative males who were either positive or negative for the XLP genotype by RFLP analysis. Elevated IgA or IgM and/or variable deficiency of IgG, IgG1, and IgG3 occurred in the sera of 13/13 RFLP-positive, EBV-negative males. No consistent abnormalities were noted in 14 RFLP-negative, EBV-negative males. We conclude that the immune defect in XLP is not solely EBV-specific, although EBV is responsible for most of the morbidity and all of the mortality. Further, serial measurement of Ig levels may provide information regarding status of EBV-negative males at risk where RFLP analysis is uninformative or in families where sporadic cases of fatal IM, acquired hypogammaglobulinemia or NHL have occurred, but wherein the genotype of XLP cannot be documented.

Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

“…This defect was observed in patients independently of EBV infection, suggesting the decrease in memory B cells results from altered SAP function. This parallels the reduced basal levels of some serum Ig isotypes observed in XLP patients prior to EBV infection (46) as well as in uninfected SAP -/-mice (15,17). However, there tended to be a further decrease in the frequency of memory B cells following EBV infection, again mirroring the progressive decline in serum Ig levels in EBV + XLP patients (1,40) and infected SAP -/-mice (17).…”

Alterations of the X-linked lymphoproliferative disease geneSH2D1A in common variable immunodeficiency syndrome

“…40 In male patients with XLP, IgG 1 and IgG 3 serum levels are often low with elevated IgA and IgM classes. 17 Therefore, in females with 1 of 2 altered SH2D1A alleles, a modest reduction in SH2D1A protein levels could result in mild laboratory alterations, such as the hyper-IgA reported in family 1. Decreased cellular levels of the SH2D1A protein could lead to immunoglobulin dysregulation through alterations in the T-B lymphocyte network.…”

“…However, immunoglobulin deficiencies and non-Hodgkin B-cell lymphomas have been observed in patients with XLP who were seronegative or polymerase chain reaction (PCR)-negative for EBV. 17,18 Immunoglobulin deficiency and chronic respiratory infections associated with XLP clinically resemble common variable immunodeficiency (CVID). 19,20 CVID is a primary immunodeficiency syndrome characterized by decreased, often fluctuating serum immunoglobulins and clinical features of recurrent bacterial infections.…”

Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency)

“…2,10,11 Less common findings are dysgammaglobulinemia, bone marrow hypoplasia, especially aplastic anemia, and lymphocytic vasculitis. 12,13 However, although HLH is almost always triggered by EBV, the other manifestations can be present even in SAPdeficient patients who have never encountered EBV. 2,3,10,11 The clinical features of the 12 patients with mutations in XIAP (hereafter denoted XIAP-deficient patients) initially described, slightly differed from the features described above.…”