Effects of Epigenetic Regulation in Chronic Pelvic Pain Syndrome

CPPS is a condition that is estimated to affect up to 15% of the male population with most diagnoses between the ages of 35-45. Designated by the presence of pain in the absence of bacterial infection for more than three months, it has unknown, probably complex etiology, which thus far have hampered efforts to determine effective treatment strategies. The heterogeneous nature of the symptoms and the length of the disease course prior to detection, presentation or diagnosis only further exacerbate these issues. This study seeks to identify defects in immune activation or regulation that may affect a subset of patients with CP/CPPS. This subset appears to have a reduced ability to mount a regulatory immune response, while simultaneously eliciting an exaggerated activated immune response. The defects that we demonstrate appear to be linked to altered methylation of genes involved in both immune regulation and immune activation. The aims of this study will provide definitive evidence of a role for epigenetic changes in immune cells in patients with CP/CPPS. This is conceptually a major advance - as a variety of factors including early life stress events, prostate infectious agents, environmental variables, all could contribute to epigenetic change and may therefore explain both the anecdotal etiologies described in this syndrome as well as the difficulty in pinpointing a precise etiological mechanism. Specifically, our data leads us to hypothesize that epigenetic alterations in regulatory and proinflammatory immune pathways underpin the development of chronic pelvic pain in CPPS. In this study, we propose to validate our preliminary findings in a larger set of CP/CPPS patients and controls as well as utilize murine models of prostatitis to understand the mechanism driving altered IL-10 and IL-7/LFA-1 mediated immune responses both at systemic and prostate levels. If epigenetic defects and functional deficits can be demonstrated, diagnosis and treatment methodologies could be better targeted at correction of these chronic deficits rather than at etiological agents/pathways that are in the past.

BACKGROUND:

Prostatitis accounts for approximately 2 million outpatient visits per year in the United States, including 1% of those to primary care physicians. Chronic pelvic pain syndrome (CPPS) accounts for 90% of all chronic prostatitis but has no well-defined etiology. It is clinically characterized by the symptoms of pain in the perineum, testes, penis, suprapubic area, dysuria and profound reductions in patient quality of life. Epidemiologic observations indicate that prostatitis conditions are the most frequent urologic diagnosis in young men and the third most frequent urologic diagnosis in men older than 50 yr, representing 8-12% of urology office visits. The NIH consensus definition and classification identifies four categories of prostatitis. Categories I and II have bacterial etiologies while the rest are believed to be non- bacterial in etiology.

Category III is subdivided into inflammatory (IIIa) and noninflammatory (IIIb) subtypes, based on the presence of white blood cells in expressed prostatic secretions (EPS). Category III prostatitis or chronic pelvic pain syndrome (CPPS) is the most common prostatitis observed in medical practice with a prevalence rate in the general population from 5% to 14.2%. CPPS is a poorly understood entity characterized by pelvic or perineal pain, irritative voiding symptoms, and sexual dysfunction.