X-linked lymphoproliferative disease: a progressive immunodeficiency

Annu Rev Immunol. 2001;19:657-82. doi: 10.1146/annurev.immunol.19.1.657.


Our understanding of the X-linked lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Agammaglobulinemia / etiology
  • Amino Acid Sequence
  • Antigen-Presenting Cells / immunology
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Disease Progression
  • Epstein-Barr Virus Infections / complications
  • Genetic Predisposition to Disease
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Lymphoma, B-Cell / etiology
  • Lymphoproliferative Disorders* / genetics
  • Lymphoproliferative Disorders* / immunology
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Multigene Family
  • Phenotype
  • Protein Conformation
  • Respiratory Tract Infections / etiology
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Structure-Activity Relationship
  • T-Lymphocyte Subsets / immunology
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • src Homology Domains


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • SH2D1A protein, human
  • SH2D1B protein, human
  • Sh2d1b1 protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Transcription Factors