Evidence for defective transmembrane signaling in B cells from patients with Wiskott-Aldrich syndrome

Hans Uwe Simon, Gordon Mills, Shuichi Hashimoto, Katherine A. Siminovitch

Research output: Contribution to journalArticle

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Abstract

B lymphocytes from patients expressing the X chromosome-linked immune deficiency disorder, Wiskott-Aldrich syndrome (WAS), fail to produce antibodies in response to stimulation with polysaccharides and other type-2 T cell-independent antigens. To investigate whether this abnormality reflects a defect in the signal transduction cascade normally triggered by ligation of surface immunoglobulin (sIg) on B cells, we have examined early signaling events induced by anti-Ig antibody stimulation of EBV B lymphoblastoid cell lines from WAS patients and healthy controls. Despite the expression of comparable levels of sIg and sIgM on WAS and control EBV B cells, WAS cells failed to manifest the increased proliferation in response to anti-Ig treatment observed in the control cell lines. WAS and control EBV B cells also differed in the magnitude of the change in cytosolic free calcium ([Ca2+]i) induced by sIg ligation; WAS cells showed either markedly diminished or no changes in [Ca2+]; levels whereas control EBV B cells consistently showed increases in [Ca2+]i. Anti-Ig-induced changes in inositol phosphate release were also markedly reduced in WAS compared with control cells. As protein tyrosine phosphorylation is thought to represent a proximal event in the activation of B cells, inducing increases in [Ca2+]i by virtue of tyrosine phosphorylation of phospholipase C (PLC)-γ, profiles of protein tyrosine phosphorylation and expression of tyrosine-phosphorylated PLC-γ1 were compared between WAS and normal EBV B cells before and after sIg cross-linking. These studies revealed that in addition to defective mobilization of Ca2+, the WAS cells manifested little or no increase in tyrosine phosphorylation of PLC-γ1 or other intracellular proteins after sIg ligation. Together these results indicate the association of WAS with a defect in the coupling of sIg to signal transduction pathways considered prerequisite for B cell activation, likely at the level of tyrosine phosphorylation. The abnormalities observed in these early transmembrane signaling events in WAS EBV B cells may play a role not only in the nonresponsiveness of WAS patient B cells to certain T independent antigens, but also in the genesis of some of the other cellular deficits exhibited by these patients.

Original languageEnglish (US)
Pages (from-to)1396-1405
Number of pages10
JournalJournal of Clinical Investigation
Volume90
Issue number4
DOIs
StatePublished - Jan 1 1992
Externally publishedYes

Fingerprint

Wiskott-Aldrich Syndrome
B-Lymphocytes
B-Cell Antigen Receptors
Human Herpesvirus 4
Tyrosine
Phosphorylation
Type C Phospholipases
T Independent Antigens
Ligation
Signal Transduction
Cell Line
Proteins
Inositol Phosphates
Immune System Diseases
X Chromosome
Antibody Formation
Polysaccharides

Keywords

  • B cell signal transduction
  • Immunodeficiency
  • Wiskott-Aldrich syndrome

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Evidence for defective transmembrane signaling in B cells from patients with Wiskott-Aldrich syndrome. / Simon, Hans Uwe; Mills, Gordon; Hashimoto, Shuichi; Siminovitch, Katherine A.

In: Journal of Clinical Investigation, Vol. 90, No. 4, 01.01.1992, p. 1396-1405.

Research output: Contribution to journalArticle

Simon, Hans Uwe ; Mills, Gordon ; Hashimoto, Shuichi ; Siminovitch, Katherine A. / Evidence for defective transmembrane signaling in B cells from patients with Wiskott-Aldrich syndrome. In: Journal of Clinical Investigation. 1992 ; Vol. 90, No. 4. pp. 1396-1405.
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