Aim. To study the possible associations of tumor ER, PR and Ki-67 expression with ESR1 and ESR2 genes polymorphisms and blood serum levels of antiidiotypic antibodies IgG2-E2 and IgG2-Pg in breast cancer patients (BCP).Materials and Methods. Blood serum levels of IgG2-E2 and IgG2-Pg were studied in 1025 BCP (478 with stage I and 547 with stages II-IV) by means of enzyme-linked immunosorbent assay. Real-time PCR was performed for ESR1(rs2234693) and ESR2 (rs4986938) genes polymorphisms detection. ER, PR and Ki-67 positive tumor cells was determined using immunohistochemistry.Results. IgG2-E2 and IgG2-Pg blood serum levels were not depended on ESR1 and ESR2 gene polymorphisms in BCP. ER+/PR+ tumors were revealed more frequently and ER-/PR- tumors less frequently in BCP at the I stage with high serum levels of both IgG2-E2 and IgG2-Pg than in BCP with their low levels: in patients with genotype TC ESR1 (91.8 % and 3.3 % vs 73.9 % and 11.1%, p = 0.015). Such differences were not revealed in patients with genotypes TT and CC ESR1. There were not discovered the desired association of ER/ PR tumor phenotype with studied antibodies and ESR2 genes polymorphisms. High levels of tumors Ki-67 positive cells (>20%) were determined less frequently in BCP at the II-IV stages with high levels of both IgG2-E2 and IgG2-Pg than in BCP with their low levels: in patients with genotypes TC ESR1 (48.4 % vs 69.7 %, p = 0.004) and GA ESR2 (46.8 % vs 66.3 %, p = 0.009). There were not revealed such differences in patients with other variants of ESR1 and ESR2 genotypes.Conclusion. Synergistic effects of IgG2-E2 and IgG2-Pg were discovered in BCP: the maintenance of ER and PR in tumors at the I stage and inhibition of tumor proliferation at the II-IV stages.

Aim. To study the possible synergistic action of steroid hormones and hormone-specific autoantibodies and anti-autoantibodies in conversion of ER+/PR+ tumors into ER-/PR- in breast cancer patients.Materials and Methods. Concentrations of estradiol (E2) and progesterone (Pg) and the levels of hormone-specific idiotypic IgA antibodies (IgA1-E2 and IgA1-Pg) as well as anti-idiotypic IgG antibodies (IgG2-E2 and IgG2-Pg) were studied in the serum of 979 breast cancer patients (432 patients with stage 1 and 547 patients with stages 2-4) by means of enzyme-linked immunosorbent assay. E2 and Pg receptors phenotype (ER/ PR) was determined using immunohistochemistry.Results. Simultaneous increase in IgA1-E2 and IgG2-E2 levels was associated with elevated E2 serum concentration (p = 0.007) in ER+/PR+ breast cancer patients. On the contrary, concurrent increase in IgA1-Pg и IgG2-Pg, was associated with lowered Pg concentration (p = 0.04). The frequency of ER+/PR+ tumors was low and ER-/PR- was high in patients with stages 2-4 breast cancer than in stage 1 in the following cases: 1) IgG2-E2 and IgA1-E2 levels were high regardless of serum E2 (p = 0.004); 2) IgG2-E2 levels were high and IgA1-E2 and E2 levels were low (p = 0.002); 3) IgG2-Pg and Pg levels were high regardless of IgA1-Pg levels (р < 0,001); 4) IgG2-E2 and IgG2-Pg levels were high regardless of E2, Pg, IgA1-E2 and IgA1-Pg levels (р < 0,001). In other combinations of hormones and hormone-specific antibodies and anti-antibodies, there have been no differences in the frequency of ER+/PR+ and ER-/PR- tumors between patients with ascending stages of breast cancer.Conclusion. We for the first time found a synergistic action of hormone-specific idiotypic and anti-idiotypic autoantibodies on the concentration of steroid hormones in the serum of breast cancer patients, and the synergistic action of steroid hormones and hormone-specific idiotypic and anti-idiotypic autoantibodies on tumor steroid receptor conversion.

BACKGROUND: Increased consumption of sweet and high-calorie foods leads to weight gain in humans and the development of metabolic syndrome. Great attention is given to a personalized approach to nutrition correction based on genetic testing. The genetic basis for human taste sensitivity to sweet stimuli remains is understudied. The role of the g.18853330 A>G (rs4920566) polymorphism of the TAS1R2 gene in preference for sweets has not been fully studied.AIM: To investigate the possible relationship between rs4920566 polymorphism in TAS1R2 gene and sensitivity to natural sugars and food preference of high-calorie sweet foods in humans.MATERIALS AND METHODS: A single-sample experimental study was carried out. The study participants were conditionally healthy students who voluntarily agreed to conduct it. Sugar sensitivity was assessed in two tasting tests. Sucrose sensitivity thresholds (STS) were determined by staircase procedure (solutions: 8.0 to 500 mM/l). To assess food preferences for sweet foods, specially designed questionnaires with a checklist of products were used. Genomic DNA samples from all study participants were obtained from buccal epithelial cells. Genomic DNA was extracted from buccal epithelial cells using the adsorption of DNA with an inorganic sorbent in the presence of a chaotropic agent. Typing of the rs4920566 polymorphism in TAS1R2 gene was performed using asymmetric real-time PCR.RESULTS: The study included 26 young men and 110 young women which the average age was 20.8±4.8 (SD) years. Gender was a significant factor affecting the taste perception of the sweetness sugars (maltose, glucose, sucrose and fructose) in students. Young men more often than young women could not distinguish the taste of four sugars (β=-2.93(0.99), p=0.003). The rs4920566 polymorphism in TAS1R2 gene did not affect the ability of students to distinguish the taste of four natural sugars. It was found that the variation series of STS values for sucrose in young women with the A allele (16.0[16.0–31.0] versus 16.0[8.0–16.0] mmol/l, pcor=0.002) and A/G genotype (16.0[16.0–31.0] vs. 16.0[8.0–16.0] mmol/l, pcor=0.010) were significantly lower compared to young men. Separately, in young women with the G/G genotype the range of STS is shifted towards higher concentrations of sucrose compared with women with the A/G genotype (16.0[16.0–31.0] vs. 16.0[8.0 -16.0] mmol/l, pcor=0.039). Testing the hypothesis about the randomness of the relationship between the rs4920566 genotypes of the TAS1R2 gene and the liking rating of foods with a sweet taste using Kruskal-Wallis test did not allow us to conclude that the A/A, A/G and G/G genotypes of the TAS1R2 gene influence the choice of sugary high-calorie foods in students.CONCLUSION: Our results are consistent with the literature data and confirm that rs4920566 polymorphism of TAS1R2 gene cannot be an informative marker for the diagnosis of metabolic conditions associated with the consumption of high-calorie sweet foods. Likely, its functions are related to the mechanisms of neurotransduction of the sweet taste signal.

Aim . To investigate the associations of cell proliferation marker Ki-67 in estrogen receptor (ER) and progesterone receptor (PR) positive (ER + / PR + ) and negative (ER - /PR - ) tumors with the ratio of antibodies against estradiol and progesterone (IgA 1 -E2/IgA 1 -Pg) in the serum of breast cancer (BC) patients. Materials and Methods . Antibodies against steroid hormones were analyzed by ELISA in the serum of 432 healthy women and 1212 patients with BC (573 patients with I stage and 639 patients with II–IV stages). Expression of Ki-67, ER and PR in tumors was determined by immunohistochemical staining. Serum estradiol and progesterone were measured by enzyme-linked immunosorbent assay. Results . In total, low IgA 1 -E2/IgA 1 -Pg (≤ 1) and high IgA 1 -E2/IgA 1 -Pg (> 1) ratio were revealed in 49.3% and 50.7% of healthy women; in 25.7% and 74.3% of stage I BC patients with tumor Ki-67 < 14 (р < 0.001; OR = 0.4 and OR = 2.8, respectively), and in 17.1% and 82.9% of stage I BC patients with tumor Ki-67 > 30 (р < 0.001; OR = 0.2 and OR = 4.7, respectively). The differences between patients with low and high tumor Ki-67 levels in relation to low and high IgA 1 -E2/IgA 1 -Pg ratio were statistically significant (p = 0.03). In stage I BC patients with ER + /PR + and tumors with Ki-67 < 14, low and high IgA 1 -E2/IgA 1 -Pg ratio were found in 25.0% and 75.0% cases (р < 0.001; OR = 0.3 and OR = 2.9, respectively). In stage I BC patients with ER + /PR + and tumors with Ki-67 > 30, low and high IgA 1 -E2/IgA 1 -Pg ratio were found in 12.9% and 87.1% cases (р < 0.001; OR = 0.2 and OR = 6.6, respectively). In patients with ER + /PR + tumors, the differences between patients with low and high tumor Ki-67 levels in relation to low and high IgA 1 -E2/IgA 1 -Pg ratio were also statistically significant (p = 0.009). In patients with ER - /PR - tumors, the differences between patients with low and high Ki-67 levels in relation to low and high IgA 1 -E2/IgA 1 -Pg ratio were not revealed. The proportion of breast cancer patients with tumor Ki-67 > 30 increased from I to II–IV BC stages regardless of IgA 1 -E2/IgA 1 -Pg ratio. Conclusion . IgA 1 -E2/IgA 1 -Pg ratio may serve as a predictor of tumor proliferative activity in stage I BC patients with ER + /PR + tumors.

Aim. To investigate the associations of idiotypic IgA antibodies against benzo[a]pyrene, estradiol and progesterone (IgA1 -Bp, IgA1 -E2, and IgA1 - Pg) with the corresponding anti-idiotypic IgG antibodies to estradiol and progesterone (IgG2 -E2 and IgG2 -Pg) and with gene polymorphisms of CYP1A1, CYP1A2, CYP1B1, CYP17A1, CYP19A1, GSTM1, GSTT1, and GSTP1 in patients with stage 1 breast cancer. Materials and Methods. Idiotypic and anti-idiotypic antibodies in the serum of 240 healthy women and 505 patients with stage 1 breast cancer were measured by enzyme-linked immunosorbent assay. Prevalence of CYP1A1 (rs4646903), CYP1A2 (rs762551), CYP1B1 (rs1056836), CYP19A1 (rs2470152), GSTM1(del), GSTT1(del), and GSTP1 (rs1695) polymorphisms in 530 healthy women and 694 patients with stage 1 breast cancer were determined by real-time polymerase chain reaction.Results. Low personal IgA1 -Bp/IgA1 -Pg < 1 and IgA1 -E2/IgA1 -Pg < 1 ratios in combination with low IgG2 -E2 ≤ 4 and high IgG2 -Pg > 2 levels were found in 20.6% of healthy women and in 4.5% of breast cancer patients (p < 0.0001; OR = 0.2). Low IgA1 -Bp/IgA1 -Pg and high IgA1 -E2/IgA1 -Pg ratios in combination with low IgG2 -E2 and high IgG2 - Pg levels were revealed in 7.4% of healthy women and 2.8% of breast cancer patients (p = 0.009; OR = 0.4). These two variants were integrated and marked as protective immunological phenotype. High IgA1 - Bp/IgA1 -Pg and high IgA1 -E2/IgA1 -Pg ratios combined with high IgG2 -Pg and high or low IgG2 -E2 levels were found in 17.2% of healthy women and27.2% of breast cancer patients (p = 0.006; OR = 1.8) and in 6.4% of healthy women and in 18.3% of breast cancer patients (p < 0.0001; OR = 3.3), correspondingly. These two variants were integrated and marked as pro-carcinogenic immunological phenotype. These associations were found only with estrogen receptor-positive (ER+) breast cancer. GSTP1 (rs1695) gene polymorphism was associated exclusively with estrogen receptor-negative (ER-) breast cancer (p = 0.004; OR = 1.56). No interrelations be tween immunological phenotypes and studied polymorphisms of CYP and GST genes have been found.Conclusion. Pro-carcinogenic immunological phenotype and rs1695 gene polymorphism within the GSTP1 gene were independent predictors of ER+ and ER- breast cancer correspondingly.

It is well known that results of breast cancer (BC) hormonal therapy depend on expression of tumor estradiol and progesterone receptors (ER and PR) in tumor tissue. Mechanisms of ER+/PR+ tumors conversion to ER+/PR- and ER-/PR- tumors remain scarcely studied. The decrease of steroid receptors expression seems to depend on action of genotoxic metabolites of environmental carcinogens (particularly, benzo[a]pyrene, BP) and endogenous steroids (in particular, estradiol, E2). The formation of these metabolites is regulated by the biotransformation enzymes. On the other hand, the formation of DNA-adducts with genotoxic metabolites may induce the synthesis of specific antibodies. Previously, it was shown that increase of the serum IgA-antibodies levels against Bp and E2 over the levels of IgA-antibodies against progesterone (IgA-Bp/IgA-Pg > 1 and IgA-E2/IgA-Pg), could be interpreted as immunological imbalance associated with high BC risk in healthy women. The purpose of this study was to detect the suggested associations between ER+/PR+ tumors conversion to ER+/PR+ and ER-/PR- tumors and immunological imbalance in the BC patients with distinct gene variants of biotransformation enzymes: CYP1A1*2A (rs 4646903), CYP1B1 (rs1056836), CYP19A1 (rs2470152), GSTT1 (del), GSTP1 (rs1695). The IgA-Bp, IgA-E2 and IgA-Pg were studied in 1321 non-smoking BC patients by non-competitive solid phase immunoassay. The conjugates of Bp, E2 and Pg with bovine serum albumin were adsorbed as target antibodies. The goat antibodies against human IgA conjugated with horseradish peroxidase were used for detection of the studied specific antibodies. Gene polymorphisms of biotransformation enzymes were analyzed by the real-time PCR. Tumor ER and PR were detected by the standard immunohistochemical methods.ER+/PR+ tumors in BC patients at the stage I (N = 534) were found in 68.7%, ER+/PR- in 15.6%, ER-/ PR- in 15.7%. In BC patients at the II-IV stage (N = 787), frequency of ER+/PR+ tumors decreased to 60.2%, ER+/PR- was similar (15.8%), and ER-/PR- increased to 24.0% (p < 0.0001). These alterations were revealed in BC patients at the IgA-Bp/IgA-Pg ratios > 1, and IgA-E2/IgA-Pg > 1 only. There were no differences found between BC patients at stage I and II-IV at the ER+/PR+, ER+/PR-, ER-/PR- frequencies when these ratios were low.The frequency of ER+/PR+ tumors in homozygotes TT of CYP19A1 was 77.1% at the I stage and 60.1% at the II-IV stages. Respectively the frequencies of ER-/PR- tumors were 11.8% and 26.1% (p < 0.001). ER+/ PR+ tumors were revealed in GSTT1 “+” BC patients at the I stage in 68.7% and at the II-IV stages in 58.0%. Respectively ER-/PR- tumors were found in 16.6% and 24.5% (p < 0.0004). The frequency of ER+/PR+ tumors was 57.1% in homozygotes GG of GSTP1 at the I stage and 60.7% at the II-IV stages. Respectively the frequencies of ER+/PR- were 14.3% and 22.2% and ER-/PR- were 28.6% and 19.0% (p < 0.001). Proportions of low and high IgA-Bp/IgA-Pg and IgA-E2/IgA-Pg ratios were the same at the any enzyme genotype of studied CYP or GST variants. In conclusion, we have revealed a sufficient contribution of immunological imbalance to the conversion of steroid receptors in breast cancer growth, being independent of several CYP and GST gene polymorphisms.

Aim. To reveal the associations of IgA antibodies to benzo[a]pyrene, estradiol and progesterone (IgA-Bp, IgA-Es, IgA-Pg) with the conversion of estrogen-receptor positive (ER+) into estrogen-receptor negative (ER-) tumors during breast cancer progression.Materials and Methods. Having collected serum samples from 338 healthy volunteers and 1407 breast cancer patients, we have profiled them for IgA-Bp, IgA-Es, IgA-Pg by means of enzyme-linked immunosorbent assay. Conjugates of bovine serum albumin with Bp, Es and Pg were used as adsorbed antigens and anti-human IgA horseradish peroxidase-conjugated antibodies were used for the detection of specific antigen-bound antibodies. Individual IgA-Bp/IgA-Pg and IgA-Es/IgA-Pg ratios were calculated. Estrogen receptor phenotype was determined using immunohistochemistry.Results. Low IgA-Bp/IgA-Pg ratios (≤ 1) in combination with low IgA-Es/IgA-Pg ratios (≤ 1) indicative of protective immunophenotype were more frequently revealed in healthy women (43.8%) in comparison with stage 1 breast cancer patients with ER+ (12.9%) and ER- (23.9%) tumors. High IgA-Bp/IgA-Pg ratios (>1) with high IgA-Es/IgA-Pg ratios (>1) suggestive of pro-carcinogenic immunological phenotype were less often detected in healthy women (27.5%) as compared with stage 1 breast cancer patients with ER+ (65.5%) and ER- (58.7%) tumors. Prevalence of protective and pro-carcinogenic phenotypes significantly differed in stage 1breast cancer patients with ER+ and ER- tumor phenotypes (p = 0.017). ER- tumor phenotype was more prevalent at II-IV tumor stages (25.6%) than at the stage 1 (16.3%). Conversion of ER+ to ER- tumors reflecting the breast cancer progression was characteristic for the patients with pro-carcinogenic immunological phenotype (p<0.0001).Conclusion. Detection of antibodies against Bp, Es and Pg may be applied as a risk marker of breast cancer development and progression.

ЦЕЛЬ ИССЛЕДОВАНИЯ Изучить связь материнского полиморфизма гена HLA-G (rs41551813, rs12722477, rs41557518 и rs66554220), перинатальных инфекций и курения в семье с риском врожденных пороков развития у плода. МАТЕРИАЛ И МЕТОДЫ Обследованы 335 женщин, вынашивающих/родивших ребенка с врожденными пороками развития (ВПР), и 418 женщин без ВПР у плода/ребенка. Инфекционный статус беременных женщин оценивали, исходя из данных лабораторных тестов: микроскопического исследования (выявление бактериального вагиноза и вульвовагинального кандидоза, Treponema pallidum); иммуноферментного анализа и полимеразной цепной реакции (ПЦР) (выявление вируса простого герпеса I и II типа, цитомегаловируса и др.; Neisseria gonorrhoeae, Chlamydia trachomatis и др.). Фактор курение в семье оценивали как курение одного или обоих партнеров. Типирование полиморфных сайтов Thr31Ser (rs41551813, HLA-G*01:03) в экзоне 2, Leu110Ile (rs12722477, HLA-G*01:04) и 1597 delC (rs41557518, HLA-G*01:05N) в экзоне 3 гена HLA-G проводили методом асимметричной ПЦР. Полиморфизм гена HLA-G 14 bp Ins/Del (rs66554220) в 3’UTR области экзона 8 детектировали с помощью электрофоретического разделения продуктов амплификации в 7% полиакриламидном геле. РЕЗУЛЬТАТЫ Проведенное исследование показало, что перинатальные инфекции матери (OR=1,75 [1,31—2,34]) и курение в семье (OR=1,75 [1,31—2,34]) являлись основными факторами риска ВПР у плода (P<0,001). Материнская аллель 110Ile HLA-G (rs12722477, HLA-G*01:04) была дополнительным фактором риска ВПР у плода после введения поправки на перинатальные инфекции и курение в семье (OR=1,86 [1,13—3,05], Pc=0,03). Материнские полиморфные сайты rs41551813, rs41557518 и rs66554220 гена HLA-G значимо не влияли на риск ВПР у плода. ЗАКЛЮЧЕНИЕ Перинатальные инфекции матери, курение в семье и материнский полиморфизм гена HLA-G rs12722477 могут быть факторами риска врожденных пороков развития у плода. Наши результаты способствуют пониманию молекулярных механизмов формирования патологии в системе «мать — плод».

The relationship between the HLA-G gene polymorphism (rs41551813, rs12722477, rs41557518), intrauterine infection and recurrent miscarriage (RM) in women were studied. The case group consisted of 180 patients with RM, defined as two or more consecutive miscarriages (min = 2; max = 8) at up to 20 weeks of gestation, and with clinically confirmed pregnancies and non-viable fetuses. At the time of examination. the women were enrolled from the Genetic Counseling Center at the Kemerovo Regional Clinical Hospital, Kemerovo, Russia, and were not pregnant. Each patient underwent a gynecological examination. We excluded women with a history of medical abortion, birth, and ectopic pregnancies. In addition, we excluded women with endocrine (e.g. diabetes) disorders. To exclude other known causes of spontaneous abortion, the following tests were performed: ultrasound examination of pelvic organs, and karyotyping in women and men. The women’s mean age in the RM group, was 29.6±4.8 (SD) years. The control group comprised 408 fertile women. These women didn’t have a history of spontaneous abortion, or a family history of congenital malformations. They have born, at least, 1-2 healthy children. Women’s mean age at birth of last child was 26.8±5.2 (SD) years. Influence of the intrauterine infection was analyzed on the basis of laboratory tests. Diagnostics of bacterial vaginosis and vulvo-vaginal candidiasis by microscopic examination was conducted. Viral agent infections (herpes simplex virus type 2, cytomegalovirus, human papilloma virus type 16/18), Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Gardnerella vaginalis and Trichomonas vaginalis were detected by enzyme-linked immunoassay and polymerase chain reaction (PCR). The data were obtained from the medical cards of the surveyed women. All the women gave a written informed consent before participating in the study. Typing of polymorphisms of Thr31Ser (rs41551813, HLA-G*01:03) in exon 2, Leu110Ile (rs12722477, HLA-G*01:04) and 1597 delС (rs41557518, HLA-G*01:05N) in exon 3 HLA-G genes were performed by realtime PCR followed by melting analysis. The study showed that the intrauterine infection was not a risk factor for RM (p = 0.30) in the examined women. It was found that the 110 Ile allele (HLA-G *01:04) was a risk factor for RM both in women with intrauterine infection [ORa = 4.50 (2.41-8.38), p = 2.09e-06], and in women without infection [ORa = 2.46 (1.44-4.21), p = 0.0009]. The cooperative influence of genetic and infections factors with the risk of RM in women was revealed [ORa+f = 3.50 (2.01-6.09), p = 8.78e-06]. Our results will be useful in understanding the molecular mechanisms of immune disorders in fetomaternal interface, and for choosing the strategy of management and treatment in women with RM.

The goal of this study was to investigate the association between the polymorphic loci of genes IL1B (rs16944), IL1RN (rs4251961), IL6 (rs1800795, rs1800796, rs1554606), IL8 (rs4073), IL10 (rs1800896), and TNFA (rs1800629) and breast cancer in women. The DNA samples of 521 women with breast cancer and 267 women without oncological pathology were studied. The study showed that age, concomitant chronic morbidity, and polymorphism of the IL6 gene are risk factors in postmenopausal women. Allele –572C (OR = 5.68; 95% CI = [2.70–11.97], pcor < 0.001), and haplotype rs1800796[C]–rs1800795[G]–rs1554606[G] (OR = 5.31, 95% CI = [1.87 – 15.10], pcor = 0.002) of the IL6 gene were associated with breast cancer. No association of loci in IL1B (rs16944), IL1RN (rs4251961), IL8 (rs4073), IL10 (rs1800896), or TNFA (rs1800629) was associated with the risk of breast cancer. The obtained data indicate that the –572C allele of the IL6 gene is associated with susceptibility in postmenopausal women to breast cancer. Our results can be useful for an understanding of the molecular mechanisms of breast cancer.

This study aims for assessing relationships between maternal HLA-G gene polymorphisms (rs41551813, rs12722477, rs41557518) and intrauterine infection with the risk of congenital malformations (CM) in infants. We studied 331 women who had offspring with CMs, and 408 women with one or more healthy children. Influence of the intrauterine infection was analyzed on the basis of laboratory tests. Diagnostics of bacterial vaginosis and vulvovaginal candidiasis by microscopic examination were conducted. Viral infections (herpes simplex virus type 2, cytomegalovirus, human papilloma virus type 16/18) as well as Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum, Gardnerella vaginalis; Trichomonas vaginalis and Toxoplasma gondii were detected by enzyme-linked immunoassay or polymerase chain reaction (PCR) techniques. The data were obtained from the medical cards of the surveyed women. The gene polymorphisms were typed for Thr31Ser (rs41551813, HLA-G*01:03) in exon 2, Leu110Ile (rs12722477, HLA-G*01:04) and 1597 delС (rs41557518, HLA-G*01:05N) in exon 3 HLA-G using real-time PCR followed by melting analysis. The study showed that maternal age was not a significant risk factor for CMs in the fetus/newborns. Meanwhile, the maternal intrauterine infections were shown to be a significant risk factor for CMs in their infants (OR = 1.57 (1.08-2.29); p = 0.002). It was found that the 110 Ile allele (HLA-G *01:04) was a risk factor for CMs incidence in the fetus/newborns (OR = 1.57 (1.08-2.29), p = 0.01). No association was found between the maternal rs41551813 and rs41557518 HLA-G genetic polymorphisms and CMs in the infants. Hence, intrauterine infections and maternal 110 Ile allele (HLA-G *01:04) may be suggested as risk factors for birth defects in the children. Our results will be useful in understanding the molecular mechanisms of immune disorders in feto-maternal interface.

Detection of postmenopausal women at high risk for breast pre-cancer and cancer is a key condition to prevent these diseases. Aim of our research was to study possible usage of immunoassay for antibodies specific to benzo[a]pyrene, estradiol, and progesterone (IgA-Bp, IgA-Es, IgA-Pg) in determination of personal risks for fibrocystic disease and breast cancer at the early stage, with respect to hormone receptor status in tumor tissues. Blood serum IgA-Bp, IgA-Es, IgA-Pg were studied by ELISA in postmenopausal women: healthy controls (n = 401), patients with fibrocystic breast disease (n = 50), and breast cancer (stage I, n = 575, stages II-IV, n = 861). High individual IgA-Bp/IgA-Pg ratios of 1.5 were found in 19.7% of healthy women, and in 50.0% of fibrocystic breast disease patients (p 0.0001; OR = 4.1). IgA-Es/IgA-Pg ratios of 1.0 were revealed in 48.4% healthy women and in 68.0% fibrocystic breast disease patients (p 0.01; OR = 2.3). IgA-Bp/IgAPg values 1.0 were found in 41.9% of healthy women, and, at higher rates, in the patients with breast cancer stage I: 68.3% ER- tumors (p 0.0001; OR = 3.0) and 75.9% ER+ tumors (p 0.0001; OR = 4.4). IgA-Es/ IgA-Pg ratios 1.0 were revealed in 48.4% of healthy women, and in patients with breast cancer stage I: 65.3% ER- tumors (p 0.003; OR = 2.0), and 76.8% ER+ tumors (p 0.0001; OR = 3.5). Some associations of studied antibodies with cancer progression were revealed. Frequency of individual cases with IgA-Bp/IgA-Pg 1.0 in patients with ER- tumors increased from 12.0% at stage I to 19.9% at stage II. Frequency of cases with IgA-Bp/IgA-Pg 1.0 in the patients with ER+ tumors decreased from 62.0% at stage I to 57.3% at stage II (p = 0.002). Frequency of cases with IgA-Es/IgA-Pg 1.0 in the patients with ER- tumors increased from 11.5% at stage I to 21.4% at stage II. Frequency of cases with IgA-Es/IgA-Pg 1.0 in patients with ER+ tumors decreased from 63.3% at stage I to 56.1% at stage II (p 0.001). The cases with individual excessive IgA-Bp and IgA-Es levels are associated with fibrocystic breast disease and ER+ breast cancer at the onset of the disease. Breast cancer progression was associated with the relative decrease of ER in tumor tissues, along with higher individual levels of IgA-Bp and IgА-Es and lower IgA-Pg levels. ELISA testing of IgА-Bp, IgА-Es, IgA-Pg could be recommended for detection of individual risk for fibrocystic breast disease and stage I of breast cancer, as well as for more efficient prevention and therapy by selective modulators of estrogen receptor (raloxifene, arzoxifene and lasofoxifine) and aromatase inhibitors (exemestane, anastrozole).

Serum concentrations of estradiol (Es) and progesterone (Pg), Es, Pg and benzo[a]pyrene-specific IgA and IgG antibodies were studied in 227 postmenopausal healthy women (HW) and 639 breast cancer patients (BCP). The high individual Pg/Es ratio ( 5.0) was revealed in HW (54.6%) and BCP (26.4%, p 0.0001, OR = 0.3) marked as “hormonal balance”. The low Pg/Es (≤ 5.0) ratio was detected more frequently in BCP (OR = 3.3) marked as “hormonal imbalance”. The high Pg/Es ratio was more common in HW with protective immunological phenotype (IgA-Bp/IgA-Pg ≤ 1 and IgA-Es/IgA-Pg ≤ 1) than with procarcinogenic immunological phenotype (IgA-Bp/IgA-Pg 1 and IgA-IgA-Es/IgA-Pg 1): 78.8 vs 47.4%, p = 0.005. The same parameters for IgG-immunological phenotypes in HW were 73.3 and 48.6%, p = 0.002. The differences between IgA-immunological phenotypes were lowered (41.6 vs 24.4%, p 0.007), whereas between IgG-phenotypes it was absent in BCP. Thus, for the first time it was revealed the influence of immunological phenotypes based on antibodies specific to the environmental chemical carcinogens and endogenous steroid hormones on the hormonal balance in HW and its reduced effects in BCP.

Previous studies found some associations between immunoglobulin class A antibodies specific to benzo[a]pyrene (IgA-Bp), estradiol (IgA-Es) and progesterone (IgA-Pg) as well as breast cancer (BC) in females and lung cancer (LC) in males. It was suggested that such antibodies affect serum Es and Pg levels.Our study was aimed at revealing putative features of mutual effects of IgA-Bp, IgA-Es and IgA-Pg on serum Es and Pg level both in healthy and BC females as well as healthy and LC males.Serum levels of Es and Pg and IgA-Bp, IgA-Es and IgA-Pg were measured by ELISA in 190 nonsmoking healthy and 518 BC females as well as 312 smoking healthy and 196 LC males.It was found that healthy subjects vs cancer patients prominently differed by assessing individual Pg/Es ratios: healthy vs BC females had it set at 6.6 vs 2.9 (p 0.0001), respectively, whereas in healthy vs LC males it was at 5.2 vs 10.1 (p 0.0001), respectively.Individual Pg/Es ratio paralleled in healthy females with high vs low IgA-Bp/IgA-Pg 1.5 and IgA-Es/IgA-Pg 1.5 ratios (3.5 vs 9.7, p 0.0001). No T such associations were observed in BC patients. In addition, the lowest individual Pg/Es ratio in healthy males was found together with IgA-Es/ IgA-Pg 1.5 ratios accompanied with IgA-Bp/IgA-Pg ≤ 1.5 (2.9) and peaked in case of concurrently low IgA-Bp/IgA-Pg ≤ 1.5 and IgA-Es/IgA-Pg ≤ 1.5 (5.2, p = 0.005) or high IgA-Bp/IgA-Pg 1.5 and IgA-Es/IgA-Pg 1.5 (6.5, p = 0.002). In contrast, the lowest Pg/Es ratio (7.4) was revealed in LC patients simultaneously bearing high IgA-Bp/IgA-Pg 1.5 and low IgA-Es/IgA-Pg ≤ 1.5 ratios compared to simultaneously low ratios (11.3, p = 0.002).In conclusion, individual Pg/Es ratios depended on individual IgA-Bp/IgA-Pg and IgA-Es/IgA-Pg ratios. A cooperative influence of serum antibodies specific to environmental chemical carcinogens and endogenous steroids on hormone balance was featured both in healthy subjects as well as BC females and LC males.The data obtained may be useful while developing new strategies to cancer prevention: by using selective modulators of estrogen receptors and aromatase inhibitors as well as for development of anticancer vaccines.

The relationship between autoantibodies specific to estradiol (Es)/ progesterone (Pg) and the concentrations of these hormones in the blood serum of healthy women and breast cancer patients has been previously revealed.Purpose: to study the association between anti-idiotypic antibodies to Es and Pg and the concentrations of these hormones in postmenopausal healthy women and breast cancer patients.Material and Methods. The levels of Es and Pg in the blood serum of 206 healthy women and 480 breast cancer patients were studied using competitive enzyme immunoassay. The levels of autoantibodies to Es and Pg and appropriate antiidiotypic antibodies in the same serums were studied using non-competitive enzyme immunoassay.Results. The high personal ratio of hormones (Pg/Es >4.0) was associated with the low breast cancer risk (OR=0.3; р<0.0001), high individual ratio of specific antibodies (IgA-Pg1/IgA-Es1>1.0; р=0.004) and high individual ratio of anti-idiotypic antibodies (IgG-Pg2/IgG-Es2>1.0; p<0.001) in healthy women, but not in breast cancer patients.Conclusion. The association between anti-idiotypic antibodies of G class specific to Es/ Pg and hormonal status was revealed in healthy women but not in breast cancer patients. Further studies on the mechanisms of immunoregulation of carcinogenesis are needed.

Previous studies found some associations between immunoglobulin class A antibodies specific to benzo[a]pyrene (IgA-Bp), estradiol (IgA-Es) and progesterone (IgA-Pg) as well as breast cancer (BC) in females and lung cancer (LC) in males. It was suggested that such antibodies affect serum Es and Pg levels. Our study was aimed at revealing putative features of mutual effects of IgA-Bp, IgA-Es and IgA-Pg on serum Es and Pg level both in healthy and BC females as well as healthy and LC males. Serum levels of Es and Pg and IgA-Bp, IgA-Es and IgA-Pg were measured by ELISA in 190 nonsmoking healthy and 518 BC females as well as 312 smoking healthy and 196 LC males. It was found that healthy subjects vs cancer patients prominently differed by assessing individual Pg/Es ratios: healthy vs BC females had it set at 6.6 vs 2.9 (p 1.5 and IgA-Es/IgA-Pg > 1.5 ratios (3.5 vs 9.7, p 1.5 ratios accompanied with IgA-Bp/IgA-Pg ≤ 1.5 (2.9) and peaked in case of concurrently low IgA-Bp/IgA-Pg ≤ 1.5 and IgA-Es/IgA-Pg ≤ 1.5 (5.2, p = 0.005) or high IgA-Bp/IgA-Pg > 1.5 and IgA-Es/IgA-Pg > 1.5 (6.5, p = 0.002). In contrast, the lowest Pg/Es ratio (7.4) was revealed in LC patients simultaneously bearing high IgA-Bp/IgA-Pg > 1.5 and low IgA-Es/IgA-Pg ≤ 1.5 ratios compared to simultaneously low ratios (11.3, p = 0.002). In conclusion, individual Pg/Es ratios depended on individual IgA-Bp/IgA-Pg and IgA-Es/IgA-Pg ratios. A cooperative influence of serum antibodies specific to environmental chemical carcinogens and endogenous steroids on hormone balance was featured both in healthy subjects as well as BC females and LC males. The data obtained may be useful while developing new strategies to cancer prevention: by using selective modulators of estrogen receptors and aromatase inhibitors as well as for development of anticancer vaccines.

The associations between polymorphisms HLA-G (rs41551813, rs12722477, rs41557518 and rs16375) and recurrent miscarriage and risk of recurrent miscarriage (RM) in women with persistent bacterial-viral infection were investigated. It is found that the HLA-G rs12722477 110Ile allele is associated with the risk of RM only in women with persistent bacterial-viral infection (OR=2,49 (1,91–5,21); Pс=0,04).

Previous studies reported some associations between IgA and IgG antibodies specific to benzo[a] pyrene (Bp), estradiol (Es) and progesterone (Pg), and breast cancer (BC) in postmenopausal women. Likewise, the individual ratios of these antibodies (IgA-Bp/IgA-Pg, IgG-Bp/IgG-Pg, IgG-Es/IgG-Pg, IgG-Es/IgG-Pg) were associated with BC. It was suggested that development of antibodies to chemical carcinogens and steroid hormones was determined by functional polymorphisms of cytokine genes. The purpose of this study was to identify the suggested associations of antibodies to Bp, Es, Pg, and their individual ratios to the following gene polymorphisms: IL1RN (rs4251961), IL1B (rs16944), IL6 (rs1800795, rs1800796, rs1554606), IL8 (rs4073), TNFA (rs1800629) and CD40 (rs6074022) detected in postmenopausal healthy women and BC patients.The serum IgA and IgG antibodies specific to Bp, Es and Pg were studied in 470 healthy women and 995 BC patients by non-competitive solid phase immunoassay. The conjugates of Bp, Es, Pg with bovine serum albumin were used as adsorbed antigen. The goat antibodies against human IgA or IgG conjugated with horseradish peroxidase were used for the detection of bound hapten-specific antibodies. Cytokine gene polymorphisms were analyzed by the real-time PCR.Associations between the studied antibodies and their ratios with the gene polymorphisms in IL1RN (rs4251961), IL6 (rs1800795), TNFA (rs1800629) and CD40 (rs6074022) were found in healthy women. Higher individual ratios of IgA-Bp/IgA-Pg (p = 0.0001), IgG-Bp/IgG-Pg (p < 0.0001), IgG-Es/IgG-Pg (p = 0.0003) were associated with the allele C gene IL1RN. The higher IgG-Es levels were more common in the persons with allele G gene IL6 (p = 0.007), and with C allele of CD40 gene (p = 0.005). The high IgA-Pg levels were associated with A allele gene of TNFA (p = 0.008). Associations of antibodies were found only with genes polymorphisms in CD40 (rs6074022) in BC patients. Higher IgG-Es levels were more common in persons with allele T gene CD40 (p = 0.007).In conclusion, we revealed the participation of cytokines in immune regulation of antibody genesis for environmental chemical carcinogens and endogenous steroid hormones in healthy women and BC patients. The future investigations of antibodies specific to Bp, Es and Pg combined with the analysis genes polymorphisms in cytokines will be useful for detection of the individual hormone-dependent cancer risks in humans.

The following immunological phenotypes were described using immunoanalysis of blood serum IgABp, IgA-Es and IgA-Pg in 400 healthy women and 1284 breast cancer (BC) patients: “protective” with the minimal BC risk (OR=0.2–0.6) in which personal IgA-Pg level exceeded both IgA-Bp and IgA-Es; “procarcinogenic” with maximal BC risk (OR=2.1–6.2) in which both IgA-Bp and IgA-Es were higher than IgA-Pg; and two “compensatory” (OR=0.7–1.2) in which IgA-Pg levels exceeded IgA-Bp or IgAEs. Existence of one or the other immunophenotype did not depended from smocking or age. The diff erences in correlations of IgA-Bp with IgA-Es and IgA-Pg were revealed at these immunophenotypes. The results would be helpful in the creation and clinical application of anticarcinogenic vaccines for cancer immunoprevention.