Skip to main content

Advertisement

SpringerLink
Log in

B lymphocytes and systemic lupus erythematosus

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoim-mune disease characterized by B cell hyperactivity in associa-tion with autoantibodies, most prominently those directed to components of the cell nucleus. The source of the antigens that drive B cell responses in SLE is unknown, although recent studies suggest mechanisms by which the self-antigens become immunogenic and stimulate responses. Among these mecha-nisms, abnormalities in the generation of apoptotic cells or their clearance may increase the availability of nuclear antigens to drive responses. In addition, autoantibody crossreactivity may promote induction of responses to disparate antigens, foreign and self, and enable a single autoantibody to cause dis-ease by crossreactive binding. In addition to reflecting increased exposure to self-antigen, autoantibody responses in SLE may result from abnormalities in B cell signaling and regu-lation by cytokines. New approaches to therapy aim to abro-gate autoantibody production by targeting specific steps in B cell activation, including blockade of T cell costimulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Cocca BA, Cline AM, Radic MZ: Blebs and apoptotic bodies are B cell autoantigens. J Immunol 2002, 169:159–166.

    PubMed  CAS  Google Scholar 

  2. Mitchell DA, Pickering MC, Warren J, et al.: C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J Immunol 2002, 168:2538–2543.

    PubMed  CAS  Google Scholar 

  3. Cohen PL, Caricchio R, Abraham V, et al.: Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 2002, 196:135–140. This study provides compelling data on the relationship between apo-ptotic cell clearance and development of autoimmunity.

    Article  PubMed  CAS  Google Scholar 

  4. Lu Q, Lemke G: Homeostatic regulation of the immune sys-tem by receptor tyrosine kinases of the Tyro 3 family. Science 2001, 293:306–311.

    Article  PubMed  CAS  Google Scholar 

  5. Boes M, Schmidt T, Linkemann K, et al.: Accelerated develop-ment of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. PNAS 2000, 97:1184–1189.

    Article  PubMed  CAS  Google Scholar 

  6. Ehrenstein MR, Cook HT, Neuberger MS: Deficiency in serum immunoglobulin M predisposes to development of IgG autoantibodies. J Exp Med 2000, 191:1253–1257.

    Article  PubMed  CAS  Google Scholar 

  7. Kim SJ, Gershov D, Ma X, et al.: I-PLA2 activation during apop-tosis promotes the exposure of membrane lysophosphatidyl-choline leading to binding by natural immunoglobulin M antibodies and complement activation. J Exp Med 2002, 196:655–665. This study indicates that IgM, but not IgG, antibodies bind to apoptotic cells and promote complement binding. As such, IgM may promote the uptake of apoptotic cells and modify their properties in inflammation.

    Article  PubMed  CAS  Google Scholar 

  8. Baumann I, Kolowos W, Voll RE, et al.: Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthri-tis Rheum 2002, 46:191–201. Increased numbers of apoptotic cells were identified in lymph nodes from patients with SLE and lymphadenopathy, suggesting that increased production of apoptotic cells or decreased clearance may be an element of the pathogenesis of SLE.

    Article  Google Scholar 

  9. Scaffidi P, Misteli T, Blanchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002, 418:191–195.

    Article  PubMed  CAS  Google Scholar 

  10. Tran HB, Ohlsson M, Beroukas D, et al.: Subcellular redistribu-tion of La/SSB autoantigen during physiologic apoptosis of the fetal mouse heart and conduction system. Arthritis Rheum 2002, 46:202–208.

    Article  PubMed  CAS  Google Scholar 

  11. Tran HB, Macardle PJ, Hiscock J, et al.: Anti-La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupus. Arthritis Rheum 2002, 46:1572–1579. This study demonstrates that La, a protein normally sequestered within cells, becomes available for antibody binding during apopto-sis. This finding shows a mechanism for direct pathogenicity of maternal anti-La antibodies in fetal heart block.

    Article  PubMed  CAS  Google Scholar 

  12. Sharma A, Isenberg DA, Diamond B: Crossreactivity of human anti-dsDNA antibodies to phosphorylcholine: clues to their origin. J Autoimmunity 2001, 16:479–484.

    Article  CAS  Google Scholar 

  13. Putterman C, Diamond B: Immunization with a peptide surro-gate for dsDNA induces autoantibody production and renal immunoglobulin deposition. J Exp Med 1998, 188:29–38.

    Article  PubMed  CAS  Google Scholar 

  14. DeGiorgio LA, Konstantinov KN, Lee SC, et al.: A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001, 7:1189–1193. This study suggests a novel mechanism by which anti-DNA antibodies can mediate central nervous system lupus, with crossreactive binding with the NR2 receptor leading to neuronal death in a mouse model.

    Article  PubMed  CAS  Google Scholar 

  15. Mostoslavsky G, Fischel R, Yachimovich N, et al.: Lupus anti-DNA autoantibodies cross-react with a glomerular structural protein: a case for tissue injury by molecular mimicry. Eur J Immunol 2001, 31:1221–1227.

    Article  PubMed  CAS  Google Scholar 

  16. Ho A, Madger LS, Barr SG, Petri M: Decreases in anti-dsDNA lev-els are associated with concurrent flares in patients with sys-temic lupus erythematosus. Arthritis Rheum 2001, 44:2342–2349.

    Article  PubMed  CAS  Google Scholar 

  17. Arbuckle MR, James JA, Kohlhase KF, et al.: Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus. Scand J Immunol 2001, 54:211–219. Using a unique resource from the military, this study demonstrates that anti-double-strand DNA antibodies are detectable in many patients years before the diagnosis of SLE. This finding suggests that pathogenic events in SLE may occur years before clinical disease onset, pointing to a role for screening in the future when disease mechanisms are better understood.

    Article  PubMed  CAS  Google Scholar 

  18. Robinson WH, DiGennaro C, Hueber W, et al.: Autoantigen microarrays for multiplex characterization of autoantibody responses. Nat Med 2002, 8:295–301. Transfer of microarray technology into the realm of autoantibodies has implications for discovering protein targets of these autoantibod-ies to define disease better and develop targeted therapies.

    Article  PubMed  CAS  Google Scholar 

  19. Pisetsky DS: Antibody responses to DNA in normal immunity and aberrant immunity. Clin Diag Lab Immunol 1998, 5:1–6.

    CAS  Google Scholar 

  20. Pisetsky DS, Wenk KS, Reich CF: The role of CpG sequences in the induction of anti-DNA antibodies. Clin Immunol 2001, 100:157–163.

    Article  PubMed  CAS  Google Scholar 

  21. Vallin H, Perers A, Alm GV, Ronnblom L: Anti-double stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-a inducer in sys-temic lupus erythematosus. J Immunol 1999, 163:6306–6313.

    PubMed  CAS  Google Scholar 

  22. Ledbetter EA, Rifkin IR, Hohlbaum AM, et al.: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002, 416:603–607. A very novel observation to explain how chromatin can drive ANA responses. Because this system involves a rheumatoid factor trans-genic mouse, the relationship to events in SLE is not clear.

    Article  Google Scholar 

  23. Vidaver R: Molecular and clinical evidence of the role of estrogen in lupus. Trends I mmunol 2002, 23:229–230. An excellent review of recent findings of mechanisms by which estrogen can contribute to the development and maintenance of autoimmunity.

    Article  CAS  Google Scholar 

  24. Mor G, Munoz A, Redlinger R, et al.: The role of the fas/fas-ligand system in the estrogen-induced thymic alteration. Am J Reprod Immunol 2001, 46:4298–4307.

    Article  Google Scholar 

  25. Grimaldi CM, Michael DJ, Diamond B: Expansion and activa-tion of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol 2001, 167:1886–1890.

    PubMed  CAS  Google Scholar 

  26. Mackay F, Browning JL: BAFF: a fundamental survival factor for B cells. Nat Rev 2002, 2:465–475. A comprehensive review of the effects of BAFF on B cell survival and acti-vation, with implications for interventions to decrease autoimmunity.

    Article  CAS  Google Scholar 

  27. Khare SD, Hsu H: The role of TALL-1 and APRIL in immune regulation. Trends Immunol 2001, 22:61–63.

    Article  PubMed  CAS  Google Scholar 

  28. Khare SD, Sarosi I, Xia XZ, et al.: Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. PNAS 2000, 97:3370–3375.

    Article  PubMed  CAS  Google Scholar 

  29. Cheema GS, Roschke V, Hilbert DM, Stohl W: Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 2001, 44:1313–1319. This study shows that patients with autoimmune diseases have ele-vated serum BAFF levels, providing a basis for anti-BAFF therapies in treating SLE and other autoimmune diseases.

    Article  PubMed  CAS  Google Scholar 

  30. Zhang J, Roschke V, Baker KP, et al.: A role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 2001, 166:6–10.

    PubMed  CAS  Google Scholar 

  31. Morel L, Blenman KR, Croker BP, Wakeland EK: The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. PNAS 2001, 98:1787–1792.

    Article  PubMed  CAS  Google Scholar 

  32. Sobel ES, Satoh M, Chen Y, et al.: The major murine systemic lupus erythematosus susceptibility locus, Sle1 results in abnormal functions of both B and T cells. J Immunol 2002, 169:2694–2700.

    PubMed  CAS  Google Scholar 

  33. Mohan C, Liu F, Xie C, Williams RC: Anti-subnucleosome reac-tivities in systemic lupus erythematosus patients and their first degree relatives. Clin Exp Immunol 2001, 123:119–126.

    Article  PubMed  CAS  Google Scholar 

  34. Yin Z, Bahtiyar G, Zhang Na, et al.: Il-10 regulates murine lupus. J Immunol 2002, 169:2148–2155.

    PubMed  CAS  Google Scholar 

  35. Llorente L, Richaud-Patin Y, Garcia-Padilla C, et al.: Clinical and biologic effects of anti-interleukin 10 monoclonal anti-body administration in systemic lupus erythematosus. Arthri-tis Rheum 2000, 43:1790–1800.

    Article  CAS  Google Scholar 

  36. Davis JC, Totoritis MC, Rosenberg J, et al.: Phase I clinical trial of a monoclonal antibody against CD40-Ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001, 28:95–101.

    PubMed  CAS  Google Scholar 

  37. Kalunian KC, Davis JC, Merrill JT, et al.: Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154. Arthritis Rheum 2002, 46:3251–3258. This well-designed and controlled study failed to show efficacy of anti-CD40L therapy for SLE. The antibody treatment, however, was well tolerated.

    Article  PubMed  CAS  Google Scholar 

  38. Boumpas DT, Furie RA, Manzi S, et al.: A short course of BG9588 (anti-CD40L antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2001, 44S:S387.

    Google Scholar 

  39. Huang W, Sinha J, Newman J, et al.: The effect of anti-CD40 Ligand antibody on B cells in human systemic lupus erythe-matosus. Arthritis Rheum 2002, 46:1554–1562.

    Article  PubMed  CAS  Google Scholar 

  40. Perrotta S, Locatelli F, LaManna A, et al.: Anti-CD20 mono-clonal antibody for life-threatening autoimmune hemolytic anemia in a patient with systemic lupus erythematosus. B J Hematol 2002, 116:465–467.

    Google Scholar 

  41. Strand V: Monoclonal antibodies and other biologic thera-pies. Lupus 2001, 10:216–221. A comprehensive review of the use of targeted monoclonal antibodies to treat SLE. The article discusses targets such as cytokines and mole-cules mediating costimulation.

    Article  PubMed  CAS  Google Scholar 

  42. Spertini F, Leimgruber A, Morel B, et al.: Idiotypic vaccination with a murine anti-dsDNA antibody: phase I study in patients with nonactive systemic lupus erythematosus with nephritis. J Rheum 1999, 26:2602–2608.

    PubMed  CAS  Google Scholar 

  43. Lindorfer MA, Schuman TA, Craig ML, et al.: A bispecific dsDNA X monoclonal antibody construct for clearance of anti-dsDNA IgG in systemic lupus erythematosus. J Immunol Methods 2001, 248:125–138.

    Article  PubMed  CAS  Google Scholar 

  44. Daikh DI, Wofsy D: Effects of anti-B7 monoclonal antibodies on humoral immune responses. J Autoimmunity 1999, 12:101–108.

    Article  CAS  Google Scholar 

  45. Girschick HJ, Grammer AC, Nanki T, et al.: Expression of recombination activating genes 1 and 2 in peripheral B cells of patients with systemic lupus erythematosus. Arthritis Rheum 2002, 46:1255–1263.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Duke University Medical Center, 151G Durham VA Medical Center, 508 Fulton Street, 27705, Durham, NC, USA

    David S. Pisetsky MD, PhD

Authors
  1. Lisa G. Criscione MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David S. Pisetsky MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Criscione, L.G., Pisetsky, D.S. B lymphocytes and systemic lupus erythematosus. Curr Rheumatol Rep 5, 264–269 (2003). https://doi.org/10.1007/s11926-003-0004-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-003-0004-x

Keywords

Search

Navigation