|
1
|
Gomes FG, Boquett JA, Kowalski TW, Bremm JM, Michels MS, Pretto L, Rockenbach MK, Vianna FSL, Schuler-Faccini L, Sanseverino MTV, Fraga LR. From bench to in silico and backwards: What have we done on genetics of recurrent pregnancy loss and implantation failure and where should we go next? Genet Mol Biol 2024; 46:e20230127. [PMID: 39186710 PMCID: PMC11346592 DOI: 10.1590/1678-4685-gmb-2023-0127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 05/22/2024] [Indexed: 08/28/2024] Open
Abstract
Human reproduction goes through many challenges to its success and in many cases it fails. Cases of pregnancy loss are common outcomes for pregnancies, and implantation failures (IF) are common in assisted reproduction attempts. Although several risk factors have already been linked to adverse outcomes in reproduction, many cases remain without a definitive cause. Genetics of female reproduction is a field that may bring some pieces of this puzzle; however, there are no well-defined genes that might be related to the risk for recurrent pregnancy loss (RPL) and IF. Here, we present a literature review of the studies of genetic association in RPL and IF carried out in the Brazilian population and complemented with a database search to explore genes previously related to RPL and IF, where a search for genes previously involved in these conditions was performed in OMIM, HuGE, and CTD databases. Finally, we present the next steps for reproductive genetics investigation, through genomic sequencing analyses and discuss future plans in the study of RPL genetics. The combined strategy of looking for literature and databases is useful to raise hypotheses and to identify underexplored genes related to RPL and IF.
Collapse
Affiliation(s)
- Flavia Gobetti Gomes
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
| | - Juliano André Boquett
- Universidade Federal do Rio Grande do Sul (UFRGS), Faculdade de Medicina, Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Porto Alegre, RS, Brazil
- University of California, Department of Neurology, San Francisco, CA, EUA
| | - Thayne Woycinck Kowalski
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Centro de Pesquisa Experimental, Laboratório de Medicina Genômica, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Núcleo de Bioinformática, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós-Graduação em Medicina, Ciências Médicas, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT), Porto Alegre, RS, Brazil
| | - João Matheus Bremm
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
| | - Marcus Silva Michels
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
| | - Luiza Pretto
- Hospital de Clínicas de Porto Alegre (HCPA), Centro de Pesquisa Experimental, Laboratório de Medicina Genômica, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós-Graduação em Medicina, Ciências Médicas, Porto Alegre, RS, Brazil
| | - Marília Körbes Rockenbach
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
| | - Fernanda Sales Luiz Vianna
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Centro de Pesquisa Experimental, Laboratório de Medicina Genômica, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós-Graduação em Medicina, Ciências Médicas, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT), Porto Alegre, RS, Brazil
| | - Lavinia Schuler-Faccini
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul (UFRGS), Faculdade de Medicina, Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT), Porto Alegre, RS, Brazil
| | - Maria Teresa Vieira Sanseverino
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Biociências, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT), Porto Alegre, RS, Brazil
- Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Escola de Medicina, Porto Alegre, Brazil
| | - Lucas Rosa Fraga
- Hospital de Clínicas de Porto Alegre (HCPA), Centro de Pesquisa Experimental, Laboratório de Medicina Genômica, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós-Graduação em Medicina, Ciências Médicas, Porto Alegre, RS, Brazil
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT), Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul (UFRGS), Instituto de Ciências Básicas da Saúde, Departamento de Ciências Morfológicas, Porto Alegre, RS, Brazil
| |
Collapse
|
|
2
|
Toadere TM, Ţichindeleanu A, Bondor DA, Topor I, Trella ŞE, Nenu I. Bridging the divide: unveiling mutual immunological pathways of cancer and pregnancy. Inflamm Res 2024; 73:793-807. [PMID: 38492049 DOI: 10.1007/s00011-024-01866-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/31/2024] [Accepted: 02/22/2024] [Indexed: 03/18/2024] Open
Abstract
The juxtaposition of two seemingly disparate physiological phenomena within the human body-namely, cancer and pregnancy-may offer profound insights into the intricate interplay between malignancies and the immune system. Recent investigations have unveiled striking similarities between the pivotal processes underpinning fetal implantation and successful gestation and those governing tumor initiation and progression. Notably, a confluence of features has emerged, underscoring parallels between the microenvironment of tumors and the maternal-fetal interface. These shared attributes encompass establishing vascular networks, cellular mobilization, recruitment of auxiliary tissue components to facilitate continued growth, and, most significantly, the orchestration of immune-suppressive mechanisms.Our particular focus herein centers on the phenomenon of immune suppression and its protective utility in both of these contexts. In the context of pregnancy, immune suppression assumes a paramount role in shielding the semi-allogeneic fetus from the potentially hostile immune responses of the maternal host. In stark contrast, in the milieu of cancer, this very same immunological suppression fosters the transformation of the tumor microenvironment into a sanctuary personalized for the neoplastic cells.Thus, the striking parallels between the immunosuppressive strategies deployed during pregnancy and those co-opted by malignancies offer a tantalizing reservoir of insights. These insights promise to inform novel avenues in the realm of cancer immunotherapy. By harnessing our understanding of the immunological events that detrimentally impact fetal development, a knowledge grounded in the context of conditions such as preeclampsia or miscarriage, we may uncover innovative immunotherapeutic strategies to combat cancer.
Collapse
Affiliation(s)
- Teodora Maria Toadere
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania.
| | - Andra Ţichindeleanu
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania.
| | - Daniela Andreea Bondor
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
| | - Ioan Topor
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
| | - Şerban Ellias Trella
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
| | - Iuliana Nenu
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
| |
Collapse
|
|
3
|
Han N, Xia W, Zhu C, Zhang X, Wang F, Yin Z, Zeng Q. Association of human leukocyte antigen-G and -F with recurrent miscarriage and implantation failure: A systematic review and meta-analysis. Am J Reprod Immunol 2023; 90:e13792. [PMID: 38009058 DOI: 10.1111/aji.13792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/21/2023] [Accepted: 10/14/2023] [Indexed: 11/28/2023] Open
Abstract
PROBLEM The immune system plays an essential role in embryonic implantation and pregnancy, but the molecular details remain controversial. In the past four decades, human leukocyte antigen (HLA)-G and -F have garnered significant attention. METHOD OF STUDY MEDLINE, EMBASE, Web of Science, and the Cochrane Trials Registry were searched from their inception dates until December 2022. Studies were selected following PRISMA guidelines. Meta-analyses were used to assess the relationship of soluble HLA-G (sHLA-G) and HLA-G 3'-untranslated region polymorphisms with recurrent miscarriage (RM) and recurrent implantation failure (RIF). Narrative synthesis was conducted to determine the association of RM with other single nucleotide polymorphisms (SNPs) and HLA-G protein in tissues and of RIF with HLA-F. Risk-of-bias was assessed using ROBINS-I. Publication bias was assessed using Egger's and Begg's tests. RESULTS Finally, 42 articles were eligible for inclusion in the systematic review (32 in the meta-analysis; 13 in narrative synthesis). We found a significant association between the 14-bp ins/del HLA-G polymorphism and RM risk, but no definitive association with RIF risk. Women with RM had lower blood concentrations of sHLA-G during pregnancy and non-pregnancy than did controls. For women in the RIF group, no significant difference was found. CONCLUSION HLA-G protein and gene expression levels may be closely related to RM. The relevance of HLA-G to RIF is still being determined. A narrative synthesis of current studies has shown that HLA-F is likely associated with RIF.
Collapse
Affiliation(s)
- Nana Han
- Clinical medical school, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wanting Xia
- Gynecology Department, Hospital of Chengdu University of TCM, Chengdu, China
| | - Can Zhu
- Clinical medical school, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xuan Zhang
- Clinical medical school, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Wang
- Clinical medical school, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhixing Yin
- Clinical medical school, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Zeng
- Gynecology Department, Hospital of Chengdu University of TCM, Chengdu, China
| |
Collapse
|
|
4
|
Hu L, He D, Zeng H. Association of parental HLA-G polymorphisms with soluble HLA-G expressions and their roles on recurrent implantation failure: A systematic review and meta-analysis. Front Immunol 2022; 13:988370. [PMID: 36532068 PMCID: PMC9751038 DOI: 10.3389/fimmu.2022.988370] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/14/2022] [Indexed: 12/04/2022] Open
Abstract
Introduction HLA-G plays a central role in immune tolerance at the maternal-fetal interface. The HLA-G gene is characterized by low allelic polymorphism and restricted tissue expression compared with classical HLA genes. HLA-G polymorphism is associated with HLA-G expression and linked to pregnancy complications. However, the association of parental HLA-G polymorphisms with soluble HLA-G (sHLA-G) expression and their roles in recurrent implantation failure (RIF) is unclear. The study aims to systematically review the association of HLA-G polymorphisms with RIF, the association of sHLA-G expression with RIF, and the association of HLA-G polymorphisms with sHLA-G expressions in patients attending in-vitro fertilization (IVF) treatment. Methods Studies that evaluated the association of HLA-G polymorphisms with RIF, the association between sHLA-G expression with RIF, and the association between HLA-G polymorphisms with sHLA-G expressions in patients attending IVF treatment were included. Meta-analysis was performed by random-effect models. Sensitivity analysis was performed by excluding one study each time. Subgroup analysis was performed based on ethnicity. Results HLA-G 14bp ins variant is associated with a lower expression of sHLA-G in seminal or blood plasma of couples attending IVF treatment. The maternal HLA-G*010101 and paternal HLA-G*010102 alleles are associated with RIF risk compared to other alleles. However, single maternal HLA-G 14bp ins/del polymorphism, HLA-G -725 C>G/T polymorphism, or circulating sHLA-G concentration was not significantly associated with RIF in the general population. HLA-G 14bp ins/ins homozygous genotype or ins variant was associated with a higher risk of RIF in the Caucasian population. Discussion Specific HLA-G alleles or HLA-G polymorphisms are associated with sHLA-G expression in couples attending IVF treatment. Several HLA-G polymorphisms may be related to RIF, considering different ethnic backgrounds. A combined genetic effect should be considered in future studies to confirm the association of HLA-G polymorphisms and sHLA-G expressions in relation to RIF.
Collapse
Affiliation(s)
- Lian Hu
- Department of Gynecology and Obstetrics, The Fourth Changsha Hospital, Changsha, China
| | - Dongmei He
- Department of Gynecology and Obstetrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hong Zeng
- Department of Reproductive Medicine Center, Foshan Maternal and Child Health Care Hospital, Southern Medical University, Guangzhou, China,Department of Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Hong Zeng,
| |
Collapse
|
|
5
|
Castelli EC, de Almeida BS, Muniz YCN, Silva NSB, Passos MRS, Souza AS, Page AE, Dyble M, Smith D, Aguileta G, Bertranpetit J, Migliano AB, Duarte YAO, Scliar MO, Wang J, Passos-Bueno MR, Naslavsky MS, Zatz M, Mendes-Junior CT, Donadi EA. HLA-G genetic diversity and evolutive aspects in worldwide populations. Sci Rep 2021; 11:23070. [PMID: 34845256 PMCID: PMC8629979 DOI: 10.1038/s41598-021-02106-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 11/01/2021] [Indexed: 12/15/2022] Open
Abstract
HLA-G is a promiscuous immune checkpoint molecule. The HLA-G gene presents substantial nucleotide variability in its regulatory regions. However, it encodes a limited number of proteins compared to classical HLA class I genes. We characterized the HLA-G genetic variability in 4640 individuals from 88 different population samples across the globe by using a state-of-the-art method to characterize polymorphisms and haplotypes from high-coverage next-generation sequencing data. We also provide insights regarding the HLA-G genetic diversity and a resource for future studies evaluating HLA-G polymorphisms in different populations and association studies. Despite the great haplotype variability, we demonstrated that: (1) most of the HLA-G polymorphisms are in introns and regulatory sequences, and these are the sites with evidence of balancing selection, (2) linkage disequilibrium is high throughout the gene, extending up to HLA-A, (3) there are few proteins frequently observed in worldwide populations, with lack of variation in residues associated with major HLA-G biological properties (dimer formation, interaction with leukocyte receptors). These observations corroborate the role of HLA-G as an immune checkpoint molecule rather than as an antigen-presenting molecule. Understanding HLA-G variability across populations is relevant for disease association and functional studies.
Collapse
Affiliation(s)
- Erick C Castelli
- Molecular Genetics and Bioinformatics Laboratory, Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu, State of São Paulo, Brazil.
- Department of Pathology, School of Medicine, São Paulo State University (UNESP), Botucatu, State of São Paulo, CEP: 18618970, Brazil.
| | - Bibiana S de Almeida
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, CEP: 14049-900, Brazil
- Laboratório Multiusuário de Estudos em Biologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - Yara C N Muniz
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - Nayane S B Silva
- Molecular Genetics and Bioinformatics Laboratory, Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu, State of São Paulo, Brazil
| | - Marília R S Passos
- Molecular Genetics and Bioinformatics Laboratory, Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu, State of São Paulo, Brazil
| | - Andreia S Souza
- Molecular Genetics and Bioinformatics Laboratory, Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu, State of São Paulo, Brazil
| | - Abigail E Page
- Department of Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Mark Dyble
- Departament of Anthropology, University College London (UCL), London, UK
| | - Daniel Smith
- Bristol Medical School (PHS), University of Bristol, Bristol, UK
| | - Gabriela Aguileta
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Jaume Bertranpetit
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Andrea B Migliano
- Departament of Anthropology, Unversity of Zurich, Zurich, Switzerland
| | - Yeda A O Duarte
- Escola de Enfermagem e Faculdade de Saúde Pública, Universidade de São Paulo (USP), São Paulo, State of São Paulo, Brazil
| | - Marília O Scliar
- Human Genome and Stem Cell Research Center, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
| | - Jaqueline Wang
- Human Genome and Stem Cell Research Center, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
| | - Maria Rita Passos-Bueno
- Human Genome and Stem Cell Research Center, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
- Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
| | - Michel S Naslavsky
- Human Genome and Stem Cell Research Center, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
- Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
- Hospital Israelita Albert Einstein, São Paulo, State of São Paulo, Brazil
| | - Mayana Zatz
- Human Genome and Stem Cell Research Center, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
- Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, State of São Paulo, Brazil
| | - Celso Teixeira Mendes-Junior
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901, Ribeirão Preto, SP, Brazil
| | - Eduardo A Donadi
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, CEP: 14049-900, Brazil.
| |
Collapse
|
|
6
|
Duygu B, Olieslagers TI, Groeneweg M, Voorter CEM, Wieten L. HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation. Front Immunol 2021; 12:680480. [PMID: 34295330 PMCID: PMC8290519 DOI: 10.3389/fimmu.2021.680480] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.
Collapse
Affiliation(s)
- Burcu Duygu
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Timo I Olieslagers
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Mathijs Groeneweg
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Christina E M Voorter
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Lotte Wieten
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| |
Collapse
|
|
7
|
Martínez-Razo LD, Martínez-Ibarra A, Vázquez-Martínez ER, Cerbón M. The impact of Di-(2-ethylhexyl) Phthalate and Mono(2-ethylhexyl) Phthalate in placental development, function, and pathophysiology. ENVIRONMENT INTERNATIONAL 2021; 146:106228. [PMID: 33157377 DOI: 10.1016/j.envint.2020.106228] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/11/2020] [Accepted: 10/19/2020] [Indexed: 05/21/2023]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a chemical widely distributed in the environment as is extensively used in the plastic industry. DEHP is considered an endocrine disruptor chemical (EDC) and humans are inevitably and unintentionally exposed to this EDC through several sources including food, beverages, cosmetics, medical devices, among others. DEHP exposure has been associated and may be involved in the development of various pathologies; importantly, pregnant women are a particular risk group considering that endocrine alterations during gestation may impact fetal programming leading to the development of several chronic diseases in adulthood. Recent studies have indicated that exposure to DEHP and its metabolite Mono(2-ethylhexyl) phthalate (MEHP) may impair placental development and function, which in turn would have a negative impact on fetal growth. Studies performed in several trophoblastic and placental models have shown the negative impact of DEHP and MEHP in key processes related to placental development such as implantation, differentiation, invasion and angiogenesis. In addition, many alterations in placental functions like hormone signaling, metabolism, transfer of nutrients, immunomodulation and oxidative stress response have been reported. Moreover, clinical-epidemiological evidence supports the association between DEHP exposure and adverse pregnancy outcomes and pathologies. In this review, we aim to summarize for the first time current knowledge about the impact of DEHP and MEHP exposure on placental development and pathophysiology, as well as the mechanisms involved. We also remark the importance of exploring DEHP and MEHP effects in different trophoblast cell populations and discuss new perspectives regarding this topic.
Collapse
Affiliation(s)
- Luis Daniel Martínez-Razo
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes" - Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico
| | - Alejandra Martínez-Ibarra
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes" - Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico
| | - Edgar Ricardo Vázquez-Martínez
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes" - Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes" - Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico.
| |
Collapse
|
|
8
|
Ebrahimi Meimand S, Rostam-Abadi Y, Rezaei N. Autism spectrum disorders and natural killer cells: a review on pathogenesis and treatment. Expert Rev Clin Immunol 2020; 17:27-35. [PMID: 33191807 DOI: 10.1080/1744666x.2020.1850273] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Autism spectrum disorder (ASD), as a wide spectrum of neurodevelopmental disorders, is characterized by early-onset impairments in social-communication, repetitive behaviors, and restrictive interests.Areas covered: Although still unknown, there are some pieces of evidence suggesting altered immune function in the etiology of ASD. This review aims to summarize studies linking Natural Killer (NK) cells to ASD by searching through databases like MEDLINE and Scopus up to October 2020. NK cells play important roles in the innate immune system and immune regulation. As parts of the immune system, they interact with the neural system as well. Immune dysregulations such as autoimmunity and improper immune responses to both internal and external stimulations, especially in early developmental stages of the brain, may induce neurodevelopmental disorders. NK cells' dysfunction in children with ASD as well as their parents have been highlighted in many studies.Expert opinion: Changes in the frequency, gene expressions, cytotoxicity features, and receptors of NK cells are reported in children with ASD. Immune therapy for children with ASD with immune abnormality has shown promising results. However, further studies are needed to elucidate the exact role of NK cells in the pathogenesis of ASD providing future treatment options for these children.
Collapse
Affiliation(s)
- Sepideh Ebrahimi Meimand
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Yasna Rostam-Abadi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| |
Collapse
|
|
9
|
Ayers CD, Carlson KS. Spontaneous Pregnancy in the Setting of Primary Ovarian Insufficiency and Breastfeeding: Does Immunosuppression Play a Role? AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e926980. [PMID: 33127872 PMCID: PMC7643410 DOI: 10.12659/ajcr.926980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Patient: Female, 34-year-old Final Diagnosis: Pregnancy • premature ovarian insufficiency Symptoms: Amenorrhea • pregnancy Medication: — Clinical Procedure: — Specialty: Obstetrics and Gynecology
Collapse
Affiliation(s)
- Caleb D Ayers
- College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Karen S Carlson
- Department of Obstetrics and Gynecology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
10
|
Quintero-Ronderos P, Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches. Reprod Sci 2020; 27:1541-1552. [PMID: 32430708 DOI: 10.1007/s43032-020-00187-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Recurrent pregnancy loss (RPL) affects up to 5% of couples. It is believed that genetic factors contribute to the disease's etiology and pathophysiology. Hundreds of genes represent coherent RPL candidates due to mammalian implantation's inherent complexity. Sanger sequencing (direct sequencing) of candidate genes has identified potential RPL causative genes (and variants), including those regulating embryo implantation and pregnancy maintenance. Although this approach is a reliable technique, the simultaneous analysis of large genomic regions is challenging. Next-generation sequencing (NGS) technology has thus emerged as a useful alternative for determining genetic variants and transcriptomic disturbances contributing to monogenic and polygenic diseases pathogenesis. However, interpreting results remains challenging as NGS experiments provide an enormous amount of complex data. The molecular aspects of specific diseases must be fully understood for accurate interpretation of NGS data. This review was thus aimed at describing (for the first time) the most relevant studies involving Sanger and NGS sequencing, leading to the description of variants related to RPL pathogenesis. Successful RPL-related NGS initiatives (including RNAseq-based studies) and future challenges are discussed. We consider that the information given here should be useful for clinicians, scientists, and students to enable a better understanding of RPL etiology. It may also provide a basis for the development of diagnostic/prognostic approaches contributing toward translational medicine.
Collapse
Affiliation(s)
- Paula Quintero-Ronderos
- Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 N° 63C-69, Bogotá, 1100100, Colombia
| | - Paul Laissue
- Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 N° 63C-69, Bogotá, 1100100, Colombia.
| |
Collapse
|
|
11
|
Akbari S, Shahsavar F, Karami R, Yari F, Anbari K, Ahmadi SAY. Recurrent Spontaneous Abortion (RSA) and Maternal KIR Genes: A Comprehensive Meta-Analysis. JBRA Assist Reprod 2020; 24:197-213. [PMID: 32049474 PMCID: PMC7169921 DOI: 10.5935/1518-0557.20190067] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Natural killer cells (NKs) are the most important cells in the fetomaternal immune tolerance induced through interaction of maternal killer-cell immunoglobulin-like receptors (KIR) and fetal human leucocyte antigens (HLA). Hence, we intend to perform a meta-analysis on the role of maternal KIR genes diversity in recurrent spontaneous abortion (RSA). The present paper is a meta-analysis of previous genetic association studies and our previous original study. The results showed that KIR3DL1 was a significantly protecting factor for RSA (p=0.044; OR=0.833 [0.698-0.995]; fixed effect model). KIR2DS2 (p=0.034; OR=1.195 [1.013-1.408]; fixed effect model) and KIR2DS3 (p=0.013; OR=1.246 [1.047-1.483]; fixed effect model) were significantly risk factors for RSA. For KIR2DS1 there was a high heterogeneity and publication bias. Briefly, the inhibitory gene KIR3DL1 was a protecting factor, and the activating genes KIR2DS2 and KIR2DS3 were risk factors for RSA. However, the effect sizes were not suitable. We suggest further studies on different causes of pregnancy loss, to find the role of KIR2DS1.
Collapse
Affiliation(s)
- Soheila Akbari
- Department of Obstetrics and Gynecology, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Farhad Shahsavar
- Department of Immunology, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Reza Karami
- Department of Obstetrics and Gynecology, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Fatemeh Yari
- Department of Reproductive Health, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Khatereh Anbari
- Social Determinants of Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | | |
Collapse
|
|
12
|
Guerini FR, Bolognesi E, Sotgiu S, Carta A, Clerici C, Chiappedi M, Ghezzo A, Zanette M, Mensi MM, Canevini MP, Zanzottera M, Agliardi C, Costa AS, Balottin U, Clerici M. HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study. Brain Behav Immun 2019; 79:314-318. [PMID: 30763769 DOI: 10.1016/j.bbi.2019.02.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 01/28/2019] [Accepted: 02/05/2019] [Indexed: 02/07/2023] Open
Abstract
Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pc = 1 × 10-3; OR:3.5, 95%CI: 1.8-6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.
Collapse
Affiliation(s)
| | | | - Stefano Sotgiu
- Section of Child Neuropsychiatry, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Italy
| | - Alessandra Carta
- Section of Child Neuropsychiatry, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Italy; Child Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Matteo Chiappedi
- Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Alessandro Ghezzo
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
| | | | - Maria M Mensi
- Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Maria P Canevini
- Child Neuropsychiatry Unit and Epilepsy Center, San Paolo Hospital, Milano, Italy; Departments of Health Sciences, University of Milano, Milano, Italy
| | | | | | | | - Umberto Balottin
- Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy; Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
| | - Mario Clerici
- IRCCS Fondazione Don Carlo Gnocchi, Milano, Italy; Pathophysiology and Transplantation, University of Milano, Milano, Italy
| |
Collapse
|
|
13
|
Quintero-Ronderos P, Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches. Reprod Sci 2019:1933719119831769. [PMID: 30879428 DOI: 10.1177/1933719119831769] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Recurrent pregnancy loss (RPL) affects up to 5% of couples. It is believed that genetic factors contribute to the disease's etiology and pathophysiology. Hundreds of genes represent coherent RPL candidates due to mammalian implantation's inherent complexity. Sanger sequencing (direct sequencing) of candidate genes has identified potential RPL causative genes (and variants), including those regulating embryo implantation and pregnancy maintenance. Although this approach is a reliable technique, the simultaneous analysis of large genomic regions is challenging. Next-generation sequencing (NGS) technology has thus emerged as a useful alternative for determining genetic variants and transcriptomic disturbances contributing to monogenic and polygenic diseases pathogenesis. However, interpreting results remains challenging as NGS experiments provide an enormous amount of complex data. The molecular aspects of specific diseases must be fully understood for accurate interpretation of NGS data. This review was thus aimed at describing (for the first time) the most relevant studies involving Sanger and NGS sequencing, leading to the description of variants related to RPL pathogenesis. Successful RPL-related NGS initiatives (including RNAseq-based studies) and future challenges are discussed. We consider that the information given here should be useful for clinicians, scientists, and students to enable a better understanding of RPL etiology. It may also provide a basis for the development of diagnostic/prognostic approaches contributing toward translational medicine.
Collapse
Affiliation(s)
- Paula Quintero-Ronderos
- 1 Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Paul Laissue
- 1 Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| |
Collapse
|
|
14
|
The association of HLA-G polymorphisms and the synergistic effect of sMICA and sHLA-G with chronic kidney disease and allograft acceptance. PLoS One 2019; 14:e0212750. [PMID: 30794652 PMCID: PMC6386361 DOI: 10.1371/journal.pone.0212750] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 02/10/2019] [Indexed: 11/19/2022] Open
Abstract
The HLA-G and MICA genes are stimulated under inflammatory conditions and code for soluble (sMICA and sHLA-G) or membrane-bound molecules that exhibit immunomodulatory properties. It is still unclear whether they would have a synergistic or antagonistic effect on the immunomodulation of the inflammatory response, such as in chronic kidney disease (CKD), contributing to a better prognosis after the kidney transplantation. In this study, we went from genetic to plasma analysis, first evaluating the polymorphism of MICA, NKG2D and HLA-G in a cohort from Southern Brazil, subdivided in a control group of individuals (n = 75), patients with CKD (n = 94), and kidney-transplant (KT) patients (n = 64). MICA, NKG2D and HLA-G genotyping was performed by polymerase chain reaction with specific oligonucleotide probes, Taqman and Sanger sequencing, respectively. Levels of soluble forms of MICA and HLA-G were measured in plasma with ELISA. Case-control analysis showed that the individuals with haplotype HLA-G*01:01/UTR-4 have a lower susceptibility to develop chronic kidney disease (OR = 0.480; p = 0.032). Concerning the group of kidney-transplant patients, the HLA-G genotypes +3010 GC (rs1710) and +3142 GC (rs1063320) were associated with higher risk for allograft rejection (OR = 5.357; p = 0.013 and OR = 5.357, p = 0.013, respectively). Nevertheless, the genotype +3010 GG (OR = 0.136; p = 0.041) was associated with kidney allograft acceptance, suggesting that it is a protection factor for rejection. In addition, the phenotypic analysis revealed higher levels of sHLA-G (p = 0.003) and sMICA (p < 0.001) in plasma were associated with the development of CKD. For patients who were already under chronic pathological stress and underwent a kidney transplant, a high sMICA (p = 0.001) in pre-transplant proved to favor immunomodulation and allograft acceptance. Even so, the association of genetic factors with differential levels of soluble molecules were not evidenced, we displayed a synergistic effect of sMICA and sHLA-G in response to inflammation. This increase was observed in CKD patients, that when undergo transplantation, had this previous amount of immunoregulatory molecules as a positive factor for the allograft acceptance.
Collapse
|
|
15
|
Hajifathaliya Z, Najafipour R, Modarressi MH, Savad S, Rashvand Z. Association between the HLA-G*0105N polymorphism and recurrent abortion in women. THE JOURNAL OF QAZVIN UNIVERSITY OF MEDICAL SCIENCES 2018. [DOI: 10.29252/qums.21.6.37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
|
|
16
|
Guerini FR, Bolognesi E, Chiappedi M, Ripamonti E, Ghezzo A, Zanette M, Sotgiu S, Mensi MM, Carta A, Canevini MP, Zanzottera M, Agliardi C, Costa AS, Balottin U, Clerici M. HLA-G coding region polymorphism is skewed in autistic spectrum disorders. Brain Behav Immun 2018; 67:308-313. [PMID: 28923404 DOI: 10.1016/j.bbi.2017.09.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 09/08/2017] [Accepted: 09/11/2017] [Indexed: 10/18/2022] Open
Abstract
Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1×10-4; Danish pc=1×10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (pc=1×10-4; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2×10-3; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6×10-4 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.
Collapse
Affiliation(s)
| | | | - Matteo Chiappedi
- Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy
| | | | - Alessandro Ghezzo
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna and Associazione Nazionale Famiglie di Persone con Disabilitá Intellettiva e/o Relazionale (ANFFAS), Macerata, Italy
| | | | - Stefano Sotgiu
- Section of Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Sassari, Italy
| | - Maria Martina Mensi
- Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy
| | - Alessandra Carta
- Section of Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Sassari, Italy
| | | | | | | | | | - Umberto Balottin
- Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Italy
| | - Mario Clerici
- Don C. Gnocchi Foundation IRCCS, Milano, Italy; Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy
| |
Collapse
|
|
17
|
Fan W, Huang Z, Li S, Xiao Z. The HLA-G 14-bp polymorphism and recurrent implantation failure: a meta-analysis. J Assist Reprod Genet 2017; 34:1559-1565. [PMID: 28707147 DOI: 10.1007/s10815-017-0994-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 06/28/2017] [Indexed: 11/27/2022] Open
Abstract
PURPOSE The human leucocyte antigen-G (HLA-G) 14-bp insertion/deletion polymorphism was implicated in recurrent implantation failure (RIF), but individual published studies showed inconclusive results. Thus, a meta-analysis was performed to clarify the effect of HLA-G 14-bp polymorphism on RIF risk. METHODS A comprehensive search for relevant articles was conducted. The odds ratios (ORs) and 95% confidence intervals (CIs) for HLA-G 14-bp polymorphism and RIF were calculated. RESULTS A total of five studies were included. In studies conducted in RIF patients and controls who had at least one spontaneous pregnancy, meta-analysis revealed no statistically significant association between the HLA-G 14-bp polymorphism and RIF in allele contrast and all genetic models in the overall population, but significant association was found in the population of Caucasian origin under allele contrast (OR = 1.73, 95% CI, 1.20, 2.50) and genetic models of +14 bp/+14 bp vs. -14 bp/-14 bp (OR = 3.09, 95% CI, 1.43, 6.65). In studies conducted in RIF patients and controls who had successful pregnancy following IVF-ET, the meta-analysis showed that there was statistically significant association between the HLA-G 14 bp polymorphism and RIF in allele contrast (OR = 1.74, 95% CI, 1.13, 2.67) and genetic models of +14 bp/+14 bp vs. -14 bp/-14 bp (OR = 10.20, 95% CI, 2.47, 42.14) and dominant model (OR = 4.34, 95% CI, 1.72, 10.92). No publication bias was found in the present studies. CONCLUSIONS This meta-analysis suggested that the HLA-G 14-bp insertion allele may increase the risk of RIF in Caucasians. Further studies with large sample size of different ethnic populations are necessary.
Collapse
Affiliation(s)
- Wei Fan
- Department of Obstetrics and Gynecology, The West China Second University Hospital, University of Sichuan, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, 20 Renmin Nanlu Road, Chengdu, 610041, People's Republic of China
| | - Zhongying Huang
- Department of Obstetrics and Gynecology, The West China Second University Hospital, University of Sichuan, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, 20 Renmin Nanlu Road, Chengdu, 610041, People's Republic of China
| | - Shangwei Li
- Department of Obstetrics and Gynecology, The West China Second University Hospital, University of Sichuan, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, 20 Renmin Nanlu Road, Chengdu, 610041, People's Republic of China
| | - Zhun Xiao
- Department of Obstetrics and Gynecology, The West China Second University Hospital, University of Sichuan, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, 20 Renmin Nanlu Road, Chengdu, 610041, People's Republic of China.
| |
Collapse
|
|
18
|
Soluble HLA-G concentrations in obese women during pregnancy and in cord blood. J Reprod Immunol 2017; 119:31-37. [DOI: 10.1016/j.jri.2016.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 11/16/2016] [Accepted: 11/18/2016] [Indexed: 12/16/2022]
|
|
19
|
Ghaebi M, Nouri M, Ghasemzadeh A, Farzadi L, Jadidi-Niaragh F, Ahmadi M, Yousefi M. Immune regulatory network in successful pregnancy and reproductive failures. Biomed Pharmacother 2017; 88:61-73. [PMID: 28095355 DOI: 10.1016/j.biopha.2017.01.016] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 12/27/2016] [Accepted: 01/02/2017] [Indexed: 12/23/2022] Open
Abstract
Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies, their frequency and function are reduced in reproductive defects such as recurrent miscarriage and preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine. Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg, γd T cell, Breg, MDSC, and NKT cells in pregnancy outcome.
Collapse
Affiliation(s)
- Mahnaz Ghaebi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliyeh Ghasemzadeh
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Laya Farzadi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Ahmadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
20
|
Gelmini GF, Costa CH, Nardi FDS, Wowk PF, Mattar SB, Schuffner A, Bicalho MDG, Roxo VMMS. Is HLA-E a possible genetic marker relevant for natural conception? Am J Reprod Immunol 2016; 76:439-442. [PMID: 27714943 DOI: 10.1111/aji.12587] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 09/13/2016] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND HLA-E products, class Ib human leukocyte antigens, act in the immunology of human reproduction as modulators of the maternal immune system during pregnancy. AIMS To evaluate HLA-E role in the establishment of a viable pregnancy. MATERIALS & METHODS HLA-E was genotyped by sequence-based typing (SBT) and analyzed for specific polymorphisms, comparing couples who underwent assisted reproduction treatment (ART) and fertile control couples. RESULTS There was a significant difference in HLA-E allele and genotype distributions between ART couples and control couples. The allele HLA-E*01:03 was observed in 63.2% of ART men and in 35.1% of fertile men (P = 0.0032). CONCLUSION These results suggest that HLA-E allelic variants may play a role in the modulation of immune responses in the context of the inability of natural conception and establishment of a viable pregnancy.
Collapse
Affiliation(s)
- Georgia Fernanda Gelmini
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
| | - Cynthia Hernandes Costa
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
| | - Fabiola da Silva Nardi
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
| | - Pryscilla Fanini Wowk
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
- Instituto Carlos Chagas, ICC-Fiocruz-PR, Curitiba (PR), Brasil
| | - Sibelle Botogosque Mattar
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
- Instituto Carlos Chagas, ICC-Fiocruz-PR, Curitiba (PR), Brasil
| | | | - Maria da Graça Bicalho
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
| | - Valéria Maria Munhoz Sperandio Roxo
- Laboratório de Imunogenética e Histocompatibilidade do Departamento de Genética da Universidade Federal do Paraná (UFPR), Curitiba (PR), Brasil
| |
Collapse
|
|
21
|
Costa CH, Gelmini GF, Nardi FS, Roxo VMMS, Schuffner A, da Graça Bicalho M. HLA-G profile of infertile couples who underwent assisted reproduction treatment. Hum Immunol 2016; 77:1179-1186. [PMID: 27615505 DOI: 10.1016/j.humimm.2016.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 07/29/2016] [Accepted: 09/06/2016] [Indexed: 11/19/2022]
Abstract
HLA-G codes for a non-classical class I (Ib) protein which is mainly expressed in trophoblast cells. Many pieces of evidence pointed out its essential role conferring immunological tolerance to the fetus. Some HLA-G alleles have been linked to enhanced or reduced HLA-G protein levels expression, which have been associated with reproductive failure. In this study 33 couples undergoing ART (assisted reproduction treatment; n=66) and 120 couples who conceived naturally (controls; n=240) were enrolled in the study. Genotyping was performed by SBT and tagged an 1837bp at 5'URR as well as exons 2, 3 and4 of HLA-G. Alleles, genotypes and haplotypes were compared between infertile and control groups using Fisher Exact Test. The haplotype HLA-G∗010101b/HLA-G∗01:01:01 showed statistically significant higher frequency in control groups. The immunogenetics of infertility is complex and might be dependent on different genes involved in the establishment of a successful pregnancy. A better understanding of HLA-G alleles and haplotypes structure and how the genetic diversity at their regulatory sites could impact on their level of expression and build up the susceptibility or protection conditions may shed light on the comprehension of immunogenetics mechanisms acting at the fetus-maternal interface.
Collapse
Affiliation(s)
- Cynthia Hernandes Costa
- Immunogenetic and Histocompatibility Laboratory, Genetic Department, Federal University of Paraná (UFPR), Curitiba (PR), Brazil
| | - Georgia Fernanda Gelmini
- Immunogenetic and Histocompatibility Laboratory, Genetic Department, Federal University of Paraná (UFPR), Curitiba (PR), Brazil
| | - Fabiola Silva Nardi
- Immunogenetic and Histocompatibility Laboratory, Genetic Department, Federal University of Paraná (UFPR), Curitiba (PR), Brazil
| | | | | | - Maria da Graça Bicalho
- Immunogenetic and Histocompatibility Laboratory, Genetic Department, Federal University of Paraná (UFPR), Curitiba (PR), Brazil.
| |
Collapse
|
|
22
|
Jiang F, Zhao H, Wang L, Guo X, Wang X, Yin G, Hu Y, Li Y, Yao Y. Role of HLA-G1 in trophoblast cell proliferation, adhesion and invasion. Biochem Biophys Res Commun 2015; 458:154-60. [DOI: 10.1016/j.bbrc.2015.01.085] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 01/18/2015] [Indexed: 01/21/2023]
|
|
23
|
Lashley LEELO, van der Westerlaken LAJ, Haasnoot GW, Drabbels JJM, Spruyt-Gerritse MJ, Scherjon SA, Claas FHJ. Maternal HLA-C2 and 14 bp insertion in HLA-G is associated with recurrent implantation failure after in vitro fertilization treatment. ACTA ACUST UNITED AC 2014; 84:536-44. [PMID: 25367742 DOI: 10.1111/tan.12452] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 08/21/2014] [Accepted: 09/12/2014] [Indexed: 12/14/2022]
Abstract
The major rate-limiting step in in vitro fertilization (IVF) success appears to be the implantation of the semi-allogeneic embryo into the maternal endometrium. To determine possible risk factors of recurrent failure of embryos to implant, we investigated immunogenetic determinants as level of human leukocyte antigen (HLA) histocompatibility, frequency of killer-cell immunoglobulin-like receptors (KIR) and HLA-C alleles and HLA-G polymorphism. We DNA typed women with recurrent implantation failure (RIF) and their partners for classical HLA Class I, HLA Class II, HLA-G and KIR alleles and compared these results with couples with successful embryo implantation after their first IVF and normal fertile couples. No association was found between RIF and the degree of histocompatibility between partners or sharing of a specific antigen. Also, no significant difference in KIR haplotype or combination of HLA-C group and KIR was observed. We did find a higher frequency of HLA-C2 and a higher frequency of 14 base pair (bp) insertion in HLA-G in women with RIF. Therefore we conclude that the degree of histocompatibility between partners is not a determining factor for the occurrence of RIF. However, presence of the HLA-C2 allotype and the HLA-G allele with a 14 bp insertion is a significant risk factor.
Collapse
Affiliation(s)
- L E E L O Lashley
- Department of Gynaecology and Obstetrics, Leiden University Medical Centre, Leiden, the Netherlands
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Associations between Individual and Combined Polymorphisms of the TNF and VEGF Genes and the Embryo Implantation Rate in Patients Undergoing In Vitro Fertilization (IVF) Programs. PLoS One 2014; 9:e108287. [PMID: 25247819 PMCID: PMC4172632 DOI: 10.1371/journal.pone.0108287] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Accepted: 08/18/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND A multiple pregnancy is now considered to be the most common adverse outcome associated with in vitro fertilization (IVF). As a consequence, the identification of women with the best chances of embryo implantation is a challenge in IVF program, in which the objective is to offer elective single-embryo transfer (eSET) without decreasing the pregnancy rate. To date, a range of hormonal and clinical parameters have been used to optimize eSET but none have significant predictive value. This variability could be due to genetic predispositions related to single-nucleotide polymorphisms (SNPs). Here, we assessed the individual and combined impacts of thirteen SNPs that reportedly influence the outcome of in vitro fertilisation (IVF) on the embryo implantation rate for patients undergoing intracytoplasmic sperm injection program (ICSI). MATERIALS AND METHODS A 13 gene polymorphisms: FSHR(Asn680Ser), p53(Arg72Pro), AMH(Ile49Ser), ESR2(+1730G>A), ESR1(-397T>C), BMP15(-9C>G), MTHFR1(677C>T), MTHFR2(1298A>C), HLA-G(-725C>G), VEGF(+405G>C), TNFα(-308A>G), AMHR(-482A>G), PAI-1(4G/5G), multiplex PCR assay was designed to genotype women undergoing ICSI program. We analyzed the total patients population (n = 428) and a subgroup with homogeneous characteristics (n = 112). RESULTS Only the VEGF(+405G>C) and TNFα(-308A>G) polymorphisms impacted fertilization, embryo implantation and pregnancy rates. Moreover, the combined VEGF+405.GG and TNFα-308.AG or AA genotype occurred significantly more frequently in women with high implantation potential. In contrast, the VEGF+405.CC and TNFα-308.GG combination was associated with a low implantation rate. CONCLUSION We identified associations between VEGF(+405G>C) and TNFα(-308A>G) polymorphisms (when considered singly or as combinations) and the embryo implantation rate. These associations may be predictive of embryo implantation and could help to define populations in which elective single-embryo transfer should be recommended (or, conversely, ruled out). However, the mechanism underlying the function of these polymorphisms in embryo implantation remains to be determined and the associations observed here must be confirmed in a larger, more heterogeneous cohort.
Collapse
|
|
25
|
Beneventi F, Simonetta M, Locatelli E, Cavagnoli C, Badulli C, Lovati E, Garbin G, Genini E, Albertini R, Tinelli C, Martinetti M, Spinillo A. Temporal Variation in Soluble Human Leukocyte Antigen-G (sHLA-G) and Pregnancy-Associated Plasma Protein A (PAPP-A) in Pregnancies Complicated by Gestational Diabetes Mellitus and in Controls. Am J Reprod Immunol 2014; 72:413-21. [DOI: 10.1111/aji.12270] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Accepted: 04/18/2014] [Indexed: 12/30/2022] Open
Affiliation(s)
- Fausta Beneventi
- Department of Obstetrics and Gynecology; IRCCS Foundation Policlinico San Matteo and University of Pavia; Pavia Italy
| | - Margherita Simonetta
- Department of Obstetrics and Gynecology; IRCCS Foundation Policlinico San Matteo and University of Pavia; Pavia Italy
| | - Elena Locatelli
- Department of Obstetrics and Gynecology; IRCCS Foundation Policlinico San Matteo and University of Pavia; Pavia Italy
| | - Chiara Cavagnoli
- Department of Obstetrics and Gynecology; IRCCS Foundation Policlinico San Matteo and University of Pavia; Pavia Italy
| | - Carla Badulli
- Immunogenetics Laboratory; Immunohematology and Transfusion Center; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Elisabetta Lovati
- First Department of Medicine; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Giulia Garbin
- Immunogenetics Laboratory; Immunohematology and Transfusion Center; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Emilia Genini
- Clinical Chemistry Laboratory; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Riccardo Albertini
- Clinical Chemistry Laboratory; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Carmine Tinelli
- Clinical Epidemiology and Biometric Unit; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Miryam Martinetti
- Immunogenetics Laboratory; Immunohematology and Transfusion Center; IRCCS Foundation Policlinico San Matteo; Pavia Italy
| | - Arsenio Spinillo
- Department of Obstetrics and Gynecology; IRCCS Foundation Policlinico San Matteo and University of Pavia; Pavia Italy
| |
Collapse
|
|
26
|
Garziera M, Toffoli G. Inhibition of host immune response in colorectal cancer: Human leukocyte antigen-G and beyond. World J Gastroenterol 2014; 20:3778-3794. [PMID: 24744572 PMCID: PMC3983436 DOI: 10.3748/wjg.v20.i14.3778] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/22/2014] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.
Collapse
|
|
27
|
Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta 2014; 35:241-8. [PMID: 24581729 DOI: 10.1016/j.placenta.2014.02.004] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/30/2014] [Accepted: 02/04/2014] [Indexed: 02/08/2023]
Abstract
The maternal immune system needs to adapt to tolerate the semi-allogeneic conceptus. Since maternal allo-reactive lymphocytes are not fully depleted, other local/systemic mechanisms play a key role in altering the immune response. The Th1/Th2 cytokine balance is not essential for a pregnancy to be normal. The immune cells, CD4+CD25+Foxp3+, also known as regulatory T cells (Tregs), step in to regulate the allo-reactive Th1 cells. In this review we discuss the role of Tregs in foeto-maternal immune tolerance and in recurrent miscarriage as well as their potential use as a new target for infertility treatment. Animal and human experiments showed Treg cell number and/or function to be diminished in miscarriages. Murine miscarriage can be prevented by transferring Tregs from normal pregnant mice. Tregs at the maternal-fetal interface prevented fetal allo-rejection by creating a "tolerant" microenvironment characterised by the expression of IL-10, TGF-β and haem oxygenase isoform 1 (HO-1) rather than by lowering Th1 cytokines. Tregs increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. In vivo experiments showed Tregs sensitisation from paternal antigens to be essential for maternal-fetal tolerance. Tregs increase throughout pregnancy and diminish in late puerperium. Recent data also support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal-fetal pathological responses to paternal antigens. These findings also permit us to consider new strategies for improving pregnancy outcomes, i.e., anti-TNF blockers and granulocyte-colony stimulating factors as well as novel approaches to therapeutically exploiting Treg + cell memory.
Collapse
Affiliation(s)
- J Alijotas-Reig
- Systemic Autoimmune Disease Unit, Department of Internal Medicine I, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain; Department of Medicine, Faculty of Medicine, Universitat Autonoma, Barcelona, Spain.
| | - E Llurba
- High Obstetric Risk Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain
| | - J Ma Gris
- Reproductive Medicine Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain
| |
Collapse
|