X-Linked Lymphoproliferative Disease in an Adult


X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis.The causative gene for XLP was identified asSH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described inSap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.

This is a preview of subscription content, log in to check access.


  1. 1.

    Purtilo DT, Cassel CK, Yang JP, Harper R. X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease).Lancet. 1975;1:935–940.

    Article  CAS  Google Scholar 

  2. 2.

    Seemayer TA, Gross TG, Egeler RM, et al. X-linked lymphoproliferative disease: twenty-five years after the discovery.Pediatr Res. 1995;38:471–478.

    Article  CAS  Google Scholar 

  3. 3.

    Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.Nat Genet. 1998;20:129–135.

    Article  CAS  Google Scholar 

  4. 4.

    Nichols KE, Harkin DP, Levitz S, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.Proc Natl Acad Sci USA. 1998;95:13765–13770.

    Article  CAS  Google Scholar 

  5. 5.

    Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.Nature. 1998;395:462–469.

    Article  CAS  Google Scholar 

  6. 6.

    Czar MJ, Kersh EN, Mijares LA, et al. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease geneSH2D1A/DSHP/SAP.Proc Natl Acad Sci USA. 2001;98:7449–7454.

    Article  CAS  Google Scholar 

  7. 7.

    Wu C, Nguyen KB, Pien GC, et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells.Nat Immunol. 2001;2:410–414.

    Article  CAS  Google Scholar 

  8. 8.

    Yasuda N, Lai PK, Rogers J, Purtilo DT. Defective control of Epstein-Barr virus-infected B-cell growth in patients with X-linked lymphoproliferative disease.Clin Exp Immunol. 1991;83:10–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Shinozaki K, Kanegane H, Matsukura H, et al. Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection.Int Immunol. 2002;14:1215–1223.

    Article  CAS  Google Scholar 

  10. 10.

    Sumazaki R, Kanegane H, Osaki M, et al.SH2D1A mutations in Japanese males with severe Epstein-Barr virus-associated illnesses.Blood. 2001;98:1268–1270.

    Article  CAS  Google Scholar 

  11. 11.

    Kanegane H, Ito Y, Ohshima K, et al. X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis.Am J Hematol. 2005;78:130–133.

    Article  Google Scholar 

  12. 12.

    Tangye SG, Lazetic S, Woollatt E, Sutherland GR, Lanier LL, Phillip JH. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.J Immunol. 1999;162:6981–6985.

    PubMed  CAS  Google Scholar 

  13. 13.

    Bottino C, Falco M, Parolini S, et al. NTB-A (correction of GNTB-A), a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease.J Exp Med. 2001;194:235–246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Sayos J, Martin M, Chen A, et al. Cell surface receptor Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP.Blood. 2001;97:3867–3874.

    Article  CAS  Google Scholar 

  15. 15.

    Bouchon A, Cella M, Grierson HL, Cohen JI, Colonna M. Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family.J Immunol. 2001;167:5517–5521.

    Article  CAS  Google Scholar 

  16. 16.

    Nichols KE, Hom J, Gong SY, et al. Regulation of NKT cells development by SAP, the protein defective in XLP.Nat Med. 2005;11:340–345.

    Article  CAS  Google Scholar 

  17. 17.

    Hugle B, Suchowerskyj P, Hellebrand H, et al. Persistent hypogammaglobulinemia following mononucleosis in boys is highly suggestive of X-linked lymphoproliferative disease: report of three cases.J Clin Immunol. 2004;24:515–522.

    Article  CAS  Google Scholar 

  18. 18.

    Cannons JL, Yu LJ, Hill B, et al. SAP regulates TH2 differentiation and PKC-8-mediated activation of NK-κB1.Immunity. 2004;21:693–706.

    Article  CAS  Google Scholar 

  19. 19.

    Malbran A, Belmonte L, Ruibal-Ares B, et al. Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection.Blood. 2004;103:1625–1631.

    Article  CAS  Google Scholar 

  20. 20.

    Gross TG, Filipovich AH, Conley ME, et al. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry.Bone Marrow Transplant. 1996;17:741–744.

    PubMed  CAS  Google Scholar 

  21. 21.

    Milone MC, Tsai DE, Hodinka RL, et al. Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy.Blood. 2005;105:994–996.

    Article  CAS  Google Scholar 

Download references

Author information



Corresponding authors

Correspondence to Takumi Hoshino or Hirokazu Kanegane or Noriko Doki or Hiroyuki Irisawa or Tohru Sakura or Yoshihisa Nojima or Shuichi Miyawaki or Toshio Miyawaki.

About this article

Cite this article

Hoshino, T., Kanegane, H., Doki, N. et al. X-Linked Lymphoproliferative Disease in an Adult. Int J Hematol 82, 55–58 (2005). https://doi.org/10.1532/IJH97.05020

Download citation

Key words

  • X-linked lymphoproliferative disease
  • Epstein-Barr virus
  • SLAM-associated protein
  • Adult
  • Th1/Th2