Anti-ovarian Autoantibodies Research Articles

AN OVERVIEW OF AUTOIMMUNITY IN IMPLANTATION FAILURE: A LITERATURE REVIEW

The aim: This review was aimed to understand the role of different types of autoantibodies like antiphospholipid, antithyroid, antisperm, antinuclear, anti-ovarian autoantibodiesand heat shock protein HSP 60 in the process of implantation in the normal way of conceiving and IVF and also to estimate that how the presence of these autoantibodies affect the normal pregnancy outcome. Materials and methods: This review process performed in the obstetrics and gynaecology postgraduate department, Bogomolets national medical university, Kyiv, Ukraine. It was a review of already published papers not to need the ethical board committee's approval. By following the literature review guidelines, this paper was written and searched for relevant studies regarding autoantibodies and implantation, published in medical literature till 2020 were included in this review process. The search is done for studies published till 2020 in the English language from the Medline database, including Google Scholar, PubMed, Web of Science and Cochrane library database. Conclusions: Our recent work found that the involvement of APA, ANA and/or ATA in recipients of oocyte donations did not affect their pregnancy outcomes. Some researchers did not give any clear conclusion about these risks, and some stated that the use of some immunodepressant agents could be useful to reduce the harmful effects of these autoantibodies associated with implantation failure. Each autoantibody has a different mechanism of action to create the pathological state, some have direct effect, and some indirectly impact implantation. In future, further high-quality studies need to be performed for better understanding.

The Role of Anti-ovarian Autoantibodies in Polycystic Ovary Syndrome

Background: Autoimmunity has been proposed in the pathogenesis of polycystic ovary syndrome (PCOS) since early 1990s. Studies of anti-ovarian antibodies (AOA) that were performed so far yielded conflicting results. Objective: This study aimed at evaluating the association between PCOS and AOA. Patients and method: The study was conducted on 80 Egyptian women who were divided into two groups: cases group of 40 women with PCOS, and a control group of 40 healthy age-matched normally cycling fertile women. For both cases and control groups, serum level of AOA was measured using ELISA. Results: Serum AOA level was significantly higher among cases than controls (p value < 0.05). No significant difference was found between cases and controls regarding their hormonal profile (estrogen, FSH, LH, and testosterone) except for the level of mid luteal progesterone which was significantly lower among cases (p value <0.05). No significant correlation was found between AOA and age, body mass index (BMI), FSH, LH, E2, mid luteal progesterone and testosterone in control group. However, a significant negative correlation between AOA and serum testosterone level was found in PCOS group. Conclusion: Our results suggest that autoimmune ovaritis may be frequently associated with PCOS. Circulating AOA may represent a practical and suitable marker for diagnosis of PCOS.

Anti-ovarian antibodies in sera of patients with ovarian tumors

Aim of paperThe purpose of this study was to assess the presence of anti-ovarian autoantibodies in sera of patients with ovarian tumors. Materials and methodsThe study group consisted of 82 patients treated at the Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland in 2007–2011. 46 patients with malignant ovarian tumors and 36 patients diagnosed with benign ovarian tumor were included into the study. Age-matched healthy control groups consisted of 15 women and 19 men. Anti-ovarian autoantibodies in serum were assessed with the use of indirect immunofluorescence. The presence of anti-ovarian autoantibodies in serum was correlated with clinical and histopathological features of the disease. ResultsSerum anti-ovarian autoantibodies were found in 59% (27/46) of patients with malignant ovarian tumors, compared to 55% (20/36) and 26% (4/15) of patients with benign ovarian tumors and healthy female controls respectively. The difference was statistically significant (P=0.04). All serum samples from the male controls were negative. Anti-ovarian antibodies occurred more often among advanced stage (III and IV stage according to FIGO, P=0.037) and grade 3 (P=0.049) ovarian cancers, however, there were no differences in median progression-free survival (P=0.388). The presence of anti-ovarian antibodies was neither influenced by histopathological type of the tumor, menopausal status, presence of ascites nor CA125 levels. Seropositivity for anti-ovarian antibodies was correlated positively with patients’ age and negatively with tumor size. ConclusionsAnti-ovarian autoantibodies develop with higher frequency in ovarian cancer comparing to healthy controls, however with similar proportion to benign ovarian tumors patients. The presence of antibodies against normal ovarian tissue correlates with ovarian cancer aggressiveness.

Review on Autoimmune Reactions in Female Infertility: Antibodies to Follicle Stimulating Hormone

Female fertility can be affected by diseases or dysfunctions of reproductive tract, neuroendocrine system, and immune system. Reproductive autoimmune failure can be associated with overall activation of immune system or with immune system reactions specifically directed against ovarian antigens. Majority of the antiovarian autoantibodies are directed against β-subunit of follicle stimulating hormone (anti-FSH). This paper summarizes a current clinical classification of female infertility in the context of general activation of autoimmunity and antiovarian autoimmunity by describing serum anti-FSH. The presence of naturally occurring anti-FSH in healthy women will be discussed. In addition, the putative impairment of ovarian folliculogenesis in case of increased production of those antibodies in infertile women will be characterized.

Fertility Issues in Women with Diabetes

Diabetes mellitus Type 1 and Type 2 should be considered in the differential diagnosis of menstrual abnormalities and infertility. The reproductive period of diabetic women may be reduced due to delayed menarche and premature menopause. During the reproductive years, diabetes has been associated with menstrual abnormalities, such as oligomenorrhea and secondary amenorrhea. It was found that better glycemic control and prevention of diabetic complications improves these irregularities and increases fertility rates close to those that are seen in the general population. Women with persistent menstrual abnormalities despite adequate treatment need to be approached by broader evaluation, which will include the examination of the hypothalamic-pituitary-ovarian axis and the hormonal status, presence of autoimmune thyroid disease and antiovarian autoantibodies, and hyperandrogenism.

Corticosteroids in patients with antiovarian antibodies undergoing in vitro fertilization: a prospective pilot study

Antiovarian autoantibodies (AOA) have been associated with reproductive failure, especially in in vitro fertilization (IVF) patients. Thus, the success rate of IVF might be improved by the use of corticosteroids. However, therapeutic trials with these drugs have yielded conflicting results, particularly because of heterogeneous inclusion criteria. Among women with previous IVF failure, we selected those who presented with a positive serum AOA assay, and analysed the efficacy of corticosteroids in improving the IVF outcome in these patients. One hundred patients with serum AOA detected by ELISA and at least two previously failed IVF attempts were selected. These patients underwent a further IVF cycle with 0.5 mg/kg prednisolone, started on the first day of the treatment cycle. In patients who became pregnant, corticosteroids were administered until the end of the first trimester of pregnancy and then progressively discontinued. AOA were assessed before and after oocyte retrieval. Clinical data of the corticosteroid-treated cycle were compared with data from the preceding IVF cycle for each patient. No adverse effects resulting from corticosteroids were observed. Post oocyte retrieval antiovarian IgG were significantly lower in corticosteroid-treated attempts when compared with the preceding cycles. Twenty-six pregnancies resulted in the birth of 30 healthy children. The pregnancy rate, implantation rate, and live birth rate were 38.8%, 17.8%, and 26.5% respectively in prednisolone-treated cycles. This study confirms the usefulness of corticosteroids in improving the success rate in a subset of patients with previous IVF failure and significant serum AOA levels.

Auto-immunité anti-ovarienne et pathologies ovariennes : cibles antigéniques et implications diagnostiques

The involvement of serum anti-ovarian autoantibodies (AOA) in ovarian pathology still remains controversial. In some cases of clinically patent ovarian failure, there seems to be a causal relationship between AOA and the ovarian disease. In patients with various organ-specific or systemic autoimmune diseases, or with unexplained, repeated reproductive failure, but otherwise normal ovarian function, it is even more difficult to determine the significance of AOA for several reasons: i) AOA recognize many different antigenic targets in the ovary ii) the antiovarian response may be transient or variable with time iii) the presence of AOA does not imply their aetiopathogenic role in the disease. The present paper reviews the clinical significance of AOA based on their ovarian targets as far as they have been identified until now.

Autoimmunity and antigenic targets in ovarian pathology.

The involvement of autoimmune mechanisms in premature ovarian failure has been put forward by numerous investigators. In various other ovarian pathologies, such as idiopathic infertility, polycystic ovary syndrome, or endometriosis, similar mechanisms have been suggested. However, the exact role of autoimmunity in the pathophysiology of these diseases still remains controversial. The diagnosis of autoimmune ovarian disease relies on several clinical, biological and histological findings, but special interest has been focused on antiovarian autoantibodies. The search for these antibodies has been undertaken by several authors and yielded somewhat conflicting results which might be conditioned by methodological differences and by the multiplicity of potential immune targets. These targets, which comprise various steroidogenic enzymes, gonadotrophins and their receptors, the corpus luteum, zona pellucida and oocyte, are reviewed. Further investigation of these targets is required to improve the diagnostic tools that will lead to a precocious and reliable diagnosis of autoimmune ovarian disease, an appropriate clinical surveillance as well as the selection of patients who may benefit from immune-modulating therapy and possibly recover ovarian function and fertility.

Interacting quantitative trait loci control loss of peripheral tolerance and susceptibility to autoimmune ovarian dysgenesis after day 3 thymectomy in mice.

Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by CD4(+)CD25(+) T cells and the development of autoimmune ovarian dysgenesis (AOD) in A/J and (C57BL/6J x A/J)F(1) (B6AF(1)) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF(1) x C57BL/6J backcross population verified Aod1 and Aod2 that were previously mapped as qualitative traits. Additionally, three new QTL intervals, Aod3, Aod4, and Aod5, on chromosomes 1, 2, and 7, respectively, influencing specific subphenotypes of AOD were identified. QTL linkage analysis using the A x B and B x A recombinant inbred lines verified Aod3 and confirmed linkage to H2. Aod5 colocalized with Mater, an ovarian-specific autoantigen recognized by anti-ovarian autoantibodies in the sera of D3Tx mice. Sequence analysis of Mater identified allelic, strain-specific splice variants between A/J and C57BL/6J mice making it an attractive candidate gene for Aod5. Interaction analysis revealed significant epistatic effects between Aod1-5 and Gasa2, a locus associated with susceptibility to D3Tx-induced autoimmune gastritis, as well as with H2. These results indicate that the QTL controlling D3Tx-induced autoimmune phenomenon are both organ specific and more generalized in their effects with respect to the genesis and activity of the immunoregulatory mechanisms maintaining peripheral tolerance.

Ovarian autoimmunity in relation to egg production in laying hens

The aim of this study was to determine whether anti-ovarian autoantibodies appear in the circulation of laying hens and whether the concentrations of these antibodies change with respect to ageing and egg laying rate. Autoantibodies to ovarian tissues in the circulation of aged (aged approximately 670 days) White Leghorn hens with low (< 50%) and high (> 90%) egg laying rates were examined by ELISA and western blotting. Young laying hens (aged 185 days) with > 95% egg production were used as controls. The results of the ELISA indicated that IgG, which bound to the ovary and small white follicles, was present in the circulation of old laying hens. More hens that laid few eggs had circulatory autoantibodies to the ovary and small white follicles, as determined by the cut-off value in ELISA (mean absorbance + 2 SD of young laying hens), than did hens that laid greater numbers of eggs, and the concentration of IgG was significantly higher in the hens that laid few eggs. In contrast, when the muscle proteins were used as antigens there were no significant differences in the absorbance values among low and high laying frequency old hens or young hens. Western blotting revealed many bands of immunoprecipitates formed by ovarian antigens and antibodies in the serum of old hens, indicating the presence of many binding sites for circulatory IgG in ovarian tissues. These results indicate that antibodies to ovarian tissues appear in the circulation of laying hens during ageing, and that the concentration of these autoantibodies is related inversely to the rate of egg laying by hens.

Ovarian autoimmunity in relation to egg production in laying hens

The aim of this study was to determine whether anti-ovarian autoantibodies appear in the circulation of laying hens and whether the concentrations of these antibodies change with respect to ageing and egg laying rate. Autoantibodies to ovarian tissues in the circulation of aged (aged approximately 670 days) White Leghorn hens with low (< 50%) and high (> 90%) egg laying rates were examined by ELISA and western blotting. Young laying hens (aged 185 days) with > 95% egg production were used as controls. The results of the ELISA indicated that IgG, which bound to the ovary and small white follicles, was present in the circulation of old laying hens. More hens that laid few eggs had circulatory autoantibodies to the ovary and small white follicles, as determined by the cut-off value in ELISA (mean absorbance + 2 SD of young laying hens), than did hens that laid greater numbers of eggs, and the concentration of IgG was significantly higher in the hens that laid few eggs. In contrast, when the muscle proteins were used as antigens there were no significant differences in the absorbance values among low and high laying frequency old hens or young hens. Western blotting revealed many bands of immunoprecipitates formed by ovarian antigens and antibodies in the serum of old hens, indicating the presence of many binding sites for circulatory IgG in ovarian tissues. These results indicate that antibodies to ovarian tissues appear in the circulation of laying hens during ageing, and that the concentration of these autoantibodies is related inversely to the rate of egg laying by hens.

Autoimmune antiovarian antibodies and their impact on the success of an IVF/ET program.

In previous papers, we referred to studies of the influence of antiovarian autoantibodies on menstrual cycle disorders in adolescent girls. We examined autoantibodies against ooplasma, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells. In infertile women in the IVF/ET program, we studied the positivity of antiovarian antibodies and cytokines, namely, TNF-alpha and IL-1 beta, in follicular fluid correlated with the following subgroups, characterized by the outcome of in vitro fertilization, as follows: G, pregnant; F, fertilized; N, nonfertilized; and O, no oocyte gained. The presence of autoantibodies corresponds to the success or failure of the IVF/ET program. Our results support the hypothesis that antiovarian autoantibodies play an important role in both the endocrine and the reproductive function of the human ovary and that it can influence them negatively.

Organ-specific autoantibodies are possible markers for reproductive failure: a prospective study in an in-vitro fertilization-embryo transfer programme.

This study was conducted to investigate the usefulness of organ-specific autoantibodies as possible markers for reproductive failure. Antithyroid and antiovarian autoantibody concentrations were measured in 78 patients with mechanical or unexplained infertility that were enrolled in an in-vitro fertilization (IVF)/embryo transfer programme with follow-up of the outcome. In all, 16 patients (20.5%) were positive for antithyroid antibodies, nine (11.5%) were positive for antiovarian autoantibodies and two (2.6%) were positive for both autoantibodies. All 23 patients who were positive for either antithyroid or antiovarian autoantibodies, or both, were defined as the study group, and 55 who were negative for autoantibodies were considered as the control group. No statistical difference in the incidence of autoantibodies was found between the patients with mechanical infertility and those with unexplained infertility. No differences were found in the mean number of oocytes retrieved, fertilization rates or mean numbers of transferred embryos between the study and the control groups. The pregnancy rate per cycle was 10.8% (7/65) in the study group, compared with 25.0% (24/96) in the control group (P < 0.05). We conclude that organ-specific autoantibodies such as antithyroid and antiovarian antibodies may serve as possible markers for reproductive failure. Further investigation is required to understand the possible immunopathological mechanism for reproduction failure in patients with organ-specific autoantibodies.

Aod2, the locus controlling development of atrophy in neonatal thymectomy-induced autoimmune ovarian dysgenesis, co-localizes with Il2, Fgfb, and Idd3.

In genetically susceptible strains of mice, such as A/J and (C57BL/6J x A/J)F1 hybrids, neonatal thymectomy-induced autoimmune ovarian dysgenesis (AOD) is characterized by the development of antiovarian autoantibodies, oophoritis, and atrophy. Temporally, atrophy may be observed during and after the regression of inflammatory infiltrates from the ovary. Histologically, lesions appear as areas devoid of ovarian follicles in all stages of development that have been replaced by luteinized interstitial cells. We report here the mapping of Aod2, the locus that controls this phenotype, to mouse chromosomes 3 within a region encoding Il2 and Fgfb. Most significant, however, is the co-localization of Aod2 to Idd3, a susceptibility gene that plays a role in autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse.

Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.

Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.

Autoimmune Oophoritis: A Clinicopathologic Assessment of 12 Cases

Twelve cases of histologically confirmed autoimmune oophoritis are described. Eight presented with symptoms and laboratory evidence of premature ovarian failure (POF). Four were diagnosed unexpectedly after hysterectomy for endometrial pathology or for sequelae of cystic enlargement of the ovaries. Two of eight patients tested had serum anti-ovarian autoantibodies (Aab), while five of seven had anti-adrenal Aab. Two women had, or subsequently developed, Addison's disease, and two patients had Hashimoto's disease at presentation. All women with this disease risk the development of adrenal failure and hypothyroidism. Microscopically, 11 cases showed a lymphoplasmacytic infiltrate that spared primordial follicles but involved, with progressive intensity, early and late preovulatory follicles and corpora lutea. Sparse perivascular and perineural inflammatory infiltrates were also present. The twelfth case appeared to be a unique case of granulomatous oophoritis, considered autoimmune because of the folliculotropic nature of the inflammatory process. Three cases showed evidence of follicular dysplasia.