Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity

Abstract

Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.

Keywords

Systemic lupus erythematosus anti-DNA antibodies B cells biomarker

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References

Tan

. Pathophysiology of antinuclear antibodies in systemic lupus erythematosus and related diseases. Adv Dent Res 1996; 10: 44–46.

Munoz

Gaipl

Herrmann

. Predictive value of anti-dsDNA autoantibodies: importance of the assay. Autoimmun Rev 2008; 7: 594–597.

Hochberg

. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725–1725.

Ter Borg

Horst

Hummel

Limburg

Kallenberg

. Measurement of increases in anti-double strand DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. Arthritis Rheum 1990; 33: 634–643.

Ghirardello

Villalta

Morozzi

. Evaluation of current methods for the measurement of serum anti double-stranded DNA antibodies. Ann N Y Acad Sci 2007; 1109: 401–406.

Isenberg

Manson

Ehrenstein

Rahman

. Fifty years of anti-dsDNA antibodies: are we approaching journey's end?. Rheumatology 2007; 46: 1052–1056.

Tew

DiLosa

Burton

. Germinal centers and antibody production in bone marrow. Immunol Rev 1992; 126: 99–112.

Sze

Toellner

García de Vinuesa

Taylor

MacLennan

. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J Exp Med 2000; 192: 813–821.

Hagiwara

Ishigatsubo

Aoki

Shirai

Tani

Okubo

. Preferential proliferation of anti-DNA producing cells of NZB mice in NZB.xid recipients. Autoimmunity 1991; 9: 123–129.

10.

Wang

Huang

Schiffer

. Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum 2003; 48: 495–506.

11.

Odendahl

Mei

Hoyer

. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 2005; 105: 1614–1621.

12.

Arnett

Edworthy

Bloch

. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.

13.

Vitali

Bombardieri

Jonsson

. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61: 554–558.

14.

Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581–590.

15.

Bombardier

Gladman

Urowitz

Caron

Chang

. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35: 630–640.

16.

Liang

Socher

Larson

Schur

. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989; 32: 1107–1118.

17.

Cook

Gladman

Pericak

Urowitz

. Prediction of short-term mortality in systemic lupus erythematosus with time dependent measures of disease activity. J Rheumatol 2000; 27: 1892–1895.

18.

Kuwana

Okazaki

Kaburaki

Kawakami

Ikeda

. Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura. J Immunol 2002; 168: 3675–3682.

19.

Kuwana

Iki

Urabe

. The role of autoantibody-producing plasma cells in immune thrombocytopenic purpura refractory to rituximab. Am J Hematol 2007; 82: 846–848.

20.

Feltkamp

Kirkwood

Maini

Aarden

. The first international standard for antibodies to double stranded DNA. Ann Rheum Dis 1988; 47: 740–746.

21.

Magder

Barr

Petri

. Decreases in anti-double stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus. Arthritis Rheum 2001; 44: 2342–2349.

22.

Ehrenstein

Katz

Griffiths

. Human IgG anti-dsDNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kid Int 1995; 48: 707–711.

23.

Pai

Zwerling

Menzies

. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149: 177–184.

24.

Jacob

Stohl

. Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past, present, and future. Autoimmunity 2101; 43: 84–97.

25.

Odendahl

Jacobi

Hansen

. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000; 165: 5970–5979.

26.

Arce

Jackson

Gill

Bennett

Banchereau

Pascual

. Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol 2001; 167: 2361–2369.

27.

Lee

Shiao

. Serum BLC/CXCL13 concentrations and renal expression of CXCL13/CXCR5 in patients with systemic lupus erythematosus and lupus nephritis. J Rheumatol 2010; 37: 45–52.

28.

Wang

Guilpain

Chong

. Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus. Arthritis Rheum 2010; 62: 3436–3446.

29.

Tan

Fang

Magder

Petri

. Differences between male and female systemic lupus erythematosus in a multi-ethnic population. J Rheumatol 2012; 39: 759–769.

30.

De Carvalho

Do Nascimento

Testagrossa

Barros

Bonfa

. Male gender results in more severe lupus nephritis. Rheumatol Int 2010; 30: 1311–1315.