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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.

Original publication

DOI

10.1073/pnas.0408681102

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

29/03/2005

Volume

102

Pages

4819 - 4823

Keywords

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