title: Defective B cell responses in the absence of SH2D1A.
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 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.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. mmorra@bidmc.harvard.edu
authors.forename: Massimo
authors.initials: M
authors.lastname: Morra
authors.forename: Robert A
authors.initials: RA
authors.lastname: Barrington
authors.forename: Ana C
authors.initials: AC
authors.lastname: Abadia-Molina
authors.forename: Susumo
authors.initials: S
authors.lastname: Okamoto
authors.forename: Aimee
authors.initials: A
authors.lastname: Julien
authors.forename: Charles
authors.initials: C
authors.lastname: Gullo
authors.forename: Anuj
authors.initials: A
authors.lastname: Kalsy
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Brigitte T
authors.initials: BT
authors.lastname: Huber
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D004406:Dysgammaglobulinemia / Q000150:complications / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006241:Haptens; D006433:Hemocyanins; D006652:Histological Techniques; D007074:Immunoglobulin G / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008217:Lymphocytic choriomeningitis virus; D008232:Lymphoproliferative Disorders / Q000150:complications / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018144:Rhadinovirus; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C098951:4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin; D006241:Haptens; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D006433:Hemocyanins