Journal of Clinical Immunology

, Volume 28, Issue 1, pp 36–43 | Cite as

Aberrant Expression of Soluble Co-stimulatory Molecules and Adhesion Molecules in Type 2 Diabetic Patients with Nephropathy

  • C. K. Wong
  • Amy W. Y. Ho
  • Peter C. Y. Tong
  • C. Y. Yeung
  • Juliana C. N. Chan
  • Alice P. S. Kong
  • Christopher W. K. Lam


Co-stimulatory molecules together with leukocyte adhesion molecules are important for T lymphocyte and leukocyte-mediated inflammatory responses. We investigated the soluble costimulatory molecules CD80, CD86, CD28, and CTLA-4 and soluble adhesion molecules in plasma of 94 type 2 diabetic patients with or without nephropathy (DN and NDN) and 20 healthy controls. Plasma concentration of sCTLA-4 was significantly lower, whereas sCD28 was significantly higher in DN patients than that in control subjects (all P < 0.05). sCD28 and sCD80 were found to be positively correlated with fasting urine albumin: creatinine ratio in DN patients but not in NDN patients. Elevated soluble adhesion molecule vascular cell adhesion molecule-1 and P-selectin could be related with the disease severity of DN (all P < 0.05). Therefore, the aberrant expression of soluble co-stimulatory molecules and adhesion molecules can be related to the activation of T cells and leukocytes in the progression of inflammation in diabetic nephropathy.


Adhesion molecules Co-stimulatory molecules Diabetic nephropathy 



The study was supported by a Direct Grant for Research, The Chinese University of Hong Kong.


  1. 1.
    Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27:813–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Madonna R, Pandolfi A, Massaro M, Consoli A, De Caterina R. Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein- kinase. Diabetologia. 2004;47:532–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Wong CK, Ho AWY, Tong PCY, et al. Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with diabetic nephropathy. Clin Exp Immunol. 2007;149:123–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Chambers CA, Allison JP. Co-stimulation in T cell responses. Curr Opin Immunol. 1997;9:396–404.PubMedCrossRefGoogle Scholar
  5. 5.
    Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review. Crit Rev Immunol. 1998;18:389–418.PubMedGoogle Scholar
  6. 6.
    Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci USA. 1990;87:5031–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Sfikakis PP, Via CS. Expression of CD28, CTLA4, CD80, and CD86 molecules in patients with autoimmune rheumatic diseases: implications for immunotherapy. Clin Immunol Immunopathol. 1997;83:195–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001;19:225–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Wong CK, Lun SWM, Ko FWS, Ip WK, Hui DSC, Lam CWK. Increased expression of plasma and cell surface costimulatory molecules CTLA-4, CD28 and CD86 in adultpatients with allergic asthma. Clin Exp Immunol. 2005;141:122–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Wong CK, Lit LCW, Li EKM, Tam LS, Lam CWK. Aberrant production of soluble costimulatory molecules CTLA-4, CD28, CD80 and CD86 in patients with systemic lupus erythematosus. Rheumatology. 2005;44:989–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Chiappara G, Gagliardo R, Siena A, et al. Airway remodelling in the pathogenesis of asthma. Curr Opin Allergy Clin Immunol. 2001;1:85–93.PubMedGoogle Scholar
  14. 14.
    Radi ZA, Kehrli ME Jr, Ackermann MR. Cell adhesion molecules, leukocyte trafficking, and strategies to reduce leukocyte infiltration. J Vet Intern Med. 2001;15:516–29.PubMedCrossRefGoogle Scholar
  15. 15.
    Mora C, Navarro JF. Inflammation and diabetic nephropathy. Curr Diab Rep. 2006;6:463–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Wong CK, Wang CB, Li MLY, Ip WK, Tian YP, Lam CWK. Induction of adhesion molecules upon the interaction between eosinophils and epithelial cells: Involvement of p38 MAPK and NF-κB. Int Immunopharmacology. 2006;6:1859–71.CrossRefGoogle Scholar
  17. 17.
    Jarvisalo MJ, Juonala M, Raitakari OT. Assessment of inflammatory markers and endothelial function. Curr Opin Clin Nutr Metab Care. 2006;9:547–52.PubMedCrossRefGoogle Scholar
  18. 18.
    World Health Organization Technical report series 727. Diabetes Mellitus. Geneva: WHO; 1985.Google Scholar
  19. 19.
    Viallard JF, Pellegrin JL, Ranchin V. Th1 (IL-2, interferon-gamma (IFN-gamma)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1999;115:189–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF. Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve. 2003;28:659–82.PubMedCrossRefGoogle Scholar
  21. 21.
    Wong CK, Szeto CC, Chan MHM, Leung CB, Li PKT, Lam CWK. Elevation of pro-inflammatory cytokines, C-reactive protein and cardiac troponin T in chronic renal failure patients on dialysis. Immunol Invest. 2007;36:47–57.PubMedCrossRefGoogle Scholar
  22. 22.
    Oaks MK, Hallett KM, Penwell RT, Stauber EC, Warren SJ, Tector AJ. A native soluble form of CTLA-4. Cell Immunol. 2000;201:144–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Magistrelli G, Jeannin P, Elson G. Identification of three alternatively spliced variants of human CD28 mRNA. Biochem Biophys Res Commun. 1999;259:34–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Hebbar M, Jeannin P, Magistrelli G, et al. Detection of circulating soluble CD28 in patients with systemic lupus erythematosus, primary Sjogren's syndrome and systemic sclerosis. Clin Exp Immunol. 2004;136:388–92.PubMedCrossRefGoogle Scholar
  25. 25.
    Orabona C, Grohmann U, Belladonna ML, et al. CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nat Immunol. 2004;5:1134–42.PubMedCrossRefGoogle Scholar
  26. 26.
    del Aguila LF, Claffey KP, Kirwan JP. TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol. 1999;276:E849–55.PubMedGoogle Scholar
  27. 27.
    Park CW, Kim JH, Lee JH, et al. High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-kappa B-dependent. Diabetologia. 2000;43:1544–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Tesch GH. Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol. 2005;16:1711–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Guler S, Cakir B, Demirbas B, et al. Plasma soluble intercellular adhesion molecule 1 levels are increased in type 2 diabetic patients with nephropathy. Horm Res. 2002;58:67–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Knudsen H, Andersen CB, Ladefoged SD. Expression of the intercellular adhesion molecule-3 (ICAM-3) in human renal tissue with relation to kidney transplants and various inflammatory diseases. APMIS. 1995;103:593–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Berney SM, Schaan T, Alexander JS, et al. ICAM-3 (CD50) cross-linking augments signaling in CD3-activated peripheral human T lymphocytes. J Leukoc Biol. 1999;65:867–74.PubMedGoogle Scholar
  32. 32.
    Montoya MC, Sancho D, Bonello G, et al. Role of ICAM-3 in the initial interaction of T lymphocytes and APCs. Nat Immunol. 2002;3:159–68.PubMedCrossRefGoogle Scholar
  33. 33.
    Murakami H, Tamasawa N, Matsui J, Yamato K, JingZhi G, Suda T. Plasma levels of soluble vascular adhesion molecule-1 and cholesterol oxidation product in type 2 diabetic patients with nephropathy. J Atheroscler Thromb. 2001;8:21–4.PubMedGoogle Scholar
  34. 34.
    Newman PJ. The biology of PECAM-1. J Clin Invest. 1997;100:S25–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Figarella-Branger D, Schleinitz N, Boutiere-Albanese B, et al. Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and in situ expression of cellular adhesion molecules implicated in the cohesion of endothelial cells in idiopathic inflammatory myopathies. J Rheumatol. 2006;33:1623–30.PubMedGoogle Scholar
  36. 36.
    Ilan N, Madri JA. PECAM-1: old friend, new partners. Curr Opin Cell Biol. 2003;15:515–24.PubMedCrossRefGoogle Scholar
  37. 37.
    Hirata K, Shikata K, Matsuda M. Increased expression of selectins in kidneys of patients with diabetic nephropathy. Diabetologia. 1998;41:185–92.PubMedCrossRefGoogle Scholar
  38. 38.
    Andre P, Hartwell D, Hrachovinova I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A. 2000;97:13835–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • C. K. Wong
    • 1
  • Amy W. Y. Ho
    • 1
  • Peter C. Y. Tong
    • 2
  • C. Y. Yeung
    • 2
  • Juliana C. N. Chan
    • 2
  • Alice P. S. Kong
    • 2
  • Christopher W. K. Lam
    • 1
    • 3
  1. 1.Department of Chemical PathologyThe Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
  2. 2.Department of Medicine and TherapeuticsThe Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
  3. 3.Macau Institute for Applied Research in Medicine and HealthMacau University of Science and Technology FoundationTaipaMacau

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