The roles of urine interleukin-13, CD80, CD28, matrix metalloproteinase-2 and granzyme B in the pathogenesis of childhood minimal change nephrotic syndrome

Abstract

Objective: Minimal change disease (MCD) is the most common cause of nephrotic syndrome in childhood but its pathogenesis remains poorly understood. A T-cell-derived factor or factors were initially alleged as contributing to the disease pathogenesis. However, podocyte CD80 expression is now a commonly discussed theory. The aim of this study was to investigate the pathogenesis of MCD by determining urine interleukin-13, CD80, CD28, matrix metalloproteinase-2 (MMP-2), and granzyme B levels. Methods: Thirty patients and thirty healthy children were evaluated in this study. Six patients had biopsy proven MCD. The remaining patients were considered to have MCD because of their age at time of diagnosis; response to steroid treatment, absence of gross hematuria, hypocomplementemia or renal failure; and normal blood pressures in the active stage. The nephrotic-phase urine interleukin-13, CD80, CD28, MMP-2, and granzyme B levels of all patients were compared with the remission-stage urine levels of the same patients and control subjects. The urine samples were collected immediately before the application of immunosuppressive drugs or other treatment modalities. Results: Significantly higher interleukin-13, CD80, CD28, and MMP-2 levels were observed in the relapse period compared with both the remission period and control subjects. There was a significant positive correlation between the active-stage urine interleukin-13 and CD80 levels (r=0.619, p

Keywords

• Minimal change disease, Interleukin-13, B7 proteins, MMP-2, granzyme B

İdrar interlökin-13, CD80, CD28, matriks metaloproteinaz-2 ve granzim B‘nin çocukluk çağı minimal değişim nefrotik sendrom patogenezindeki rolleri

Öz

Amaç: Minimal değişiklik hastalığı çocuklarda nefrotik sendromun en sık nedenidir ve patogenezi hala aydınlatılamamıştır. Başlangıçta T hücresi kaynaklı faktör ya da faktörlerin hastalığın patogenezinden sorumlu olduğu ileri sürülmüştür. Fakat günümüzde hastalığın patogenezinde podosit CD80 ekspresyonu ön plana çıkmıştır. Bizim bu çalışmada amacımız hastaların idrar interlökin-13, CD80, CD28, matriks metaloproteinaz-2 ve granzim b düzeylerine bakarak hastalığın patogenezini anlamaya çalışmaktır. Yöntemler: Bu amaçla 30 hasta ve 30 sağlıklı çocuktan oluşan kontrol grubu ile çalıştık. 6 hastanın biyopsi sonucu minimal değişiklik hastalığı idi. Diğer hastalara hastalığın ilk aktif dönemindeki başlangıç yaşı, steroid tedavisine verdikleri cevap, hastalığın tanısı sırasında gros hematüri, hipokomplementemi, renal yetmezlik ve hipertansiyon olmaması nedeniyle minimal değişiklik hastalığı tanısı konuldu. Hastaların aktif faz idrar interlökin-13, CD80, CD28, matriks metaloproteinaz-2 ve granzim b düzeyleri aynı hastaların remisyon dönemi ve kontrol grubu ile karşılaştırıldı. İmmünsüpresif ilaçlar ya da diğer tedavi modaliteleri başlamadan hemen önce idrar örnekleri alındı. Bulgular: Hastalığın aktif döneminde remisyon ve kontrol grubuna göre istatistiksel olarak anlamlı idrar interlökin-13, CD80, CD28 ve MMP-2 yüksekliği saptadık. Nefrotik faz idrar interlökin-13 düzeyleri ile CD80 düzeyleri arasında pozitif korelasyon mevcuttu (r=0,619, p

Anahtar Kelimeler

• Minimal değişiklik hastalığı, interlökin-13, B7 proteinleri, MMP-2, granzim B

References

1. Niaudet P, Boyer O. Idiopathic Nephrotic Syndrome in Children: Clinical Aspects. In Ellis D. Avner (ed.) Pedi- atric Nephrology. 6th ed. Springer-Verlag, Heidelberg; 2009, pp 667-702.
2. Shalhoub RJ. Pathogenesis of lipoid nephrosis: A dis- order of T cell function. Lancet 1974;2:556-560.
3. Tejani AT, Butt K, Trachtman H, et al. Cyclosporine A induced remission of relapsing nephrotic syndrome in children. Kidney Int 1988;33:729-734.
4. Ali AA, Wilson E, Moorhead JF, et al. Minimal change glomerular nephritis. Normal kidneys in an abnormal environment? Transplantation 1994;58:849-852.
5. Koyama A, Fujisaki M, Kobayashi M, et al. A glomeruler permeability factor produced by human T cell hybrid- omas. Kidney Int 1991; 40: 453-460.
6. Lagrue G, Laurent J. Allergy and lipoid nephrosis. Adv Nephrol Necker Hosp 1983;12:151-175.
7. Yokoyama H, Kida H, Tani Y, et al. Immunodynamics of minimal change nephrotic syndrome in adults T and B lymphocyte subsets and serum Ig levels. Clin Exp Immunol 1985;61:601-607.
8. Izuhara K, Arima K, Yasunaga S, et al. IL-4 and IL-13: Their pathological roles in allergic diseases and their potential in developing new therapies. Curr Drug Tar- gets Inflamm Allergy 2002;1:263-269.

9. Lai KW, Wei CL, Tan LK, et al. Overexpression of inter- leukin-13 induces minimal change like nephropathy in rats. J Am Soc Nephrol 2007;18:1476-1485.
10. Reiser J, von Gersdorff G, Loos M, et al. Induction of B7-1 in podocytes is associated with nephrotic syn- drome. J Clin Invest 2004;113:1390-1397.
11. Garin EH, Diaz LN, Mu W, et al. Urinary CD80 excre- tion increases in idiopathic minimal change disease. J Am Soc Nephrol 2009;20:260-266.
12. Garin E, Mu W, Arthur JM, et al. Urinary CD80 is el- evated in minimal change disease but not in focal seg- mental glomerulosclerosis. Kidney Int 2010;78:296- 302.
13. Abbas AK, Lichtman AH, Pillai S. Cellular and Mo- lecular Immunology. Saunders Elsevier, Philadelphia; 2010, pp 194-198.
14. Urushihara M, Kagami S, Kuhara T, et al. Glomerular distribution and gelatinolytic activity of matrix metal- loproteinases in human glomerulonephritis. Nephrol Dial Transplant. 2002;17:1189-1196.
15. Wasilewska AM, Zoch-Zwiers WM. Urinary levels of matrix metalloproteinases and their tissue inhibitors in nephrotic children. Pediatr Nephrol 2008;23:1795- 1802.
16. Czech AK, Bennett M, Devarajan P. Distinct metallo- proteinase excretion patterns in focal segmental glo- merulosclerosis. Pediatr Nephrol 2011;26:2179-2184.
17. Afonina I, Cullen S, Martin SJ. Cytotoxic and non- cytotoxic roles of the CTL/NK protease granzyme B. Immunol Rev 2010;235:105-116.
18. Araya C, Diaz L, Wasserfall C, et al. T regulatory cell function in idiopathic minimal lesion nephrotic syn- drome. Pediatr Nephrol 2009;24:1691-1698.
19. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lym- phocytes. Blood 2006;107:3925-3932.
20. Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-me- diated suppression of tumor clearance. Immunity 2007;27:635-646.
21. Musial K, Ciszak L, Kosmaczewska A, et al. Zeta chain expression in T and NK cells in peripheral blood of children with nephrotic children. Pediatr Nephrol 2010;25:119-127.
22. Nephrotic syndrome in children: prediction of histopa- thology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int 1978;13:159- 165.
23. Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629-637.
24. Viqnali DA. Multiplexed particle-based flow cytometric assays. J Immunol Methods 2000;243:243-255.
25. Yap HK, Cheung W, Murugasu B, et al. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syn- drome: evidence for increased IL-13 mRNA expres- sion in relapse. J Am Soc Nephrol 1999;10:529-537.
26. Yiğit O, Acioğlu E, Gelişgen R, et al. The effect of of corticosteroid on metalloproteinase levels of nasal polyposis. Laryngoscope 2011;121:667-673.
27. Weitoft T, Larsson A, Rönnblom L. Serum levels of sex steroids hormones and matrix metalloproteinases after intra-articular glucocorticoid treatment in female patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:422-424.
28. Reiser J, Mundel P. Danger signaling by glomerular podocytes defines a novel function of inducible B7-1 in the pathogenesis of nephrotic syndrome. J Am Soc Nephrol 2004;15:2246-2248.
29. Pacquement H, Sinnassamy P, Quintana E, et al. Nephrotic syndrome and B leukemia. Arch Fr Pediatr 1989;46:741-742.
30. Shimada M, Araya C, Rivard C, et al. Minimal change diasease: a “two hit” podocyte immun disorder? Pedi- atr Nephrol 2011;26:645-649.
31. Parry RG, Gillespie KM, Mathieson PW. Effects of type 2 cytokines on glomerular epithelial cells. Exp Nephrol 2001;9:275-283.
32. Tang QZ, Henriksen KJ, Boden EK, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 2003;171:3348-3352.
33. Takabatake Y, Li XK, Mizui M, et al. A superagonistic monoclonal antibody for CD28 ameliorates crescen- tic glomerulonephritis in wistar-kyoto rats. Mol Med 2011;17:686-696.
34. Miyasato K, Takabatake Y, Kaimori J, et al. CD28 su- peragonist-induced regulatory T cell expansion ame- liorates mesangioproliferative glomerulonephritis in rats. Clin Exp Nephrol 2011;15:50-57.
35. Eddy AA. Molecular insights into renal interstitial fibro- sis. J Am Soc Nephrol 1996;7:2495-2508.
36. Lenz O, Elliot SJ, Stetler-Stevenson WG. Matrix me- talloproteinases in renal development and disease. J Am Soc Nephrol 2000;11:574-581.
37. Tobbli JE, Bevione P, Di Gennaro F, et al. Understand- ing the mechanisms of proteinuria: therapeutic impli- cations. Int J Nephrol 2012;2012:546039.
38. Fanq Z, He F, Chen S, et al. Albumin modulates the production of matrix metalloproteinase-2 and -9 in podocytes. J Huazhonq Univ Sci Technoloq Med Sci 2009;29:710-714.
39. Baricos WH, Murphy G, Zhou YW, et al. Degradation of glomerular basement membrane by purified mam- malian metalloproteinases. Biochem J 1988;254:609- 612.
40. Endo T, Nakabayashi K, Sekiuchi M, et al. Matrix me- talloproteinase-2, matrix metalloproteinase-9, and tis- sue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: study based on an enzyme-linked assay and immunohisto- chemical staining. Clin Exp Nephrol 2006;10:253-261.
41. Kaneko K, Tuchiya K, Fujinaga R, et al. Th1/Th2 bal- ance in childhood idiopathic nephrotic syndrome. Clin Nephrol 2002;58:393-397.
42. Irving BA, Chan AC, Weiss A. Functional characteriza- tion of signal transducing motif present in the T cell an- tigen receptor zeta chain. J Exp Med. 1993;177:1093- 1103.
43. Bronstein-Sitton N, Wang L, Cuhen L, Baniyash M. Expression of the T cell antigen receptor zeta chain following activation is controlled at distinct check- points. J Biol Chem 1999;274:23659-23665.
44. Fujinaka H, Yamamoto T, Feng L, et al. Anti-perforin antibody treatment ameliorates experimental cres- centic glomerulonephritis in WKY rats. Kidney Int 2007;72:823-830.
45. von Kempis J, Dudler J, Hasler P et al. Use of abatacept in rheumatoid arthritis. Swiss Med Wkly. 2012;142: w13581.
46. Gallagher MP, Goland RS, Greenbaum CJ. Making progress: preserving beta cells in type 1 diabetes. Ann N Y Acad Sci 2011;1243:119-134.
47. Viglietta V, Bourcier K, Buckle GJ, et al. CTLA4Ig treatment in patients with multiple sclerosis: an open- label, phase 1 clinical trial. Neurology 2008; 71: 917- 924.
48. Mok CC. Abatacept for systemic erythematosus: the outlook. Expert Opin Biol Ther 2012 ;12:1559-1561.
49. Weisman MH, Durez P, Hallegua D, et al. Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. J Rheumatol 2006;33:2162-2166.
50. Álvarez-Quiroga C, Abud-Mendoza C, Doníz-Padilla L, et al. CTLA-4-Ig therapy diminishes the frequency but enhances the function of Treg cells in patients with rheumatoid arthritis. J Clin Immunol 2011;31:588-595.
51. Corren J, Lemanske RF, Hanania NA et al. Lebriki- zumab treatment in adults with asthma. N Engl J Med 2011;365:1088-1098.
52. Steinmann-Niggli K, Ziswiler R, Kung M, Marti HP. In- hibition of matrix metalloproteinases attenuates anti- Thy 1.1 nephritis. J Am Soc Nephrol 1998;9:397-407.