Skip to main content

Advertisement

SpringerLink
Log in

Assessment of CD40 and CD40L expression in rheumatoid arthritis patients, association with clinical features and DAS28

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

The predominance of the effector mechanisms by CD4 + T cells is a characteristic of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). The CD40/CD40L costimulatory pathway contributes to these pathogenic mechanisms by promoting autoantibody production and inflammation. Aberrant expression of CD40 and CD40L in RA patients has been shown, the latter prevailing in females. However, contrasting results have emerged regarding the clinical associations of these findings. We determined the association of CD40 and CD40L expression with the clinical activity evaluated through DAS28 in RA patients. A total of 38 female RA patients and 10 age- and sex-matched control subjects were included. CD40 and CD40L mRNA expression was quantified by real-time qPCR, cell surface proteins were determined by flow cytometry, and protein soluble forms were determined by ELISA. The expansion of a CD4 + T cell subpopulation expressing CD40 was identified in the RA group. In addition, high frequencies of CD4 + CD40L + T cells expressing high levels of CD40L, increased levels of sCD40L and overexpression of CD40L mRNA were observed in these patients. Moreover, there was a gradual increase in CD40L when data were stratified according to DAS28, except for very active patients. No correlation was observed between the levels of mRNA, cell surface protein and soluble protein of CD40 and CD40L with the clinical features of RA patients. There is an altered expression of CD40L in female RA patients in association with clinical activity assessed by DAS28, these findings support the evidence that suggests CD40L as a marker of clinical activity.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001.

    PubMed  Google Scholar 

  2. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46:183–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis—shaping the immunological landscape. Nat Rev Rheumatol. 2016;12:63–8.

    CAS  PubMed  Google Scholar 

  4. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229:189.

    Google Scholar 

  5. Peters AL, Stunz LL, Bishop GA. CD40 and autoimmunity: the dark side of a great activator. Semin Immunol. 2009;21:293–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Contin C, Pitard V, Itai T, Nagata S, Moreau JF, Déchanet-Merville J. Membrane-anchored CD40 is processed by the tumor necrosis factor-alfa-converting enzyme: implications for CD40 signaling. J Biol Chem. 2003;278:32801–9.

    CAS  PubMed  Google Scholar 

  7. Menchén L, Marín-Jiménez I, Arias-Salgado EG, et al. Matrix metalloproteinase 9 is involved in Crohn’s disease-associated platelet hyperactivation through the release of soluble CD40 ligand. Gut. 2009;58:920–8.

    PubMed  Google Scholar 

  8. Reinboldt S, Wenzel F, Rauch BH, et al. Preliminary evidence for a matrix metalloproteinase-2 (MMP-2)-dependent shedding of soluble CD40 ligand (sCD40L) from activated platelets. Platelets. 2009;20:441–4.

    CAS  PubMed  Google Scholar 

  9. Choi WS, Jeon OH, Kim DS. CD40 ligand shedding is regulated by interaction between matrix metalloproteinase-2 and platelet integrin αIIbβ3. J Thromb Haemost. 2010;8:1364–71.

    CAS  PubMed  Google Scholar 

  10. Yacoub D, Benslimane N, Al-Zoobi L, Hassan G, Nadiri A, Mourad W. CD154 is released from T-cells by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and ADAM17 in a CD40 protein-dependent manner. J Biol Chem. 2013;288:36083–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Eshel D, Toporik A, Efrati T, Nakav S, Chen A, Douvdevani A. Characterization of natural human antagonistic soluble CD40 isoforms produced through alternative splicing. Mol Immunol. 2008;46:250–7.

    CAS  PubMed  Google Scholar 

  12. MacDonald KP, Nishioka Y, Lipsky PE, Thomas R. Functional CD40 ligand is expressed by T cells in rheumatoid arthritis. J Clin Invest. 1997;100:2404–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu MF, Chao SC, Wang CR, Lei HY. Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity. 2001;34:107–13.

    CAS  PubMed  Google Scholar 

  14. Guo Y, Walsh AM, Fearon U, et al. CD40L-dependent pathway is active at various stages of rheumatoid arthritis disease progression. J Immunol. 2017;198:4490–501.

    CAS  PubMed  Google Scholar 

  15. Berner B, Wolf G, Hummel KM, Müller GA, Reuss-Borst MA. Increased expression of CD40 ligand (CD154) on CD4 + T cells as a marker of disease activity in rheumatoid arthritis. Ann Rheum Dis. 2000;59:190–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kosmaczewska A, Ciszak L, Swierkot J, Szteblich A, Wiland P, Frydecka I. Alterations in both the activatory and inhibitory potential of peripheral blood CD4 + T cells in rheumatoid arthritis patients correlate with disease progression. Pathol Oncol Res. 2014;20:235–43.

    CAS  PubMed  Google Scholar 

  17. Tamura N, Kobayashi S, Kato K, et al. Soluble CD154 in rheumatoid arthritis: elevated plasma levels in cases with vasculitis. J Rheumatol. 2001;28:2583–90.

    CAS  PubMed  Google Scholar 

  18. Goules A, Tzioufas AG, Manousakis MN, Kirou KA, Crow MK, Routsias JG. Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases. J Autoimmun. 2006;26:165–71.

    CAS  PubMed  Google Scholar 

  19. Pamuk GE, Vural Ö, Turgut B, Demir M, Pamuk ÖN, Çakir N. Increased platelet activation markers in rheumatoid arthritis: are they related with subclinical atherosclerosis? Platelets. 2008;19:146–54.

    CAS  PubMed  Google Scholar 

  20. Liao J, Liang G, Xie S, et al. CD40L demethylation in CD4 + T cells from women with rheumatoid arthritis. Clin Immunol. 2012;145:13–8.

    CAS  PubMed  Google Scholar 

  21. Chen JM, Guo J, Wei CD, et al. The association of CD40 polymorphisms with CD40 serum levels and risk of systemic lupus erythematosus. BMC Genet. 2015;16:121.

    PubMed  PubMed Central  Google Scholar 

  22. Waid DM, Wagner RJ, Putnam A, et al. A unique T cell subset described as CD4loCD40 + T cells (TCD40) in human type 1 diabetes. Clin Immunol. 2007;124:138–48.

    CAS  PubMed  Google Scholar 

  23. Waid DM, Schreiner T, Vaitaitis G, Carter JR, Corboy JR, Wagner DH. Defining a new biomarker for the autoimmune component of Multiple Sclerosis: Th40 cells. J Neuroimmunol. 2014;270:75–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–9.

    CAS  Google Scholar 

  25. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–8.

    CAS  Google Scholar 

  26. Munroe ME, Bishop GA. A Costimulatory Function for T Cell CD40. J Immunol. 2007;178:671–82.

    CAS  PubMed  Google Scholar 

  27. Cho CS, Cho ML, Min SY, et al. CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor. J Immunol. 2000;164:5055–61.

    CAS  PubMed  Google Scholar 

  28. Gotoh H, Kawaguchi Y, Harigai M, et al. Increased CD40 expression on articular chondrocytes from patients with rheumatoid arthritis: contribution to production of cytokines and matrix metalloproteinases. J Rheumatol. 2004;31:1506–12.

    CAS  PubMed  Google Scholar 

  29. Lee HY, Jeon HS, Song EK, et al. CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL-mediated osteoclastogenesis: evidence of NF-κB-dependent, CD40-mediated bone destruction in rheumatoid arthritis. Arthritis Rheum. 2006;54:1747–58.

    CAS  PubMed  Google Scholar 

  30. Román-Fernández IV, Ávila-Castillo DF, Cerpa-Cruz S, et al. CD40 functional gene polymorphisms and mRNA expression in rheumatoid arthritis patients from western Mexico. Genet Mol Res. 2016;15:gmr15048775.

    Google Scholar 

  31. Román-Fernández IV, Sánchez-Zuno GA, Padilla-Gutiérrez JR, et al. The 3′-UTR (CA)n microsatellite on CD40LG gene as a possible genetic marker for rheumatoid arthritis in Mexican population: impact on CD40LG mRNA expression. Clin Rheumatol. 2018;37:345–53.

    PubMed  Google Scholar 

  32. Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B. Demethylation of CD40LG on the Inactive X in T Cells from Women with Lupus. J Immunol. 2007;179:6352–8.

    CAS  PubMed  Google Scholar 

  33. Huang WX, Huang P, Hillert J. Systemic upregulation of CD40 and CD40 ligand mRNA expression in multiple sclerosis. Mult Scler. 2000;6:61–5.

    CAS  PubMed  Google Scholar 

  34. Lian XR, Xiao R, Hu XH, et al. DNA demethylation of CD40L in CD4 + T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 2012;64:2338–45.

    CAS  PubMed  Google Scholar 

  35. Tung CH, Lu MC, Lai NS, Wu SF. Tumor necrosis factor-α blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis. PLoS ONE. 2017;12:1–12.

    Google Scholar 

  36. Wu SF, Chang CB, Hsu JM, et al. Hydroxychloroquine inhibits CD154 expression in CD4 + T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017;19:183.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Valenzuela HF, Effros RB. Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol. 2002;105:117–25.

    CAS  PubMed  Google Scholar 

  38. Vallejo AN, Weyand CM, Goronzy JJ. T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med. 2004;10:119–24.

    CAS  PubMed  Google Scholar 

  39. Van Kooten C, Gaillard C, Galizzi JP, et al. B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40. Eur J Immunol. 1994;24:787–92.

    PubMed  Google Scholar 

  40. Vakkalanka RK, Woo C, Kirou KA, Koshy M, Berger D, Crow MK. Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis Rheum. 1999;42:871–81.

    CAS  PubMed  Google Scholar 

  41. Chang YH, Lin IL, Tsay GJ, et al. Elevated circulatory MMP-2 and MMP-9 levels and activities in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Biochem. 2008;41:955–9.

    CAS  PubMed  Google Scholar 

  42. Sanchooli J, Ramroodi N, Sanadgol N, Sarabandi V, Ravan H, Rad RS. Relationship between metalloproteinase 2 and 9 concentrations and soluble CD154 expression in Iranian patients with multiple sclerosis. Kaohsiung J Med Sci. 2014;30:235–42.

    PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by funding from the National Council of Science and Technology (CONACYT, Grant No. 180663), CONACYT-México-Universidad de Guadalajara, awarded to Muñoz-Valle JF. The funding source had no involvement in any phase of the study.

Author information

Authors and Affiliations

  1. Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    Ilce Valeria Román-Fernández, Mariel García-Chagollán, Claudia Azucena Palafox-Sánchez, Samuel García-Arellano, Gabriela Athziri Sánchez-Zuno & José Francisco Muñoz-Valle

  2. Servicio de Reumatología, O.P.D. Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Guadalajara, Jalisco, Mexico

    Sergio Cerpa-Cruz

  3. División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico

    Luis Felipe Jave-Suárez

Authors
  1. Ilce Valeria Román-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariel García-Chagollán
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sergio Cerpa-Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis Felipe Jave-Suárez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Azucena Palafox-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samuel García-Arellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriela Athziri Sánchez-Zuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. José Francisco Muñoz-Valle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Francisco Muñoz-Valle.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All procedures were performed following the ethical guidelines established in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by Comité de ética en Investigación y Bioseguridad, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara (reference No. 0122017).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Román-Fernández, I.V., García-Chagollán, M., Cerpa-Cruz, S. et al. Assessment of CD40 and CD40L expression in rheumatoid arthritis patients, association with clinical features and DAS28. Clin Exp Med 19, 427–437 (2019). https://doi.org/10.1007/s10238-019-00568-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-019-00568-5

Keywords

Search

Navigation