Document Type

Article

Publication Date

Winter 2-16-2005

Abstract

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 naïve 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.

Comments

The copy of record is available from the publisher at http://www.pnas.org/content/102/13/4819.full.pdf?with-ds=yes. Copyright © 2005 by The National Academy of Sciences of the USA. All rights reserved.

doi:10.1073/pnas.0408681102

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