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Published in: Arthritis Research & Therapy 1/2018

Open Access 01-12-2018 | Research article

The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic autoimmune rheumatic disease

Authors: Yuriy Baglaenko, Nan-Hua Chang, Sindhu R. Johnson, Waleed Hafiz, Kieran Manion, Dario Ferri, Babak Noamani, Dennisse Bonilla, Sina Rusta-Sellehy, Larissa Lisnevskaia, Earl Silverman, Arthur Bookman, Carolina Landolt-Marticorena, Joan Wither

Published in: Arthritis Research & Therapy | Issue 1/2018

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Abstract

Background

Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD.

Methods

Healthy ANA controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString.

Results

A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered  with patients with early SARD, rather than ANA healthy controls.

Conclusions

ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.
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Literature
1.
go back to reference Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, Caeiro F, Massardo L, Villa AR, Pons-Estel BA. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 2005;52(4):1138–47.CrossRef Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, Caeiro F, Massardo L, Villa AR, Pons-Estel BA. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 2005;52(4):1138–47.CrossRef
2.
go back to reference Kallenberg CG. Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions. Curr Opin Rheumatol. 1995;7(6):568–73.CrossRef Kallenberg CG. Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions. Curr Opin Rheumatol. 1995;7(6):568–73.CrossRef
3.
go back to reference Reveille JD, Wilson RW, Provost TT, Bias WB, Arnett FC. Primary Sjogren’s syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984;101(6):748–56.CrossRef Reveille JD, Wilson RW, Provost TT, Bias WB, Arnett FC. Primary Sjogren’s syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984;101(6):748–56.CrossRef
4.
go back to reference Rodriguez-Reyna TS, Alarcon-Segovia D. Overlap syndromes in the context of shared autoimmunity. Autoimmunity. 2005;38(3):219–23.CrossRef Rodriguez-Reyna TS, Alarcon-Segovia D. Overlap syndromes in the context of shared autoimmunity. Autoimmunity. 2005;38(3):219–23.CrossRef
5.
go back to reference Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526–33.CrossRef Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526–33.CrossRef
6.
go back to reference Eriksson C, Kokkonen H, Johansson M, Hallmans G, Wadell G, Rantapaa-Dahlqvist S. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden. Arthritis Res Ther. 2011;13(1):R30.CrossRef Eriksson C, Kokkonen H, Johansson M, Hallmans G, Wadell G, Rantapaa-Dahlqvist S. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden. Arthritis Res Ther. 2011;13(1):R30.CrossRef
7.
go back to reference Julkunen H, Eronen M. Long-term outcome of mothers of children with isolated heart block in Finland. Arthritis Rheum. 2001;44(3):647–52.CrossRef Julkunen H, Eronen M. Long-term outcome of mothers of children with isolated heart block in Finland. Arthritis Rheum. 2001;44(3):647–52.CrossRef
8.
go back to reference Theander E, Jonsson R, Sjostrom B, Brokstad K, Olsson P, Henriksson G. Prediction of Sjogren's syndrome years before diagnosis and identification of patients with early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol. 2015;67(9):2427–36.CrossRef Theander E, Jonsson R, Sjostrom B, Brokstad K, Olsson P, Henriksson G. Prediction of Sjogren's syndrome years before diagnosis and identification of patients with early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol. 2015;67(9):2427–36.CrossRef
9.
go back to reference Frandsen PB, Kriegbaum NJ, Ullman S, Hoier-Madsen M, Wiik A, Halberg P. Follow-up of 151 patients with high-titer U1RNP antibodies. Clin Rheumatol. 1996;15(3):254–60.CrossRef Frandsen PB, Kriegbaum NJ, Ullman S, Hoier-Madsen M, Wiik A, Halberg P. Follow-up of 151 patients with high-titer U1RNP antibodies. Clin Rheumatol. 1996;15(3):254–60.CrossRef
10.
go back to reference Calvo-Alen J, Alarcon GS, Burgard SL, Burst N, Bartolucci AA, Williams HJ. Systemic lupus erythematosus: predictors of its occurrence among a cohort of patients with early undifferentiated connective tissue disease: multivariate analyses and identification of risk factors. J Rheumatol. 1996;23(3):469–75.PubMed Calvo-Alen J, Alarcon GS, Burgard SL, Burst N, Bartolucci AA, Williams HJ. Systemic lupus erythematosus: predictors of its occurrence among a cohort of patients with early undifferentiated connective tissue disease: multivariate analyses and identification of risk factors. J Rheumatol. 1996;23(3):469–75.PubMed
11.
go back to reference Danieli MG, Fraticelli P, Salvi A, Gabrielli A, Danieli G. Undifferentiated connective tissue disease: natural history and evolution into definite CTD assessed in 84 patients initially diagnosed as early UCTD. Clin Rheumatol. 1998;17(3):195–201.CrossRef Danieli MG, Fraticelli P, Salvi A, Gabrielli A, Danieli G. Undifferentiated connective tissue disease: natural history and evolution into definite CTD assessed in 84 patients initially diagnosed as early UCTD. Clin Rheumatol. 1998;17(3):195–201.CrossRef
12.
go back to reference Danieli MG, Fraticelli P, Franceschini F, Cattaneo R, Farsi A, Passaleva A, Pietrogrande M, Invernizzi F, Vanoli M, Scorza R, et al. Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol. 1999;17(5):585–91.PubMed Danieli MG, Fraticelli P, Franceschini F, Cattaneo R, Farsi A, Passaleva A, Pietrogrande M, Invernizzi F, Vanoli M, Scorza R, et al. Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol. 1999;17(5):585–91.PubMed
13.
go back to reference Cavazzana I, Franceschini F, Belfiore N, Quinzanini M, Caporali R, Calzavara-Pinton P, Bettoni L, Brucato A, Cattaneo R, Montecucco C. Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients. Clin Exp Rheumatol. 2001;19(4):403–9.PubMed Cavazzana I, Franceschini F, Belfiore N, Quinzanini M, Caporali R, Calzavara-Pinton P, Bettoni L, Brucato A, Cattaneo R, Montecucco C. Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients. Clin Exp Rheumatol. 2001;19(4):403–9.PubMed
14.
go back to reference Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, Szucs G, Danko K, Szegedi G. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2003;21(3):313–20.PubMed Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, Szucs G, Danko K, Szegedi G. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2003;21(3):313–20.PubMed
15.
go back to reference Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. 2004;22(3 Suppl 33):S14–8.PubMed Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. 2004;22(3 Suppl 33):S14–8.PubMed
16.
go back to reference Stahl Hallengren C, Nived O, Sturfelt G. Outcome of incomplete systemic lupus erythematosus after 10 years. Lupus. 2004;13(2):85–8.CrossRef Stahl Hallengren C, Nived O, Sturfelt G. Outcome of incomplete systemic lupus erythematosus after 10 years. Lupus. 2004;13(2):85–8.CrossRef
17.
go back to reference Vila LM, Mayor AM, Valentin AH, Garcia-Soberal M, Vila S. Clinical outcome and predictors of disease evolution in patients with incomplete lupus erythematosus. Lupus. 2000;9(2):110–5.CrossRef Vila LM, Mayor AM, Valentin AH, Garcia-Soberal M, Vila S. Clinical outcome and predictors of disease evolution in patients with incomplete lupus erythematosus. Lupus. 2000;9(2):110–5.CrossRef
18.
go back to reference Robertson JM, James JA. Preclinical systemic lupus erythematosus. Rheum Dis Clin N Am. 2014;40(4):621–35.CrossRef Robertson JM, James JA. Preclinical systemic lupus erythematosus. Rheum Dis Clin N Am. 2014;40(4):621–35.CrossRef
19.
go back to reference Munroe ME, Young KA, Kamen DL, Guthridge JM, Niewold TB, Costenbader KH, Weisman MH, Ishimori ML, Wallace DJ, Gilkeson GS, et al. Discerning risk of disease transition in relatives of systemic lupus erythematosus patients utilizing soluble mediators and clinical features. Arthritis Rheumatol. 2017;69(3):630-42. Munroe ME, Young KA, Kamen DL, Guthridge JM, Niewold TB, Costenbader KH, Weisman MH, Ishimori ML, Wallace DJ, Gilkeson GS, et al. Discerning risk of disease transition in relatives of systemic lupus erythematosus patients utilizing soluble mediators and clinical features. Arthritis Rheumatol. 2017;69(3):630-42.
20.
go back to reference Brito-Zeron P, Theander E, Baldini C, Seror R, Retamozo S, Quartuccio L, Bootsma H, Bowman SJ, Dorner T, Gottenberg JE, et al. Early diagnosis of primary Sjogren's syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol. 2016;12(2):137–56.CrossRef Brito-Zeron P, Theander E, Baldini C, Seror R, Retamozo S, Quartuccio L, Bootsma H, Bowman SJ, Dorner T, Gottenberg JE, et al. Early diagnosis of primary Sjogren's syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol. 2016;12(2):137–56.CrossRef
21.
go back to reference Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, Goulet JR, Rich E, Grodzicky T, Raymond Y, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58(12):3902–12.CrossRef Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, Goulet JR, Rich E, Grodzicky T, Raymond Y, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58(12):3902–12.CrossRef
22.
go back to reference Valentini G, Marcoccia A, Cuomo G, Vettori S, Iudici M, Bondanini F, Santoriello C, Ciani A, Cozzolino D, De Matteis GM, et al. Early systemic sclerosis: analysis of the disease course in patients with marker autoantibody and/or capillaroscopic positivity. Arthritis Care Res. 2014;66(10):1520–7.CrossRef Valentini G, Marcoccia A, Cuomo G, Vettori S, Iudici M, Bondanini F, Santoriello C, Ciani A, Cozzolino D, De Matteis GM, et al. Early systemic sclerosis: analysis of the disease course in patients with marker autoantibody and/or capillaroscopic positivity. Arthritis Care Res. 2014;66(10):1520–7.CrossRef
23.
go back to reference Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.CrossRef Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.CrossRef
24.
go back to reference van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747–55.CrossRef van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747–55.CrossRef
25.
go back to reference Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61(6):554–8.CrossRef Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61(6):554–8.CrossRef
26.
go back to reference Armstrong SM, Wither JE, Borowoy AM, Landolt-Marticorena C, Davis AM, Johnson SR. Development, sensibility, and validity of a systemic autoimmune rheumatic disease case ascertainment tool. J Rheumatol. 2017;44(1):18–23.CrossRef Armstrong SM, Wither JE, Borowoy AM, Landolt-Marticorena C, Davis AM, Johnson SR. Development, sensibility, and validity of a systemic autoimmune rheumatic disease case ascertainment tool. J Rheumatol. 2017;44(1):18–23.CrossRef
27.
go back to reference Wither J, Johnson SR, Liu T, Noamani B, Bonilla D, Lisnevskaia L, Silverman E, Bookman A, Landolt-Marticorena C. Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis. Arthritis Res Ther. 2017;19(1):41.CrossRef Wither J, Johnson SR, Liu T, Noamani B, Bonilla D, Lisnevskaia L, Silverman E, Bookman A, Landolt-Marticorena C. Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis. Arthritis Res Ther. 2017;19(1):41.CrossRef
28.
go back to reference Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–27.CrossRef Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–27.CrossRef
29.
go back to reference Arce E, Jackson DG, Gill MA, Bennett LB, Banchereau J, Pascual V. 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(4):2361–9.CrossRef Arce E, Jackson DG, Gill MA, Bennett LB, Banchereau J, Pascual V. 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(4):2361–9.CrossRef
30.
go back to reference Chang NH, McKenzie T, Bonventi G, Landolt-Marticorena C, Fortin PR, Gladman D, Urowitz M, Wither JE. Expanded population of activated antigen-engaged cells within the naive B cell compartment of patients with systemic lupus erythematosus. J Immunol. 2008;180(2):1276–84.CrossRef Chang NH, McKenzie T, Bonventi G, Landolt-Marticorena C, Fortin PR, Gladman D, Urowitz M, Wither JE. Expanded population of activated antigen-engaged cells within the naive B cell compartment of patients with systemic lupus erythematosus. J Immunol. 2008;180(2):1276–84.CrossRef
31.
go back to reference Jacobi AM, Odendahl M, Reiter K, Bruns A, Burmester GR, Radbruch A, Valet G, Lipsky PE, Dorner T. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2003;48(5):1332–42.CrossRef Jacobi AM, Odendahl M, Reiter K, Bruns A, Burmester GR, Radbruch A, Valet G, Lipsky PE, Dorner T. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2003;48(5):1332–42.CrossRef
32.
go back to reference Jacobi AM, Reiter K, Mackay M, Aranow C, Hiepe F, Radbruch A, Hansen A, Burmester GR, Diamond B, Lipsky PE, et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthritis Rheum. 2008;58(6):1762–73.CrossRef Jacobi AM, Reiter K, Mackay M, Aranow C, Hiepe F, Radbruch A, Hansen A, Burmester GR, Diamond B, Lipsky PE, et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthritis Rheum. 2008;58(6):1762–73.CrossRef
33.
go back to reference Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dorner T. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol. 2000;165(10):5970–9.CrossRef Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dorner T. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol. 2000;165(10):5970–9.CrossRef
34.
go back to reference Szabo K, Papp G, Szanto A, Tarr T, Zeher M. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjogren’s syndrome and systemic lupus erythematosus. Clin Exp Immunol. 2016;183(1):76–89.CrossRef Szabo K, Papp G, Szanto A, Tarr T, Zeher M. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjogren’s syndrome and systemic lupus erythematosus. Clin Exp Immunol. 2016;183(1):76–89.CrossRef
35.
go back to reference Roberts ME, Kaminski D, Jenks SA, Maguire C, Ching K, Burbelo PD, Iadarola MJ, Rosenberg A, Coca A, Anolik J, et al. Primary Sjogren’s syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells. Arthritis Rheumatol. 2014;66(9):2558–69.CrossRef Roberts ME, Kaminski D, Jenks SA, Maguire C, Ching K, Burbelo PD, Iadarola MJ, Rosenberg A, Coca A, Anolik J, et al. Primary Sjogren’s syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells. Arthritis Rheumatol. 2014;66(9):2558–69.CrossRef
36.
go back to reference Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM. Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjogren's syndrome. J Immunol. 2001;167(7):3610–8.CrossRef Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM. Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjogren's syndrome. J Immunol. 2001;167(7):3610–8.CrossRef
37.
go back to reference Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, Burmester GR, Lipsky PE, Dorner T. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren's syndrome. Arthritis Rheum. 2002;46(8):2160–71.CrossRef Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, Burmester GR, Lipsky PE, Dorner T. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren's syndrome. Arthritis Rheum. 2002;46(8):2160–71.CrossRef
38.
go back to reference Wei C, Jenks S, Sanz I. Polychromatic flow cytometry in evaluating rheumatic disease patients. Arthritis Res Ther. 2015;17:46.CrossRef Wei C, Jenks S, Sanz I. Polychromatic flow cytometry in evaluating rheumatic disease patients. Arthritis Res Ther. 2015;17:46.CrossRef
39.
go back to reference Streicher K, Morehouse CA, Groves CJ, Rajan B, Pilataxi F, Lehmann KP, Brohawn PZ, Higgs BW, McKeever K, Greenberg SA, et al. The plasma cell signature in autoimmune disease. Arthritis Rheumatol. 2014;66(1):173–84.CrossRef Streicher K, Morehouse CA, Groves CJ, Rajan B, Pilataxi F, Lehmann KP, Brohawn PZ, Higgs BW, McKeever K, Greenberg SA, et al. The plasma cell signature in autoimmune disease. Arthritis Rheumatol. 2014;66(1):173–84.CrossRef
40.
go back to reference Cho YN, Kee SJ, Lee SJ, Seo SR, Kim TJ, Lee SS, Kim MS, Lee WW, Yoo DH, Kim N, et al. Numerical and functional deficiencies of natural killer T cells in systemic lupus erythematosus: their deficiency related to disease activity. Rheumatology (Oxford). 2011;50(6):1054–63.CrossRef Cho YN, Kee SJ, Lee SJ, Seo SR, Kim TJ, Lee SS, Kim MS, Lee WW, Yoo DH, Kim N, et al. Numerical and functional deficiencies of natural killer T cells in systemic lupus erythematosus: their deficiency related to disease activity. Rheumatology (Oxford). 2011;50(6):1054–63.CrossRef
41.
go back to reference Papp G, Horvath IF, Barath S, Gyimesi E, Sipka S, Szodoray P, Zeher M. Altered T-cell and regulatory cell repertoire in patients with diffuse cutaneous systemic sclerosis. Scand J Rheumatol. 2011;40(3):205–10.CrossRef Papp G, Horvath IF, Barath S, Gyimesi E, Sipka S, Szodoray P, Zeher M. Altered T-cell and regulatory cell repertoire in patients with diffuse cutaneous systemic sclerosis. Scand J Rheumatol. 2011;40(3):205–10.CrossRef
42.
go back to reference Riccieri V, Parisi G, Spadaro A, Scrivo R, Barone F, Moretti T, Bernardini G, Strom R, Taccari E, Valesini G. Reduced circulating natural killer T cells and gamma/delta T cells in patients with systemic sclerosis. J Rheumatol. 2005;32(2):283–6.PubMed Riccieri V, Parisi G, Spadaro A, Scrivo R, Barone F, Moretti T, Bernardini G, Strom R, Taccari E, Valesini G. Reduced circulating natural killer T cells and gamma/delta T cells in patients with systemic sclerosis. J Rheumatol. 2005;32(2):283–6.PubMed
43.
go back to reference van der Vliet HJ, von Blomberg BM, Nishi N, Reijm M, Voskuyl AE, van Bodegraven AA, Polman CH, Rustemeyer T, Lips P, van den Eertwegh AJ, et al. Circulating V(alpha24+) Vbeta11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol. 2001;100(2):144–8.CrossRef van der Vliet HJ, von Blomberg BM, Nishi N, Reijm M, Voskuyl AE, van Bodegraven AA, Polman CH, Rustemeyer T, Lips P, van den Eertwegh AJ, et al. Circulating V(alpha24+) Vbeta11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol. 2001;100(2):144–8.CrossRef
44.
go back to reference Wither J, Cai YC, Lim S, McKenzie T, Roslin N, Claudio JO, Cooper GS, Hudson TJ, Paterson AD, Greenwood CM, et al. Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity. Arthritis Res Ther. 2008;10(5):R108.CrossRef Wither J, Cai YC, Lim S, McKenzie T, Roslin N, Claudio JO, Cooper GS, Hudson TJ, Paterson AD, Greenwood CM, et al. Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity. Arthritis Res Ther. 2008;10(5):R108.CrossRef
45.
go back to reference Alexander T, Sattler A, Templin L, Kohler S, Gross C, Meisel A, Sawitzki B, Burmester GR, Arnold R, Radbruch A, et al. Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis. 2013;72(9):1549–58.CrossRef Alexander T, Sattler A, Templin L, Kohler S, Gross C, Meisel A, Sawitzki B, Burmester GR, Arnold R, Radbruch A, et al. Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis. 2013;72(9):1549–58.CrossRef
46.
go back to reference Golding A, Hasni S, Illei G, Shevach EM. The percentage of FoxP3+Helios+ Treg cells correlates positively with disease activity in systemic lupus erythematosus. Arthritis Rheum. 2013;65(11):2898–906.CrossRef Golding A, Hasni S, Illei G, Shevach EM. The percentage of FoxP3+Helios+ Treg cells correlates positively with disease activity in systemic lupus erythematosus. Arthritis Rheum. 2013;65(11):2898–906.CrossRef
47.
go back to reference Fonseca VR, Romao VC, Agua-Doce A, Santos M, Lopez-Presa D, Ferreira AC, Fonseca JE, Graca L. The ratio of blood T follicular regulatory cells to T follicular helper cells marks ectopic lymphoid structure formation While activated follicular helper t cells indicate disease activity in primary Sjogren’s syndrome. Arthritis Rheumatol. 2018;70(5):774–84.CrossRef Fonseca VR, Romao VC, Agua-Doce A, Santos M, Lopez-Presa D, Ferreira AC, Fonseca JE, Graca L. The ratio of blood T follicular regulatory cells to T follicular helper cells marks ectopic lymphoid structure formation While activated follicular helper t cells indicate disease activity in primary Sjogren’s syndrome. Arthritis Rheumatol. 2018;70(5):774–84.CrossRef
48.
go back to reference Verstappen GM, Nakshbandi U, Mossel E, Haacke EA, van der Vegt B, Vissink A, Bootsma H, Kroese FGM. Is the T follicular regulatory / T follicular helper cell ratio in blood a biomarker for ectopic lymphoid structure formation in Sjogren's syndrome? Arthritis Rheumatol. 2018;70(8):1354-5..CrossRef Verstappen GM, Nakshbandi U, Mossel E, Haacke EA, van der Vegt B, Vissink A, Bootsma H, Kroese FGM. Is the T follicular regulatory / T follicular helper cell ratio in blood a biomarker for ectopic lymphoid structure formation in Sjogren's syndrome? Arthritis Rheumatol. 2018;70(8):1354-5..CrossRef
49.
go back to reference Schmitt N, Bentebibel SE, Ueno H. Phenotype and functions of memory Tfh cells in human blood. Trends Immunol. 2014;35(9):436–42.CrossRef Schmitt N, Bentebibel SE, Ueno H. Phenotype and functions of memory Tfh cells in human blood. Trends Immunol. 2014;35(9):436–42.CrossRef
50.
go back to reference Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, Manku H, Vyse TJ, Roncador G, Huttley GA, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010;62(1):234–44.CrossRef Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, Manku H, Vyse TJ, Roncador G, Huttley GA, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010;62(1):234–44.CrossRef
51.
go back to reference Szabo K, Papp G, Barath S, Gyimesi E, Szanto A, Zeher M. Follicular helper T cells may play an important role in the severity of primary Sjogren's syndrome. Clin Immunol. 2013;147(2):95–104.CrossRef Szabo K, Papp G, Barath S, Gyimesi E, Szanto A, Zeher M. Follicular helper T cells may play an important role in the severity of primary Sjogren's syndrome. Clin Immunol. 2013;147(2):95–104.CrossRef
52.
go back to reference Osnes LT, Nakken B, Bodolay E, Szodoray P. Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies - novel tool for diagnostics and patient follow-up. Autoimmun Rev. 2013;12(10):967–71.CrossRef Osnes LT, Nakken B, Bodolay E, Szodoray P. Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies - novel tool for diagnostics and patient follow-up. Autoimmun Rev. 2013;12(10):967–71.CrossRef
53.
go back to reference Szodoray P, Gal I, Barath S, Aleksza M, Horvath IF, Gergely PJ, Szegedi G, Nakken B, Zeher M. Immunological alterations in newly diagnosed primary Sjogren's syndrome characterized by skewed peripheral T-cell subsets and inflammatory cytokines. Scand J Rheumatol. 2008;37(3):205–12.CrossRef Szodoray P, Gal I, Barath S, Aleksza M, Horvath IF, Gergely PJ, Szegedi G, Nakken B, Zeher M. Immunological alterations in newly diagnosed primary Sjogren's syndrome characterized by skewed peripheral T-cell subsets and inflammatory cytokines. Scand J Rheumatol. 2008;37(3):205–12.CrossRef
54.
go back to reference Szodoray P, Nakken B, Barath S, Gaal J, Aleksza M, Zeher M, Sipka S, Szilagyi A, Zold E, Szegedi G, et al. Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease. Int Immunol. 2008;20(8):971–9.CrossRef Szodoray P, Nakken B, Barath S, Gaal J, Aleksza M, Zeher M, Sipka S, Szilagyi A, Zold E, Szegedi G, et al. Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease. Int Immunol. 2008;20(8):971–9.CrossRef
55.
go back to reference Dolff S, Abdulahad WH, Westra J, Doornbos-van der Meer B, Limburg PC, Kallenberg CG, Bijl M. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther. 2011;13(5):R157.CrossRef Dolff S, Abdulahad WH, Westra J, Doornbos-van der Meer B, Limburg PC, Kallenberg CG, Bijl M. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther. 2011;13(5):R157.CrossRef
56.
go back to reference Dolff S, Bijl M, Huitema MG, Limburg PC, Kallenberg CG, Abdulahad WH. Disturbed Th1, Th2, Th17 and T(reg) balance in patients with systemic lupus erythematosus. Clin Immunol. 2011;141(2):197–204.CrossRef Dolff S, Bijl M, Huitema MG, Limburg PC, Kallenberg CG, Abdulahad WH. Disturbed Th1, Th2, Th17 and T(reg) balance in patients with systemic lupus erythematosus. Clin Immunol. 2011;141(2):197–204.CrossRef
57.
go back to reference Fujii H, Hasegawa M, Takehara K, Mukaida N, Sato S. Abnormal expression of intracellular cytokines and chemokine receptors in peripheral blood T lymphocytes from patients with systemic sclerosis. Clin Exp Immunol. 2002;130(3):548–56.CrossRef Fujii H, Hasegawa M, Takehara K, Mukaida N, Sato S. Abnormal expression of intracellular cytokines and chemokine receptors in peripheral blood T lymphocytes from patients with systemic sclerosis. Clin Exp Immunol. 2002;130(3):548–56.CrossRef
58.
go back to reference Kohriyama K, Katayama Y. Disproportion of helper T cell subsets in peripheral blood of patients with primary Sjogren’s syndrome. Autoimmunity. 2000;32(1):67–72.CrossRef Kohriyama K, Katayama Y. Disproportion of helper T cell subsets in peripheral blood of patients with primary Sjogren’s syndrome. Autoimmunity. 2000;32(1):67–72.CrossRef
59.
go back to reference Sudzius G, Mieliauskaite D, Butrimiene I, Siaurys A, Mackiewicz Z, Dumalakiene I. Activity of T-helper cells in patients with primary Sjogren's syndrome. In Vivo. 2013;27(2):263–8.PubMed Sudzius G, Mieliauskaite D, Butrimiene I, Siaurys A, Mackiewicz Z, Dumalakiene I. Activity of T-helper cells in patients with primary Sjogren's syndrome. In Vivo. 2013;27(2):263–8.PubMed
60.
go back to reference Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C. Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther. 2011;13(5):R166.CrossRef Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C. Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther. 2011;13(5):R166.CrossRef
61.
go back to reference van Woerkom JM, Kruize AA, Wenting-van Wijk MJ, Knol E, Bihari IC, Jacobs JW, Bijlsma JW, Lafeber FP, van Roon JA. Salivary gland and peripheral blood T helper 1 and 2 cell activity in Sjogren's syndrome compared with non-Sjogren's sicca syndrome. Ann Rheum Dis. 2005;64(10):1474–9.CrossRef van Woerkom JM, Kruize AA, Wenting-van Wijk MJ, Knol E, Bihari IC, Jacobs JW, Bijlsma JW, Lafeber FP, van Roon JA. Salivary gland and peripheral blood T helper 1 and 2 cell activity in Sjogren's syndrome compared with non-Sjogren's sicca syndrome. Ann Rheum Dis. 2005;64(10):1474–9.CrossRef
62.
go back to reference Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, Thomas K, Walker D, Kamp S, Frost JM, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis. 2012;71(3):463–8.CrossRef Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, Thomas K, Walker D, Kamp S, Frost JM, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis. 2012;71(3):463–8.CrossRef
63.
go back to reference Mackay F, Silveira PA, Brink R. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol. 2007;19(3):327–36.CrossRef Mackay F, Silveira PA, Brink R. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol. 2007;19(3):327–36.CrossRef
64.
go back to reference Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307–36.CrossRef Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307–36.CrossRef
65.
go back to reference Cucak H, Yrlid U, Reizis B, Kalinke U, Johansson-Lindbom B. Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. Immunity. 2009;31(3):491–501.CrossRef Cucak H, Yrlid U, Reizis B, Kalinke U, Johansson-Lindbom B. Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. Immunity. 2009;31(3):491–501.CrossRef
66.
go back to reference Ittah M, Miceli-Richard C, Eric Gottenberg J, Lavie F, Lazure T, Ba N, Sellam J, Lepajolec C, Mariette X. B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjogren's syndrome. Arthritis Res Ther. 2006;8(2):R51.CrossRef Ittah M, Miceli-Richard C, Eric Gottenberg J, Lavie F, Lazure T, Ba N, Sellam J, Lepajolec C, Mariette X. B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjogren's syndrome. Arthritis Res Ther. 2006;8(2):R51.CrossRef
67.
go back to reference Le Bon A, Thompson C, Kamphuis E, Durand V, Rossmann C, Kalinke U, Tough DF. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J Immunol. 2006;176(4):2074–8.CrossRef Le Bon A, Thompson C, Kamphuis E, Durand V, Rossmann C, Kalinke U, Tough DF. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J Immunol. 2006;176(4):2074–8.CrossRef
68.
go back to reference Su C, Duan X, Zheng J, Liang L, Wang F, Guo L. IFN-alpha as an adjuvant for adenovirus-vectored FMDV subunit vaccine through improving the generation of T follicular helper cells. PLoS One. 2013;8(6):e66134.CrossRef Su C, Duan X, Zheng J, Liang L, Wang F, Guo L. IFN-alpha as an adjuvant for adenovirus-vectored FMDV subunit vaccine through improving the generation of T follicular helper cells. PLoS One. 2013;8(6):e66134.CrossRef
69.
go back to reference Chang NH, Li TT, Kim JJ, Landolt-Marticorena C, Fortin PR, Gladman DD, Urowitz MB, Wither JE. Interferon-alpha induces altered transitional B cell signaling and function in systemic lupus erythematosus. J Autoimmun. 2015;58:100–10.CrossRef Chang NH, Li TT, Kim JJ, Landolt-Marticorena C, Fortin PR, Gladman DD, Urowitz MB, Wither JE. Interferon-alpha induces altered transitional B cell signaling and function in systemic lupus erythematosus. J Autoimmun. 2015;58:100–10.CrossRef
70.
go back to reference Slight-Webb S, Lu R, Ritterhouse LL, Munroe ME, Maecker HT, Fathman CG, Utz PJ, Merrill JT, Guthridge JM, James JA. Autoantibody-positive healthy individuals display unique immune profiles that may regulate autoimmunity. Arthritis Rheumatol. 2016;68(10):2492–502.CrossRef Slight-Webb S, Lu R, Ritterhouse LL, Munroe ME, Maecker HT, Fathman CG, Utz PJ, Merrill JT, Guthridge JM, James JA. Autoantibody-positive healthy individuals display unique immune profiles that may regulate autoimmunity. Arthritis Rheumatol. 2016;68(10):2492–502.CrossRef
71.
go back to reference Szodoray P, Nakken B, Barath S, Csipo I, Nagy G, El-Hage F, Osnes LT, Szegedi G, Bodolay E. Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders. Hum Immunol. 2013;74(12):1510–8.CrossRef Szodoray P, Nakken B, Barath S, Csipo I, Nagy G, El-Hage F, Osnes LT, Szegedi G, Bodolay E. Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders. Hum Immunol. 2013;74(12):1510–8.CrossRef
72.
go back to reference Doherty DG, Melo AM, Moreno-Olivera A, Solomos AC. Activation and regulation of B cell responses by invariant natural killer T cells. Front Immunol. 2018;9:1360.CrossRef Doherty DG, Melo AM, Moreno-Olivera A, Solomos AC. Activation and regulation of B cell responses by invariant natural killer T cells. Front Immunol. 2018;9:1360.CrossRef
73.
go back to reference Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M, Nyman J, Marjanovic ND, Kowalczyk MS, Wang C, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature. 2018;558(7710):454–9.CrossRef Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M, Nyman J, Marjanovic ND, Kowalczyk MS, Wang C, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature. 2018;558(7710):454–9.CrossRef
74.
go back to reference Munroe ME, Lu R, Zhao YD, Fife DA, Robertson JM, Guthridge JM, Niewold TB, Tsokos GC, Keith MP, Harley JB, et al. Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis. 2016;75(11):2014–21.CrossRef Munroe ME, Lu R, Zhao YD, Fife DA, Robertson JM, Guthridge JM, Niewold TB, Tsokos GC, Keith MP, Harley JB, et al. Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis. 2016;75(11):2014–21.CrossRef
75.
go back to reference Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, Flano E, Mejias A, Albrecht RA, Blankenship D, et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med. 2013;5(176):176ra132.CrossRef Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, Flano E, Mejias A, Albrecht RA, Blankenship D, et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med. 2013;5(176):176ra132.CrossRef
76.
go back to reference Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, Su LF, Cubas R, Davis MM, Sette A, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758–69.CrossRef Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, Su LF, Cubas R, Davis MM, Sette A, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758–69.CrossRef
77.
go back to reference Degn SE, van der Poel CE, Firl DJ, Ayoglu B, Al Qureshah FA, Bajic G, Mesin L, Reynaud CA, Weill JC, Utz PJ, et al. Clonal evolution of autoreactive germinal centers. Cell. 2017;170(5):913–26 e919.CrossRef Degn SE, van der Poel CE, Firl DJ, Ayoglu B, Al Qureshah FA, Bajic G, Mesin L, Reynaud CA, Weill JC, Utz PJ, et al. Clonal evolution of autoreactive germinal centers. Cell. 2017;170(5):913–26 e919.CrossRef
78.
go back to reference Schroeder K, Herrmann M, Winkler TH. The role of somatic hypermutation in the generation of pathogenic antibodies in SLE. Autoimmunity. 2013;46(2):121–7.CrossRef Schroeder K, Herrmann M, Winkler TH. The role of somatic hypermutation in the generation of pathogenic antibodies in SLE. Autoimmunity. 2013;46(2):121–7.CrossRef
79.
go back to reference Lu R, Munroe ME, Guthridge JM, Bean KM, Fife DA, Chen H, Slight-Webb SR, Keith MP, Harley JB, James JA. Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun. 2016;74:182–93.CrossRef Lu R, Munroe ME, Guthridge JM, Bean KM, Fife DA, Chen H, Slight-Webb SR, Keith MP, Harley JB, James JA. Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun. 2016;74:182–93.CrossRef
Metadata
Title
The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic autoimmune rheumatic disease
Authors
Yuriy Baglaenko
Nan-Hua Chang
Sindhu R. Johnson
Waleed Hafiz
Kieran Manion
Dario Ferri
Babak Noamani
Dennisse Bonilla
Sina Rusta-Sellehy
Larissa Lisnevskaia
Earl Silverman
Arthur Bookman
Carolina Landolt-Marticorena
Joan Wither
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-018-1752-3

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