Rheumatology International

, Volume 34, Issue 2, pp 235–241 | Cite as

Could the complement component C4 or its fragment C4d be a marker of the more severe conditions in patients with primary Sjögren’s syndrome?

  • Gintaras Sudzius
  • Diana Mieliauskaite
  • Almantas Siaurys
  • Rita Viliene
  • Irena Butrimiene
  • Dainius Characiejus
  • Irena DumalakieneEmail author
Original Article


Our aim is to evaluate the complement component C4 (C4) and its fragment C4d (C4d) levels, focusing on their associations with other markers of B cells’ activity in patients with primary Sjögren’s syndrome (pSS). Humoral factors C4, C4d, B cell-activating factor (BAFF), κ and λ free light chains (FLCs) and IgG (by immunoassay) were investigated in 58 patients with pSS and in 28 healthy controls. We observed significantly higher levels of BAFF, κ and λ FLC and IgG, and significantly lower level of C4 in pSS patients, while the level of C4d was similar in the both groups. Significantly higher levels of BAFF, κ and λ FLCs, IgG, and significantly lower C4 level were found in anti-SSA/SSB antibodies (Abs) seropositive pSS patients’ group comparing with healthy controls. Level of C4d was significantly lower in anti-SSA/SSB Abs seropositive pSS patients comparing with seronegative pSS patients and healthy controls. C4d correlated with C4, anti-SSB Abs level and κ/λ ratio. Significantly higher κ FLC and IgG levels were found in anti-SSA/SSB Abs seronegative pSS patients comparing with healthy controls. Anti-SSA/SSB seropositivity in pSS patients is associated with the decreased level of C4d. These results show that C4d can be an appropriate marker of antibody response and complement activation in pSS patients with Abs, and possibly may show the more severe condition—exhaustion of C4. Further studies are required to determine whether C4d assessment could be a relevant biomarker for the more severe condition and the worse prognosis of pSS.


Primary Sjögren’s syndrome Complement C4 Complement fragment C4d Immunoglobulin free light chain B cell-activating factor IgG 



This research was funded by a grant number LIG—23/2010 from the Research Council of Lithuania.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Pers JO, Daridon C, Devauchelle V, Jousse S, Saraux A, Jamin C, Youinou P (2005) BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann N Y Acad Sci 1050:34–39. doi: 10.1196/annals.1313.004 PubMedCrossRefGoogle Scholar
  2. 2.
    Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE 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. doi: 10.1136/ard.61.6.554 PubMedCrossRefGoogle Scholar
  3. 3.
    Candon S, Gottenberg JE, Bengoufa D, Chatenoud L, Mariette X (2009) Quantitative assessment of antibodies to ribonucleoproteins in primary Sjögren syndrome: correlation with B-cell biomarkers and disease activity. Ann Rheum Dis 68:1208–1212. doi: 10.1136/ard.2008.095257 PubMedCrossRefGoogle Scholar
  4. 4.
    Gottenberg JE, Busson M, Cohen-Solal J, Lavie F, Abbed K, Kimberly RP et al (2005) Correlation of serum B lymphocyte stimulator and beta2 microglobulin with autoantibody secretion and systemic involvement in primary Sjogren’s syndrome. Ann Rheum Dis 64:1050–1055. doi: 10.1136/ard.2004.030643 PubMedCrossRefGoogle Scholar
  5. 5.
    Gottenberg JE, Aucouturier F, Goetz J, Sordet C, Jahn I, Busson M et al (2007) Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren’s syndrome. Ann Rheum Dis 66:23–27. doi: 10.1136/ard.2006.052159 PubMedCrossRefGoogle Scholar
  6. 6.
    Gottenberg JE, Seror R, Benessiano J, Inamo K, Dieude P, Dubost JJ et al (2010) Correlation of Serum BAFF and Markers of B-Cell Activation with Systemic Involvement Assessed by the EULAR Sjögren’s Syndrome Disease Activity Index: Results from the ASSESS Prospective Cohort. [abstract]. Arthritis Rheum 62 Suppl 10:1890. doi:  10.1002/art.29655
  7. 7.
    Gottenberg J-E, Seror R, Miceli-Richard C, Benessiano J, Devauchelle-Pensec V, Dieude P et al (2013) Serum levels of Beta2-Microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren’s syndrome. Data at enrollment in the prospective ASSESS cohort. PLoS One 8:e59868. doi: 10.1371/journal.pone.0059868 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Zadura AF, Theander E, Blom AM, Trouw LA (2009) Complement inhibitor C4b-binding protein in primary Sjögren’s syndrome and its association with other disease markers. Scand J Immunol 69:374–380. doi: 10.1111/j.1365-3083.2009.02229.x PubMedCrossRefGoogle Scholar
  9. 9.
    Ramos-Casals M, Brito-Zerón P, Yagüe J, Akasbi M, Bautista R, Ruano M et al (2005) Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjögren’s syndrome. Rheumatology 44:89–94. doi: 10.1093/rheumatology/keh407 PubMedCrossRefGoogle Scholar
  10. 10.
    Theander E, Manthorpe R, Jacobsson LTH (2004) Mortality and causes of death in primary Sjögren’s syndrome: a prospective cohort study. Arthritis Rheum 50:1262–1269. doi: 10.1002/art20176 PubMedCrossRefGoogle Scholar
  11. 11.
    Nickeleit V, Zeiler M, Gudat F, Thiel G, Mihatsch MJ (2002) Detection of the complement degradation product C4d in renal allografts: diagnostic and therapeutic implications. J Am Soc Nephrol 13:242–251PubMedGoogle Scholar
  12. 12.
    Smith RN, Brousaides N, Grazette L, Saidman S, Semigran M, Disalvo T et al (2005) C4d deposition in cardiac allografts correlates with alloantibody. J Heart Lung Transplant 24:1202–1210PubMedCrossRefGoogle Scholar
  13. 13.
    Nickeleit V, Mihatsch MJ (2003) Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 18:2232–2239PubMedCrossRefGoogle Scholar
  14. 14.
    Manzi S, Navratil JS, Ruffing MJ, Liu CC, Danchenko N, Nilson SE et al (2004) Measurement of erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus. Arthritis Rheum 50:3596–3604PubMedCrossRefGoogle Scholar
  15. 15.
    Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E et al (2010) EULAR Sjögren’s Task Force. EULAR Sjögren’s’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren’s syndrome. Ann Rheum Dis 69(6):1103–1109PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A et al (2011) EULAR Sjögren’s Task Force. EULAR Sjögren’s’s Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjögren’s syndrome. Ann Rheum Dis 70(6):968–972PubMedCrossRefGoogle Scholar
  17. 17.
    Daridon C, Youinou P, Pers JO (2008) BAFF, APRIL, TWE-PRIL: who’s who? Autoimmun Rev 7:267–271PubMedCrossRefGoogle Scholar
  18. 18.
    Jonsson MV, Szodoray P, Jellestad S, Jonsson R, Skarstein K (2005) Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjögren’s syndrome. J Clin Immunol 25:189–201PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang J, Roschke V, Baker KP, Wang Z, Alarcón GS, Fessler BJ et al (2001) Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 166:6–10PubMedGoogle Scholar
  20. 20.
    Cheema GS, Roschke V, Hilbert DM, Stohl W (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44:1313–1319PubMedCrossRefGoogle Scholar
  21. 21.
    Zhu XJ, Shi Y, Peng J, Guo CS, Shan NN, Qin P et al (2009) The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood 114:5362–5367PubMedCrossRefGoogle Scholar
  22. 22.
    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. doi: 10.1186/ar2210 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Davids MS, Murali MR, Kuter DJ (2010) Serum free light chain analysis. Am J Hematol 85:787–790PubMedCrossRefGoogle Scholar
  24. 24.
    Ioannidis JP, Vassiliou VA, Moutsopoulos HM (2002) Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum 46:741–747PubMedCrossRefGoogle Scholar
  25. 25.
    Rajkumar SV, Kyle RA, Therneau TM, Melton LJ 3rd, Bradwell AR, Clark RJ et al (2005) Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 106:812–817PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Gintaras Sudzius
    • 1
  • Diana Mieliauskaite
    • 2
  • Almantas Siaurys
    • 1
  • Rita Viliene
    • 1
  • Irena Butrimiene
    • 2
    • 3
  • Dainius Characiejus
    • 1
    • 4
  • Irena Dumalakiene
    • 1
    • 5
    Email author
  1. 1.Department of ImmunologyState Research Institute Centre for Innovative MedicineVilniusLithuania
  2. 2.Department of Innovative Diagnostic Treatment and Health Monitoring TechnologyState Research Institute Centre for Innovative MedicineVilniusLithuania
  3. 3.Faculty of MedicineVilnius UniversityVilniusLithuania
  4. 4.Department of Pathology, Forensic Medicine and Pharmacology, Faculty of MedicineVilnius UniversityVilniusLithuania
  5. 5.Department of Chemistry and Bioengineering, Faculty of Fundamental SciencesVilnius Gediminas Technical UniversityVilniusLithuania

Personalised recommendations