Abstract
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), characterized by chronic pain in the perineum or lower abdomen regions, is a frequent disorder in men. Previous studies demonstrated that the immune mediators, including interleukin (IL)-1β, IL-6, interferon-γ, tumor necrosis factor-α, and immunoglobulins, are elevated in the expressed prostate secretions and seminal fluid of CP/CPPS men. The memory T, T helper 1 (Th1), Th17, and Th22 cells increase in the peripheral blood of CP/CPPS men. Additionally, prostate antigens specific-autoreactive T cells are identified in CP/CPPS patients. After generally reviewing and comparing the inflammatory responses in autoimmune diseases and CP/CPPS, we presumed that CP/CPPS is more likely to be defined as an autoimmune disease. Thus, a better understanding of autoimmune diseases would contribute to a deeper understanding of the CP/CPPS and provide new inspirations for the treatment of this disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Not applicable.
References
Abdelatif OM, Chandler FW, McGuire BS Jr (1991) Chlamydia trachomatis in chronic abacterial prostatitis: demonstration by colorimetric in situ hybridization. Hum Pathol 22:41–44. https://doi.org/10.1016/0046-8177(91)90059-x
Ablin RJ, Gonder MJ, Soanes WA (1971) Localization of immunoglobulins in human prostatic tissue. J Immunol 107:603–604
Alexander RB, Brady F, Ponniah S (1997) Autoimmune prostatitis: evidence of T cell reactivity with normal prostatic proteins. Urology 50:893–899. https://doi.org/10.1016/s0090-4295(97)00456-1
Awasthi A, Kumar H (2019) T cell subtypes and its therapeutic potential in autoimmune diseases and cancer. Int Rev Immunol 38:181–182. https://doi.org/10.1080/08830185.2019.1673472
Basdeo SA, Cluxton D, Sulaimani J et al (2017) Ex-Th17 (Nonclassical Th1) cells are functionally distinct from classical Th1 and Th17 cells and are not constrained by regulatory T cells. J Immunol 198:2249–2259. https://doi.org/10.4049/jimmunol.1600737
Bates S, Talbot M (2000) Short course oral prednisolone therapy in chronic abacterial prostatitis and prostatodynia: case reports of three responders and one non-responder. Sex Transm Infect 76:398–399. https://doi.org/10.1136/sti.76.5.398
Bates SM, Hill VA, Anderson JB et al (2007) A prospective, randomized, double-blind trial to evaluate the role of a short reducing course of oral corticosteroid therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome. BJU Int 99:355–359. https://doi.org/10.1111/j.1464-410X.2007.06667.x
Bettelli E, Sullivan B, Szabo SJ et al (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200:79–87. https://doi.org/10.1084/jem.20031819
Breser ML, Lino AC, Motrich RD et al (2016) Regulatory T cells control strain specific resistance to experimental autoimmune prostatitis. Sci Rep 6:33097. https://doi.org/10.1038/srep33097
Breser ML, Salazar FC, Rivero VE et al (2017) Immunological mechanisms underlying chronic pelvic pain and prostate inflammation in chronic pelvic pain syndrome. Front Immunol 8:898. https://doi.org/10.3389/fimmu.2017.00898
Chen J, Zhan C, Zhang L, Zhang L et al (2019) The hypermethylation of Foxp3 promoter impairs the function of Treg cells in EAP. Inflammation 42:1705–1718. https://doi.org/10.1007/s10753-019-01030-0
Dalhoff A, Shalit I (2003) Immunomodulatory effects of quinolones. Lancet Infect Dis 3:359–371. https://doi.org/10.1016/s1473-3099(03)00658-3
Dimitrakov J, Guthrie D (2009) Genetics and phenotyping of urological chronic pelvic pain syndrome. J Urol 181:1550–1557. https://doi.org/10.1016/j.juro.2008.11.119
Doble A, Walker MM, Harris JR et al (1990) Intraprostatic antibody deposition in chronic abacterial prostatitis. Br J Urol 65:598–605. https://doi.org/10.1111/j.1464-410x.1990.tb14827.x
Donadio AC, Depiante-Depaoli M (1997) Inflammatory cells and MHC class II antigens expression in prostate during time-course experimental autoimmune prostatitis development. Clin Immunol Immunopathol 85:158–165. https://doi.org/10.1006/clin.1997.4427
Dunphy EJ, Eickhoff JC, Muller CH et al (2004) Identification of antigen-specific IgG in sera from patients with chronic prostatitis. J Clin Immunol 24:492–502. https://doi.org/10.1023/B:JOCI.0000040920.96065.5a
Esensten JH, Muller YD, Bluestone JA et al (2018) Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: the next frontier. J Allergy Clin Immunol 142:1710–1718. https://doi.org/10.1016/j.jaci.2018.10.015
Fava A, Petri M (2019) Systemic lupus erythematosus: diagnosis and clinical management. J Autoimmun 96:1–13. https://doi.org/10.1016/j.jaut.2018.11.001
Franco JV, Turk T, Jung JH et al (2019) Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome. Cochrane Database Syst Rev 10:Cd012552. https://doi.org/10.1002/14651858.CD012552.pub2
Geem D, Harusato A, Flannigan K et al (2015) Harnessing regulatory T cells for the treatment of inflammatory bowel disease. Inflamm Bowel Dis 21:1409–1418. https://doi.org/10.1097/mib.0000000000000343
Ghilardi N, Pappu R, Arron JR et al (2020) 30 Years of biotherapeutics development-what have we learned? Annu Rev Immunol 38:249–287. https://doi.org/10.1146/annurev-immunol-101619-031510
Haase S, Linker RA (2021) Inflammation in multiple sclerosis. Ther Adv Neurol Disord 14:17562864211007688. https://doi.org/10.1177/17562864211007687
Habermacher GM, Chason JT, Schaeffer AJ (2006) Prostatitis/chronic pelvic pain syndrome. Annu Rev Med 57:195–206. https://doi.org/10.1146/annurev.med.57.011205.135654
Haribhai D, Chatila TA, Williams CB (2016) Immunotherapy with iTreg and nTreg cells in a murine model of inflammatory bowel disease. Methods Mol Biol 1422:197–211. https://doi.org/10.1007/978-1-4939-3603-8_19
Hill JA, Benoist C, Mathis D (2007) Treg cells: guardians for life. Nat Immunol 8:124–125. https://doi.org/10.1038/ni0207-124
Hou Y, DeVoss J, Dao V et al (2009) An aberrant prostate antigen-specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans. J Clin Investig 119:2031–2041. https://doi.org/10.1172/jci38332
Hou DS, Long WM, Shen J et al (2012) Characterisation of the bacterial community in expressed prostatic secretions from patients with chronic prostatitis/chronic pelvic pain syndrome and infertile men: a preliminary investigation. Asian J Androl 14:566–573. https://doi.org/10.1038/aja.2012.30
John H, Barghorn A, Funke G et al (2001) Noninflammatory chronic pelvic pain syndrome: immunological study in blood, ejaculate and prostate tissue. Eur Urol 39:72–78. https://doi.org/10.1159/000052415
John H, Maake C, Barghorn A et al (2003) Immunological alterations in the ejaculate of chronic prostatitis patients: clues for autoimmunity. Andrologia 35:294–299. https://doi.org/10.1046/j.1439-0272.2003.00573.x
Karatas OF, Turkay C, Bayrak O et al (2010) Helicobacter pylori seroprevalence in patients with chronic prostatitis: a pilot study. Scand J Urol Nephrol 44:91–94. https://doi.org/10.3109/00365590903535981
Keetch DW, Humphrey P, Ratliff TL (1994) Development of a mouse model for nonbacterial prostatitis. J Urol 152:247–250. https://doi.org/10.1016/s0022-5347(17)32871-9
Kouiavskaia DV, Southwood S, Berard CA et al (2009) T-cell recognition of prostatic peptides in men with chronic prostatitis/chronic pelvic pain syndrome. J Urol 182:2483–2489. https://doi.org/10.1016/j.juro.2009.07.067
Krieger JN, Nyberg L Jr, Nickel JC (1999) NIH consensus definition and classification of prostatitis. JAMA 282:236–237. https://doi.org/10.1001/jama.282.3.236
Krieger JN, Riley DE, Vesella RL et al (2000) Bacterial dna sequences in prostate tissue from patients with prostate cancer and chronic prostatitis. J Urol 164:1221–1228. https://doi.org/10.1016/S0022-5347(05)67145-5
Kuchroo VK, Ohashi PS, Sartor RB et al (2012) Dysregulation of immune homeostasis in autoimmune diseases. Nat Med 18:42–47. https://doi.org/10.1038/nm.2621
Kumar P, Saini S, Khan S et al (2019) Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells. Cell Immunol 339:41–49. https://doi.org/10.1016/j.cellimm.2018.09.008
Liu Y, Wazir J, Tang M et al (2021a) Experimental autoimmune prostatitis: different antigens induction and antigen-specific therapy. Int Urol Nephrol 53:607–618. https://doi.org/10.1007/s11255-020-02703-8
Liu Y, Zhang Y, Zhang M et al (2021b) Activated autophagy restored the impaired frequency and function of regulatory T cells in chronic prostatitis. Prostate 81:29–40. https://doi.org/10.1002/pros.24073
Lu JC, Shen JM, Hu XC et al (2018) Identification and preliminary study of immunogens involved in autoimmune prostatitis in human males. Prostate. https://doi.org/10.1002/pros.23684
Ma WT, Chang C, Gershwin ME et al (2017) Development of autoantibodies precedes clinical manifestations of autoimmune diseases: a comprehensive review. J Autoimmun 83:95–112. https://doi.org/10.1016/j.jaut.2017.07.003
Magistro G, Wagenlehner FM, Grabe M et al (2016) Contemporary management of chronic prostatitis/chronic pelvic pain syndrome. Eur Urol 69:286–297. https://doi.org/10.1016/j.eururo.2015.08.061
Meng LQ, Yang FY, Wang MS et al (2018) Quercetin protects against chronic prostatitis in rat model through NF-κB and MAPK signaling pathways. Prostate 78:790–800. https://doi.org/10.1002/pros.23536
Miller LJ, Fischer KA, Goralnick SJ et al (2002) Interleukin-10 levels in seminal plasma: implications for chronic prostatitis-chronic pelvic pain syndrome. J Urol 167(2 Pt 1):753–756
Motrich RD, Maccioni M, Molina R et al (2005) Presence of INFgamma-secreting lymphocytes specific to prostate antigens in a group of chronic prostatitis patients. Clin Immunol 116:149–157. https://doi.org/10.1016/j.clim.2005.03.011
Motrich RD, Breser ML, Molina RI et al (2020) Patients with chronic prostatitis/chronic pelvic pain syndrome show T helper type 1 (Th1) and Th17 self-reactive immune responses specific to prostate and seminal antigens and diminished semen quality. BJU Int 126:379–387. https://doi.org/10.1111/bju.15117
Murphy SF, Schaeffer AJ, Thumbikat P (2014) Immune mediators of chronic pelvic pain syndrome. Nat Rev Urol 11:259–269. https://doi.org/10.1038/nrurol.2014.63
Murphy SF, Anker JF, Mazur DJ et al (2019) Role of Gram-positive bacteria in chronic pelvic pain syndrome (CPPS). Prostate 79:160–167. https://doi.org/10.1002/pros.23721
Nadler RB, Koch AE, Calhoun EA et al (2000) IL-1beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis. J Urol 164:214–218
Nickel JC, Alexander RB, Schaeffer AJ et al (2003a) Leukocytes and bacteria in men with chronic prostatitis/chronic pelvic pain syndrome compared to asymptomatic controls. J Urol 170:818–822. https://doi.org/10.1097/01.ju.0000082252.49374.e9
Nickel JC, Downey J, Clark J et al (2003b) Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial. Urology 62:614–617. https://doi.org/10.1016/s0090-4295(03)00583-1
Nickel JC, Atkinson G, Krieger JN et al (2012) Preliminary assessment of safety and efficacy in proof-of-concept, randomized clinical trial of tanezumab for chronic prostatitis/chronic pelvic pain syndrome. Urology 80:1105–1110. https://doi.org/10.1016/j.urology.2012.07.035
Nickel JC, Stephens A, Landis JR et al (2015) Search for microorganisms in men with urologic chronic pelvic pain syndrome: a culture-independent analysis in the MAPP research network. J Urol 194:127–135. https://doi.org/10.1016/j.juro.2015.01.037
Pansadoro V, Emiliozzi P, Defidio L et al (1996) Prostate-specific antigen and prostatitis in men under fifty. Eur Urol 30:24–27. https://doi.org/10.1159/000474140
Papeš D, Pasini M, Jerončić A et al (2017) Detection of sexually transmitted pathogens in patients with chronic prostatitis/chronic pelvic pain: a prospective clinical study. Int J STD AIDS 28:613–615. https://doi.org/10.1177/0956462417691440
Park H, Sim SM, Lee G (2015) The presence of Chlamydia is associated with increased leukocyte counts and pain severity in men with chronic pelvic pain syndrome. Urology 85:574–579. https://doi.org/10.1016/j.urology.2014.11.008
Ponniah S, Arah I, Alexander RB (2000) PSA is a candidate self-antigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome. Prostate 44:49–54. https://doi.org/10.1002/1097-0045(20000615)44:1%3c49::aid-pros7%3e3.0.co;2-7
Quick ML, Wong L, Mukherjee S et al (2013) Th1-Th17 cells contribute to the development of uropathogenic Escherichia coli-induced chronic pelvic pain. PLoS One 8:e60987. https://doi.org/10.1371/journal.pone.0060987
Ramesh R, Kozhaya L, McKevitt K et al (2014) Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211:89–104. https://doi.org/10.1084/jem.20130301
Rudick CN, Berry RE, Johnson JR et al (2011) Uropathogenic Escherichia coli induces chronic pelvic pain. Infect Immun 79:628–635. https://doi.org/10.1128/iai.00910-10
Ruszkowski J, Lisowska KA, Pindel M et al (2019) T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target. Clin Exp Nephrol 23:291–303. https://doi.org/10.1007/s10157-018-1665-0
Shortliffe LM, Wehner N (1986) The characterization of bacterial and nonbacterial prostatitis by prostatic immunoglobulins. Medicine 65:399–414. https://doi.org/10.1097/00005792-198611000-00005
Shoskes DA, Albakri Q, Thomas K et al (2002) Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response. J Urol 168:331–335
Sparks JA (2019) Rheumatoid arthritis. Ann Intern Med 170:itc1–itc16. https://doi.org/10.7326/aitc201901010
Stancik I, Plas E, Juza J et al (2008) Effect of antibiotic therapy on interleukin-6 in fresh semen and postmasturbation urine samples of patients with chronic prostatitis/chronic pelvic pain syndrome. Urology 72:336–339. https://doi.org/10.1016/j.urology.2008.04.005
Stern A, Skalsky K, Avni T et al (2017) Corticosteroids for pneumonia. Cochrane Database Syst Rev 12:Cd007720. https://doi.org/10.1002/14651858.CD007720.pub3
Strauss AC, Dimitrakov JD (2010) New treatments for chronic prostatitis/chronic pelvic pain syndrome. Nat Rev Urol 7:127–135. https://doi.org/10.1038/nrurol.2010.4
Talbot M, Bates S (2001) Variability of the symptoms of chronic abacterial prostatitis/chronic pelvic pain syndrome during intermittent therapy with rectal prednisolone foam for ulcerative colitis. Int J STD AIDS 12:752–753. https://doi.org/10.1258/0956462011924137
Tomaskovic I, Ruzic B, Trnski D et al (2009) Chronic prostatitis/chronic pelvic pain syndrome in males may be an autoimmune disease, potentially responsive to corticosteroid therapy. Med Hypotheses 72:261–262. https://doi.org/10.1016/j.mehy.2008.10.020
Vyas SP, Hansda AK, Goswami R (2019) Rheumatoid arthritis: ‘melting pot’ of T helper subsets. Int Rev Immunol 38:212–231. https://doi.org/10.1080/08830185.2019.1621865
Wang L, Wang FS, Gershwin ME (2015) Human autoimmune diseases: a comprehensive update. J Intern Med 278:369–395. https://doi.org/10.1111/joim.12395
Wazir J, Ullah R, Li S et al (2019) Efficacy of acupuncture in the treatment of chronic prostatitis-chronic pelvic pain syndrome: a review of the literature. Int Urol Nephrol 51:2093–2106. https://doi.org/10.1007/s11255-019-02267-2
Xiao ZX, Miller JS, Zheng SG (2021) An updated advance of autoantibodies in autoimmune diseases. Autoimmun Rev 20:102743. https://doi.org/10.1016/j.autrev.2020.102743
Xie H, Chen HD, Huang HC et al (2010) Bacterial 16S rRNA genes and expression of IL-1β, TNF-α and IgA in prostate tissues. Zhonghua Yi Xue Za Zhi 90:1970–1973
Yang MG, Zhao XK, Wu ZP et al (2009) Corticoid combined with an antibiotic for chronic nonbacterial prostatitis. Zhonghua Nan Ke Xue 15:237–240
Yang S, Fujikado N, Kolodin D et al (2015) Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348:589–594. https://doi.org/10.1126/science.aaa7017
Yasuda K, Takeuchi Y, Hirota K (2019) The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol 41:283–297. https://doi.org/10.1007/s00281-019-00733-8
Yeh JF, Akinci A, Al Shaker M et al (2017) Monoclonal antibodies for chronic pain: a practical review of mechanisms and clinical applications. Mol Pain 13:1744806917740233. https://doi.org/10.1177/1744806917740233
Zhan CS, Chen J, Chen J et al (2020) CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis. FASEB J 34:14006–14023. https://doi.org/10.1096/fj.201902910RRR
Zhang J, Zhang X, Cai Z et al (2019) The lifetime risk and prognosis of chronic prostatitis/chronic pelvic pain syndrome in the middle-aged chinese males. Am J Mens Health 13:1557988319865380. https://doi.org/10.1177/1557988319865380
Zhang J, Liang C, Shang X et al (2020a) Chronic prostatitis/chronic pelvic pain syndrome: a disease or symptom? Current perspectives on diagnosis, treatment, and prognosis. Am J Mens Health 14:1557988320903200. https://doi.org/10.1177/1557988320903200
Zhang M, Liu Y, Chen J et al (2020b) Single-cell multi-omics analysis presents the landscape of peripheral blood T-cell subsets in human chronic prostatitis/chronic pelvic pain syndrome. J Cell Mol Med 24:14099–14109. https://doi.org/10.1111/jcmm.16021
Zheng J, Tang J, Yin S et al (2014) Comparison of polymerase chain reaction and immunologic methods for the detection of nanobacterial infection in type-III prostatitis. Urology 84:731.e739–713. https://doi.org/10.1016/j.urology.2014.05.038
Funding
This work was supported by the National Natural Science Foundation of China (81630019) and Scientific Research Foundation of the Institute for Translational Medicine of Anhui Province (2017ZHYX02).
Author information
Authors and Affiliations
Contributions
Conception and design: MZ and CL. Collection and assembly of data: LC and MZ. Manuscript writing: LC, and MZ. Final approval of manuscript: all the authors.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material. Supplemental Fig. 1. The morphology and immune mediators of the prostate in BHP patients suffering CP/CPPS. A The inflammatory cells infiltrated the prostate gland, which destroyed the prostate gland for BPH patients suffering CP/CPPS by HE staining. B CD4 and IFN-γ were detected in epithelial cells of prostate glands from BPH patients suffering CP/CPPS by immunofluorescence stain. C For BPH patients suffering CP/CPPS, C3, collagen-I, and TNF-α were mainly deposited in the epithelial cells of the prostate gland, IgA and IgM were deposited in the stromal cells, and collagen-III and IL-1β were deposited in both of the epithelial cells and stromal cells. Note: The prostate tissue was obtained from a BPH patient suffering CP/CPPS. This 80 years old patient had a history of CP/CPPS for more than 30 years with an NIH-CPSI score of 20 and a body mass index (BMI) of 19.10 kg/m2, and the BPH was diagnosed in August 2019. Other urologic diseases, including cancer and urolithiasis, were not found in this patient. BPH benign prostate hyperplasia, C3 complement 3, IFN-γ interferon-γ, IgA immunoglobulin A, IgM immunoglobulin M, TNF-α tumor necrosis factor-α
5_2021_628_MOESM1_ESM.jpg
Supplementary file1. Supplemental Fig. 1. The morphology and immune mediators of the prostate in BHP patients suffering CP/CPPS. A The inflammatory cells infiltrated the prostate gland, which destroyed the prostate gland for BPH patients suffering CP/CPPS by HE staining. B CD4 and IFN-γ were detected in epithelial cells of prostate glands from BPH patients suffering CP/CPPS by immunofluorescence stain. C For BPH patients suffering CP/CPPS, C3, collagen-I, and TNF-α were mainly deposited in the epithelial cells of the prostate gland, IgA and IgM were deposited in the stromal cells, and collagen-III and IL-1β were deposited in both of the epithelial cells and stromal cells. Note: The prostate tissue was obtained from a BPH patient suffering CP/CPPS. This 80 years old patient had a history of CP/CPPS for more than 30 years with an NIH-CPSI score of 20 and a body mass index (BMI) of 19.10 kg/m2, and the BPH was diagnosed in August 2019. Other urologic diseases, including cancer and urolithiasis, were not found in this patient. BPH benign prostate hyperplasia, C3 complement 3, IFN-γ interferon-γ, IgA immunoglobulin A, IgM immunoglobulin M, TNF-α tumor necrosis factor-α (JPG 2255 kb)
About this article
Cite this article
Chen, L., Zhang, M. & Liang, C. Chronic Prostatitis and Pelvic Pain Syndrome: Another Autoimmune Disease?. Arch. Immunol. Ther. Exp. 69, 24 (2021). https://doi.org/10.1007/s00005-021-00628-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00005-021-00628-3