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Rheumatology International

, Volume 38, Issue 6, pp 1063–1073 | Cite as

Association between memory B-cells and clinical and immunological features of primary Sjögren’s syndrome and Sicca patients

  • Filipe Barcelos
  • Catarina Martins
  • Ana Papoila
  • Carlos Geraldes
  • Joana Cardigos
  • Glória Nunes
  • Teresa Lopes
  • Nuno Alves
  • José Vaz-Patto
  • Jaime Branco
  • Luís-Miguel Borrego
Observational Research

Abstract

B-cells play a pivotal role in primary Sjögren’s syndrome (pSS) pathogenesis. We aim to (1) evaluate the distribution of B-lymphocyte subpopulations in pSS and Sicca patients, (2) establish cut-off points that discriminate pSS from controls, (3) evaluate the association between memory B-cells and phenotypic features in pSS. We included 57 pSS patients, 68 Sicca and 24 healthy controls. Circulating B-cells were characterized by flow cytometry as naïve and memory subsets and classified from Bm1 to Bm5. Compared to controls, pSS patients had lower percentages (29.5 vs 44.4%) and absolute numbers (47 vs 106 cells/µl) of memory B-cells. Through ROC curves, a cut-off of ≤ 58 total memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.60 for pSS, and was met by 59.6% of pSS patients, 38.8% of Sicca and 12.5% of controls. A cut-off of < 23.5 Switched-memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.54 and was met by 54.4% of pSS patients, 37.3% of Sicca and 12.5% of controls. In pSS, lower total memory B-cells count was associated with longer disease duration (14.3 vs 8.1 years, p = 0.006) and more active disease profile, as evaluated by the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) (3.1 vs 1.4, p = 0.043). Decreased numbers of memory B-cells clearly discriminated pSS from controls and can also have prognostic value. It remains to be clarified whether Sicca patients with decreased memory B-cells represent pSS and if B-cell profiling could help in the diagnosis of pSS.

Keywords

Sjögren’s syndrome Flow cytometry Memory B cells Diagnosis Autoimmunity 

Notes

Acknowledgements

The first author gratefully acknowledges Academia Cuf/José de Mello Saúde and Sociedade Portuguesa de Reumatologia for its financial support.

Author contributions

FB conceived the original research idea, while all of the authors designed the study and created the study protocol. FB and JVP recruited the patients and collected the data. JC and NA recruited the healthy controls and collected the data. CM, GN and TL analyzed the blood samples using flow cytometry. CG and ALP performed the statistical analysis. JCB and LMB supervised all the work and the research protocol. All of the authors contributed to data analysis and interpretation. FB drafted the manuscript, and all of the authors revised it and contributed to it intellectually. All of the authors have approved the final version of the manuscript.

Funding

The project was partially financed by Academia Cuf/José de Mello Saúde, Carnaxide, Portugal, and Sociedade Portuguesa de Reumatologia, Lisbon, Portugal.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Ethics committee of Hospital Cuf Descobertas, 8/09/2014, Ethics committee of Instituto Português de Reumatologia, 3/07/2015 and NOVA Medical School Ethics (no. 17/2016/CEFCM). All patients have signed an informed consent to participate according to the Declaration of Helsinki.

Supplementary material

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References

  1. 1.
    Kassan SS, Moutsopoulos HM (2004) Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med 164:1275–1284.  https://doi.org/10.1001/archinte.164.12.1275 CrossRefPubMedGoogle Scholar
  2. 2.
    Mavragani CP, Moutsopoulos HM (2014) Sjögren’s syndrome. Annu Rev Pathol Mech Dis 9:273–285.  https://doi.org/10.1146/annurev-pathol-012513-104728 CrossRefGoogle Scholar
  3. 3.
    Kyriakidis NC, Kapsogeorgou EK, Tzioufas AG (2014) A comprehensive review of autoantibodies in primary Sjögren’s syndrome: clinical phenotypes and regulatory mechanisms. J Autoimmun 51:67–74CrossRefPubMedGoogle Scholar
  4. 4.
    Guellec D, Cornec D, Jousse-Joulin S et al (2013) Diagnostic value of labial minor salivary gland biopsy for Sjögren’s syndrome: a systematic review. Autoimmun Rev 12:416–420CrossRefPubMedGoogle Scholar
  5. 5.
    Fisher BA, Brown RM, Bowman SJ, Barone F (2015) A review of salivary gland histopathology in primary Sjögren’s syndrome with a focus on its potential as a clinical trials biomarker. Ann Rheum Dis 74:1–6.  https://doi.org/10.1136/annrheumdis-2015-207499 CrossRefGoogle Scholar
  6. 6.
    Vitali C, Bombardieri S, Jonsson R et al (2002) Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558.  https://doi.org/10.1136/ard.61.6.554 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Shiboski SC, Shiboski CH, Criswell LA et al (2012) American College of Rheumatology classification criteria for Sjögren syndrome: a data-driven, expert consensus approach in the SICCA cohort. Arthritis Care Res 64:475–487CrossRefGoogle Scholar
  8. 8.
    Shiboski CH, Shiboski SC, Seror R et al (2017) 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome. Ann Rheum Dis 76:9–16.  https://doi.org/10.1136/annrheumdis-2016-210571 CrossRefPubMedGoogle Scholar
  9. 9.
    Brito-Zerón P, Theander E, Baldini C et al (2016) Early diagnosis of primary Sjögren’s syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol 8409:1–20.  https://doi.org/10.1586/1744666X.2016.1109449 Google Scholar
  10. 10.
    Theander E, Jonsson R, Sjöström B et al (2015) Prediction of Sjögren’s syndrome years before diagnosis and identification of patients with early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol 67:2427–2436.  https://doi.org/10.1002/art.39214 CrossRefPubMedGoogle Scholar
  11. 11.
    Trier NH, Nielsen I, Friis T et al (2016) Comparison of antibody assays for detection of autoantibodies to Ro 52, Ro 60 and La associated with primary Sjögren’s syndrome. J Immunol Methods 433:44–50.  https://doi.org/10.1016/j.jim.2016.03.001 CrossRefPubMedGoogle Scholar
  12. 12.
    Daniels TE, Cox D, Shiboski CH et al (2011) Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren’s syndrome among 1726 registry participants. Arthritis Rheum 63:2021–2030.  https://doi.org/10.1002/art.30381 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sack U, Boldt A, Mallouk N et al (2016) Cellular analyses in the monitoring of autoimmune diseases. Autoimmun Rev 15:883–889CrossRefPubMedGoogle Scholar
  14. 14.
    Carvajal Alegria G, Gazeau P, Hillion S et al (2017) Could lymphocyte profiling be useful to diagnose systemic autoimmune diseases? Clin Rev Allergy Immunol 53:219–236.  https://doi.org/10.1007/s12016-017-8608-5 CrossRefPubMedGoogle Scholar
  15. 15.
    Shen L, Suresh L, Lindemann M et al (2012) Novel autoantibodies in Sjogren’s syndrome. Clin Immunol 145:251–255.  https://doi.org/10.1016/j.clim.2012.09.013 CrossRefPubMedGoogle Scholar
  16. 16.
    Jousse-Joulin S, Milic V, Jonsson MV et al (2016) Is salivary gland ultrasonography a useful tool in Sjögren’s syndrome? A systematic review. Rheumatology 55:789–800.  https://doi.org/10.1093/rheumatology/kev385 CrossRefPubMedGoogle Scholar
  17. 17.
    Nocturne G, Mariette X (2013) Advances in understanding the pathogenesis of primary Sjögren’s syndrome. Nat Rev Rheumatol 9:544–556CrossRefPubMedGoogle Scholar
  18. 18.
    Hansen A, Lipsky PE, Dörner T (2007) B cells in Sjögren’s syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue. Arthritis Res Ther 9:218.  https://doi.org/10.1186/ar2210 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hansen A, Daridon C, Dörner T (2010) What do we know about memory B cells in primary Sjögren’s syndrome? Autoimmun Rev 9:600–603CrossRefPubMedGoogle Scholar
  20. 20.
    Corsiero E, Sutcliffe N, Pitzalis C et al (2014) Accumulation of self-reactive naïve and memory B cell reveals sequential defects in B cell tolerance checkpoints in Sjögren’s Syndrome. PLoS One.  https://doi.org/10.1371/journal.pone.0114575 PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kroese FGM, Abdulahad WH, Haacke E et al (2014) B-cell hyperactivity in primary Sjögren’s syndrome. Expert Rev Clin Immunol 10:483–499.  https://doi.org/10.1586/1744666X.2014.891439 CrossRefPubMedGoogle Scholar
  22. 22.
    Fragkioudaki S, Mavragani CP, Moutsopoulos HM (2016) Predicting the risk for lymphoma development in Sjogren syndrome: an easy tool for clinical use. Medicine (Baltimore) 95:e3766.  https://doi.org/10.1097/MD.0000000000003766 CrossRefGoogle Scholar
  23. 23.
    LeBien T, Tedder T (2008) B lymphocytes: how they develop and function. Blood 112:1570–1580.  https://doi.org/10.1182/blood CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bohnhorst J, Thoen JE, Natvig JB, Thompson KM (2001) Significantly depressed percentage of CD27+ (memory) B cells among peripheral blood B cells in patients with primary Sjogren’s syndrome. Scand J Immunol 54:421–427.  https://doi.org/10.1046/j.1365-3083.2001.00989.x CrossRefPubMedGoogle Scholar
  25. 25.
    Roberts MEP, Kaminski D, Jenks SA et al (2014) Primary Sjögren’s syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD + unswitched memory B cells. Arthritis Rheumatol 66:2558–2569.  https://doi.org/10.1002/art.38734 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hansen A, Odendahl M, Reiter K et al (2002) Diminished peripheral blood memory b cells and accumulation of memory B cells in the salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum 46:2160–2171.  https://doi.org/10.1002/art.10445 CrossRefPubMedGoogle Scholar
  27. 27.
    Klein U, Rajewsky K, Küppers R (1998) Human immunoglobulin (Ig)M + IgD + peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med 188:1679–1689.  https://doi.org/10.1084/jem.188.9.1679 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bohnhorst JO, Bjorgan MB, Thoen JE et al (2001) 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 167:3610–3618.  https://doi.org/10.4049/jimmunol.167.7.3610 CrossRefPubMedGoogle Scholar
  29. 29.
    Pascual V (1994) Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med 180:329–339.  https://doi.org/10.1084/jem.180.1.329 CrossRefPubMedGoogle Scholar
  30. 30.
    Binard A, Le Pottier L, Devauchelle-Pensec V et al (2009) Is the blood B-cell subset profile diagnostic for Sjögren’s syndrome? Ann Rheum Dis 68:1447–1452.  https://doi.org/10.1136/ard.2008.096172 CrossRefPubMedGoogle Scholar
  31. 31.
    Cornec D, Saraux A, Pers J-O et al (2014) Diagnostic accuracy of blood B-cell subset profiling and autoimmunity markers in Sjögren’s syndrome. Arthritis Res Ther 16:R15.  https://doi.org/10.1186/ar4442 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Seror R, Ravaud P, Bowman SJ et al (2010) EULAR Sjogren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis 69:1103–1109.  https://doi.org/10.1136/ard.2009.110619 CrossRefPubMedGoogle Scholar
  33. 33.
    Seror R, Bootsma H, Saraux A et al (2016) Defining disease activity states and clinically meaningful improvement in primary Sjögren’s syndrome with EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum Dis 75:382–389.  https://doi.org/10.1136/annrheumdis-2014-206008 CrossRefPubMedGoogle Scholar
  34. 34.
    Szabó K, Papp G, Szántó A et al (2016) A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren’s syndrome and systemic lupus erythematosus. Clin Exp Immunol 183:76–89.  https://doi.org/10.1111/cei.12703 CrossRefPubMedGoogle Scholar
  35. 35.
    Hamza N, Bos N, Kallenberg CGM (2012) B-cell populations and sub-populations in Sjögren’s syndrome. Presse Med 41:e475-83.  https://doi.org/10.1016/j.lpm.2012.05.021 CrossRefPubMedGoogle Scholar
  36. 36.
    Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22:1041–1050CrossRefPubMedGoogle Scholar
  37. 37.
    Brito-Zerón P, Acar-Denizli N, Zeher M et al (2017) Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren’s syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjögren Project Consortium. Ann Rheum Dis 76:1042–1050.  https://doi.org/10.1136/annrheumdis-2016-209952 CrossRefPubMedGoogle Scholar
  38. 38.
    Slade JDHB (1983) Prednisone-induced alterations of circulating human lymphocyte subsets. J Lab Clin Med 101:479–487.  https://doi.org/10.5555/URI:PII:0022214383901580 PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.CEDOC, Chronic Diseases Research Center, Immunology, NOVA Medical School|FCMUniversidade Nova de LisboaLisbonPortugal
  2. 2.Departement of RheumatologyInstituto Português de ReumatologiaLisbonPortugal
  3. 3.Department of RheumatologyHospital Cuf DescobertasLisbonPortugal
  4. 4.CEAUL, Centro de Estatística e AplicaçõesUniversidade de LisboaLisbonPortugal
  5. 5.NOVA Medical School|FCMUniversidade Nova de LisboaLisbonPortugal
  6. 6.Department of Ophthalmology, Centro Hospitalar de Lisboa CentralHospital de Santo António dos CapuchosLisbonPortugal
  7. 7.Department of OphthalmologyHospital Cuf DescobertasLisbonPortugal
  8. 8.Department of RheumatologyInstituto Português de ReumatologiaLisbonPortugal
  9. 9.Chronic Diseases Research Center, NOVA Medical School|FCMUniversidade Nova de LisboaLisbonPortugal
  10. 10.Department of Rheumatology, Centro Hospitalar de Lisboa OcidentalHospital de Egas MonizLisbonPortugal
  11. 11.Department of ImmunoalergyHospital Cuf DescobertasLisbonPortugal

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