Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1992 October; 90(4): 1396–1405.
PMCID: PMC443185

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


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+]i 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)-gamma, profiles of protein tyrosine phosphorylation and expression of tyrosine-phosphorylated PLC-gamma 1 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-gamma 1 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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • ALDRICH RA, STEINBERG AG, CAMPBELL DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 1954 Feb;13(2):133–139. [PubMed]
  • Spitler LE, Levin AS, Stites DP, Fudenberg HH, Huber H. The Wiskott-Aldrich syndrome. Immunologic studies in nine patients and selected family members. Cell Immunol. 1975 Oct;19(2):201–218. [PubMed]
  • Oppenheim JJ, Blaese RM, Waldmann TA. Defective lymphocyte transformation and delayed hypersensitivity in Wiskott-Aldrich syndrome. J Immunol. 1970 Apr;104(4):835–844. [PubMed]
  • Cooper MD, Chae HP, Lowman JT, Krivit W, Good RA. Wiskott-Aldrich syndrome. An immunologic deficiency disease involving the afferent limb of immunity. Am J Med. 1968 Apr;44(4):499–513. [PubMed]
  • Morio T, Takase K, Okawa H, Oguchi M, Kanbara M, Hiruma F, Yoshino K, Kaneko T, Asamura S, Inoue T, et al. The increase of non-MHC-restricted cytotoxic cells (gamma/delta-TCR-bearing T cells or NK cells) and the abnormal differentiation of B cells in Wiskott-Aldrich syndrome. Clin Immunol Immunopathol. 1989 Aug;52(2):279–290. [PubMed]
  • Prchal JT, Carroll AJ, Prchal JF, Crist WM, Skalka HW, Gealy WJ, Harley J, Malluh A. Wiskott-Aldrich syndrome: cellular impairments and their implication for carrier detection. Blood. 1980 Dec;56(6):1048–1054. [PubMed]
  • Greer WL, Kwong PC, Peacocke M, Ip P, Rubin LA, Siminovitch KA. X-chromosome inactivation in the Wiskott-Aldrich syndrome: a marker for detection of the carrier state and identification of cell lineages expressing the gene defect. Genomics. 1989 Jan;4(1):60–67. [PubMed]
  • Higgins EA, Siminovitch KA, Zhuang DL, Brockhausen I, Dennis JW. Aberrant O-linked oligosaccharide biosynthesis in lymphocytes and platelets from patients with the Wiskott-Aldrich syndrome. J Biol Chem. 1991 Apr 5;266(10):6280–6290. [PubMed]
  • Golding B, Muchmore AV, Blaese RM. Newborn and Wiskott-Aldrich patient B cells can be activated by TNP-Brucella abortus: evidence that TNP-Brucella abortus behaves as a T-independent type 1 antigen in humans. J Immunol. 1984 Dec;133(6):2966–2971. [PubMed]
  • Scher I. The CBA/N mouse strain: an experimental model illustrating the influence of the X-chromosome on immunity. Adv Immunol. 1982;33:1–71. [PubMed]
  • Gold MR, Law DA, DeFranco AL. Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor. Nature. 1990 Jun 28;345(6278):810–813. [PubMed]
  • Campbell MA, Sefton BM. Protein tyrosine phosphorylation is induced in murine B lymphocytes in response to stimulation with anti-immunoglobulin. EMBO J. 1990 Jul;9(7):2125–2131. [PubMed]
  • Padeh S, Levitzki A, Gazit A, Mills GB, Roifman CM. Activation of phospholipase C in human B cells is dependent on tyrosine phosphorylation. J Clin Invest. 1991 Mar;87(3):1114–1118. [PMC free article] [PubMed]
  • Chien MM, Ashman RF. Phospholipid synthesis by activated human B lymphocytes. J Immunol. 1983 Jun;130(6):2568–2573. [PubMed]
  • Grupp SA, Harmony JA. Increased phosphatidylinositol metabolism is an important but not an obligatory early event in B lymphocyte activation. J Immunol. 1985 Jun;134(6):4087–4094. [PubMed]
  • Rigley KP, Harnett MM, Phillips RJ, Klaus GG. Analysis of signaling via surface immunoglobulin receptors on B cells from CBA/N mice. Eur J Immunol. 1989 Nov;19(11):2081–2086. [PubMed]
  • Mills GB, Cheung RK, Grinstein S, Gelfand EW. Interleukin 2-induced lymphocyte proliferation is independent of increases in cytosolic-free calcium concentrations. J Immunol. 1985 Apr;134(4):2431–2435. [PubMed]
  • Margolis B, Zilberstein A, Franks C, Felder S, Kremer S, Ullrich A, Rhee SG, Skorecki K, Schlessinger J. Effect of phospholipase C-gamma overexpression on PDGF-induced second messengers and mitogenesis. Science. 1990 May 4;248(4955):607–610. [PubMed]
  • Mills GB, Stewart DJ, Mellors A, Gelfand EW. Interleukin 2 does not induce phosphatidylinositol hydrolysis in activated T cells. J Immunol. 1986 Apr 15;136(8):3019–3024. [PubMed]
  • Kamps MP, Sefton BM. Identification of multiple novel polypeptide substrates of the v-src, v-yes, v-fps, v-ros, and v-erb-B oncogenic tyrosine protein kinases utilizing antisera against phosphotyrosine. Oncogene. 1988 Apr;2(4):305–315. [PubMed]
  • Ledbetter JA, Tonks NK, Fischer EH, Clark EA. CD45 regulates signal transduction and lymphocyte activation by specific association with receptor molecules on T or B cells. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8628–8632. [PubMed]
  • Sekar MC, Roufogalis BD. Muscarinic-receptor stimulation enhances polyphosphoinositide breakdown in guinea-pig ileum smooth muscle. Biochem J. 1984 Oct 15;223(2):527–531. [PubMed]
  • Holub BJ. The Mn2+-activated incorporation of inositol into molecular species of phosphatidylinositol in rat liver microsomes. Biochim Biophys Acta. 1974 Oct 16;369(1):111–122. [PubMed]
  • Carter RH, Park DJ, Rhee SG, Fearon DT. Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2745–2749. [PubMed]
  • Reth M, Hombach J, Wienands J, Campbell KS, Chien N, Justement LB, Cambier JC. The B-cell antigen receptor complex. Immunol Today. 1991 Jun;12(6):196–201. [PubMed]
  • Alés-Martínez JE, Cuende E, Martínez C, Parkhouse RM, Pezzi L, Scott DW. Signalling in B cells. Immunol Today. 1991 Jun;12(6):201–205. [PubMed]
  • Sakaguchi N, Kashiwamura S, Kimoto M, Thalmann P, Melchers F. B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties. EMBO J. 1988 Nov;7(11):3457–3464. [PubMed]
  • Hombach J, Tsubata T, Leclercq L, Stappert H, Reth M. Molecular components of the B-cell antigen receptor complex of the IgM class. Nature. 1990 Feb 22;343(6260):760–762. [PubMed]
  • van Noesel CJ, van Lier RA, Cordell JL, Tse AG, van Schijndel GM, de Vries EF, Mason DY, Borst J. The membrane IgM-associated heterodimer on human B cells is a newly defined B cell antigen that contains the protein product of the mb-1 gene. J Immunol. 1991 Jun 1;146(11):3881–3888. [PubMed]
  • Campbell KS, Hager EJ, Friedrich RJ, Cambier JC. IgM antigen receptor complex contains phosphoprotein products of B29 and mb-1 genes. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3982–3986. [PubMed]
  • Chen JZ, Stall AM, Herzenberg LA, Herzenberg LA. Differences in glycoprotein complexes associated with IgM and IgD on normal murine B cells potentially enable transduction of different signals. EMBO J. 1990 Jul;9(7):2117–2124. [PubMed]
  • Gold MR, Jakway JP, DeFranco AL. Involvement of a guanine-nucleotide-binding component in membrane IgM-stimulated phosphoinositide breakdown. J Immunol. 1987 Dec 1;139(11):3604–3613. [PubMed]
  • Harnett MM, Klaus GG. G protein coupling of antigen receptor-stimulated polyphosphoinositide hydrolysis in B cells. J Immunol. 1988 May 1;140(9):3135–3139. [PubMed]
  • Harnett MM, Klaus GG. G protein regulation of receptor signalling. Immunol Today. 1988 Oct;9(10):315–320. [PubMed]
  • Justement LB, Wienands J, Hombach J, Reth M, Cambier JC. Membrane IgM and IgD molecules fail to transduce Ca2+ mobilizing signals when expressed on differentiated B lineage cells. J Immunol. 1990 May 1;144(9):3272–3280. [PubMed]
  • Nasmith PE, Mills GB, Grinstein S. Guanine nucleotides induce tyrosine phosphorylation and activation of the respiratory burst in neutrophils. Biochem J. 1989 Feb 1;257(3):893–897. [PubMed]
  • Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K. Association of B cell antigen receptor with protein tyrosine kinase Lyn. Science. 1991 Jan 11;251(4990):192–194. [PubMed]
  • Dymecki SM, Niederhuber JE, Desiderio SV. Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells. Science. 1990 Jan 19;247(4940):332–336. [PubMed]
  • Charbonneau H, Tonks NK, Walsh KA, Fischer EH. The leukocyte common antigen (CD45): a putative receptor-linked protein tyrosine phosphatase. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7182–7186. [PubMed]
  • Tonks NK, Charbonneau H, Diltz CD, Fischer EH, Walsh KA. Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase. Biochemistry. 1988 Nov 29;27(24):8695–8701. [PubMed]
  • Brunswick M, Finkelman FD, Highet PF, Inman JK, Dintzis HM, Mond JJ. Picogram quantities of anti-Ig antibodies coupled to dextran induce B cell proliferation. J Immunol. 1988 May 15;140(10):3364–3372. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation