Immune mediators of chronic pelvic pain syndrome

Abstract

The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease.

Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1. Hypothetical model of CPPS

(A) Intercellular homeostatic signaling demonstrating; differentiation of CD4 T-cells in a context dependent manner; Regulation of mast cell activation by direct interaction e.g. through OX40 receptor; Activation of Mast cells and subsequent deactivation. And how these signaling cascades interact to stimulate neurons. The system is tightly controlled and regulated with numerous checkpoints. (B) Schematic representation of modulated immune system in CPPS. 1. We hypothesize that an initiating event, such as bacterial infection, drives prostatic epithelial cell damage and 2. Promotes secretion and activation of pro-inflammatory cytokines, chemokines and presentation of antigen via APCs 3. These signaling cascades result in CD4 T-cell activation which is initially of Th1-type (IFNgamma) but Th17 activation is also implicated in the pathway possibly at later stages of chronic pain development. 4. Data suggests a loss of IL-10 secreting suppressive T-regs and a skewing towards Th1/17 responses, this may be attributable to genetic polymorphisms regulating expression of these factors. 5. The loss of suppression of mast cells as a result of unchecked T-cell activation results in a positive feedback loop in the mast cell resulting in; 7. degranulation and releases of proteases such as tryptase, chymase and allergy mediators such as histamine., and 8. cytokine secretion (IL6, IL17, TNFa, IL6) resulting in recruitment of inflammatory cells. Together 7. and 8. can disrupt the Blood Brain Barrier, 9. and/or directly 10. demyelinate neurons. Taken together these processes result in 11. neuronal activation and sensitization. The mast cell mediates these events and positive feedback loops increase these processes through 6. Further epithelial cell damage, 12., is one consequence of such increased mast cell activity. Prostate antigens generated from damage to the epithelium in the presence of an activated CD4 T-cell response, with unchecked mast cell degranulation and increased numbers of CD8 Tcells can result in development of 13. autoimmunity, which only further exacerbates these mechanisms.

Figure 1. Hypothetical model of CPPS

(A) Intercellular homeostatic signaling demonstrating; differentiation of CD4 T-cells in a context dependent manner; Regulation of mast cell activation by direct interaction e.g. through OX40 receptor; Activation of Mast cells and subsequent deactivation. And how these signaling cascades interact to stimulate neurons. The system is tightly controlled and regulated with numerous checkpoints. (B) Schematic representation of modulated immune system in CPPS. 1. We hypothesize that an initiating event, such as bacterial infection, drives prostatic epithelial cell damage and 2. Promotes secretion and activation of pro-inflammatory cytokines, chemokines and presentation of antigen via APCs 3. These signaling cascades result in CD4 T-cell activation which is initially of Th1-type (IFNgamma) but Th17 activation is also implicated in the pathway possibly at later stages of chronic pain development. 4. Data suggests a loss of IL-10 secreting suppressive T-regs and a skewing towards Th1/17 responses, this may be attributable to genetic polymorphisms regulating expression of these factors. 5. The loss of suppression of mast cells as a result of unchecked T-cell activation results in a positive feedback loop in the mast cell resulting in; 7. degranulation and releases of proteases such as tryptase, chymase and allergy mediators such as histamine., and 8. cytokine secretion (IL6, IL17, TNFa, IL6) resulting in recruitment of inflammatory cells. Together 7. and 8. can disrupt the Blood Brain Barrier, 9. and/or directly 10. demyelinate neurons. Taken together these processes result in 11. neuronal activation and sensitization. The mast cell mediates these events and positive feedback loops increase these processes through 6. Further epithelial cell damage, 12., is one consequence of such increased mast cell activity. Prostate antigens generated from damage to the epithelium in the presence of an activated CD4 T-cell response, with unchecked mast cell degranulation and increased numbers of CD8 Tcells can result in development of 13. autoimmunity, which only further exacerbates these mechanisms.