Crucial role of interferon-gamma in experimental autoimmune prostatitis.

PURPOSE: An autoimmune etiology is proposed in some patients with chronic nonbacterial prostatitis since they show interferon-gamma secreting lymphocytes specific to prostate antigens in the periphery and increased interferon-gamma in seminal plasma. We investigated the involvement of interferon-gamma in an animal model of autoimmune prostatitis. MATERIALS AND METHODS: Experimental autoimmune prostatitis was studied in the no-obese diabetic and C57Bl/6 (Harlan, Zeist, The Netherlands) susceptible mouse strains, and in the IRF-1 KO and STAT-1 KO mouse strains deficient in transcription factors involved in interferon-gamma signaling. RESULTS: Experimental autoimmune prostatitis was characterized by prostate specific interferon-gamma secreting cells in the periphery and by T-helper 1 related cytokines in the target organ. Increased interferon-gamma and interleukin-12 were observed in the prostate of autoimmune animals while interleukin-10 and interleukin-4 were decreased and unaltered, respectively. The absence of transcription factors involved in the interferon-gamma signaling cascade, IRF-1 and STAT-1, made mice resistant to experimental autoimmune prostatitis. IRF-1 KO and STAT-1 KO mice immunized with prostate antigens did not show infiltration or alterations in the prostate. They did not have the typical prostate specific autoimmune response and showed decreased interferon-gamma, interleukin-12 and interleukin-10, and augmented interleukin-4 in the prostate. CONCLUSIONS: Our results argue for a crucial role of interferon-gamma as a key factor in the pathogenesis of the disease. Intense research is promptly required to identify the pathogenic mechanisms underlying chronic prostatitis/chronic pelvic pain syndrome to find a more rational therapy.

Impact of vitamin D receptor activity on experimental autoimmune prostatitis.

Chronic non bacterial prostatitis is a chronic inflammatory syndrome. Its etiology and physiopathology are unclear and treatments are empirical and ineffective in most cases. Autoimmunity has been proposed as an etiology. In the present report, we investigated the impact of vitamin D receptor silencing, by use of VDR-KO NOD mice and the immune-modulating effect of the vitamin D3 analog TX527 on the development of Experimental Autoimmune Prostatitis in NOD mice. VDR-KO NOD mice developed a more aggressive form of autoimmune prostatitis characterized by a greater lymphoproliferative response against prostate antigen in vitro (6.92+/-4.77 vs. 2.47+/-0.41 21 days after disease induction, p<0.05) and higher levels of specific INFgamma secretion (471+/-6 vs. 386+/-5pg/ml, p<0.01). This was accompanied in vivo by more severe lesions and augmented mononuclear cell infiltration in the prostate gland. On the other hand, although analog-treated mice showed a significant reduction in the spleen T-cell specific proliferative response against prostate antigen in vitro, no effect on disease development was observed. We conclude that vitamin D receptor modulation holds the promise of interfering with autoimmune prostatitis. Introduction of more powerful analogs, or combinations with anti-T-cell reagents may represent therapeutic solutions for these group of patients.

Autoimmune etiology in chronic prostatitis syndrome: an advance in the understanding of this pathology.

The prostate is the target of many inflammatory and neoplastic disorders that affect men of all ages. Pathological conditions of the prostate gland range from infection of this organ by ascending bacteria from infected urine, to chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) of a still unknown etiology (accompanied with inflammation and lymphocyte infiltration of the gland), to benign hyperplasia and cancer. Patients under 50 years of age usually suffer from CP/CPPS, a chronic inflammatory syndrome characterized by pelvic pain, irritative voiding symptoms, and sexual dysfunction complaints. In this review, we summarize the current knowledge regarding immunological alterations present in CP/ CPPS patients. Remarkably, an inflammation state, in the absence of an invading infectious agent, is established in these patients, suggesting that an autoimmune process could be involved. In fact, specific autoimmune response to prostate antigens has recently been reported in CP/CPPS patients. Autoimmune response to prostate gland affects the seminal quality reported in these patients and may have critical consequences in their fertility. It is anticipated that preclinical studies in experimental models for CP/CPSS will provide important insights into the etiopathogenic mechanisms involved in this disease. We discuss here the similarities and the differences between human disease and experimental models and argue for the importance of the prostate gland in male reproductive function. Ultimately, we suggest that a state of inflammation, originally incited by an autoimmune response within the prostate, together with a diminished prostate functionality, may compromise male fertility.

Presence of INFgamma-secreting lymphocytes specific to prostate antigens in a group of chronic prostatitis patients.

Acute and chronic infectious prostatitis are the best understood of the prostate syndromes, but they are the least frequent. In contrast, although chronic non-infectious prostatitis is the most frequent syndrome, its cause has proved elusive despite years of investigation. In the present study, we analyzed a group of patients with infectious and non-infectious chronic prostatitis in order to search for the presence of a possible autoimmune response to prostate antigens. We demonstrated the presence of lymphocytes able to proliferate in response to known human prostate antigens such as PSA and PAP only in a group of patients with non-infectious chronic prostatitis. We observed that, as in other autoimmune diseases, a proliferative response against two or more autoantigens was a common feature. Moreover, when INFgamma and IL-10 levels were measured in culture supernatants, significantly elevated levels of INFgamma were detected only in samples from patients with positive proliferative response to prostate antigens. Interestingly, only these patients showed significantly elevated levels of inflammatory cytokines (IL-1 and TNF-alpha) in seminal plasma, arguing for a local inflammation of non-infectious cause. Our results show that INFgamma-secreting lymphocytes specific to prostate antigens are in fact detected in 34% of the patients with chronic non-infectious prostatitis. We speculate that these cells could be involved in the inflammatory process taking place in the prostate gland and therefore could alter its biological function.

Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens.

BACKGROUND: The relationship between chronic prostatitis and fertility has been controversial for many years. We have previously shown the presence of a cellular autoimmune response against prostate antigens in a group of chronic prostatitis patients. Our main goal was to investigate whether chronic prostatitis (either caused by an infection or an autoimmune response to the prostate gland) could have a deleterious effect on semen quality. METHODS: Forty-four patients diagnosed as suffering from chronic prostatitis were included and divided into groups according to the presence of infection and/or cellular autoimmune response against prostate antigens. Healthy normal individuals were included as controls. Measurements for sperm concentration, motility, morphology, prostate and seminal vesicle markers, antisperm antibodies, white blood cells and pro-inflammatory cytokines were performed accordingly. RESULTS: The most severe abnormalities were seen in patients with no evident infection and an autoimmune response against prostate antigens. Moreover, significantly increased levels of pro-inflammatory cytokines were detected in seminal plasma from these patients. CONCLUSIONS: This study shows that chronic prostatitis patients with cellular autoimmune response to prostate antigens present important alterations in their semen quality parameters. We speculate that an autoimmune response against prostate antigens and the inflammatory process involved may affect male fertility.

Cow's milk stimulated lymphocyte proliferation and TNFalpha secretion in hypersensitivity to cow's milk protein.

Although there is no reliable single laboratory test available for the diagnosis of cow's milk allergy, if an allergic mechanism is suspected, a number of laboratory studies may be useful in delineating specific proteins responsible for these disorders. In the current study we analyzed in vitro lymphocyte proliferation assays, specific secretion of TNFalpha in supernatant cultures and specific IgE, IgG, and IgA in a group of patients with hypersensitivity to cow's milk antigens. The stimulation index against a cow's milk antigen mixture, alpha-lactalbumin, beta-lactoglobulin, and casein was significant higher in the group of patients maintained on cow's milk-free diet for less than 4 months compared with the values observed in the control group and in the group of patients without a close contact to cow's milk proteins. A significant increase in TNF-alpha secretion was observed in supernatants from patients with close contact to cow's milk (CM). Specific IgE was detected in 59.3% of the patients, with higher specific IgE levels in patients who were not positive for the proliferation assay, suggesting a clear difference in the two mechanisms proposed as effectors in this disease. No differences in specific IgG and IgA levels were observed between the patient group and the control group, with a great dispersion among individuals in all groups tested. We conclude that a combination of the assays tested in this study, such as proliferative assay of peripheral blood mononuclear cells to CM, the quantitation of TNFalpha in culture supernatants, and serum specific IgE determination, are useful laboratory tests to identify cow's milk allergy among patients with immediate and non immediate adverse reactions, reducing the need for food allergen challenges in young children.

Prostatein or steroid binding protein (PSBP) induces experimental autoimmune prostatitis (EAP) in NOD mice.

In a previous study, we showed that nonobese diabetic (NOD) mice, a strain that present an inherited predisposition to develop both spontaneous and induced autoimmune lesions, are susceptible to the induction of experimental autoimmune prostatitis (EAP), developing a severe inflammatory reaction in the prostate, accompanied by humoral and T-cell-mediated responses. In this study we asked whether the protein steroid binding protein (PSBP) or prostatein (a major autoantigen in the rat model of EAP) is a potential autoantigen in the NOD mouse model and examined the ability of purified PSBP to induce EAP in this strain. Our results indicate clearly that NOD male mice react immunologically to PSBP by developing lymphocytic inflammatory lesions in prostatic tissue and producing both a cellular- and humoral-specific autoimmune response. But our results suggest also the existence of other prostatic autoantigens present only in total prostate extract. Such additional antigens could enhance the autoimmune response and result in more severe forms of inflammation. We also analyzed the respective contributions of MHC antigens and CD4/CD8 T-cell subsets in NOD mice lacking expression of beta 2-microglobulin (NOD.beta2m degrees/degrees) or MHC class II beta chain (NOD.Abeta degrees/degrees) and demonstrate an essential role for CD4(+) T cells in the development of EAP in the NOD model. In conclusion, we demonstrate that PSBP is an autoantigen recognized by the NOD immune system, capable of generating humoral and cellular autoimmune responses and of inducing EAP. Moreover, using selected knock-out NOD mice we demonstrate an essential role for CD4(+) T cells in the development of EAP.