The Immunochemical Pattern of BPH

The presence of activated T-cells in the hyperplastic prostate gland is known since the Theyer study at early 1990s [ ]. Peripheral blood T-cells express VEGF, a potent epithelial mitogen, while they secrete other growth factors, like HB-EGF and bFGF/FGF-2 [ ]. Therefore, the presence of T-cells in the prostate might have a potential role in the gland hyperplasia, affecting the local environment by producing stromal and epithelial factors, causing prostatic hyperplasia.

The immunological pattern of the inflammatory process in the prostate was the study object for several studies. In their investigation, Di Siverio et al. [ ] examined histologically 3942 patients’ biopsies, describing 43% cases with inflammation. Chronic type was the predominant (69% of them). Although the severity of the symptoms was characterized as mild in most of the cases, there has been a clear association with the age and prostate volume. In an older study, Irani and Robert [ , ] suggested a grading of prostatic inflammation, based on the hypothesis that the extension of the inflammatory cells could imply the whole histological grading of the inflammatory aggressiveness ( Table 3.1 ).

Prostate is normally populated by a small number of inflammatory cells (leukocytes) that increase with age, consisting of scattered stromal and epithelial T and B lymphocytes, macrophages, and mast cells [ ]. The normal prostate gland is infiltrated around the periglandular area mainly by T lymphocytes and more particularly 70% CD8 cells. In the fibromuscular stroma, there are lymphoid aggregations, consisting of B lymphocytes, CD4 T lymphocytes over 50%, while CD8 cells are in a smaller ratio [ ]. However, in the prostate of adult men, the infiltration pattern is usually described as different, mainly because of the inflammatory process been present. Steiner et al. [ ] showed that the inflammatory infiltrates are mostly represented by CD3 T lymphocytes (70–80%), CD19 and CD20 B lymphocytes (10–15%), and macrophages (15%). There is, also, an interesting reverse of CD8 to CD4 T cells and finally the CD4 cells become prevalent in the inflammatory areas. Robert’s study [ ] came to be even more confirmative, as the investigation on 282 patients with BPH proved the presence of T lymphocytes in the 80% of cases, associated with 52% of antigen-presenting cells, such as B lymphocytes, and 82% of macrophages.

Another situation neighboring inflammation in the prostate is proliferative inflammatory atrophy, firstly described by De Marzo et al. [ ]. In this condition, the epithelium becomes atrophic or hyperplastic due to atrophy, something that also occurs in association with the chronic inflammation. The main characteristic is the presence of inflammatory cells in both epithelial and stromal areas, as well as stromal atrophy with variable amount of fibrosis.

The Inflammatory Pattern of BPH

The inflammatory pattern in BPH is based on the cytokine secretion from the inflammatory cells, hypoxia due to the increased oxygen demand by the cell proliferation, and eventually tissue damage. These cytokines are involved in the regulation of the immune response but may also interact with stromal and epithelial cells in the prostate [ ].

BPH tissue is populated by T-B lymphocytes and macrophages, which are responsible for the release of IL-2, IFN-γ, and TGF-β. This may support the fibromuscular growth in BPH [ ]. Moreover, some proinflammatory cytokines, such as IL-15 and IFN-γ in the stromal cells, IL-17 in the T-cells, and IL-8 in the epithelium, are upregulated in a BPH condition [ ].

T cells concentration is gradually increased, due to the action of the proinflammatory cytokines and when they reach a certain threshold, the surrounding cells are killed and replaced by fibromuscular nodules [ ]. The maintenance and progression of this immune inflammation process in the aging prostate is been regulated by the dendritic cells [ , ].

The Origin of Chronic Prostate Inflammation

Although the correlation of LUTS and BPH is well described in several studies, their accurate pathophysiological connection is not yet absolutely clear. A variety of pathogens are implicated, including bacterial infections, urine reflux with chemical inflammation, dietary factors, hormones, autoimmune response [ , ], and a combination of these factors.

Viruses, sexually transmitted organisms, and Gram-negative pathogens have been detected in the prostate and have been responsible for a chronic inflammatory situation leading to LUTS. Hence, chronic infections or colonization of human papilloma virus, human herpes simplex virus type 2, Neisseria gonorrhoea , Chlamydia trachomatis , Treponema pallidum , Trichomonas vaginalis , or even E. coli could imply a good connection between a chronic prostate inflammation and lower urinary tract symptoms [ , , ].

Chemical irritation due to urine reflux may be another etiological factor contributing to the development of prostate inflammation [ ]. In this case, the pathway begins from the crystalline urine, which can be realized by dying cells, engaging caspase-1-activating NALP3, a multiprotein complex presented in leukocytes mostly in macrophages [ ]. The next step is the stimulation for the production of cytokines and the incoming of more inflammatory cells.

Corpora amylacea in the prostate is considered as another possible source of inflammation [ , ]. In fact, corpora amylacea are frequently found adjacent to the damaged epithelium inducing focal inflammatory infiltration.

Prostate injury secondary to the earlier-mentioned etiologies can damage prostate epithelial cells and consequently provoke an immunological reaction, by releasing immunogenic antigens. This is based on the hypothesis that some prostatic proteins are not physiologically tolerated by the immune system and when they are released an autoimmune response is determined [ , ].

The interaction between gonadal sex hormones with the immune system is, also, well known and may be a key for the activation of lymphocytes in the prostate tissue. Estrogens are commonly considered proinflammatory hormones being involved in the susceptibility to inflammation by regulating the IFN-γ production in lymphocytes [ ]. They, additionally, induce the accumulation of CD 4 (Th1 type) T cells, responding to the antigen, and moreover they stimulate the production of the Th2 antiinflammatory cytokines (IL-4, TGF-β). Those substances are usually present in the BPH nodules. Also, IL-4 and IL-3 are overexpressed in advanced BPH and they are known to increase the production of 3b-hydroxydehydrogenase/isomerize type1 (3b-HSD) by prostate epithelial cells, an essential catalyst in the metabolism of androgens [ ]. The role of the diet factors, such as food wealthy in animal fat, has been investigated in animal models, showing variety of changes in the prostate tissue, with the role of mast cells and macrophage to be predominant inside the prostate [ , ].

The main hypothesis that all the above proposed mechanisms support is the development of a chronic epithelial injury in the prostate. Consequently, this may facilitate the growth of the inflammatory response, increasing the prostatic inflammatory infiltrates.

The Role of Inflammatory Cytokines

The proinflammatory cytokines are released by the inflammatory cells and may, in parallel, induce cyclooxygenase-2 (COX-2) expression in BPH, which is associated with the increased cell proliferation [ , ]. There is evidence supporting that IL-17, an upregulator of COX-2, is overexpressed in patients with BPH, mainly produced by T-cells, while this process requires additional factors, as IL-23 [ , ]. The pathway including IL-17 and IL-23 interaction is involved in promoting the inflammation response in BPH.

Penna et al. [ ] showed in tissue samples of men with BPH that stromal cells have an antigenic action, stimulating CD4 T-cells to produce IFN-γ and IL-17. Afterward, the production of IL-8 and IL-6 is induced and finally fibroblast growth factor 2 (FGF-2) is produced. This may be a connection of the stromal cell autoimmune response and the prostate proliferation [ ].

The possible role for TGF-β has also been investigated. TGF-β is an inflammatory cytokine regulating proliferation and differentiation in BPH. In the study of Descazeaud et al. [ ], the role of TGF-b receptor II protein (TGFBRII) was evaluated in 231 patients with BPH. The results showed a significant correlation between TGFBRII with prostatic volume and inflammation. Certainly, the expression of this protein was more evident in cases with CD4 T cells within the prostate.

Local hypoxia may also play a role in the prostate inflammation and furthermore in the development of BPH. Reactive oxygen species (ROS) seem to be released under hypoxia situations, leading to growth factor release, reaction with the epithelial and stromal cells, and finally gland enlargement [ ]. The main growth factors involved in this condition is FGF-7, TGF-b, FGF-2, and IL-8 [ ].

Taoka et al., in their investigations on hyperplastic prostatic tissues, proved significantly low levels of macrophage inhibitory cytokine-1 (MIC-1) in specimen with inflammation. This cytokine is expressed and/or increased in a normal prostate [ ].

It is rather obvious that a clear cause and effect relationship between prostate inflammation and BPH is not yet well understood. T-cells activity in the inflammation pattern may stimulate the proliferation of stromal and epithelial cells. Additionally, tissue damage and chronic, repetitive wound healing result in the development of BPH nodules.