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Immunological aspects of human reproduction. EDITORIAL
Publicado em 07 de Dezembro de 11 pela Clinical and Developmental Immunology, disponível no Pub Med.
Resumo:
The scientific community of immunologists has been interested in immunological aspects of reproduction since the beginning of last century. Although many questions of reproductive immunology still remain unanswered, several important results have been obtained during recent years. Most importantly, the topic has achieved more wider impact than before. Presently, immunology of human reproduction involves not only the interaction between the maternal immune system and the fetus-placenta status, but also many diverse aspects of reproduction ranging from human game- togenesis to immuno(epi)genetic aspects of diseases of the reproductive system of females and males. Since fertility rates are falling in many countries implying wider usage of various assisted reproduction technologies to overcome reproductive failure, the topic of immunology of human reproduction is receiving increasing attention. Conversely, immunology journals are publishing more papers on every aspect of the immunology of reproduction. The completion of this special issue of Clinical and Developmental Immunology is a good example.
The present issue of this journal is presenting six reviews and eight original papers on diverse immunological aspects of human reproduction.
The first review of S. J. Chen et al. concentrates on abnormalities in the maternal-fetal immunological relation- ship and the current immunological therapeutic strategies for pathological disorders developing during pregnancy. In the next review paper, K. H. Kikkatalo et al. point out the importance of autoimmune reactions in the develop- ment of female infertility and unravel the role of immune reactions against follicle stimulating hormone (FSH) in modulation of female reproductive function. In another review related to hormones and immune reactivity inter- actions, N. Vrachnis et al. present data on the role of progesterone and corticotropin-releasing hormone (CRH) in myometrium and show their interaction with the immune system during labor. Review paper of M. D. Benson discusses the immunology of amniotic fluid embolism that is one of the leading causes of maternal mortality and morbidity in many countries. In their review about placental IgG transfer in healthy and pathological pregnancies, P. Palmeira et al. analyse the factors participating in IgG transfer. D. V. Vujaklija et al. have chosen to analyse the mechanisms related to cell death at the maternal-fetal interface. In their paper, cytotoxic cells as well as the role of granulysin are under deep scrutiny.
In the original research paper series, the study of J. Calleja-Agius et al. presents the results of the influence of abnormal placental karyotype on inflammatory response evaluated by tumor necrosis factor (TNF) alpha, TNF receptors, and interleukin-10 measurements within villous tissue and blood from women with miscarriage. In the next paper by S. Cardaropoli et al., the fetal growth is studied in connection with macrophage migration inhibitory factor (MIF) and its role in preeclampsia pathogenesis is presented. A. Sarapik et al. bring new data on levels of cytokines, chemokines, and other inflammatory markers in the follicular fluid of patients with different in vitro fertilization (IVF) outcome. The paper of R. Raghupa- thy et al. presents data about production of pro- and anti-inflammatory cytokines by peripheral blood mononuclear cells stimulated with trophoblast antigens. These authors show that in case of intrauterine growth restriction, a proinflammatory bias exists in comparison with normal pregnancy. In the paper of M. T. Ahlen et al., the impact of the maternal anti-human platelet antigen 1a (HPA1a or GPIIIa) antibodies in determination of neonatal alloimmune thrombocytopenia is analyzed according to maternal ABO genotypes. W. X. Xu and coauthors are presenting their results on the characterization of B-cell epitopes on human zona pellucida glycoprotein-3, the sperm receptor protein known to have a critical role in fertilization. C. Agostinis et al. have focused their work in assessing the role of mannose binding lectin (MBL) in preeclampsia where this immunologically active substance could also contribute to the endovascular invasion of trophoblast cells. In their paper, W. Zaigui et al. show that functional polymorphism of the gene of Foxp3, a transcription factor involved in regulatory T-cells function, may confer susceptibility to unexplained recurrent spontaneous abortion.
Follicular Proinflammatory Cytokines and Chemokines as Markers of IVF Success
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
Cytokines are key modulators of the immune system and also contribute to regulation of the ovarian cycle. In this study, Bender MedSystems FlowCytomix technology was used to analyze follicular cytokines (proinflammatory: IL-1β, IL-6, IL-18, IFN-γ, IFN- α, TNF-α, IL-12, and IL-23;, and anti-inflammatory: G-CSF),chemokines (MIP-1α, MIP-1β, MCP-1, RANTES, and IL-8),and other biomarkers (sAPO-1/Fas, CD44(v6)) in 153 women undergoing in vitro fertilization (IVF). Cytokine origin was studied by mRNA analysis of granulosa cells. Higher follicular MIP-1α and CD44(v6) were found to correlate with polycystic ovary syndrome, IL-23, INF-γ, and TNF-α with endometriosis, higher CD44(v6) but lower IL-β and INF-α correlated with tubal factor infertility, and lower levels of IL-18 and CD44(v6) characterized unexplained infertility. IL-12 positively correlated with oocyte fertilization and embryo development, while increased IL-18, IL-8, and MIP-1β were associated with successful IVF-induced pregnancy.
Association between Functional Polymorphisms of Foxp3 Gene and the Occurrence of Unexplained Recurrent Spontaneous Abortion in a Chinese Han Population
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
Unexplained recurrent spontaneous abortion (URSA) is an alloimmune disease associated with the failure of fetal-maternal immunologic tolerance in which the regulatory T lymphocytes (Treg) play a pivotal role. It is well known that Forkhead box P3 (Foxp3) is a crucial regulatory factor for the development and function of Treg cells. It has also been established that deficiency of the Foxp3 gene suppresses the regulatory function of Treg cells. To determine if functional polymorphisms at the Foxp3 loci are associated with URSA in humans, we genotyped four common polymorphisms of Foxp3 gene in 146 unrelated URSA patients and 112 healthy women. The results showed that rs3761548A/C and rs2232365A/G polymorphisms were significantly associated with URSA. Additionally, we found that the allelic distribution of rs5902434 del/ATT in URSA group was slightly different from that in the control group. We conclude that functional polymorphisms of the Foxp3 gene may confer an important susceptibility to URSA in the Chinese Han population, probably by altering Foxp3 function and/or its expression.
Intrauterine Growth Restriction: Cytokine Profiles of Trophoblast Antigen-Stimulated Maternal Lymphocytes
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
Intrauterine growth restriction (IUGR) is an important perinatal syndrome that poses several serious short- and long-term effects. We studied cytokine production by maternal peripheral blood lymphocytes stimulated by trophoblast antigens. 36 women with a diagnosis of IUGR and 22 healthy women with normal fetal growth were inducted. Peripheral blood mononuclear cells were stimulated with trophoblast antigens and levels of the proinflammatory cytokines IL-6, IL-8, IL-12, IL-23, IFNγ, and TNFα and the anti-inflammatory cytokines IL-4, IL-10, and IL-13 were measured in culture supernatants by ELISA. IL-8 was produced at higher levels by blood cells of the IUGR group than normal pregnant women, while IL-13 was produced at lower levels. IL-8, IFNγ, and TNFα were higher in IUGR with placental insufficiency than in normal pregnancy. IL-12 levels were higher and IL-10 levels were lower in IUGR with placental insufficiency than in IUGR without placental insufficiency. We suggest that a stronger pro- inflammatory bias exists in IUGR as compared to normal pregnancy and in IUGR with placental insufficiency when compared to IUGR without placental insufficiency. Several ratios of proinflammatory to anti-inflammatory cytokines also support the existence of an inflammatory bias in IUGR.
The Development of Severe Neonatal Alloimmune Thrombocytopenia due to Anti-HPA-1a Antibodies Is Correlated to Maternal ABO Genotypes
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
Background. Maternal alloantibodies against HPA-1a can cross placenta, opsonize foetal platelets, and induce neonatal alloimmune thrombocytopenia (NAIT). In a study of 100, 448 pregnant women in Norway during 1995–2004, 10.6% of HPA-1a negative women had detectable anti-HPA-1a antibodies. Design and Methods. A possible correlation between the maternal ABO blood group phenotype, or underlying genotype, and severe thrombocytopenia in the newborn was investigated. Results. We observed that immunized women with blood group O had a lower risk of having a child with severe NAIT than women with group A; 20% with blood group O gave birth to children with severe NAIT, compared to 47% among the blood group A mothers (relative risk 0.43; 95% CI 0.25–0.75). Conclusion. The risk of severe neonatal alloimmune thrombocytopenia due to anti-HPA-1a antibodies is correlated to maternal ABO types, and this study indicates that the observation is due to genetic properties on the maternal side.
Inflammatory Cytokines in Maternal Circulation and Placenta of Chromosomally Abnormal First Trimester Miscarriages
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
The impact of abnormal placental karyotype on the inflammatory response within the villous tissue and peripheral circulation of women with miscarriage was evaluated. Villous (n = 38) and venous blood samples (n = 26) were obtained from women with missed miscarriage. Tissue chromosome analysis indicated 23 abnormal and 15 normal karyotypes. Concentration of tumour necrosis factor alpha (TNFα),TNF-R1 and TNF-R2, and interleukin (IL)-10 were measured using flowcytometric bead array in fresh villous homogenate, cultured villous extracts, culture medium, maternal whole blood, and plasma. Plasma TNFα/IL- 10 ratios were significantly (P < 0.05) lower in miscarriages with abnormal karyotype. In the abnormal karyotype group, there were significantly higher levels of TNFα (P < 0.01),IL-10 (P < 0.01),TNF-R1 (P < 0.001),and TNF-R2 (P < 0.001) in the villous extracts and culture-conditioned medium compared to normal karyotype group. In miscarriage with abnormal karyotype, there is an exacerbated placental inflammatory response, in contrast to miscarriage of normal karyotype where maternal systemic response is increased.
MBL Interferes with Endovascular Trophoblast Invasion in Pre-Eclampsia
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
The spiral arteries undergo physiologic changes during pregnancy, and the failure of this process may lead to a spectrum of preg- nancy disorders, including pre-eclampsia. Our recent data indicate that decidual endothelial cells (DECs),covering the inner side of the spiral arteries, acquire the ability to synthesize C1q, which acts as a link between endovascular trophoblast and DECs favouring the process of vascular remodelling. In this study, we have shown that sera obtained from pre-eclamptic patients strongly inhibit the interaction between extravillous trophoblast (EVT) and DECs, preventing endovascular invasion of trophoblast cells. We further demonstrated that mannose-binding lectin (MBL),one of the factor increased in pre-eclamptic patient sera, strongly inhibits the interaction of EVT with C1q interfering with the process of EVT adhesion to and migration through DECs. These data suggest that the increased level of MBL in pre-eclampsia may contribute to the failure of the endovascular invasion of trophoblast cells.
Cell Death Mechanisms at the Maternal-Fetal Interface: Insights into the Role of Granulysin
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
During mammal pregnancy, a sensitive balance between hormones, cytokines, humoral factors, and local cellular interactions must be established. Cytotoxic cells infiltrating the decidua are heavily equipped with cytolytic molecules, in particular perforin and granulysin. Granulysin is especially abundant in NK cells which are able to spontaneously secrete high quantities of granulysin. Besides being a potent bactericidal and tumoricidal molecule, granulysin is also found to be a chemoattractant and a proinflammatory molecule. The precise role(s) of granulysin at the maternal-fetal interface has not been elucidated yet. It is possible that it behaves as a double-edged sword simultaneously acting as an immunomodulatory and a host defense molecule protecting both the mother and the fetus from a wide spectrum of pathogens, and on the other hand, in case of an NK cell activation, acting as an effector molecule causing the apoptosis of semiallograft trophoblast cells and consequently leading to various pregnancy disorders or pregnancy loss.
Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA),immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy.
Review on Autoimmune Reactions in Female Infertility: Antibodies to Follicle Stimulating Hormone
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
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.
Immune Aspects and Myometrial Actions of Progesterone and CRH in Labor
Publicado em Janeiro de 12 pela Clinical and Developmental Immunology, disponível no Pub Med Central.
Resumo:
Progesterone and corticotropin-releasing hormone (CRH) have a critical role in pregnancy and labor, as changes related to these hormones are crucial for the transition from myometrial quiescence to contractility. The mechanisms related to their effect differ between humans and other species, thus, despite extensive research, many questions remain to be answered regarding their mediation in human labor. Immune responses to progesterone and CRH are important for labor. Progesterone acts as an immunomodulator which controls many immune actions during pregnancy, and its withdrawal releases the inhibitory action on inflammatory pathways. In humans, a “functional” progesterone withdrawal occurs with onset of labor through changes in progesterone metabolism, progesterone receptors, and other molecules that either facilitate or antagonize progesterone function. Placental CRH acts on the fetal pituitary-adrenal axis to stimulate adrenal production of androgens and cortisol and also acts directly on myometrial cells via its receptors. CRH also affects inflammatory signals and vice versa. Interactions between progesterone and CRH additionally occur during labor. We describe the role of these two hormones in human myometrium and their interactions with the immune system during labor.