Andrology & Gynecology: Current Research Association of Antisperm Antibodies with Bacterial
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Andrology & Gynecology: Current Research Association of Antisperm Antibodies with Bacterial
Vijay Prabha et al., Androl Gynecol: Curr Res 2014, 2:1 http://dx.doi.org/10.4172/2327-4360.1000118 Andrology & Gynecology: Current Research Review Article Association of Antisperm Antibodies with Bacterial Infection: An Insight to Infertility Deepali Thaper1, Harpreet Vander1 and Vijay Prabha1* Abstract Among other factors, immunological predictors associated with humoral immunity against sperm antigens can be a reason for human infertility. A hypothesis for the induction of antisperm antibodies (ASA) is the cross-reactivity of spermatozoa antigens and exogenous antigens. Common antigenicity has been established between spermatozoa and bacteria, viruses, fungi and allergens. Recent evidence suggests that many antigens shared among unrelated cell types are surface membrane or lipid conjugate complex carbohydrates. Although the complex pattern of cellular glycosylation is tissue specific, the expression of specific carbohydrate sequences may occur on several unrelated cell types eg. blood leucocytes, kidney, deciduas, endometrium, tonsil, skin, lung, liver, adrenal gland, brain and ovary. Thus, epitope specific monoclonal antibodies (mAbs) rose against the components of one cell type might be expected to recognize these rather universal glycosylated antigenic determinants on other cells. In fact, certain mAbs specifically those which react to immunodominant (often heavily glycosylated) determinants, show varying degrees of cross-reactivity with seemingly unrelated tissues depending on the epitope recognized by the mAb and the degree of structural similarity with the epitope. Cross-reactivity between certain epitopes on the bacterial surface and spermatozoa, particularly involving carbohydrate determinants might be one potential triggering mechanism for induction of antisperm antibodies in males and females. Keywords Antisperm antibodies; Human infertility; Glycosylation Introduction Infertility, the inability to conceive after twelve months of contraceptive-free unprotected intercourse, is considered as a worldwide problem which affects approximately 15% of all couples [1]. Earlier only physiological causes of infertility were taken into consideration but gradually the focus shifted towards the immunological reasons behind it. For instance, the blood-testis barrier shelters the antigenic spermatozoa from the circulating immune cells. However, autoantigenic germ cells migrate through bloodtestis barrier and are exposed to circulating immune cells leading to *Corresponding author: Vijay Prabha, Department of Microbiology, Panjab University, Chandigarh 160014, India, Tel: 91-172-2534140; Fax: 91-1722541770; E-mail: [email protected] Received: June 26, 2013 Accepted: January 30, 2014 Published: February 05, 2014 International Publisher of Science, Technology and Medicine a SciTechnol journal production of antisperm antibodies, thereby reducing the ejaculate quality and hence fertility [2]. The prevalence of such autoantibodies in general population ranges from 0-2%, but, it is greatly increased in infertile men, ranging from 7-26%. Although several risk factors for ASA development have been defined (testicular torsion, variocele, cryptorchidism, vasectomy and genital tract infections) but there are no specific indications [3]. Morever, the presence of ‘natural’ antisperm antibodies in virgin girls [4] and boys before puberty [5] still remains unanswered. Therefore, without losing focus, researchers gave a new dimension in terms of molecular mimicry existing between spermatozoa and microorganisms which might be playing a hidden role in production of ASAs. Several reports suggested the presence of cross-reactive antigens between spermatozoa and bacteria, Escherichia coli, Salmonella typhi [6,7] and Helicobacter pylori [8]. Equils et al. [9] have shown an amazing analogy between the chlamydial heat shock proteins and human proteins. Also, increased ASA levels have been reported among patients suffering from ulcerative colitis [10]. Witkin and Toth [11] explored the relationships between Ureaplasma urealyticum infection, antisperm antibodies, and infertility. The discovery of heterogeneous antigens, similar to the specific antigens of the spermatozoa, in microorganisms not only helps to elucidate the mechanisms of development of sterility on the basis of crossed immunologic reactions, but also opens the way for the practical use of harmless bacterial “spermovaccines”, essential for fertility control in man and animals. This review summarizes the results of several studies which have been undertaken to analyse a potential relation of antisperm antibodies in serum or semen with microbial findings. Chlamydia trachomatis Chlamydia trachomatis infection has become the most commonly prevalent and most damaging genital tract infection in the world. The common manifestations of C. trachomatis as salpingitis [12] and pelvic inflammatory disease [13] are well accredited in women with infertility problems [14]. Because of the alterations it causes in the epithelium and mucus composition, and by the presence of inflammatory cells, it has been cited as a major cause of tubal obstructions, lacerations and ectopic pregnancy, and can result in pelvic inflammatory disease (PID), adnexitis, local or diffuse peritonitis, and formation of adhesions which may disrupt the passing of oocytes through the tubes. So, the fact that this infection interferes seriously with human reproduction, which may preclude the couples from having a reproductive future, has put this infection under spotlight. Regarding this, several authors have reported the presence of circulating antibodies to C. trachomatis in women. To cite a few: Moore et al. [15] have focussed on the presence of circulating antibodies to C. trachomatis in women with signs of tubal damage as compared to none in a group of controls with normal fallopian. On the similar grounds, Gump et al. [16] reported a 64% incidence of chlamydial antibodies in women with residual inflammatory adnexal lesions, compared to 28% in women with normal adnexae. Genital infections such as Chlamydia may elicit an adjuvant like effect and inadvertent humoral immunity to inseminated spermatozoa [17]. Another study has shown an amazing analogy between the 10 kDa and 57 kDa chlamydial HSP (cHSP10 and cHSP57/60, respectively) All articles published in Andrology & Gynecology: Current Research are the property of SciTechnol, and is protected by copyright laws. Copyright © 2014, SciTechnol, All Rights Reserved. Citation: Deepali T, Vander H, Vijay P (2014) Association of Antisperm Antibodies with Bacterial Infection: An Insight to Infertility. Androl Gynecol: Curr Res 2:1. doi:http://dx.doi.org/10.4172/2327-4360.1000118 and human proteins. This suggests that at molecular level, there should be cross-reactivity between the human HSP60 and cHSP60, which leads to the formation of antibodies against the HSP60 in the serum and follicular fluid of women exposed to C. trachomatis; these antibodies seem to have a negative impact on embryonal growth, and increase the probability of adverse pregnancy outcomes. Also, HSP57/60 has been found to play an important role in inducing trophoblast apoptosis by stimulating the toll-like receptor 4 (TLR4), which naturally mediates immune responses in placenta [9]. A greater probability of tubal scaring and ectopic pregnancy has been speculated in women with serum antibodies against cHSP60 and positive for C. trachomatis as compared to only seronegative women. [18]. There also seems to be a cross-reactivity between HSP10 and an embryonic protein, the early pregnancy factor (EPF), and this may cause abortions [19]. The cHSP10, too, probably correlates to the severity of the disease in females and with the presence of tubal factor infertility; HSP60 has consequently been proposed as a prognostic criterion for the assessment of chlamydial infections in women and, together with other humoral parameters, as a means for priori diagnosis of tubal factor infertility [20]. Since this organism has a predilection for inducing inflammatory changes of deep pelvic organs in the female and many men were also found positive for antichlamydial antibodies in semen but not in serum [21], this raised a curiosity so as to check its relevant pathological significance in males as well, speculating that the significance of the organism in men may lie in their capacity to retain a reservoir of bacteria in their sex glands which can inoculate the female partner repeatedly. Over time, such a chronic infection in the female may cause tubal or endometrial pathology. This presumably explains the higher incidence of active chlamydial infection in the male partners of women with tubal pathology [22,23]. With focus shifting towards the male partner, it was observed that C. trachomatis is capable of attaching to sperm [24] and seems to impair sperm motility, and cause premature death, perhaps as an effect of the chlamydial lipopolysaccharide [25]. Toth et al. [26] worked on the same lines and noted that the incidence of vaginitis, salpingitis, herpes and urinary tract infection in 1350 infertile couples was generally higher in women whose husbands had reported a previous history of genitourinary infection. Several early reports have suggested a relationship between a genital infection and the production of sperm autoantibodies. ASA’s are produced in both women [27] and men [28] and may be found systemically (in the blood and lymph) and in local secretions (in seminal or cervico-vaginal fluids). Antibodies in the blood and lymph belong predominantly to the immunoglobulin G (IgG) isotype, while those found in the external secretions are predominantly of the IgA isotype [29,30]. Studies conducted by Fjallbrant and Obrant [31] and Quesada et al. [32] showed that in contrast to men without antisperm antibodies, the frequency of prostatovesiculitis was significantly higher in men with antibodies against spermatozoa. Furthermore, Shahmanesh et al. [33] reported the correlation between the presence of an organism causing a sexually transmitted disease and predisposition of men to the development of sperm antibodies. As reported by Witkin and Toth [11], a marked increase in the incidence of sperm antibodies (47 vs 5%) was observed in non-symptomatic men (under fertility investigation) with a previous history of prostatitis or urethritis. Moreover, similar study conducted by Soffer et al. [34] reported a highly significant increase (14 vs 1.2%) in the number of ASA in the seminal plasma of men with mycoplasmal or chlamydial infections Volume 2 • Issue 1 • 1000118 as compared to the non-infected controls. This could be speculated that a previous exposure to C. trachomatis, as determined by serum antibody, could be related to the presence of sperm agglutinating antibodies [35]. There could be two possible mechanisms responsible for this induction of antibodies: (a) inflammation might have led to the migration of immune cells into the genital tract where they might have then reacted with spermatozoa; (b) antibodies may be formed to common antigens between the bacteria and spermatozoa. The second possibility opened new horizons, thus paving the way for molecular mimicry between bacteria and spermatozoa to be considered as the next challenge. Marconi et al. [36] evaluated chronic inflammatory and infectious diseases of the male genital tract analyzing common bacteria including C. trachomatis and Neisseria gonorrhea, yeasts and Mycoplasma and established that there is no association between these diseases of the male genital tract and the presence of ASA in semen. The disagreement in earlier studies may have occurred due to use of different detecting methods employed to screen ASA and also different studies have taken various cut off levels for ASA as the significant level. Subsequent studies focussing on the cross reactivity between certain epitopes on the bacterial surface and spermatozoa, particularly involving carbohydrate determinants were carried out. Witkin [37] found a significant correlation between C. trachomatis antibody titres in serum from infertile women and antisperm antibodies on ejaculated spermatozoa of their partners. Similar results have been reported by Hirano et al. [38] wherein they have observed a significantly high titers of sperm immobilizing antibodies in infertile women with past C. trachomatis infection in contrast to those without any past record of C. trachomatis infection. Possible underlying mechanism could be: Since C. trachomatis has been associated with an increased concentration of seminal T-cells bearing γδ T-cell receptor, hence leading to release of proinflammatory cytokines which further activates macrophages. The inflammatory response, so produced, causes the production of antibodies against microbial antigens and spermatozoa accounting for the mimicry between the two at the molecular level [39-42]. Heat Shock Proteins serve as important antigens of infectious agents, and are among the most conserved molecules in phylogeny. Since bacterial and human HSP share ~50% amino acid homology [43], so, a prolonged exposure of immune system to cHSP60 and simultaneous exposure to both cHSP60 and hHSP60 may lead to autoantibody formation [44]. Pospisil et al. [45] have found demonstrable amounts of antisperm antibodies in 80% of the rabbits inoculated intratesticularly with a strain of C. psittaci. Also, after successful processing of statistical data and graphic presentation, they could zero down upon a close similarity between the dynamics of antiChlamydia and antisperm antibodies. These results are of significant contribution to the knowledge of formation of antisperm antibodies as a result of a previous testicular Chlamydia infection. Helicobacter pylori Helicobacter pylori are well acknowledged to cause various gastrointestinal disorders varying from chronic gastritis to gastric adenocarcinoma and lymphoma. Besides, it might also be associated with extraintestinal conditions and may also play a significant role in development of autoimmune disease [46]. From the time when the role of common antigenicity was seen in some organisms, few studies have been done to link infertility and H. pylori on similar grounds of molecular mimicry. Perez-Perez et al. [47] showed the presence of serum anti-H. • Page 2 of 6 • Citation: Deepali T, Vander H, Vijay P (2014) Association of Antisperm Antibodies with Bacterial Infection: An Insight to Infertility. Androl Gynecol: Curr Res 2:1. doi:http://dx.doi.org/10.4172/2327-4360.1000118 pylori antibodies in 17% of 277 couples attending an infertility centre and whereas both the partners were seropositive only in 6.6% cases. Figura et al. [8] while exploring the involvement of H. pylori infections in infertility found that the infection was more prevalent in tests than controls. The infected individuals showed the presence of anti H. pylori antibodies that could cross-react with spermatozoa. These antibodies were present in semen and follicular fluids. Moreover, they found that the sera to H. pylori whole antigens and Vacoulating cytotoxin A (VacA) could react with the tails and the pericentriolar area of human spermatozoa (which are rich in tubulin); a linear homology was also observed at amino acid level between β-tubulin and three H. pylori proteins, flagellin, VacA and cytotoxin-associated gene A (CagA). They set forth an explanation that being the only flagellated human cells, spermatozoa may share homology with bacterial flagella (structures endowed with the same function are normally highly conserved during their evolution), and therefore may cross-react with antibodies produced against flagellated organisms, such as H. pylori. Collodel et al. [48] in their study showed that the sperm quality of patients infected by CagA-positive strains was significantly reduced compared to that of CagA-negative patients: motility and the fertility index were diminished, while the frequency of apoptosis and necrosis was increased. The presence of antisperm antibodies was also observed by Ambrosini et al. [49]. The concentration of anti-H. pylori antibodies in the cervical mucus of women during the ovulatory period in their study correlated with the serum concentration. In positive samples, the slide test showed abnormal penetration of spermatozoa through the semen–mucus interface. They further established that these anti-H. pylori antibodies in cervical mucus may be considered a new local factor in female infertility. Ureaplasma urealyticum The male reproductive tract is known to be colonized by four different species of mycoplasmas namely, M. hominis, Ureaplasma urealyticum, M. fermentans and M. genitalium [50], out of which, U. urealyticum extracts the major attention as a facultative pathogen in male urogenital tract infections, associated with nonspecific urethritis and prostatitis [51] but in cases of non-bacterial prostatitis, it has been reported as a cause of the inflammation in 11-15% of the cases [52,53]. U. urealyticum lacks a cell wall, has a unique ability to hydrolyze urea and is one of the smallest self-replicating prokaryotes. Because U. urealyticum is an inhabitant of the human lower genital tract, infections are considered to be sexually transmitted and occur more frequently during fertile ages. Although the contributory role of U. urealyticum in infertility has yet to be conclusively established, considerable data have been compiled to support the theory that U. urealyticum can cause infertility [54-57]. Hass [58] and Witkin [59] showed that U. urealyticum could break down the bloodtestis or blood-excurrent duct barrier, resulting in inoculation with spermatozoa antigens. Earlier reports have implicated its role as an aetiological agent in male infertility since this microorganism can attach firmly to the spermatozoa [60], causing reduced sperm motility and poor sperm morphology [61-63]. Bacterial survival within the host depends on its ability to evade the immune responses to infection. For pathogenic mycoplasmas, the phenomena of phenotypic plasticity and molecular mimicry are responsible for improper or inefficient recognition of bacteria by the immune system of host. Witkin and Toth [11] explored the possible relationships between U. urealyticum infection, antisperm antibodies, and infertility. They found that the incidence of antisperm antibodies in men with U. urealyticum infection was significantly higher than that Volume 2 • Issue 1 • 1000118 in the control subjects. Similar findings were reported by Quesada et al. [32], who also noted that fertility in men with U. urealyticum infection was improved only after antibiotic therapy, whereas little improvement was seen in a group of men with infection plus antisperm antibodies. Since U. urealyticum adheres to the sperm surface, hence the possibility of sperm damage by the metabolic products released by this microorganism cannot be ignored. In this regard, it could be postulated that the bacterium causes membrane changes which result in the exposure of spermatozoa antigens to the immune system leading to autoantibodies against sperm and hence causing infertility related problems [34]. Ye et al. [64] first reported the existence of cross-reactive antigens between U. urealyticum and human sperm. Cole [65] and Shibata et al. [66] in their respective studies have reported that mAb gainst HLA-B27 antigens show cross-reactivity with several microbial ureases including those of U. urealyticum and U. parvum. Furthermore, UreC subunit of ureaplasmal urease shares some sequence homology with the synthetic immunogen used to raise the mAb to HLA-B27. This feature suggests that molecular mimicry between microbial urease and HLA-B27 could account for autoimmune responses, including antisperm antibodies [67]. Wu et al. [68] reported similar results, which provided some new clues as to the potential mechanism(s) of how U. urealyticum caused the production of antisperm antibodies leading to infertility. Recently Shi et al. [69] have confirmed the existence of cross-reactive antigens (61, 50 and 25 kDa) between U. urealyticum and hSMP (human sperm membrane protein). This is the first systematic study on cross-reactive antigens between U. urealyticum and hSMP. The N-terminal amino acids of the U. urealyticum 25-kDa protein were sequenced to be MKRPLIIGVG and database analysis showed identity with UreG of U. urealyticum. Further, they identified a common pentapeptide between UreG and NASP (nuclear autoantigenic sperm protein), one of the human sperm proteins. This pentapeptide, IERLT, corresponded to published amino acids 21 to 25 in UreG and amino acids 398 to 402 in human NASP. The results provide strong evidence for the underlying cause of infertility in men infected with U. urealyticum and displayed positive anti-sperm antibodies in their serum and/or semen. UreG is a Ni2+ binding GTPase involved in the regulation of expression and the maturation of urease and hydrogenase. NASP encodes a H1 histone-binding protein (778 amino acids, 86 kDa) that is involved in transporting histones into the nucleus of dividing cells [70]. Multiple isoforms are encoded by transcript variants of this gene. The somatic form is expressed in all mitotic cells, is localized to the nucleus, and is coupled to the cell cycle. The testicular form is expressed in embryonic tissues, tumor cells, and the testis. In male germ cells, this protein is localized to the cytoplasm of primary spermatocytes and the periacrosomal region of mature spermatozoa [71]. Recently, Al-Daghistani and Fram [41] have also recorded that women with infertility related to autoantibodies directed towards reproductive tissue (testis and ovaries) showed a significantly higher prevalence of M. hominis (19.2% and 7.3% respectively) and U. urealyticum (13.7% and 9.8%) compared with women without autoantibody-related infertility and compared with fertile women. Repeated exposure to Mycoplasma infection may be one of the stimulators that lead to the formation of autoantibodies as a result of some antigenic crossreactivity between bacteria and human spermatozoa. Gastrointestinal flora Inflammatory bowel diseases (IBD) are an outcome of an exaggerated and inappropriate mucosal immune response to normal constituents of the mucosal microflora. These are chronic • Page 3 of 6 • Citation: Deepali T, Vander H, Vijay P (2014) Association of Antisperm Antibodies with Bacterial Infection: An Insight to Infertility. Androl Gynecol: Curr Res 2:1. doi:http://dx.doi.org/10.4172/2327-4360.1000118 inflammatory and relapsing diseases of the gastrointestinal tract which cause impairment of gastrointestinal structure and function. IBD comprises of both Crohn’s disease and ulcerative colitis (UC). A pathologic activation of the mucosal immune system in response to antigens serves as a key factor in the pathogenesis of IBD [72]. Since there is a loss of integrity of the mucosal membrane, absorption studies have shown an increased permeability of intestine to macromolecules in patients with IBD. Knoflach et al. [73] have observed the elevated titers of serum antibodies against different dietary antigens. The possible explanation to the observation that there is an increased intestinal permeability in patients with IBD could be that there might be some sharing between common epitopes between alimentary antigens or antigens of the common intestinal flora and human spermatozoa. Earlier reports have suggested that there exists some similarity between antigens of E. coli and human spermatozoa. The studies conducted by Popivanov et al. [74] have suggested that E. coli cells of serotypes 08, 09 and 086 contain heterogenetic antigens similar to the cellular antigens of human spermatozoa and represented mainly on the surface of the bacteria and spermatozoa. These antigens cannot be classed with the heterogeneous antigens similar to the group antigens of ABO system, for the former could not be detected in the chosen strains by the method of absorption of specific sera against A, B and O antigens. The possibility evidently cannot be ruled out that these antigens may belong to the mannans of the bacterial cell walls, which have been shown to be similar to the cellular carbohydrates of the human spermatozoa. Following the similar path, a study was carried out in our laboratory, which showed that Fluorescein Isothiocyanate (FITC) labelled sperm immobilization factor (SIF) isolated from Staphylococcus aureus not only binds to spermatozoa but to various gram positive and gram negative bacteria viz. Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica typhi, Shigella flexneri, Enterococcus faecalis, Bacillus cereus and Proteus mirabilis. Therefore it could be hypothesized that there is a common SIF binding motif on spermatozoa and bacteria. Moreover, the co-incubation along with SIF receptor isolated and purified from spermatozoa completely inhibited binding of SIF to all the bacteria tested. 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Gastroenterology 92: 479-485. 74.Popivanov RP, Zhukov-Verezhnikov NN, Bulanov ID, Podoplelov II, Mishchenko BA (1981) [Heterogenetic antigens of E. coli similar to human • Page 5 of 6 • Citation: Deepali T, Vander H, Vijay P (2014) Association of Antisperm Antibodies with Bacterial Infection: An Insight to Infertility. Androl Gynecol: Curr Res 2:1. doi:http://dx.doi.org/10.4172/2327-4360.1000118 sperm antigens]. Biull Eksp Biol Med 92: 316-317. bacteria: A fluorescent microscopy study. Current Microscopy Contributions to Advances in Science and Technology, Méndez-Vilas, Formatex Research Center, Spain, 112-118. 75.Prabha V, Vander H (2012) Molecular similarities between spermatozoa and Author Affiliations 1 Top Department of Microbiology, Panjab University, Chandigarh, India Submit your next manuscript and get advantages of SciTechnol submissions 50 Journals 21 Day rapid review process 1000 Editorial team 2 Million readers Publication immediately after acceptance Quality and quick editorial, review processing Submit your next manuscript at ● www.scitechnol.com/submission Volume 2 • Issue 1 • 1000118 • Page 6 of 6 •