An aberrant prostate antigen–specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

Hou, Yayi; DeVoss, Jason; Dao, Vinh; Kwek, Serena S.; Simko, Jeffrey P.; McNeel, Douglas G.; Anderson, Mark S.; Fong, Lawrence

doi:10.1172/jci38332

Cited by 44 publications

(61 citation statements)

References 42 publications

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“…Consequently, we were not able to determine the basal cell differentiation program under the chronic inflammatory conditions. Therefore other models for prostatitis may be used to investigate the differentiation potential of basal cells during non-bacteria-induced prostatitis and during chronic prostatic inflammation (46)(47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Kwon¹,

Zhang²,

Ittmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

171

154

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Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER; mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Pten fl/fl ) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.prostate stem cells | cells-of-origin for cancer

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Section: Discussionmentioning

confidence: 99%

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Kwon¹,

Zhang²,

Ittmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

171

154

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“…Prostate-specific antigens are prominently represented in the mouse and human thymus, and indeed, Aire-deficient mice experience dramatic onset of prostatitis. 107 Seminal vesicles, testis and epididymis are also severely affected in Aire-deficient males on the Balb/c genetic background, which almost completely infertile (Warren and Petroff, manuscript in preparation). One of the most strongly represented organs in both murine and human thymus is the placenta; indeed, chorionic gonadotropin (CGA) protein is confirmed in the human thymus ( Figure 6), which raises the intriguing possibility that central tolerance is critical for tolerance to placenta-specific antigens.…”

Section: Future Directionsmentioning

confidence: 99%

Ovarian autoimmune disease: clinical concepts and animal models

et al. 2014

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The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.

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“…Evidence of an autoimmune basis in CP/CPPS comes from a number of studies in humans. Self-reactivity of T cells from men with CP/CPPS to seminal plasma proteins and normal prostatic proteins, such as prostate-specific Ag and prostatic acid phosphatase, has already been reported (5)(6)(7)(8). In addition, increased levels of TNF-a, IL1b, and IFN-g in seminal fluid of men with CP/CPPS (9)(10)(11), the presence of IFN-g-secreting lymphocytes specific to prostate Ags (5), and the presence of prostatic intra-acinar T cell-rich infiltrates in CP/CPPS patients (12) have also been described.…”

mentioning

confidence: 94%

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Breser

Motrich

Sánchez

et al. 2013

The Journal of Immunology

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Experimental autoimmune prostatitis (EAP) is considered a valid model for the human disease chronic prostatitis/chronic pelvic pain syndrome. In this report, we analyzed phenotypic characteristics of T cells that gain access to the prostate and induce leukocyte recruitment in mice with different susceptibility to EAP. After EAP induction, NOD mice developed a specific cellular response characterized by a mixed Th1/Th17 pattern with specific T cells mainly expressing CXCR3 that infiltrated and damaged the prostate. In contrast, BALB/c mice, as well as NOD-IFN-γ−/−, exhibited only Th17 cells mainly expressing CCR6 that were not capable of infiltrating the prostate gland. Adoptive transfer experiments of T cells from NOD or NOD–IFN-γ−/− mice to NOD-SCID recipients showed that only T cells from NOD mice successfully infiltrated the prostate. However, after “in vitro” or “in vivo” treatment with rIFN-γ, T cells from NOD–IFN-γ−/− mice became capable of homing to the prostate and induced leukocyte recruitment. Chemokine levels in prostate tissue from NOD mice showed increased expression levels of CXCR3 ligands. Additional experiments using adoptive transfer of sorted CXCR3+CD3+ T cells or administrating a CXCR3 antagonist treatment confirmed these previous results. Altogether, our results demonstrate that the expression of CXCR3 on effector T cells is essential for their homing to the prostate gland in EAP. CXCR3 emerges as a potential therapeutic target to control chronic prostatitis/chronic pelvic pain syndrome.

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An aberrant prostate antigen–specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

Cited by 44 publications

References 42 publications

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Ovarian autoimmune disease: clinical concepts and animal models

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

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