Blood, 15 September 2001, Vol. 98, No. 6, pp. 1986-1987
CORRESPONDENCE
To the editor:
Manifestations of X-linked
lymphoproliferative disease without prior Epstein-Barr virus
exposure
Dutz et al recently stated that X-linked lymphoproliferative
disease (XLP) is a disease that presents as an Epstein-Barr virus (EBV)-specific immune defect.1 In contrast, we and others
clearly have shown that prior EBV infection is not necessary for the
development of XLP phenotypes dysgammaglobulinemia (mostly low
immunoglobulin G [IgG]; increased IgM) and/or malignant
lymphoma.2-4 It is likely that EBV may only trigger the
most serious complication, fulminant mononucleosis. Moreover, in 2 boys
with XLP, normal EBV-specific HLA-restricted cytotoxicity was clearly
demonstrated.5 Furthermore, the authors stated that
EBV-associated hemophagocytosis (VAHS) is a less common
expression of XLP.1 In contrast, VAHS has been reported in
80% to 90% of XLP patients with fatal mononucleosis.6,7 VAHS is therefore the second most common phenotype in patients with XLP.
The diagnosis of hypogammaglobulinemia of the reported patient was
already made at age 13 months.1 The authors do not discuss why this boy received regular intravenous immunoglobulin (IVIG) for the
first time at age 10 years when severe bronchiectasis had already
developed and chorioiditis resulted in gradual blindness. Monthly IVIG
substitution initiated at an earlier age would probably have prevented
these serious complications.
The authors further report very low copy numbers of EBV genomes in
vascular tissue of the reported patient with XLP.1 It is
arguable whether these findings really play a significant role in the
pathogenesis of XLP-associated lymphocytic vasculitis. EBV has recently
been shown to infect endothelial cells.8 It remains to be
elucidated whether low amounts of latent EBV may also be identified in
vascular tissue of deceased immunocompetent EBV-seropositive individuals.
Volker Schuster, Kerstin Steppberger, and Michael Borte
Correspondence: Volker Schuster, Department of Pediatrics,
Division of Immunology, University of Leipzig, Leipzig,
Germany;
e-mail: schv{at}medizin.uni-leipzig.de
References
1.
Dutz JP, Benoit L, Wang X, et al.
Lymphocytic vasculitis in X-linked lymphoproliferative disease.
Blood.
2001;97:95-100[Abstract/Free Full Text].
2.
Gross TG, Kelly CM, Davis JR, Pirruccello SJ, Sumegi J, Seemayer TA.
Manifestations of X-linked lymphoproliferative disease (XLP) without evidence of Epstein-Barr virus (EBV) infection.
Clin Immunol Immunopathol.
1995;75:281.
3.
Brandau O, Schuster V, Weiss M, et al.
Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).
Hum Mol Genet.
1999;8:2407-2413[Abstract/Free Full Text].
4.
Sumegi J, Huang D, Lanyi A, et al.
Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease.
Blood.
2000;96:3118-3125[Abstract/Free Full Text].
5.
Rousset F, Souillet G, Roncarolo MG, Lamelin JP.
Studies of EBV-lymphoid cell interactions in two patients with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity.
Clin Exp Immunol.
1986;63:280-289[Medline]
[Order article via Infotrieve].
6.
Mroczek EC, Weisenburger DD, Grierson HL, Markin R, Purtilo DT.
Fatal infectious mononucleosis and virus-associated hemophagocytic syndrome.
Arch Pathol Lab Med.
1987;111:530-535[Medline]
[Order article via Infotrieve].
7.
Seemayer TA, Gross TG, Egeler RM, et al.
X-linked lymphoproliferative disease: twenty-five years after the discovery.
Pediatr Res.
1995;38:471-478[Medline]
[Order article via Infotrieve].
8.
Jones K, Rivera C, Sgadari C, et al.
Infection of human endothelial cells with Epstein-Barr virus.
J Exp Med.
1995;182:1213-1221[Abstract/Free Full Text].
Response:
The expanding clinical phenotype of SAP/SH2D1A mutations
The specific aims of our paper were to report a new mutation in
the gene for X-linked lymphoproliferative disease (XLP), to draw
attention to a rare clinical manifestation of XLP (systemic vasculitis,
including chorioretinitis), and to provide evidence that Epstein-Barr
viral (EBV) infection or reactivation within endothelial cells may
precipitate cytotoxic T lymphocyte (CTL)-mediated vasculitis. Schuster
and colleagues raise a number of interesting points with regard
to our paper, none of which detract from the above points.
The majority of patients with XLP present clinically upon exposure to
EBV and the vast majority have had a history of EBV infection.1 The study of defined kindreds and the advent
of molecular diagnostics with the identification of the gene
responsible for the disease have allowed an expansion of the XLP
clinical phenotype and have confirmed that in some cases, prior EBV
infection is not required for all manifestations of the
disease.2 This has been supported, in abstract
form3 and by papers published after the submission of our
manuscript.4 Similarly, while a number of patients present
with a clinical picture compatible with virus-associated hemophagocytic
syndrome (VAHS), until recently, VAHS in a single male patient with no
family history would certainly be considered a less recognized
expression of XLP. Arico et al have now shown that VAHS is linked with
mutations of the XLP gene and that clinical presentations compatible
with VAHS should prompt molecular investigations for XLP.5
Intravenous immunoglobulin (IVIG) can be used to treat significant
hypogammaglobulinemia in some patients with XLP. The patient in
question did not receive IVIG because the attending staff did not
consider the moderate dysgammaglobulinemia significant enough to
warrant IVIG treatment initially. Moreover, when IVIG was considered, compliance with therapy was problematic due to the remoteness of the
patient's home and attendant difficulties in accessing health care.
EBV has been known for some time to infect endothelial cells in
vitro,6 and murine 
-herpesvirus 68 has also been shown to infect endothelium in mice lacking the IFN-
receptor.7 This is the reason we set forth to identify
viral genome in the endothelium of the vasculitic lesions.
Cell-mediated immune (CMI) dysfunction, including defective natural
killer cell function has been documented in patients with XLP, and
defective CMI may result in altered EBV tissue tropism as we suggest.
We agree that many more patients, as well as controls, would need to be
studied to definitively answer this issue. The functionality of
EBV-specific CTL remains a subject for debate.8,9 Normal
EBV-specific CTL function, as has been detected in some patients with
XLP, might indeed explain the targeted assault and damage of the
infected vascular structures that we have demonstrated.
Rusung Tan, Jan Dutz, Loralyn Benoit, Derek de Sa, and Anne Junker
Correspondence: Rusung Tan, Departments of Pathology and
Laboratory Medicine, University of British Columbia and BC's
Children's Hospital, 4480 Oak St, Vancouver, BC, Canada,
V6H 3V4
References
1.
Seemayer TA, Gross TG, Egeler RM, et al.
X-linked lymphoproliferative disease: twenty-five years after the discovery.
Pediatr Res.
1995;38:471-478.
2.
Brandau O, Schuster V, Weiss M, et al.
Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).
Hum Mol Genet.
1999;8:2407-2413.
3.
Gross T, Kelly C, Davis J, Pirruccelllo S, Sumegi J, Seemayer T.
Manifestations of X-linked lymphoproliferative disease (XLP) without evidence of Epstein-Barr virus (EBV) infection [abstract].
Clin Immunol Immunophathol.
1995;75:281.
4.
Sumegi J, Huang D, Lanyi A, et al.
Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease.
Blood.
2000;96:3118-3125.
5.
Arico M, Imashuku S, Clementi R, et al.
Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene.
Blood.
2001;97:1131-1133[Abstract/Free Full Text].
6.
Jones K, Rivera C, Sgadari C, et al.
Infection of human endothelial cells with Epstein-Barr virus.
J Exp Med.
1995;182:1213-1221.
7.
Weck KE, Dal Canto AJ, Gould JD, et al.
Murine gamma-herpesvirus 68 causes severe large-vessel arteritis in mice lacking interferon-gamma responsiveness: a new model for virus-induced vascular disease.
Nat Med.
1997;3:1346-1353[CrossRef][Medline]
[Order article via Infotrieve].
8.
Harada S, Bechtold T, Seeley JK, Purtilo DT.
Cell-mediated immunity to Epstein-Barr virus (EBV) and natural killer (NK)-cell activity in the X-linked lymphoproliferative syndrome.
Int J Cancer.
1982;30:739-744[Medline]
[Order article via Infotrieve].
9.
Rousset F, Souillet G, Roncarolo MG, Lamelin JP.
Studies of EBV-lymphoid cell interactions in two patients with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity.
Clin Exp Immunol.
1986;63:280-289.
