Immunoregulation in the testis and its implication in fertility and infections

The testis is designated as one of the immune previleged sites in the body and harbours a unique immunoregulatory environment, which is important for preventing an immune response against sperm antigens which otherwise are recognized as “foreign” by the immune system. The blood-testis barrier along with the unique immune cells repertoire and various immunoregulatory & immunosuppressive factors secreted by the Leydig cells, Sertoli cells and peritubular cells act in concert to maintain the tolerogenic environment in the testis. Abberations in immunotolerant mechanisms in the testis can lead to generation of anti-sperm antibodies that have an association with male infertility. It can also lead to inflammatory conditions of the male reproductive tract manifested as epididymitis and orchitis, generally due to bacterial or viral infections. In addition, non-infectious epididymitis and orchitis, having autoimmune origin have also been reported in males. While the immune privilege status of human testis protects the germ cells from an immune attack, it can also make the testis a succeptible reservoir for viruses such as human immunodeficiency virus-1, Zika virus and severe acute respiratory syndrome coronavirus-2, all of which have adverse consequences on male reproduction.

Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation

BackgroundVaricocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system.ResultsThe testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB).ConclusionsThe testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

SIMILARLY HIGH SEROPREVALENCE OF ANTI-HELICOBACTER PYLORI ANTIBODIES IN MEN AND WOMEN WITH AND WITHOUT IDIOPATHIC INFERTILITY

Our study aimed to compare the seroprevalence of anti-Helicobacter pylori antibodies in patients with and without unexplained infertility. Three groups were compared, i.e., patients with idiopathic infertility (Group A, n=105); fertile patients with Helicobacter pylori-associated diseases (Group B, n=105) and fertile subjects lacking H. pylori-related disease (Group C, n=105). Anti-sperm antibodies (ASA) and anti- H. pylori antibodies (AHPA) were evaluated. Similarly high seroprevalence of AHPA in all studied patients was found (p>0.05). Odds ratio calculated against infertility for AHPA-positive patients was 0.97 (95% confidential interval from 0.57 to 1.68, p=0.113). The AHPA-seroprevalence of samples from men was 1.3 - 1.8 times higher than those from women. Also, for ASA-seroprevalence, the men-to-women ratio was up to 2 times higher. We calculated the odds ratio for male and female groups separately and again did not obtain statistical significance in the odds ratios neither for men nor for women. Our findings failed to reveal H. pylori seropositivity as a possible risk factor for idiopathic infertility neither in men nor in women.

Neisseria Gonorrheae: A Cause of Male Infertility

Background: Gonorrhoea is a sexually transmitted infection that is commonly related to male infertility. The infection affects sperm transport through the urinary tract and subsequent damage of the testicular tubes. The infection also impair sperm production as the infection is rarely asymptomatic and can be difficult to diagnose, it is possible that its contribution to male infertility is underestimated. Infection of the genitals results in a purulent (pus-like) discharge from the genitals which may be foul smelling, inflammation, redness, swelling, dysuria, and a burning sensation during urination. As with Chlamydia, it is possible to have a Gonorrhea infection without noticeable symptoms, and which can cause permanent scarring and blockage in the sperm production duct. Gonorrhoea is a bacterial infection and is treatable with antibiotics. Laboratory studies reveal that N. gonorrhoeae infection can impair motility, viability and spermatogenesis; increase anti-sperm antibodies are associated with a decrease in semen parameters as a result of the production of anti-sperm antibodies in the genital tract. Aim: The study aimed at reviewing the possible role of gonorrhoea in male infertility. Method: Research publications such as Pubmed, Scopus, Medline etc. Results: over 115 journals of international repute were obtained, out of which 50 were found to be closely relevant such as; the implication of N. gonorrheae in male infertility, complication of N. gonorrhea infection, N. gonorrhea e and male infertility and were reviewed. Conclusion: N. gonorrhoae was found implicative in male infertility and the need for comprehensive modern laboratory methods for the diagnosis of the infection and also to included routine laboratory tests.

The prognostic value of seminal anti-sperm antibodies screening in men prepared for ICSI: a call to change the current antibody-directed viewpoint of sperm autoimmunity testing

Aims: We aimed to prospectively evaluate the prognostic value of seminal anti-sperm antibodies (ASA) screening in couples prepared for intracytoplasmic sperm injection (ICSI). Methods: A prospective comparative study was conducted, including 184 non-azoospermic infertile men scheduled for ICSI. For each patient, detection of ASA in seminal plasma using the ELISA technique was done and its relation to standard semen parameters and ICSI outcomes, including fertilization, embryo development, and pregnancy rates, was analyzed. Results: Sperm count, motility, and morphology were negatively affected by existence of seminal ASA ( p = 0.012, 0.006, and 0.011, respectively). However, no statistically significant difference was detected between patients with positive and negative seminal ASA regarding the median values of fertilization (56.3% versus 66.7%, p = 0.091), percentage of couples with grade A embryo development (91.4% versus 89.9%, p = 0.520), and pregnancy rates (31.4% versus 32.2%, p = 0.98) after ICSI. Conclusion: ICSI seems able to overcome the problem of ASA in semen. The routine screening of ASA in men prepared for ICSI has no additional prognostic value and cannot be recommended for the time being, until more specific antigen-concerned testing can be developed.

Relationship Between Post-Pubertal Mumps Infection In Males With Infertilityand Its Effect on The Result of Seminal Fluid Analysis and Occurrence of Immunological Infertility

Background: Mumps caused by paramyxovirus in the same group as parainfluenza and Newcastle disease virus, orchitis is the widely recognized complication in post-pubertal males. Approximately 50% of patients with orchitis have some degree of testicular atrophy, but sterility is rare. Objective: To demonstrate the effect of the post-pubertal mumps infection on the result of seminal fluid analysis and to know if infection by mumps after puberty can lead to immunological infertility and production of anti-sperm antibodies. Patients and Methods: Cross-sectional study in which 300 infertile males attending microbiology laboratory in Rizgary teaching hospital in Erbil city in Iraqi Kurdistan from November 2017- September 2018. Questionnaire was prepared for each male which included: name, age, occupation, history of mumps infection after puberty. Seminal fluid collected from each patient after 3 days of abstinence and analyzed according to WHO guidelines. Seminal fluid and serum obtained from each infertile male for the detection of anti-sperm antibodies by ELISA (enzyme-linked immunosorbent assay). Results: The mean age of the participant in the study was (32.805 year) with the maximum and minimum age was (50, 18) years respectively. The incidence of post-pubertal mumps was (13.3%) and the incidence of abnormal seminal fluid analysis was (10%) and the highest abnormal seminal fluid variables among infertile males with post-pubertal mumps was oligoasthenozoospermia (43%) and the anti-sperm antibodies in the semen of infertile males with post-pubertal mumps infection was (60%) while the frequency of anti-sperm antibodies in the serum in infertile males with a history of post-pubertal mumps was (40%) which was higher than those with no history of post-pubertal mumps with highly significant relation statistically. Conclusion: Abnormal seminal fluid analysis result may be due to post-pubertal mumps and it can lead to (Asthenozoospermia, Oligospermia, and Teratozoospermia). The highest percentage of abnormal seminal fluid variables was Oligoasthenozoospermia the occurrence of anti-sperm antibodies can be the sequence of post-pubertal mumps and by itself can lead to abnormality in the seminal fluid analysis. Mumps can lead to male infertility by affecting the seminal fluid parameters and also by the production of anti-sperm antibodies which can lead to subfertility in adult males. Keywords: Paramyxovirus, post-pubertal mumps, anti-sperm antibodies

Dynamics of sperm antibody levels in adolescents with left-sided varicocele

Varicocele means a varicose vein of the spermatic cord, being among the most common disorders diagnosed in childhood and adolescence, which suggests a high risk for infertility. Varicocele is considered an additional factor for immune-dependent infertility which results from damaged hemato-testicular barrier due to venous blood stasis, hyperthermia, testicular ischemia. Our objective was to determine levels of the sperm antibodies in serum and ejaculate in adolescents with left-sided varicocele, in order to assess the changing levels of sperm antibodies in blood serum at different ages during the postoperative period, depending on the degree of varicocele. For adolescents with left-sided varicocele and without varicocele, the serum levels of sperm antibodies were determined annually at the age of 14 to 17 years, as well as registration of sperm antibodies titer in seminal fluid at the age of 17 years. The levels of sperm antibodies in blood serum were traced in dynamics for the main group and comparison group, also comparing the groups with different degrees of varicocele, like as the patients before and after surgical varicocele correction. We did not reveal increased levels of the sperm antibodies over reference values in any subject under study. The level changes of sperm antibodies in serum showed an increase in these indexes at the age of 15-16 years in adolescents of both groups with a trend for a decrease in the comparison group by 17 years of age, however, without such tendency in the main group. No significant differences were found in the levels of sperm antibodies in blood serum depending on the degree of varicocele, and on the time after varicocelectomy.

Secondary Infertility: A Neglected Aspect of Buerger’s Disease

Aim: During the gathering of demographic data for the biobank on Buerger’s Disease (BD), we found that, after the clinical manifestation of BD, the patients usually became infertile, and the age of their last child was compatible with the time of disease diagnosis. The aim of this study was to evaluate the underlying cause of secondary infertility in BD patients.Method: Anti-sperm antibodies (ASA), testosterone, luteinising hormone (LH), and follicle-stimulating hormone (FSH) in the sera of 39 male BD patients were measured and compared with 39 age-matched Caucasian male controls.Results: Six patients declared that they suffered from impotency. The ASA level was positive in 25.6% of the patients and 2.4% of the controls (p = 0.003, CC = 6.96). The mean levels of testosterone in the patients and controls were 393.12 ± 32.9ng/dl and 354.37 ± 30.9ng/dl, respectively. The mean levels of LH in the patients and controls were 0.88 ± 0.12mIU/r and 0.85 ± 0.1mIU/r, respectively. The mean levels of FSH in the patients and controls were 4.1 ± 0.35mIU/r and 3.56 ± 0.33mIU/r, respectively. No significant difference in the serum levels of testosterone, LH, or FSH was found between the patients and controls (p > 0.05). The spermograms of three ASA-negative patients demonstrated impaired sperm motility.Conclusion: Anti-sperm antibodies, disturbed genital circulation, autonomic dysfunction and sperm motility may be responsible for secondary infertility in Buerger’s Disease. Ethical code: MUMS-941842

The Prognostic Value of Seminal Anti-Sperm Antibodies Screening in Men Prepared for ICSI: A Call to Change the Current Antibody-directed Viewpoint of Sperm Autoimmunity Testing.

Objective: To prospectively evaluate the prognostic value of seminal anti-sperm antibodies screening in couples prepared for intracytoplasmic sperm injection.Methods: A prospective comparative study was conducted, including 184 non-azoospermic infertile men scheduled for ICSI. For each patient, detection of anti-sperm antibodies in seminal plasma using ELISA technique was done and its relation to standard semen parameters and ICSI outcomes, including fertilization, embryo development, and pregnancy rates, were analyzed.Results: Sperm count, motility, and morphology were negatively affected by existence of seminal ASA (p=0.012, 0.006, and 0.011, respectively). However, no statistically significant difference was detected between patients with positive and negative seminal ASA regarding the median values of fertilization (56.3% Vs. 66.7%, p =0.091), percentage of couples with grade A embryo development (91.4% vs. 89.9%, p= 0.520), and pregnancy rates (31.4% vs. 32.2%, p =0.98) after ICSI.Conclusion: ICSI seems able to overcome the problem of ASA in semen. The routine screening of ASA in men prepared for ICSI has no additional prognostic value and cannot be recom­mended for the time being, until more specific antigen-concerned testing can be developed.