Evaluation of Regulatory T-Cells (Tregs) in Benign Prostatic Pathologies: A Pilot Study
Yıl 2021,
Cilt: 16 Sayı: 1, 1 - 6, 08.02.2021
Erhan Ateş
,
Akın Amasyalı
Erman Oryaşın
,
İrfan Yavaşoğlu
Mustafa Yılmaz
Bülent Bozdoğan
,
Haluk Erol
Öz
Objective: We aimed to evaluate the number and function of regulatory T (Treg) cells in peripheral blood and prostate tissues of patients with histopathologically diagnosed benign prostate hyperplasia (BPH) and asymptomatic chronic prostatitis.
Material and Methods: Blood and histopathological data of 19 patients (BPH=10, ACP=9) that underwent transurethral prostate resection were evaluated. Treg cell count in peripheral blood and prostatic tissue with flowcytometry, Forkhead box P3 (FOXP3) expression in prostatic tissue by reverse transcription polymerase chain reaction (PCR), and IL-17 measurement in blood samples with ELISA were performed.
Results: Flowcytometric analyses showed that mean CD4+T cell count and mean FOXP3 levels in both peripheral blood (CD4+T, p= 0.752; FOXP3, p= 1.000) and prostate tissue (CD4+T, p= 0.458; FOXP3, p= 0.590) were higher in the BPH group compared to the chronic prostatitis group. However this difference was not statistically significant. Similarly, the mean blood IL-17 levels were also higher in BPH groups, but the difference was not statistically significant (p= 0.870). The PCR analyses showed that mean FOXP3 gene expression in the tissue was higher in the chronic prostate group, but again there was no statistically significant difference between the groups (p= 0.116).
Conclusion: Since no statistically significant difference was found between BPH and chronic prostatitis in terms of Treg cell number and function in peripheral blood and prostatic tissue, our study supports the thesis that both these pathologies could be autoimmune inflammatory diseases.
Kaynakça
- 1. Delongchamps NB, de la Roza G, Chandan V, Jones R, Sunheimer R, Threatte G, Jumbelic M, Haas GP. Evaluation of prostatitis in autopsied prostates--is chronic inflammation more associated with benign prostatic hyperplasia or cancer? J Urol 2008; 179:1736-40.
- 2. Potts JM: Prospective identification of National Institutes of Health category IV prostatitis in men with elevated prostate specific antigen. J Urol 2000; 164:1550-3.
- 3. Nickel JC, Roehrborn CG, O’Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. Examination of the relationship between symptoms of prostatitis and histologic inflammation: baseline data from the REDUCE chemoprevention trial. J Urol 2007;178:896-901.
- 4. Nickel JC, Downey J, Young I, Boag S. Asymptomatic inflammation and/or infection in benign prostatic hyperplasia. BJU Int 1999; 84:976-81.
- 5. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. NatRevCancer 2007; 7: 256–69.
- 6. Bostwick DG, de la Roza G, Dundore P, Corica FA, Iczkowski KA. Intraepithelial and stromal lymphocytes in the normal humanprostate. Prostate 2003; 55: 187–93.
- 7. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–45
- 8. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self tolerans and negative control of immune responses. Ann Rev Immunol 2004;22:531-62.
- 9. Valenci A, Lipsky PE. CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol. 2007 Nov;3(11):619-26.
- 10. Steiner GE, Stix U, Handisurya A. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Invest 2003;83:1131– 46.
- 11. Kramer G, Steiner GE, Handisurya A, Stix U, Haitel A, Knerer B, Gessl A, Lee C, Marberger M. Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate 2002;52:43–58.
- 12. Steiner GE, Newman ME, Paikl D, Stix U, Memaran-Dagda N, Lee C, Marberger MJ. Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 2003;56:171–82.
- 13. Jin X, Lin T, Yang G, Cai H, Tang B, Liao X, Li H, Chen X, Gong L, Xu H, Sun Y, Tan P, Yin J, Ma H, Ai J, Wang K, Wei Q, Yang L, Li H. Use of Tregs as a cell-based therapy via CD39 for benign prostate hyperplasia with inflammation. J Cell Mol Med. 2020 May;24(9):5082-96.
- 14. Bai J, Wang S, Liu J, Ye Z, Yu X, Xi Q, Hu D, Su S. Characterization of circulating CD4+CD25 high regulatory T cells in men with chronic prostatitis/chronic pelvic pain syndrome. Urology2010; 75: 938–42.
- 15. Daniels N, Ewing S, Zmuda J, Wilt T, Bauer D. Correlates and prevalence of prostatitis in a large community-based cohort of older men. Urology 2006;66(5):964-70.
- 16. Theyer G, Kramer G, Assmann I, Sherwood E, Preinfalk W, Marberger M, Zechner O, Steiner GE. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab Invest 1992;66:96–107.
- 17. Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006;18:349–56.
- 18. Wan YY, Flavell RD. How diverse- CD4 effector T cells and their functions. J Mol Cell Biol 2009;1:20-36.
- 19. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17- deficient mice. J Immunol 2003;171:6173–7.
- 20. Kramer G, Marberger M. Could inflammation be a key component in the progression of benign prostatic hyperplasia? Curr Opin Urol 2006; 16:25–9.
- 21. Wang L, Yang JR, Yang LY, Liu ZT. Chronic inflammation in benign prostatic hyperplasia: implications for therapy. Med Hypotheses 2008; 70:1021–3.
- 22. Penna G, Fibbi B, Amuchastegui S, Cossetti C, Aquilano F, Laverny G, Gacci M, Crescioli C, Maggi M, Adorini L. Human benign prostatic hyperplasia stromal cells as inducers and targets of chronic immuno-mediated inflammation. J Immunol 2009; 182:4056–64.
- 23. De Nunzio C, Kramer G, Marberger M, Montironi R, Nelson W, Schröder F, Sciarra A, Tubaro A. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. EurUrol 2011; 60:106–17.
- 24. Ablin RJ, Gonder MJ, Soanes WA. Localization of immunoglobulins in human prostatic tissue. J Immunol 1971 Aug;107(2):603-4.
- 25. Ponniah S, Arah I, Alexander RB. PSA is a candidate self antigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome. Prostate 2000;44:49–54.
- 26. Davidsson S, Andren O, Ohlson AL, Carlsson J, Andersson SO, Giunchi F, Rider JR, Fiorentino M. FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer. Prostate. 2018;78(1):40-7.
- 27. López–Hoyos M, Segundo DS, Fernández-Fresnedo G, Marin MJ, González-Martin V, Arias M. Regulatory T cells in renal transplantation and modulation by immunosuppression. Transplantation 2009; 88: 31-9.
- 28. Gupta S, Shang W, Sun Z. Mechanisms regulating the development and function of natural regulatory T cells. Arch Immunol Ther Exp. 2008;56:85-102.
Benign Prostatik Patolojilerde Regülatuvar T Hücrelerinin (Treg) Değerlendirilmesi: Pilot Çalışma
Yıl 2021,
Cilt: 16 Sayı: 1, 1 - 6, 08.02.2021
Erhan Ateş
,
Akın Amasyalı
Erman Oryaşın
,
İrfan Yavaşoğlu
Mustafa Yılmaz
Bülent Bozdoğan
,
Haluk Erol
Öz
Amaç: Histopatolojik olarak benign prostat hiperplazisi (BPH) ve asemptomatik kronik prostatit(AKP) tanısı alan hastaların periferik kan ve prostat dokularındaki regülatuvar T (Treg) hücrelerinin sayı ve işlevini değerlendirmeyi amaçladık.
Gereç ve Yöntemler: Transüretral prostat rezeksiyonu yapılan 19 hastanın (BPH = 10, AKP = 9) kan ve histopatolojik verileri değerlendirildi. Flowsitometri ile periferik kan ve prostat dokusunda Treg hücre sayımı, revers transkripsiyon polimeraz zincir reaksiyonu (PCR) ile prostatik dokuda Forkhead box P3 (FOXP3) ekspresyonu ve ELISA ile kan örneklerinde IL-17 ölçümü yapıldı.
Bulgular: Flowsitometrik analizler, hem periferik kanda (CD4 + T, p = 0.752; FOXP3, p = 1.000) hem de prostat dokusunda (CD4 + T, p = 0.458; FOXP3, p = 0.590) ortalama CD4 + T hücre sayısı ve ortalama FOXP3 düzeylerinin BPH grubunda kronik prostatit grubuna göre daha yüksek olduğunu göstermiştir. Ancak bu fark istatistiksel olarak anlamlı değildi. Benzer şekilde, ortalama IL-17 seviyeleri de BPH grubunda yüksekti, ancak fark istatistiksel olarak anlamlı değildi (p = 0.870). PCR analizleri, dokudaki ortalama FOXP3 gen ekspresyonunun kronik prostat grubunda daha yüksek olduğunu, ancak yine gruplar arasında istatistiksel olarak anlamlı bir fark olmadığını gösterdi (p = 0.116).
Sonuç: Periferik kandaki ve prostatik dokusundaki Treg hücre sayısı ve fonksiyonu açısından BPH ile kronik prostatit arasında istatistiksel olarak anlamlı bir fark bulunamadığından, çalışmamız her iki patolojinin de otoimmün inflamatuvar hastalıklar olabileceği tezini desteklemektedir.
Kaynakça
- 1. Delongchamps NB, de la Roza G, Chandan V, Jones R, Sunheimer R, Threatte G, Jumbelic M, Haas GP. Evaluation of prostatitis in autopsied prostates--is chronic inflammation more associated with benign prostatic hyperplasia or cancer? J Urol 2008; 179:1736-40.
- 2. Potts JM: Prospective identification of National Institutes of Health category IV prostatitis in men with elevated prostate specific antigen. J Urol 2000; 164:1550-3.
- 3. Nickel JC, Roehrborn CG, O’Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. Examination of the relationship between symptoms of prostatitis and histologic inflammation: baseline data from the REDUCE chemoprevention trial. J Urol 2007;178:896-901.
- 4. Nickel JC, Downey J, Young I, Boag S. Asymptomatic inflammation and/or infection in benign prostatic hyperplasia. BJU Int 1999; 84:976-81.
- 5. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. NatRevCancer 2007; 7: 256–69.
- 6. Bostwick DG, de la Roza G, Dundore P, Corica FA, Iczkowski KA. Intraepithelial and stromal lymphocytes in the normal humanprostate. Prostate 2003; 55: 187–93.
- 7. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–45
- 8. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self tolerans and negative control of immune responses. Ann Rev Immunol 2004;22:531-62.
- 9. Valenci A, Lipsky PE. CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol. 2007 Nov;3(11):619-26.
- 10. Steiner GE, Stix U, Handisurya A. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Invest 2003;83:1131– 46.
- 11. Kramer G, Steiner GE, Handisurya A, Stix U, Haitel A, Knerer B, Gessl A, Lee C, Marberger M. Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate 2002;52:43–58.
- 12. Steiner GE, Newman ME, Paikl D, Stix U, Memaran-Dagda N, Lee C, Marberger MJ. Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 2003;56:171–82.
- 13. Jin X, Lin T, Yang G, Cai H, Tang B, Liao X, Li H, Chen X, Gong L, Xu H, Sun Y, Tan P, Yin J, Ma H, Ai J, Wang K, Wei Q, Yang L, Li H. Use of Tregs as a cell-based therapy via CD39 for benign prostate hyperplasia with inflammation. J Cell Mol Med. 2020 May;24(9):5082-96.
- 14. Bai J, Wang S, Liu J, Ye Z, Yu X, Xi Q, Hu D, Su S. Characterization of circulating CD4+CD25 high regulatory T cells in men with chronic prostatitis/chronic pelvic pain syndrome. Urology2010; 75: 938–42.
- 15. Daniels N, Ewing S, Zmuda J, Wilt T, Bauer D. Correlates and prevalence of prostatitis in a large community-based cohort of older men. Urology 2006;66(5):964-70.
- 16. Theyer G, Kramer G, Assmann I, Sherwood E, Preinfalk W, Marberger M, Zechner O, Steiner GE. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab Invest 1992;66:96–107.
- 17. Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006;18:349–56.
- 18. Wan YY, Flavell RD. How diverse- CD4 effector T cells and their functions. J Mol Cell Biol 2009;1:20-36.
- 19. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17- deficient mice. J Immunol 2003;171:6173–7.
- 20. Kramer G, Marberger M. Could inflammation be a key component in the progression of benign prostatic hyperplasia? Curr Opin Urol 2006; 16:25–9.
- 21. Wang L, Yang JR, Yang LY, Liu ZT. Chronic inflammation in benign prostatic hyperplasia: implications for therapy. Med Hypotheses 2008; 70:1021–3.
- 22. Penna G, Fibbi B, Amuchastegui S, Cossetti C, Aquilano F, Laverny G, Gacci M, Crescioli C, Maggi M, Adorini L. Human benign prostatic hyperplasia stromal cells as inducers and targets of chronic immuno-mediated inflammation. J Immunol 2009; 182:4056–64.
- 23. De Nunzio C, Kramer G, Marberger M, Montironi R, Nelson W, Schröder F, Sciarra A, Tubaro A. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. EurUrol 2011; 60:106–17.
- 24. Ablin RJ, Gonder MJ, Soanes WA. Localization of immunoglobulins in human prostatic tissue. J Immunol 1971 Aug;107(2):603-4.
- 25. Ponniah S, Arah I, Alexander RB. PSA is a candidate self antigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome. Prostate 2000;44:49–54.
- 26. Davidsson S, Andren O, Ohlson AL, Carlsson J, Andersson SO, Giunchi F, Rider JR, Fiorentino M. FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer. Prostate. 2018;78(1):40-7.
- 27. López–Hoyos M, Segundo DS, Fernández-Fresnedo G, Marin MJ, González-Martin V, Arias M. Regulatory T cells in renal transplantation and modulation by immunosuppression. Transplantation 2009; 88: 31-9.
- 28. Gupta S, Shang W, Sun Z. Mechanisms regulating the development and function of natural regulatory T cells. Arch Immunol Ther Exp. 2008;56:85-102.