Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1996 Dec 1; 98(11): 2549–2557.
PMCID: PMC507712

B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events.


To understand the molecular mechanisms that are responsible for the B cell overactivity that is observed in patients with SLE, we have conducted experiments in which the surface immunoglobulin (sIg)-mediated early cell signaling events were studied. The anti-sIgM-mediated free intracytoplasmic calcium ([Ca2+]i) responses were significantly higher in SLE B cells compared with responses of normal individuals and to those of patients with other systemic autoimmune rheumatic diseases. The anti-IgD mAb induced [Ca2+]i responses were also higher in lupus B cells than in controls. The magnitude of anti-sIgM-mediated Ca2+ release from intracellular stores was also increased in B cells from SLE patients compared with normal controls. The amount of inositol phosphate metabolites produced upon crosslinking of sIgM was slightly higher in patients with lupus than in normal controls, although the difference was not statistically significant. In contrast, the degree of anti-sIgM-induced protein tyrosine phosphorylation was obviously increased in lupus patients. Our study demonstrates clearly for the first time that SLE B cells exhibit aberrant early signal transduction events, including augmented calcium responses after crosslinking of the B cell receptor and increased antigen-receptor-mediated phosphorylation of protein tyrosine residues. Because the above abnormalities did not correlate with disease activity or treatment status, we propose that they may have pathogenic significance.

Full Text

The Full Text of this article is available as a PDF (238K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Theofilopoulos AN, Prud'Homme GJ, Dixon FJ. Autoimmune aspects of systemic lupus erythematosus. Concepts Immunopathol. 1985;1:190–218. [PubMed]
  • Ginsburg WW, Finkelman FD, Lipsky PE. Circulating and pokeweed mitogen-induced immunoglobulin-secreting cells in systemic lupus erythematosus. Clin Exp Immunol. 1979 Jan;35(1):76–88. [PMC free article] [PubMed]
  • Koffler D, Agnello V, Thoburn R, Kunkel HG. Systemic lupus erythematosus: prototype of immune complex nephritis in man. J Exp Med. 1971 Sep 1;134(3 Pt 2):169s–179s. [PubMed]
  • Raz E, Brezis M, Rosenmann E, Eilat D. Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney. J Immunol. 1989 May 1;142(9):3076–3082. [PubMed]
  • Morimoto C, Steinberg AD, Letvin NL, Hagan M, Takeuchi T, Daley J, Levine H, Schlossman SF. A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody. J Clin Invest. 1987 Mar;79(3):762–768. [PMC free article] [PubMed]
  • Inghirami G, Simon J, Balow JE, Tsokos GC. Activated T lymphocytes in the peripheral blood of patients with systemic lupus erythematosus induce B cells to produce immunoglobulin. Clin Exp Rheumatol. 1988 Jul-Sep;6(3):269–276. [PubMed]
  • Shivakumar S, Tsokos GC, Datta SK. T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol. 1989 Jul 1;143(1):103–112. [PubMed]
  • Salata M, Golbus J, Richardson BC. Diminished response to an inhibitory signal in lymphocytes from patients with systemic lupus erythematosus. Clin Exp Immunol. 1988 Mar;71(3):439–444. [PMC free article] [PubMed]
  • Flescher E, Fossum D, Ballester A, Maizel A, Sharma S, Talal N. Characterization of B cell growth in systemic lupus erythematosus. Effects of recombinant 12-kDa B cell growth factor, interleukin 4 and transforming growth factor-beta. Eur J Immunol. 1990 Nov;20(11):2425–2430. [PubMed]
  • Golbus J, Salata M, Greenwood J, Hudson J, Richardson BC. Increased immunoglobulin response to gamma-interferon by lymphocytes from patients with systemic lupus erythematosus. Clin Immunol Immunopathol. 1988 Jan;46(1):129–140. [PubMed]
  • Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Morel-Fourrier B, Brouet JC, Alarcon-Segovia D, Galanaud P, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med. 1995 Mar 1;181(3):839–844. [PMC free article] [PubMed]
  • Tsokos GC, Balow JE. Spontaneous and pokeweed mitogen-induced plaque-forming cells in systemic lupus erythematosus. Clin Immunol Immunopathol. 1981 Nov;21(2):172–183. [PubMed]
  • Tsokos GC, Magrath IT, Balow JE. Epstein-Barr virus induces normal B cell responses but defective suppressor T cell responses in patients with systemic lupus erythematosus. J Immunol. 1983 Oct;131(4):1797–1801. [PubMed]
  • Dong X, Hamilton KJ, Satoh M, Wang J, Reeves WH. Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen. J Exp Med. 1994 Apr 1;179(4):1243–1252. [PMC free article] [PubMed]
  • Reininger L, Radaszkiewicz T, Kosco M, Melchers F, Rolink AG. Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells. J Exp Med. 1992 Nov 1;176(5):1343–1353. [PMC free article] [PubMed]
  • Murakami M, Yoshioka H, Shirai T, Tsubata T, Honjo T. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. Int Immunol. 1995 May;7(5):877–882. [PubMed]
  • Wen L, Roberts SJ, Viney JL, Wong FS, Mallick C, Findly RC, Peng Q, Craft JE, Owen MJ, Hayday AC. Immunoglobulin synthesis and generalized autoimmunity in mice congenitally deficient in alpha beta(+) T cells. Nature. 1994 Jun 23;369(6482):654–658. [PubMed]
  • Rosen A, Casciola-Rosen L, Ahearn J. Novel packages of viral and self-antigens are generated during apoptosis. J Exp Med. 1995 Apr 1;181(4):1557–1561. [PMC free article] [PubMed]
  • Cambier JC, Pleiman CM, Clark MR. Signal transduction by the B cell antigen receptor and its coreceptors. Annu Rev Immunol. 1994;12:457–486. [PubMed]
  • Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. [PubMed]
  • Coggeshall KM, McHugh JC, Altman A. Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5660–5664. [PMC free article] [PubMed]
  • Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. [PubMed]
  • Coggeshall KM, Cambier JC. B cell activation. VIII. Membrane immunoglobulins transduce signals via activation of phosphatidylinositol hydrolysis. J Immunol. 1984 Dec;133(6):3382–3386. [PubMed]
  • Bijsterbosch MK, Klaus GG. Crosslinking of surface immunoglobulin and Fc receptors on B lymphocytes inhibits stimulation of inositol phospholipid breakdown via the antigen receptors. J Exp Med. 1985 Dec 1;162(6):1825–1836. [PMC free article] [PubMed]
  • Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. [PubMed]
  • Berridge MJ. Inositol trisphosphate and calcium signalling. Nature. 1993 Jan 28;361(6410):315–325. [PubMed]
  • Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573–584. [PubMed]
  • Fisher CL, Ghysdael J, Cambier JC. Ligation of membrane Ig leads to calcium-mediated phosphorylation of the proto-oncogene product, Ets-1. J Immunol. 1991 Mar 15;146(6):1743–1749. [PubMed]
  • Girard S, Clapham D. Acceleration of intracellular calcium waves in Xenopus oocytes by calcium influx. Science. 1993 Apr 9;260(5105):229–232. [PubMed]
  • Gelfand EW, Cheung RK, Grinstein S, Mills GB. Characterization of the role for calcium influx in mitogen-induced triggering of human T cells. Identification of calcium-dependent and calcium-independent signals. Eur J Immunol. 1986 Aug;16(8):907–912. [PubMed]
  • Lechleiter JD, Clapham DE. Molecular mechanisms of intracellular calcium excitability in X. laevis oocytes. Cell. 1992 Apr 17;69(2):283–294. [PubMed]
  • Gardner P. Calcium and T lymphocyte activation. Cell. 1989 Oct 6;59(1):15–20. [PubMed]
  • Oshimi Y, Miyazaki S. Fas antigen-mediated DNA fragmentation and apoptotic morphologic changes are regulated by elevated cytosolic Ca2+ level. J Immunol. 1995 Jan 15;154(2):599–609. [PubMed]
  • Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. [PubMed]
  • Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992 Jun;35(6):630–640. [PubMed]
  • Rabinovitch M, DeStefano MJ. Macrophage spreading in vitro. I. Inducers of spreading. Exp Cell Res. 1973 Mar 15;77(1):323–334. [PubMed]
  • Rabinovitch PS, June CH, Grossmann A, Ledbetter JA. Heterogeneity among T cells in intracellular free calcium responses after mitogen stimulation with PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence with flow cytometry. J Immunol. 1986 Aug 1;137(3):952–961. [PubMed]
  • Vassilopoulos D, Kovacs B, Tsokos GC. TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus. J Immunol. 1995 Aug 15;155(4):2269–2281. [PubMed]
  • Kammer GM, Khan IU, Malemud CJ. Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymphocytes. J Clin Invest. 1994 Jul;94(1):422–430. [PMC free article] [PubMed]
  • Berridge MJ, Dawson RM, Downes CP, Heslop JP, Irvine RF. Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J. 1983 May 15;212(2):473–482. [PMC free article] [PubMed]
  • Abney ER, Cooper MD, Kearney JF, Lawton AR, Parkhouse RM. Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity. J Immunol. 1978 Jun;120(6):2041–2049. [PubMed]
  • Niklinska BB, Yamada H, O'Shea JJ, June CH, Ashwell JD. Tyrosine kinase-regulated and inositol phosphate-independent Ca2+ elevation and mobilization in T cells. J Biol Chem. 1992 Apr 5;267(10):7154–7159. [PubMed]
  • Takata M, Sabe H, Hata A, Inazu T, Homma Y, Nukada T, Yamamura H, Kurosaki T. Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways. EMBO J. 1994 Mar 15;13(6):1341–1349. [PMC free article] [PubMed]
  • Cooke MP, Abraham KM, Forbush KA, Perlmutter RM. Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn). Cell. 1991 Apr 19;65(2):281–291. [PubMed]
  • Katagiri T, Urakawa K, Yamanashi Y, Semba K, Takahashi T, Toyoshima K, Yamamoto T, Kano K. Overexpression of src family gene for tyrosine-kinase p59fyn in CD4-CD8- T cells of mice with a lymphoproliferative disorder. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10064–10068. [PMC free article] [PubMed]
  • Kim KM, Reth M. Signaling difference between class IgM and IgD antigen receptors. Ann N Y Acad Sci. 1995 Sep 7;766:81–88. [PubMed]
  • Wilson HA, Greenblatt D, Taylor CW, Putney JW, Tsien RY, Finkelman FD, Chused TM. The B lymphocyte calcium response to anti-Ig is diminished by membrane immunoglobulin cross-linkage to the Fc gamma receptor. J Immunol. 1987 Mar 15;138(6):1712–1718. [PubMed]
  • Reth M. Antigen receptors on B lymphocytes. Annu Rev Immunol. 1992;10:97–121. [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]
  • Cambier JC, Campbell KS. Membrane immunoglobulin and its accomplices: new lessons from an old receptor. FASEB J. 1992 Oct;6(13):3207–3217. [PubMed]
  • Reth M. Antigen receptor tail clue. Nature. 1989 Mar 30;338(6214):383–384. [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]
  • Clark MR, Campbell KS, Kazlauskas A, Johnson SA, Hertz M, Potter TA, Pleiman C, Cambier JC. The B cell antigen receptor complex: association of Ig-alpha and Ig-beta with distinct cytoplasmic effectors. Science. 1992 Oct 2;258(5079):123–126. [PubMed]
  • Pleiman CM, D'Ambrosio D, Cambier JC. The B-cell antigen receptor complex: structure and signal transduction. Immunol Today. 1994 Sep;15(9):393–399. [PubMed]
  • Hutchcroft JE, Harrison ML, Geahlen RL. B lymphocyte activation is accompanied by phosphorylation of a 72-kDa protein-tyrosine kinase. J Biol Chem. 1991 Aug 15;266(23):14846–14849. [PubMed]
  • Hutchcroft JE, Harrison ML, Geahlen RL. Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor. J Biol Chem. 1992 Apr 25;267(12):8613–8619. [PubMed]
  • Songyang Z, Shoelson SE, McGlade J, Olivier P, Pawson T, Bustelo XR, Barbacid M, Sabe H, Hanafusa H, Yi T, et al. Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Mol Cell Biol. 1994 Apr;14(4):2777–2785. [PMC free article] [PubMed]
  • Gold MR, Matsuuchi L, Kelly RB, DeFranco AL. Tyrosine phosphorylation of components of the B-cell antigen receptors following receptor crosslinking. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3436–3440. [PMC free article] [PubMed]
  • Burkhardt AL, Brunswick M, Bolen JB, Mond JJ. Anti-immunoglobulin stimulation of B lymphocytes activates src-related protein-tyrosine kinases. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7410–7414. [PMC free article] [PubMed]
  • Graziadei L, Riabowol K, Bar-Sagi D. Co-capping of ras proteins with surface immunoglobulins in B lymphocytes. Nature. 1990 Sep 27;347(6291):396–400. [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]
  • Gold MR, Crowley MT, Martin GA, McCormick F, DeFranco AL. Targets of B lymphocyte antigen receptor signal transduction include the p21ras GTPase-activating protein (GAP) and two GAP-associated proteins. J Immunol. 1993 Jan 15;150(2):377–386. [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]
  • Burkhardt AL, Brunswick M, Bolen JB, Mond JJ. Anti-immunoglobulin stimulation of B lymphocytes activates src-related protein-tyrosine kinases. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7410–7414. [PMC free article] [PubMed]
  • Alés-Martinez JE, Scott DW, Phipps RP, Casnellie JE, Kroemer G, Martinez C, Pezzi L. Cross-linking of surface IgM or IgD causes differential biological effects in spite of overlap in tyrosine (de)phosphorylation profile. Eur J Immunol. 1992 Mar;22(3):845–850. [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]
  • Tisch R, Roifman CM, Hozumi N. Functional differences between immunoglobulins M and D expressed on the surface of an immature B-cell line. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6914–6918. [PMC free article] [PubMed]
  • Carsetti R, Köhler G, Lamers MC. A role for immunoglobulin D: interference with tolerance induction. Eur J Immunol. 1993 Jan;23(1):168–178. [PubMed]
  • Hirose K, Iino M. Heterogeneity of channel density in inositol-1,4,5-trisphosphate-sensitive Ca2+ stores. Nature. 1994 Dec 22;372(6508):791–794. [PubMed]
  • Kasai H, Petersen OH. Spatial dynamics of second messengers: IP3 and cAMP as long-range and associative messengers. Trends Neurosci. 1994 Mar;17(3):95–101. [PubMed]
  • Jayaraman T, Ondrias K, Ondriasová E, Marks AR. Regulation of the inositol 1,4,5-trisphosphate receptor by tyrosine phosphorylation. Science. 1996 Jun 7;272(5267):1492–1494. [PubMed]
  • Papadogiannakis N, Nordström TE, Andersson LC, Wolff CH. cAMP inhibits the OKT3-induced increase in cytoplasmic free calcium in the Jurkat T cell line: the degree of inhibition correlates inversely with the amount of CD3 binding ligand used. Eur J Immunol. 1989 Oct;19(10):1953–1956. [PubMed]
  • Park DJ, Min HK, Rhee SG. Inhibition of CD3-linked phospholipase C by phorbol ester and by cAMP is associated with decreased phosphotyrosine and increased phosphoserine contents of PLC-gamma 1. J Biol Chem. 1992 Jan 25;267(3):1496–1501. [PubMed]
  • Alava MA, DeBell KE, Conti A, Hoffman T, Bonvini E. Increased intracellular cyclic AMP inhibits inositol phospholipid hydrolysis induced by perturbation of the T cell receptor/CD3 complex but not by G-protein stimulation. Association with protein kinase A-mediated phosphorylation of phospholipase C-gamma 1. Biochem J. 1992 May 15;284(Pt 1):189–199. [PMC free article] [PubMed]
  • Oleson DR, DeFelice LJ, Quinn MF, Donahoe RM. Cyclic adenosine 3',5'-monophosphate increases the open probability of potassium channels in activated human T cells. J Immunol. 1996 Aug 1;157(3):1080–1086. [PubMed]
  • Premack BA, Gardner P. Signal transduction by T-cell receptors: mobilization of Ca and regulation of Ca-dependent effector molecules. Am J Physiol. 1992 Dec;263(6 Pt 1):C1119–C1140. [PubMed]
  • Schulman H. The multifunctional Ca2+/calmodulin-dependent protein kinases. Curr Opin Cell Biol. 1993 Apr;5(2):247–253. [PubMed]
  • Trump BF, Berezesky IK. The role of cytosolic Ca2+ in cell injury, necrosis and apoptosis. Curr Opin Cell Biol. 1992 Apr;4(2):227–232. [PubMed]
  • Linker-Israeli M. Cytokine abnormalities in human lupus. Clin Immunol Immunopathol. 1992 Apr;63(1):10–12. [PubMed]
  • Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994 Apr 1;152(7):3685–3692. [PubMed]
  • Russell JH, Rush B, Weaver C, Wang R. Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4409–4413. [PMC free article] [PubMed]
  • Bossu P, Singer GG, Andres P, Ettinger R, Marshak-Rothstein A, Abbas AK. Mature CD4+ T lymphocytes from MRL/lpr mice are resistant to receptor-mediated tolerance and apoptosis. J Immunol. 1993 Dec 15;151(12):7233–7239. [PubMed]

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


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...