Defective B cell responses in the absence of SH2D1A

Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4819-23. doi: 10.1073/pnas.0408681102. Epub 2005 Mar 17.


More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A(-/-) mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A(-/-) mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A(-/-) B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A(-/-) mice with CD4(+) T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naive SH2D1A(-/-) B cells became evident upon cotransfer with non-primed wt CD4(+) cells into Rag2(-/-) recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • B-Lymphocytes / immunology*
  • Dysgammaglobulinemia / complications
  • Dysgammaglobulinemia / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Haptens
  • Hemocyanins
  • Histological Techniques
  • Immunoglobulin G / blood
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Lymphocytic choriomeningitis virus
  • Lymphoproliferative Disorders / complications
  • Lymphoproliferative Disorders / immunology*
  • Mice
  • Mice, Inbred Strains
  • Rhadinovirus
  • Signal Transduction / immunology*
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • T-Lymphocytes / immunology*


  • 4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin
  • Haptens
  • Immunoglobulin G
  • Intracellular Signaling Peptides and Proteins
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Hemocyanins