Skip to main content

Advertisement

SpringerLink
Log in

Decreased mRNA Expressions of CD40L in Patients with Neuromyelitis Optica Spectrum Disorder

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that preferentially affects central nerve system. Herein, we evaluated changes of CD40L and CD40 mRNA expressions in NMOSD and controls to explore their potential roles in development of NMOSD. The expressions of CD40L and CD40 mRNA in peripheral blood mononuclear cells (PBMCs) from patients with NMOSD and healthy controls were detected by quantitative real-time PCR (qPCR). Kruskal-Wallis tests were used to compare expression levels of CD40L and CD40 mRNA between groups, and Spearman correlation analysis was performed to evaluate correlation between mRNA expression levels and annual relapse rate (ARR) of NMOSD. A total of 71 patients with NMOSD and 42 gender- and age-matched healthy volunteers were recruited in our study. Compared with healthy controls, expression of CD40L mRNA was significantly decreased in untreated patients with NMOSD, and similar trends were observed also in CD40 mRNA expression although the difference was not significant. Other than that, immunosuppressants not only successfully increased CD40L and CD40 mRNA levels during remission of NMOSD, but also corrected the negative correlation between CD40L mRNA expression and annual relapse rate (ARR) of patients NMOSD. These results favored the long-term prognosis of NMOSD patients. Our results suggest that decreased expressions of CD40L mRNA may be involved in developing of NMOSD and the proper CD40L mRNA levels benefit to prevent attacks of NMOSD. Nevertheless, the relationship between protein and mRNA expressions of CD40L and their underlying roles in the pathogenesis of NMOSD remains to be further studied.

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

  • Aarts S, Seijkens T, van Dorst K et al (2017) The CD40-CD40L dyad in experimental autoimmune encephalomyelitis and multiple sclerosis. Front Immunol 8:1791

    Article  Google Scholar 

  • Anstey A, Lear JT (1998) Azathioprine: clinical pharmacology and current indications in autoimmune disorders. BioDrugs 9:33–47

    Article  CAS  Google Scholar 

  • Bennett JL, O'Connor KC, Bar-Or A et al (2015) B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm 2:e104

    Article  Google Scholar 

  • Bishop GA, Hostager BS (2003) The CD40-CD154 interaction in B cell-T cell liaisons. Cytokine Growth Factor Rev 14:297–309

    Article  CAS  Google Scholar 

  • Bruscolini A, Sacchetti M, La Cava M et al (2018) Diagnosis and management of neuromyelitis optica spectrum disorders - an update. Autoimmun Rev 17:195–200

    Article  Google Scholar 

  • Chen H, Qiu W, Zhang Q et al (2017) Comparisons of the efficacy and tolerability of mycophenolate mofetil and azathioprine as treatments for neuromyelitis optica and neuromyelitis optica spectrum disorder. Eur J Neurol 24:219–226

    Article  CAS  Google Scholar 

  • Cooper GS, Stroehla BC (2003) The epidemiology of autoimmune diseases. Autoimmun Rev 2:119–125

    Article  Google Scholar 

  • Dos PG, Sato DK, Becker J, Fujihara K (2016) Th17 cells pathways in multiple sclerosis and Neuromyelitis Optica Spectrum disorders: pathophysiological and therapeutic implications. Mediat Inflamm 2016:5314541

    Google Scholar 

  • Eaton WW, Rose NR, Kalaydjian A, Pedersen MG, Mortensen PB (2007) Epidemiology of autoimmune diseases in Denmark. J Autoimmun 29:1–9

    Article  Google Scholar 

  • Fan X, Lin C, Han J et al (2015) Follicular helper CD4+ T cells in human Neuroautoimmune diseases and their animal models. Mediat Inflamm 2015:638968

    Article  Google Scholar 

  • Field J, Shahijanian F, Schibeci S et al (2015) The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: implications for gene function. PLoS One 10:e127080

    Google Scholar 

  • Foy TM, Aruffo A, Bajorath J, Buhlmann JE, Noelle RJ (1996) Immune regulation by CD40 and its ligand GP39. Annu Rev Immunol 14:591–617

    Article  CAS  Google Scholar 

  • Gerritse K, Laman JD, Noelle RJ, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E (1996) CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A 93:2499–2504

    Article  CAS  Google Scholar 

  • Houzen H, Kondo K, Niino M, Horiuchi K, Takahashi T, Nakashima I, Tanaka K (2017) Prevalence and clinical features of neuromyelitis optica spectrum disorders in northern Japan. Neurology 89:1995–2001

    Article  Google Scholar 

  • Iezzi G, Sonderegger I, Ampenberger F, Schmitz N, Marsland BJ, Kopf M (2009) CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells. Proc Natl Acad Sci U S A 106:876–881

    Article  Google Scholar 

  • Jarius S, Wildemann B (2013) Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature. Brain Pathol 23:661–683

    Article  CAS  Google Scholar 

  • Li G, Diogo D, Wu D et al (2013) Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway. PLoS Genet 9:e1003487

    Article  CAS  Google Scholar 

  • Liu J, Zhang Q, Shi Z, Yang M, Lian Z, Chen H, Feng H, du Q, Zhang Y, Miao X, Li H, Zhou H (2018) Increased expression of the membrane-bound CD40 ligand on peripheral CD4(+) T cells in the acute phase of AQP4-IgG-seropositive neuromyelitis optica spectrum disorders. J Neuroimmunol 325:64–68

    Article  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  Google Scholar 

  • Masuda H, Mori M, Uchida T, Uzawa A, Ohtani R, Kuwabara S (2017) Soluble CD40 ligand contributes to blood-brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder. J Neuroimmunol 305:102–107

    Article  CAS  Google Scholar 

  • Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M (2014) Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol 71:324–330

    Article  Google Scholar 

  • Pandit L, Asgari N, Apiwattanakul M, Palace J, Paul F, Leite MI, Kleiter I, Chitnis T, GJCF International Clinical Consortium & Biorepository for Neuromyelitis Optica (2015) Demographic and clinical features of neuromyelitis optica: a review. Mult Scler 21:845–853

    Article  CAS  Google Scholar 

  • Ratelade J, Verkman AS (2012) Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol 44:1519–1530

    Article  CAS  Google Scholar 

  • Schonbeck U, Mach F, Libby P (2000) CD154 (CD40 ligand). Int J Biochem Cell Biol 32:687–693

    Article  CAS  Google Scholar 

  • Shaffer AR, Young RM, Staudt LM (2012) Pathogenesis of human B cell lymphomas. Annu Rev Immunol 30:565–610

    Article  CAS  Google Scholar 

  • Shi Z, Zhang Q, Chen H, Miao X, Liu J, Lian Z, Feng H, Zhou H (2017) Association of CD40 gene polymorphisms with susceptibility to Neuromyelitis Optica Spectrum disorders. Mol Neurobiol 54:5236–5242

    Article  CAS  Google Scholar 

  • Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747

    Article  CAS  Google Scholar 

  • Stout RD, Suttles J (1996) The many roles of CD40 in cell-mediated inflammatory responses. Immunol Today 17:487–492

    Article  CAS  Google Scholar 

  • Takahashi F, Morita K, Katai K et al (1998) Effects of dietary pi on the renal Na+−dependent pi transporter NaPi-2 in thyroparathyroidectomized rats. Biochem J 333(Pt 1):175–181

    Article  CAS  Google Scholar 

  • Varrin-Doyer M, Spencer CM, Schulze-Topphoff U, Nelson PA, Stroud RM, Cree BA, Zamvil SS (2012) Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol 72:53–64

    Article  CAS  Google Scholar 

  • Vazgiourakis VM, Zervou MI, Choulaki C, Bertsias G, Melissourgaki M, Yilmaz N, Sidiropoulos P, Plant D, Trouw LA, Toes RE, Kardassis D, Yavuz S, Boumpas DT, Goulielmos GN (2011) A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis. Ann Rheum Dis 70:2184–2190

    Article  CAS  Google Scholar 

  • Wagner M, Sobczynski M, Bilinska M et al (2015) MS risk allele rs1883832T is associated with decreased mRNA expression of CD40. J Mol Neurosci 56:540–545

    Article  CAS  Google Scholar 

  • Wilson R, Makuch M, Kienzler AK, Varley J, Taylor J, Woodhall M, Palace J, Leite MI, Waters P, Irani SR (2018) Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica. Brain 141:1063–1074

    Article  Google Scholar 

  • Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815

    Article  CAS  Google Scholar 

  • Wingerchuk DM, Banwell B, Bennett JL et al (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177–189

    Article  Google Scholar 

  • Yamamoto K, Itoh M, Okamura T et al (2012) Relative levels of the inflammatory cytokine TNFalpha and the soluble CD40 ligand profile in serum correlate with the thyrotoxic activity of Graves' disease. Thyroid 22:516–521

    Article  CAS  Google Scholar 

  • Yan J, Lei J, Chen L, Deng H, Dong D, Jin T, Liu X, Yuan R, Qiu Y, Ge J, Peng X, Shao J (2018) Human leukocyte antigen F locus adjacent transcript 10 overexpression disturbs WISP1 protein and mRNA expression to promote hepatocellular carcinoma progression. Hepatology 68:2268–2284

    Article  CAS  Google Scholar 

  • Zeka B, Hastermann M, Hochmeister S, Kögl N, Kaufmann N, Schanda K, Mader S, Misu T, Rommer P, Fujihara K, Illes Z, Leutmezer F, Sato DK, Nakashima I, Reindl M, Lassmann H, Bradl M (2015) Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS. Acta Neuropathol 130:783–798

    Article  CAS  Google Scholar 

  • Zeka B, Hastermann M, Kaufmann N et al (2016) Aquaporin 4-specific T cells and NMO-IgG cause primary retinal damage in experimental NMO/SD. Acta Neuropathol Commun 4:82

    Article  Google Scholar 

  • Zwerner J, Fiorentino D (2007) Mycophenolate mofetil. Dermatol Ther 20:229–238

    Article  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Sisi Wu and Miss Xuemei Chen (West China Hospital, Sichuan University) for their technical support in qPCR. We are also grateful to patients with NMOSD and healthy volunteers in China for their participations and supports.

Funding

The work was funded by the National Key Basic Research and Development Program of China (No. 2017YFC0907704) and the Fundamental Research Funds for the Central Universities of China (No. 2017SCU11049).

Author information

Author notes

  1. Ziyan Shi and Ling Feng contributed equally to this work and should be considered as joint first authors

Authors and Affiliations

  1. Department of Neurology, West China Hospital, Sichuan University, No.28 Dianxin Nan Street, Chengdu, 610041, Sichuan, China

    Ziyan Shi, Ling Feng, Zhiyun Lian, Ju Liu, Hongxi Chen, Qin Du, Ying Zhang, Qin Zhang & Hongyu Zhou

  2. Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Mu Yang

  3. Translational Centre for Oncoimmunology, Sichuan Cancer Hospital and research Institute, Sichuan Cancer Center, No.55 South Renmin Road, Chengdu, 610000, China

    Mu Yang

Authors
  1. Ziyan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiyun Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ju Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongxi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qin Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hongyu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mu Yang or Hongyu Zhou.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

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

Electronic supplementary material

ESM 1

(DOCX 704 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, Z., Feng, L., Lian, Z. et al. Decreased mRNA Expressions of CD40L in Patients with Neuromyelitis Optica Spectrum Disorder. J Mol Neurosci 70, 610–617 (2020). https://doi.org/10.1007/s12031-019-01467-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-019-01467-w

Keywords

Search

Navigation