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1
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Nelson JL, Lambert NC. The when, what, and where of naturally-acquired microchimerism. Semin Immunopathol 2025; 47:20. [PMID: 40067465 DOI: 10.1007/s00281-024-01029-2] [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: 05/13/2024] [Accepted: 11/14/2024] [Indexed: 05/13/2025]
Abstract
Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.
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Affiliation(s)
- J Lee Nelson
- Department of Medicine, University of Washington, Seattle, WA, USA.
- Translational Science and Therapeutics Fred Hutchinson Cancer Center, Seattle, USA.
| | - Nathalie C Lambert
- INSERM UMRs 1097 Arthrites, Microchimérisme et Inflammations (ARTHEMIS), Aix Marseille Université, Marseille, France.
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2
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Jacobsen DP, Fjeldstad HE, Olsen MB, Sugulle M, Staff AC. Microchimerism and pregnancy complications with placental dysfunction. Semin Immunopathol 2025; 47:21. [PMID: 40067448 PMCID: PMC11897092 DOI: 10.1007/s00281-025-01045-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 01/27/2025] [Indexed: 03/15/2025]
Abstract
Cells cross the placenta during pregnancy, resulting in proliferation of semiallogeneic cells in the mother and fetus decades later. This phenomenon, termed microchimerism, is documented across mammalian species, implying an evolutionary benefit. Still, short- and long-term effects remain uncertain. Here, we review the dynamics of microchimerism of fetal, maternal, and mother of the proband origin in relation to increasing gestational age and pregnancy complications associated with placental dysfunction including preeclampsia, fetal growth restriction, preterm labor, recurrent miscarriage, and diabetes. We use the two-stage model of preeclampsia as a framework. We recently published a series of papers independently linking increased fetal microchimerism to markers of placental dysfunction (stage 1), severe maternal hypertension (stage 2) and poor glucose control. Placental dysfunction may influence the intrinsic properties of fetal stem cells. Mesenchymal and hematopoietic stem cells isolated from cord blood during preeclampsia display reduced proliferative potential in vitro. Moreover, preeclampsia is shown to disrupt paracrine signaling in mesenchymal stem cells of the umbilical cord. Undesired properties in cells transferred to the mother could have profound negative effects on maternal health. Finally, recent studies indicate that microchimerism is involved in inducing maternal-fetal tolerance. Disruption of this process is associated with pregnancy complications. Long term, the persistence of microchimerism is necessary to sustain specific regulatory T cell populations in mice. This likely plays a role in the proband's future pregnancies and long-term maternal and offspring health. Current evidence indicates that advancements in our understanding of microchimerism could be instrumental in promoting reproductive and long-term health.
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Affiliation(s)
- Daniel Pitz Jacobsen
- Faculty of Medicine, University of Oslo, Oslo, Norway.
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway.
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo University Hospital, Kirkeveien 166, Box 4956, Oslo, Nydalen, Oslo, 0450, 0424, PO, Norway.
| | - Heidi E Fjeldstad
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
| | - Maria B Olsen
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Meryam Sugulle
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
| | - Anne Cathrine Staff
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
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3
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Pham G, Shao TY, Kinder JM, Peng Y, Turner LH, Way SS. Pregnancy induced displacement of preexisting microchimeric cells in the absence of maternal B and T cells. Front Immunol 2024; 15:1478465. [PMID: 39539542 PMCID: PMC11557343 DOI: 10.3389/fimmu.2024.1478465] [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: 08/12/2024] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Bidirectional exchange of cells between mother and fetus occurs during pregnancy, and persistence of these genetically foreign cells establishes long-term microchimerism in both individuals after parturition. Since women can have multiple pregnancies, and all mothers were once daughters themselves, the microchimeric milieu in each woman could theoretically contain cells from a variety of origins, including from their own mothers as well as their babies from each pregnancy. Interestingly and in sharp contrast to this prediction, we recently showed preexisting populations of microchimeric cells are lost following pregnancy and associated with seeding of new fetal microchimeric cells. Complete loss of preexisting microchimeric cells in this context draws parallels to immunological rejection with synchronized elimination of cells and tissues that express defined discordant antigens. This perspective evaluates this provocative hypothesis regarding pregnancy induced rejection of microchimeric cells, including new experimental data comparing microchimerism levels in mice simultaneously lacking B and T cells before pregnancy, and after parturition with primary and secondary pregnancies.
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Affiliation(s)
| | | | | | | | | | - Sing Sing Way
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Staff AC, Fjeldstad HE, Olsen MB, Øgaard J, Viken MK, Kramer CSM, Eikmans M, Kroneis T, Sallinger K, Kanaan SB, Sugulle M, Jacobsen DP. Foetal Microchimerism Correlates With Foetal-Maternal Histocompatibility Both During Pregnancy and Postpartum. HLA 2024; 104:e15717. [PMID: 39435899 DOI: 10.1111/tan.15717] [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: 07/04/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/23/2024]
Abstract
Foetal cells are detectable in women decades postpartum, a state termed foetal microchimerism. The interplay between these semi-allogeneic foetal cells and the mother could be affected by genetic mismatches in the HLA loci. Here, we relate HLA allele and molecular mismatch values to the presence and quantity of foetal microchimerism in the maternal circulation during pregnancy and postpartum. A total of 76 pregnant women were included, of which 59 were followed up 1-8 years postpartum. Maternal and foetal DNA was genotyped for HLA class I and II loci. Foetal cells in maternal buffy coat were detected by qPCR, targeting inherited paternal alleles. Antibody-verified eplet mismatch and Predicted Indirectly Recognisable HLA Epitopes (PIRCHE) scores were calculated to quantify foetal-maternal histocompatibility from the mother's perspective. Circulating foetal cells were detected in 50.0% (38/76) of women during pregnancy, and 25.4% (15/59) postpartum. During pregnancy, HLA class II antibody-verified eplet mismatch load and PIRCHE scores correlated negatively with the presence and quantity of foetal cells in the maternal circulation. Postpartum, HLA class I allele mismatches correlated negatively with foetal microchimerism presence, while HLA class II allele mismatches, HLA class I and II antibody-verified eplet mismatch load, and PIRCHE-I and PIRCHE-II scores correlated negatively with both microchimerism presence and quantity. The correlation between mismatch parameters aimed at evaluating the risk of humoral and T cell-mediated allorecognition and foetal microchimerism was more evident postpartum than during pregnancy. The observed predictive effect of foetal-maternal histocompatibility on foetal microchimerism suggests that circulating foetal cells are subject to clearance by the maternal immune system. We propose that allorecognition of foetal cells in the maternal circulation and tissues influences any long-term effect that foetal microchimerism may have on maternal health.
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Affiliation(s)
- Anne Cathrine Staff
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Heidi E Fjeldstad
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Maria B Olsen
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Jonas Øgaard
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Norwegian PSC Research Center, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marte K Viken
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Cynthia S M Kramer
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Eikmans
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Thomas Kroneis
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Katja Sallinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | | | - Meryam Sugulle
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Daniel P Jacobsen
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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Venanzi FM, Bini M, Nuccio A, De Toma A, Lambertini M, Ogliari FR, Oresti S, Viganò MG, Brioschi E, Polignano M, Naldini MM, Riva S, Ferrara M, Fogale N, Damiano G, Russo V, Reni M, Veronesi G, Foggetti G, Conforti F, Bulotta A, Ferrara R. Sex dimorphism and cancer immunotherapy: May pregnancy solve the puzzle? Cancer Treat Rev 2023; 121:102648. [PMID: 37918169 DOI: 10.1016/j.ctrv.2023.102648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/09/2023] [Accepted: 10/25/2023] [Indexed: 11/04/2023]
Abstract
In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials.
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Affiliation(s)
- Francesco Maria Venanzi
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Marta Bini
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Antonio Nuccio
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | | | - Matteo Lambertini
- Department of Medical Oncology, Clinical di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy
| | - Francesca Rita Ogliari
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Sara Oresti
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Grazia Viganò
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elena Brioschi
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maggie Polignano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Matteo Maria Naldini
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Silvia Riva
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Michele Ferrara
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Fogale
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giuseppe Damiano
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Vincenzo Russo
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Michele Reni
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Giulia Veronesi
- Università Vita-Salute San Raffaele, Milan, Italy; Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giorgia Foggetti
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy
| | - Fabio Conforti
- Oncology Unit, Humanitas Gavazzeni, 24125 Bergamo, Italy
| | - Alessandra Bulotta
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Roberto Ferrara
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy.
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6
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Jacobsen DP, Fjeldstad HE, Sugulle M, Johnsen GM, Olsen MB, Kanaan SB, Staff AC. Fetal microchimerism and the two-stage model of preeclampsia. J Reprod Immunol 2023; 159:104124. [PMID: 37541161 DOI: 10.1016/j.jri.2023.104124] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 06/21/2023] [Accepted: 07/25/2023] [Indexed: 08/06/2023]
Abstract
Fetal cells cross the placenta during pregnancy and some have the ability to persist in maternal organs and circulation long-term, a phenomenon termed fetal microchimerism. These cells often belong to stem cell or immune cell lineages. The long-term effects of fetal microchimerism are likely mixed, potentially depending on the amount of fetal cells transferred, fetal-maternal histocompatibility and fetal cell-specific properties. Both human and animal data indicate that fetal-origin cells partake in tissue repair and may benefit maternal health overall. On the other hand, these cells have been implicated in inflammatory diseases by studies showing increased fetal microchimerism in women with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. During pregnancy, preeclampsia is associated with increased cell-transfer between the mother and fetus, and an increase in immune cell subsets. In the current review, we discuss potential mechanisms of transplacental transfer, including passive leakage across the compromised diffusion barrier and active recruitment of cells residing in the placenta or fetal circulation. Within the conceptual framework of the two-stage model of preeclampsia, where syncytiotrophoblast stress is a common pathophysiological pathway to maternal and fetal clinical features of preeclampsia, we argue that microchimerism may represent a mechanistic link between stage 1 placental dysfunction and stage 2 maternal cardiovascular inflammation and endothelial dysfunction. Finally, we postulate that fetal microchimerism may contribute to the known association between placental syndromes and increased long-term maternal cardiovascular disease risk. Fetal microchimerism research represents an exciting opportunity for developing new disease biomarkers and targeted prophylaxis against maternal diseases.
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Affiliation(s)
- Daniel P Jacobsen
- Faculty of Medicine, University of Oslo, Oslo, Norway; Division of Obstetrics and Gynaecology, Oslo University Hospital, Ullevål, Oslo, Norway.
| | | | - Meryam Sugulle
- Faculty of Medicine, University of Oslo, Oslo, Norway; Division of Obstetrics and Gynaecology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Guro M Johnsen
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Maria B Olsen
- Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Sami B Kanaan
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Chimerocyte, Inc., Seattle, WA, USA
| | - Anne Cathrine Staff
- Faculty of Medicine, University of Oslo, Oslo, Norway; Division of Obstetrics and Gynaecology, Oslo University Hospital, Ullevål, Oslo, Norway
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7
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Mukherjee I, Singh S, Karmakar A, Kashyap N, Mridha AR, Sharma JB, Luthra K, Sharma RS, Biswas S, Dhar R, Karmakar S. New immune horizons in therapeutics and diagnostic approaches to Preeclampsia. Am J Reprod Immunol 2023; 89:e13670. [PMID: 36565013 DOI: 10.1111/aji.13670] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 11/02/2022] [Accepted: 12/10/2022] [Indexed: 12/25/2022] Open
Abstract
Hypertensive disorders of pregnancy (HDP) are one of the commonest maladies, affecting 5%-10% of pregnancies worldwide. The American College of Obstetricians and Gynecologists (ACOG) identifies four categories of HDP, namely gestational hypertension (GH), Preeclampsia (PE), chronic hypertension (CH), and CH with superimposed PE. PE is a multisystem, heterogeneous disorder that encompasses 2%-8% of all pregnancy-related complications, contributing to about 9% to 26% of maternal deaths in low-income countries and 16% in high-income countries. These translate to 50 000 maternal deaths and over 500 000 fetal deaths worldwide, therefore demanding high priority in understanding clinical presentation, screening, diagnostic criteria, and effective management. PE is accompanied by uteroplacental insufficiency leading to vascular and metabolic changes, vasoconstriction, and end-organ ischemia. PE is diagnosed after 20 weeks of pregnancy in women who were previously normotensive or hypertensive. Besides shallow trophoblast invasion and inadequate remodeling of uterine arteries, dysregulation of the nonimmune system has been the focal point in PE. This results from aberrant immune system activation and imbalanced differentiation of T cells. Further, a failure of tolerance toward the semi-allogenic fetus results due to altered distribution of Tregs such as CD4+FoxP3+ or CD4+CD25+CD127(low) FoxP3+ cells, thereby creating a cytotoxic environment by suboptimal production of immunosuppressive cytokines like IL-10, IL-4, and IL-13. Also, intracellular production of complement protein C5a may result in decreased FoxP3+ regulatory T cells. With immune system dysfunction as a major driver in PE pathogenesis, it is logical that therapeutic targeting of components of the immune system with pharmacologic agents like anti-inflammatory and immune-modulating molecules are either being used or under clinical trial. Cholesterol synthesis inhibitors like Pravastatin may improve placental perfusion in PE, while Eculizumab (monoclonal antibody inhibiting C5) and small molecular inhibitor of C5a, Zilucoplan are under investigation. Monoclonal antibody against IL-17(Secukinumab) has been proposed to alter the Th imbalance in PE. Autologous Treg therapy and immune checkpoint inhibitors like anti-CTLA-4 are emerging as new candidates in immune horizons for PE management in the future.
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Affiliation(s)
- Indrani Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.,Amity Institute of Biotechnology (AIB), Amity University, Noida, India
| | - Sunil Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Abhibrato Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Neha Kashyap
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Asit Ranjan Mridha
- Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi, India
| | - Jai Bhagwan Sharma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Kalpana Luthra
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Radhey Shyam Sharma
- Ex-Head and Scientist G, Indian Council of Medical Research, New Delhi, India
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University, Noida, India
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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8
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Lleo A. Geoepidemiology and the key role of sex chromosomes on autoimmune diseases. PRINCIPLES OF GENDER-SPECIFIC MEDICINE 2023:331-346. [DOI: 10.1016/b978-0-323-88534-8.00051-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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9
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Ozaki M, Glasgow A, Oglesby IK, Ng WL, Kelly S, Greene CM, Durcan L, Hurley K. Sexual Dimorphism in Interstitial Lung Disease. Biomedicines 2022; 10:biomedicines10123030. [PMID: 36551792 PMCID: PMC9775147 DOI: 10.3390/biomedicines10123030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/14/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Interstitial lung diseases (ILD) are a group of heterogeneous progressive pulmonary disorders, characterised by tissue remodelling and/or fibrotic scarring of the lung parenchyma. ILD patients experience lung function decline with progressive symptoms, poor response to treatment, reduced quality of life and high mortality. ILD can be idiopathic or associated with systemic or connective tissue diseases (CTD) but idiopathic pulmonary fibrosis (IPF) is the most common form. While IPF has a male predominance, women are affected more greatly by CTD and therefore associated ILDs. The mechanisms behind biological sex differences in these progressive lung diseases remain unclear. However, differences in environmental exposures, variable expression of X-chromosome related inflammatory genes and sex hormones play a role. Here, we will outline sex-related differences in the incidence, progression and mechanisms of action of these diseases and discuss existing and novel cellular and pre-clinical studies. Furthermore, we will highlight how sex-differences are not adequately considered in pre-clinical disease models, how gender bias exists in clinical diagnosis and how women are underrepresented in clinical trials. Future action on these observations will hopefully shed light on the role of biological sex in disease development, identify potential targets for intervention and increase female participant numbers in clinical trials.
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Affiliation(s)
- Mari Ozaki
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, D09 YD60 Dublin 9, Ireland
- Tissue Engineering Research Group, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland
| | - Arlene Glasgow
- Department of Clinical Microbiology, Royal College of Surgeons in Ireland, D09 YD60 Dublin 9, Ireland
| | - Irene K. Oglesby
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, D09 YD60 Dublin 9, Ireland
- Tissue Engineering Research Group, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland
| | - Wan Lin Ng
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, D09 YD60 Dublin 9, Ireland
- Department of Rheumatology, Beaumont Hospital, D09V2N0 Dublin 9, Ireland
| | - Sile Kelly
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, D09 YD60 Dublin 9, Ireland
| | - Catherine M. Greene
- Department of Clinical Microbiology, Royal College of Surgeons in Ireland, D09 YD60 Dublin 9, Ireland
| | - Laura Durcan
- Department of Rheumatology, Beaumont Hospital, D09V2N0 Dublin 9, Ireland
| | - Killian Hurley
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, D09 YD60 Dublin 9, Ireland
- Tissue Engineering Research Group, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland
- Correspondence:
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10
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Diagnostic Pitfall in Atypical Febrile Presentation in a Patient with a Pregnancy-Specific Dermatosis—Case Report and Literature Review. Medicina (B Aires) 2022; 58:medicina58070847. [PMID: 35888566 PMCID: PMC9315689 DOI: 10.3390/medicina58070847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/04/2022] Open
Abstract
Pruritic urticarial papules and plaques of pregnancy (PUPPP) usually occurs in the third trimester of pregnancy in primiparous women. It is a self-limiting inflammatory disorder with a still unknown pathogenic mechanism. The abdominal wall overdistension, with a subsequent inflammatory response due to damage to the connective tissue, represents a pathogenesis explanation. Clinical features involve intensely pruritic urticarial rash with edematous, erythematous papules and plaques. The clinical picture and dermal biopsy establish the diagnosis. Topical corticosteroids and oral antihistamines are usually sufficient, but sometimes systemic corticosteroids are necessary. Maternal and fetal prognosis is excellent, and the lesions resolve after birth with no scarring or pigmentary change. We present a case of a 36-year-old patient with a 32-week pregnancy who was admitted with a generalized pruritic rash accompanied by fever. The final diagnosis was decided after multiple pathology exclusions. Treatment consisted of systemic corticoid therapy. The patient gave birth by cesarean section to a healthy newborn without dermatological lesions or other conditions. Adding more PUPPP cases to the literature portfolio will bring more awareness to this under-recognized and under-reported skin disorder. We trust this case will encourage other physicians to publish more cases of pregnancy-specific dermatoses.
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11
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Biliary atresia: Graft-versus-host disease with maternal microchimerism as an etiopathogenesis. Transfus Apher Sci 2022; 61:103410. [DOI: 10.1016/j.transci.2022.103410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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12
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Cómitre-Mariano B, Martínez-García M, García-Gálvez B, Paternina-Die M, Desco M, Carmona S, Gómez-Gaviro MV. Feto-maternal microchimerism: Memories from pregnancy. iScience 2022; 25:103664. [PMID: 35072002 PMCID: PMC8762399 DOI: 10.1016/j.isci.2021.103664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
There is a bidirectional transplacental cell trafficking between mother and fetus during pregnancy in placental mammals. The presence and persistence of fetal cells in maternal tissues are known as fetal microchimerism (FMc). FMc has high multilineage potential with a great ability to differentiate and functionally integrate into maternal tissue. FMc has been found in various maternal tissues in animal models and humans. Its permanence in the maternal body up to decades after delivery suggests it might play an essential role in maternal pathophysiology. Studying the presence, localization, and characteristics of FMc in maternal tissues is key to understanding its impact on the woman's body. Here we comprehensively review the existence of FMc in different species and organs and tissues, aiming to better characterize their possible role in human health and disease. We also highlight several methodological considerations that would optimize the detection, quantification, and functional determination of FMc.
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Affiliation(s)
- Blanca Cómitre-Mariano
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain
| | - Magdalena Martínez-García
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Monforte de Lemos 3-5, Instituto de Salud Carlos III, Pabellón 11, planta baja, 28029 Madrid, Spain
| | - Bárbara García-Gálvez
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain
| | - María Paternina-Die
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Monforte de Lemos 3-5, Instituto de Salud Carlos III, Pabellón 11, planta baja, 28029 Madrid, Spain
| | - Manuel Desco
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Monforte de Lemos 3-5, Instituto de Salud Carlos III, Pabellón 11, planta baja, 28029 Madrid, Spain.,Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Avenida de la Universidad, 30, 28911 Leganés, Spain.,Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, C/ Melchor Fernandez Almagro 3, 28029 Madrid, Spain
| | - Susanna Carmona
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Monforte de Lemos 3-5, Instituto de Salud Carlos III, Pabellón 11, planta baja, 28029 Madrid, Spain
| | - María Victoria Gómez-Gaviro
- Instituto de Investigación Sanitaria Gregorio Marañón. (IiSGM), C/Doctor Esquerdo 46, 28007 Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/ Monforte de Lemos 3-5, Instituto de Salud Carlos III, Pabellón 11, planta baja, 28029 Madrid, Spain.,Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Avenida de la Universidad, 30, 28911 Leganés, Spain
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13
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Lee KA, Kim J, Choi W, Kim HS, Seo GH. Pregnancy-associated risk factors and incidence of systemic sclerosis in primiparous women: A nationwide population-based cohort study. Mod Rheumatol 2022; 32:149-154. [PMID: 33775221 DOI: 10.1080/14397595.2021.1906513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/06/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVES To evaluate the pregnancy-related risk factors and incidence rate (IR) of systemic sclerosis (SSc) in primipara using the Health Insurance Review and Assessment database, covering all medical claims in South Korea. METHODS From the database, 2,260,952 primipara aged 18-49 years from 2008 to 2018 were identified. The patients were followed up after their index delivery until December 2019. A Cox proportional hazard analysis was performed to identify the association of pregnancy-related factors with SSc development. RESULTS The SSc IR was 0.62 cases per 100,000 patient-years. Primipara had a higher risk of developing SSc after 3 years postpartum than in the first 3 years of delivery (OR = 1.98, 95% CI: 1.36-2.78, p < .001). A multivariate analysis showed that older age (35-49 years) (HR = 2.14, 95% CI: 1.05-4.35, p = .037) and a Caesarean section (CS) (HR = 1.86, 95% CI: 1.10-3.15, p = .021) are risk factors for SSc. At 3 years postpartum, CS (HR = 2.97, 95% CI: 1.39-6.32, p = .005) and a female infant (HR = 2.28, 95% CI: 1.11-4.71, p = .026) were associated with SSc development. CONCLUSION Having a CS, late childbirth, and a female infant are the risk factors for SSc in primipara. This study establishes the IR of SSc in primipara.
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Affiliation(s)
- Kyung-Ann Lee
- Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, South Korea
| | - JongSun Kim
- Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, South Korea
| | - Wonho Choi
- Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, South Korea
| | - Hyun-Sook Kim
- Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, South Korea
| | - Gi Hyeon Seo
- Department of Healthcare Review and Assessment Committee, Health Insurance Review and Assessment Service, Wonju, South Korea
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14
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Pregnancy-associated pemphigus – case report. GINECOLOGIA.RO 2022. [DOI: 10.26416/gine.36.2.2022.6549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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15
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Sabbatinelli G, Fantasia D, Palka C, Morizio E, Alfonsi M, Calabrese G. Isolation and Enrichment of Circulating Fetal Cells for NIPD: An Overview. Diagnostics (Basel) 2021; 11:diagnostics11122239. [PMID: 34943476 PMCID: PMC8700692 DOI: 10.3390/diagnostics11122239] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 11/26/2021] [Accepted: 11/28/2021] [Indexed: 11/17/2022] Open
Abstract
Prenatal diagnosis plays a crucial role in clinical genetics. Non-invasive prenatal diagnosis using fetal cells circulating in maternal peripheral blood has become the goal of prenatal diagnosis, to obtain complete fetal genetic information and avoid risks to mother and fetus. The development of high-efficiency separation technologies is necessary to obtain the scarce fetal cells from the maternal circulation. Over the years, multiple approaches have been applied, including choice of the ideal cell targets, different cell recovering technologies, and refined cell isolation yield procedures. In order to provide a useful tool and to give insights about limitations and advantages of the technologies available today, we review the genetic research on the creation and validation of non-invasive prenatal diagnostic testing protocols based on the rare and labile circulating fetal cells during pregnancy.
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Affiliation(s)
- Giulia Sabbatinelli
- Dipartimento di Neuroscienze, Imaging & Scienze Cliniche, Scuola Superiore G. D’Annunzio, University of Chieti, 66100 Chieti, Italy;
| | - Donatella Fantasia
- UOSD Genetica Oncoematologica, Dipartimento di Oncologico-Ematologico, Ospedale Spirito Santo, ASL Pescara, 65124 Pescara, Italy;
| | - Chiara Palka
- UOC Genetica Medica, Ospedale S.S. Annunziata, ASL2 Chieti, 66100 Chieti, Italy; (C.P.); (M.A.)
| | - Elisena Morizio
- Genetica Medica, Dipartimento di Tecnologie Avanzate in Medicina e Odontoiatria, School of Medicine, University of Chieti, 66100 Chieti, Italy;
| | - Melissa Alfonsi
- UOC Genetica Medica, Ospedale S.S. Annunziata, ASL2 Chieti, 66100 Chieti, Italy; (C.P.); (M.A.)
| | - Giuseppe Calabrese
- UOSD Genetica Oncoematologica, Dipartimento di Oncologico-Ematologico, Ospedale Spirito Santo, ASL Pescara, 65124 Pescara, Italy;
- Genetica Medica, Dipartimento di Tecnologie Avanzate in Medicina e Odontoiatria, School of Medicine, University of Chieti, 66100 Chieti, Italy;
- Correspondence:
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16
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Suah AN, Tran DKV, Khiew SH, Andrade MS, Pollard JM, Jain D, Young JS, Yin D, Chalasani G, Alegre ML, Chong AS. Pregnancy-induced humoral sensitization overrides T cell tolerance to fetus-matched allografts in mice. J Clin Invest 2021; 131:140715. [PMID: 33393512 PMCID: PMC7773355 DOI: 10.1172/jci140715] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/02/2020] [Indexed: 12/19/2022] Open
Abstract
Immunological tolerance to semiallogeneic fetuses is necessary to achieving successful first pregnancy and permitting subsequent pregnancies with the same father. Paradoxically, pregnancy is an important cause of sensitization, resulting in the accelerated rejection of offspring-matched allografts. The underlying basis for divergent outcomes following reencounter of the same alloantigens on transplanted organs versus fetuses in postpartum females is incompletely understood. Using a mouse model that allows concurrent tracking of endogenous fetus-specific T and B cell responses in a single recipient, we show that semiallogeneic pregnancies simultaneously induce fetus-specific T cell tolerance and humoral sensitization. Pregnancy-induced antibodies, but not B cells, impeded transplantation tolerance elicited by costimulation blockade to offspring-matched cardiac grafts. Remarkably, in B cell-deficient mice, allogeneic pregnancy enabled the spontaneous acceptance of fetus-matched allografts. The presence of pregnancy-sensitized B cells that cannot secrete antibodies at the time of heart transplantation was sufficient to precipitate rejection and override pregnancy-established T cell tolerance. Thus, while induction of memory B cells and alloantibodies by pregnancies establishes formidable barriers to transplant success for multigravid women, our observations raise the possibility that humoral desensitization will not only improve transplantation outcomes, but also reveal an unexpected propensity of multiparous recipients to achieve tolerance to offspring-matched allografts.
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Affiliation(s)
- Ashley N Suah
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Dong-Kha V Tran
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Stella Hw Khiew
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Michael S Andrade
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Jared M Pollard
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Dharmendra Jain
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - James S Young
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Dengping Yin
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Geetha Chalasani
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Anita S Chong
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
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17
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Abstract
From the clinical standpoint, systemic sclerosis (SSc) is characterized by skin and internal organ fibrosis, diffuse fibroproliferative vascular modifications, and autoimmunity. Clinical presentation and course are highly heterogenous and life expectancy variably affected mostly dependent on lung and heart involvement. SSc touches more women than men with differences in disease severity and environmental exposure. Pathogenetic events originate from altered homeostasis favored by genetic predisposition, environmental cues and a variety of endogenous and exogenous triggers. Epigenetic modifications modulate SSc pathogenesis which strikingly associate profound immune-inflammatory dysregulation, abnormal endothelial cell behavior, and cell trans-differentiation into myofibroblasts. SSc myofibroblasts show enhanced survival and enhanced extracellular matrix deposition presenting altered structure and altered physicochemical properties. Additional cell types of likely pathogenic importance are pericytes, platelets, and keratinocytes in conjunction with their relationship with vessel wall cells and fibroblasts. In SSc, the profibrotic milieu is favored by cell signaling initiated in the one hand by transforming growth factor-beta and related cytokines and in the other hand by innate and adaptive type 2 immune responses. Radical oxygen species and invariant receptors sensing danger participate to altered cell behavior. Conventional and SSc-specific T cell subsets modulate both fibroblasts as well as endothelial cell dysfunction. Beside autoantibodies directed against ubiquitous antigens important for enhanced clinical classification, antigen-specific agonistic autoantibodies may have a pathogenic role. Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. Advances in system biology applied to the wealth of data generated by unbiased screening are allowing to subgroup patients based on distinct pathogenic mechanisms. Deciphering heterogeneity in pathogenic mechanisms will pave the way to highly needed personalized therapeutic approaches.
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18
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Bianchi DW, Khosrotehrani K, Way SS, MacKenzie TC, Bajema I, O'Donoghue K. Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism. Clin Chem 2020; 67:351-362. [PMID: 33417673 PMCID: PMC10072000 DOI: 10.1093/clinchem/hvaa304] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 10/28/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Originally studied as a mechanism to understand eclampsia-related deaths during pregnancy, fetal cells in maternal blood have more recently garnered attention as a noninvasive source of fetal material for prenatal testing. In the 21st century, however, intact fetal cells have been largely supplanted by circulating cell-free placental DNA for aneuploidy screening. Instead, interest has pivoted to the ways in which fetal cells influence maternal biology. In parallel, an increasing appreciation of the consequences of maternal cells in the developing fetus has occurred. CONTENT In this review, we highlight the potential clinical applications and functional consequences of the bidirectional trafficking of intact cells between a pregnant woman and her fetus. Fetal cells play a potential role in the pathogenesis of maternal disease and tissue repair. Maternal cells play an essential role in educating the fetal immune system and as a factor in transplant acceptance. Naturally occurring maternal microchimerism is also being explored as a source of hematopoietic stem cells for transplant in fetal hematopoietic disorders. SUMMARY Future investigations in humans need to include complete pregnancy histories to understand maternal health and transplant success or failure. Animal models are useful to understand the mechanisms underlying fetal wound healing and/or repair associated with maternal injury and inflammation. The lifelong consequences of the exchange of cells between a mother and her child are profound and have many applications in development, health, and disease. This intricate exchange of genetically foreign cells creates a permanent connection that contributes to the survival of both individuals.
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Affiliation(s)
- Diana W Bianchi
- National Human Genome Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Kiarash Khosrotehrani
- Experimental Dermatology Group, The University of Queensland, UQ Diamantina Institute, Brisbane, Queensland, Australia
| | - Sing Sing Way
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Tippi C MacKenzie
- Center for Maternal-Fetal Precision Medicine and the Department of Surgery, University of California, San Francisco, CA, USA
| | - Ingeborg Bajema
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Keelin O'Donoghue
- Irish Centre for Maternal and Child Health (INFANT), University College Cork, Cork, Ireland
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19
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Chung MP, Kolstad KD, Dontsi M, Postlethwaite D, Manwani P, Zhao H, Kesh S, Simard JF, Chung L. Increased Rates of Obstetric Complications Prior to Systemic Sclerosis Diagnosis. Arthritis Care Res (Hoboken) 2020; 74:912-917. [PMID: 33290624 DOI: 10.1002/acr.24533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/03/2020] [Accepted: 12/03/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To investigate whether obstetric complications prior to systemic sclerosis (SSc) diagnosis are more common compared to the general obstetric population. METHODS A case-control study was performed at Kaiser Permanente Northern California to compare prior obstetric complications in adult women who later developed SSc (cases) with women from the general obstetric population who did not develop SSc (controls; matched 10:1 by age and year of delivery) from 2007-2016. Exposures included past hypertensive disorders of pregnancy (preeclampsia, eclampsia, gestational hypertension), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), maternal infections, neonatal intensive care unit (NICU) admission, and preterm birth. Fischer's exact tests were used to compare categorical variables. Conditional logistic regression models estimated the odds ratio (OR) and corresponding 95% confidence intervals for the outcome SSc. RESULTS Seventeen SSc cases and 170 non-SSc controls were identified, with median maternal age at delivery 34 years (range 23-46 years) and median time from delivery to SSc diagnosis 2 years (range 0.2-7.3 years). SSc cases were more likely to be Hispanic and Black. Prior obstetric complications appeared higher in women with an eventual SSc diagnosis compared to controls (70.6% vs. 50%), including hypertensive disorders (17.7% vs. 9.4%), PROM (11.8% vs. 4.1%), IUGR (5.9% vs 1.8%), maternal infection (29.4% vs. 14.1%), NICU admissions (23.5% vs. 7.7%), and preterm delivery (29.4% vs. 21.8%). Cases had a higher odds of delivering infants requiring NICU admission (OR=4.7, 95% CI 1.2-18.8). CONCLUSIONS Women who eventually develop SSc had trends towards more complicated pregnancy histories before overt diagnosis.
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Affiliation(s)
- Melody P Chung
- Department of Internal Medicine, Kaiser Permanente Santa Clara, Santa Clara, CA, USA.,Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Kathleen D Kolstad
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Makdine Dontsi
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | | | - Poonam Manwani
- Department of Internal Medicine, Kaiser Permanente Santa Clara, Santa Clara, CA, USA
| | - Hongyu Zhao
- Department of Internal Medicine, Kaiser Permanente Santa Clara, Santa Clara, CA, USA
| | - Sumana Kesh
- Department of Internal Medicine, Kaiser Permanente Santa Clara, Santa Clara, CA, USA
| | - Julia F Simard
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.,Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
| | - Lorinda Chung
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.,Division of Immunology and Rheumatology, Palo Alto Health Care System, Palo Alto, CA, USA
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20
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Donor HLA-DR Drives the Development of De Novo Autoimmunity Following Lung and Heart Transplantation. Transplant Direct 2020; 6:e607. [PMID: 33062840 PMCID: PMC7515617 DOI: 10.1097/txd.0000000000001062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/28/2020] [Accepted: 08/10/2020] [Indexed: 11/26/2022] Open
Abstract
Individuals harbor preexisting HLA−DR/DQ−restricted responses to collagen type V (ColV) mediated by Th17 cells under Treg control, both specific to peptides that bind to inherited HLA class II antigens. Yet after transplant, the donor−DR type somehow influences graft outcome. We hypothesized that, long after a lung or heart allograft, the particular HLA−DR type of the mismatched transplant donor transforms the specificity of the “anti−self” response. This could explain why, over long term, certain donor DRs could be more immunogenic than others.
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21
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Barth C, de Lange AMG. Towards an understanding of women's brain aging: the immunology of pregnancy and menopause. Front Neuroendocrinol 2020; 58:100850. [PMID: 32504632 DOI: 10.1016/j.yfrne.2020.100850] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 03/23/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023]
Abstract
Women are at significantly greater risk of developing Alzheimer's disease and show higher prevalence of autoimmune conditions relative to men. Women's brain health is historically understudied, and little is therefore known about the mechanisms underlying epidemiological sex differences in neurodegenerative diseases, and how female-specific factors may influence women's brain health across the lifespan. In this review, we summarize recent studies on the immunology of pregnancy and menopause, emphasizing that these major immunoendocrine transition phases may play a critical part in women's brain aging trajectories.
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Affiliation(s)
- Claudia Barth
- Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Ann-Marie G de Lange
- Department of Psychology, University of Oslo, Oslo, Norway; Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
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22
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23
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Borse MP, Sahoo TK, Anand KV, Kumar M, Panda D. Postpartum Polymyositis Following Intrauterine Fetal Death. Indian J Crit Care Med 2020; 24:731-734. [PMID: 33024387 PMCID: PMC7519596 DOI: 10.5005/jp-journals-10071-23541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Polymyositis (PM) is an uncommon inflammatory myopathy that affects striated muscles. It causes weakness of the limb girdles, neck, and pharyngeal muscles. We are presenting a case of PM which manifested after intrauterine death (IUD). The patient was referred to our hospital for breathing difficulty, 4 days after delivery of a dead fetus. Initially, she was treated in line of puerperal sepsis and peripartum cardiomyopathy. Patient's cardiopulmonary functions improved but she had persistent high-grade fever. Gross muscle weakness was found on day 5 of admission, involving all four limbs, predominantly in proximal muscles and she had dark colored urine. Laboratory tests revealed myoglobinuria, high serum creatine phosphokinase (CPK) levels, and high lactate dehydrogenase (LDH) levels. Polymyositis diagnosed on the basis of high CPK levels, magnetic resonance imaging (MRI) of cervical spine, electromyography (EMG), and muscle biopsy findings. We question, whether the PM could be pathogenically related to the pregnancy? Literature review of the previously reported cases of PM/dermatomyositis and our case report suggests that pregnancy can trigger the new onset of PM.
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Affiliation(s)
- Manmohan P Borse
- Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India
| | - Tapas K Sahoo
- Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India
| | - Kumar V Anand
- Department of Neurology, Medanta Hospital, Ranchi, Jharkhand, India
| | - Manoj Kumar
- Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India
| | - Debasish Panda
- Critical Care Department, Medanta Hospital, Ranchi, Jharkhand, India
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24
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Jafarinia M, Amoon M, Javid A, Vakili S, Sadeghi E, Azadi D, Alsahebfosoul F. Male microchimerism in peripheral blood from women with multiple sclerosis in Isfahan Province. Int J Immunogenet 2019; 47:175-179. [PMID: 31833227 DOI: 10.1111/iji.12465] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/24/2019] [Accepted: 11/27/2019] [Indexed: 12/20/2022]
Abstract
Multiple sclerosis (MS) is referred to as an organ-specific T-cell-mediated autoimmune disease of the central nervous system (CNS). Different genetic and environmental factors increase the risk of developing MS. In recent years, microchimerism (Mc) has been widely studied in autoimmune diseases, although the exact role of this phenomenon in human health is not known well. Microchimerism is the low level presence of DNA or cells from one individual into the tissue or circulation of another individual. In the current study, we evaluated the association of fetal microchimerism (FMc) with MS in Isfahan province. In this study, we enrolled 68 women in four groups. Two groups were MS patients with or without a pregnancy for a son, and the other two groups were MS-negative patients with or without a pregnancy for a son. The presence of the male genome assessed and compared in these groups. Four millilitres of peripheral blood were collected from all subjects in the tube containing EDTA and DNA was extracted. Real-time PCR assay was used for the DAZ (deleted in azoospermia) region Yq 11.23 as a marker for male microchimerism in all subjects. Our results showed that the percentage of DAZ (male genome)-positive women was significantly higher in MS-positive women given birth to a son in comparison with the other three groups. Our results also revealed no significant correlation between the percentage of DAZ-positive women and Expanded Disability Status Scale (EDSS) score and age of onset in the patients' group. For future studies, we suggest enrolling subjects who MS diagnosis occurred before and after pregnancy with a son. Comparing FMc in these two groups might provide a better understanding of the possible role of FMc in later development of MS.
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Affiliation(s)
- Morteza Jafarinia
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mina Amoon
- Department of Biology, Faculty of Science and Engineering, Science and Arts University, Yazd, Iran
| | - Ameneh Javid
- Department of Biology, Faculty of Science and Engineering, Science and Arts University, Yazd, Iran
| | - Sina Vakili
- Biochemistry Department, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Erfan Sadeghi
- Department of Biostatistics and Epidemiology, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran.,Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Davood Azadi
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran.,Department of Laboratory Sciences, Khomein University of Medical Sciences, Khomein, Iran
| | - Fereshteh Alsahebfosoul
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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25
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Fjeldstad HE, Johnsen GM, Staff AC. Fetal microchimerism and implications for maternal health. Obstet Med 2019; 13:112-119. [PMID: 33093862 DOI: 10.1177/1753495x19884484] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/28/2019] [Indexed: 12/22/2022] Open
Abstract
This review paper outlines the definition, pathophysiology, and potential maternal health consequences of cellular fetal microchimerism, the maternal acquisition of intact cells of fetal origin during pregnancy. Increased rates and amounts of cellular fetal microchimerism are associated with several placental syndromes, including preeclampsia and fetal growth restriction. The discovery of cellular fetal microchimerism and methods of detection are briefly outlined, and we present the mechanisms hypothesized to govern pregnancy-related and long-term maternal health effects of cellular fetal microchimerism. Specifically, we discuss the potential implications of cellular fetal microchimerism in wound healing, autoimmunity, cancer, and possibly cardiovascular disease. Cellular fetal microchimerism represents a novel area of research on maternal and transgenerational health and disease, providing exciting opportunities for developing new disease biomarkers and precision medicine with targeted prophylaxis against long-term maternal disease.
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Affiliation(s)
- Heidi Es Fjeldstad
- Division of Obstetrics and Gyneacology, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Guro M Johnsen
- Division of Obstetrics and Gyneacology, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Anne Cathrine Staff
- Division of Obstetrics and Gyneacology, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
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26
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Kim MH, Akbari O, Genyk Y, Kohli R, Emamaullee J. Immunologic benefit of maternal donors in pediatric living donor liver transplantation. Pediatr Transplant 2019; 23:e13560. [PMID: 31402535 DOI: 10.1111/petr.13560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/18/2019] [Accepted: 07/08/2019] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Long-term follow-up has suggested that pediatric LDLT may have superior outcomes compared to deceased donor recipients. In this review, we describe the subset of LDLT recipients with maternal donors that have lower reported rates of rejection and improved allograft survival. RECENT FINDINGS Pediatric LDLT recipients, particularly those with a primary diagnosis of biliary atresia who receive grafts from their mothers, have been reported to have lower rates of acute cellular rejection post-transplant and graft failure. Maternal-fetal microchimerism and the persistence of regulatory T cells may be related to improved outcomes observed in recipients with maternal donors. Further, recent studies have shown that up to 60% of pediatric LDLT recipients can undergo intentional withdrawal of immunosuppression and achieve long-term operational tolerance. The impact of graft type on operational tolerance has not been thoroughly investigated; however, investigation of tolerant pediatric LDLT patients with maternal donors may provide key insights into the mechanisms of immune tolerance. SUMMARY While excellent outcomes can be achieved in pediatric LDLT, there is still a measurable decrease in graft and patient survival over time post-transplant. Recipients of maternal donor liver transplants are a subset of patients who may be advantaged toward improved outcomes by means of immune tolerance.
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Affiliation(s)
- Michelle H Kim
- Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yuri Genyk
- Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Pediatric Liver Care Center, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Rohit Kohli
- Pediatric Liver Care Center, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Juliet Emamaullee
- Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Pediatric Liver Care Center, Children's Hospital Los Angeles, Los Angeles, CA, USA
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27
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Lambert NC. Nonendocrine mechanisms of sex bias in rheumatic diseases. Nat Rev Rheumatol 2019; 15:673-686. [PMID: 31597952 DOI: 10.1038/s41584-019-0307-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2019] [Indexed: 12/22/2022]
Abstract
Rheumatic diseases affect a wide range of individuals of all ages, but the most common diseases occur more frequently in women than in men, at ratios of up to ten women to one man. Despite a growing number of studies on sex bias in rheumatic diseases, sex-specific health care is limited and sex specificity is not systematically integrated into treatment regimens. Women and men differ in three major biological points: the number of X chromosomes per cell, the type and quantities of sex hormones present and the ability to be pregnant, all of which have immunological consequences. Could a greater understanding of these differences lead to a new era of personalized sex-specific medicine? This Review focuses on the main genetic and epigenetic mechanisms that have been put forward to explain sex bias in rheumatic diseases, including X chromosome inactivation, sex chromosome aneuploidy and microchimerism. The influence of sex hormones is not discussed in detail in this Review, as it has been well described elsewhere. Understanding the sex-specific factors that contribute to the initiation and progression of rheumatic diseases will enable progress to be made in the diagnosis, treatment and management of all patients with these conditions.
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Affiliation(s)
- Nathalie C Lambert
- INSERM UMRs 1097 Arthrites Autoimmunes, Aix Marseille Université, Marseille, France.
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28
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Hahn S, Hasler P, Vokalova L, van Breda SV, Than NG, Hoesli IM, Lapaire O, Rossi SW. Feto-Maternal Microchimerism: The Pre-eclampsia Conundrum. Front Immunol 2019; 10:659. [PMID: 31001268 PMCID: PMC6455070 DOI: 10.3389/fimmu.2019.00659] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/11/2019] [Indexed: 12/15/2022] Open
Abstract
Feto-maternal microchimerism (FMM) involves bidirectional cross-placental trafficking during pregnancy, leading to a micro-chimeric state that can persist for decades. In this manner a pregnant woman will harbor cells from her mother, as well as, cells from her child. Historically, eclampsia, a severe disorder of pregnancy provided the basis for FMM following the detection of trophoblast cells in the lungs of deceased women. Bi-directional cell trafficking between mother and fetus is also altered in pre-eclampsia and has been suggested to contribute to the underlying etiology. FMM has been implicated in tolerance promotion, remission of auto-inflammatory disorders during pregnancy, or the development of autoimmune conditions post-partum. The underlying mechanism whereby the host immune system is modulated is unclear but appears to involve HLA class II molecules, in that incompatibility between mother and fetus promotes remission of rheumatoid arthritis, whereas feto-maternal HLA compatibility may assist in the post-partum initiation of scleroderma. Couples having a high degree of HLA class II compatibility have an increased risk for pre-eclampsia, while the occurrence of scleroderma and rheumatoid arthritis is greater in pre-eclamptic cases than in women with normal pregnancies, suggesting a long term autoimmune predisposition. Since pregnant women with pre-eclampsia exhibit significantly lower levels of maternally-derived micro-chimerism, the question arises whether pre-eclampsia and post-partum development of autoimmune conditions occur due to the failure of the grandmothers cells to adequately regulate an inappropriate micro-chimeric constellation.
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Affiliation(s)
- Sinuhe Hahn
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Paul Hasler
- Division of Rheumatology, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland
| | - Lenka Vokalova
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Shane Vontelin van Breda
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland.,Division of Rheumatology, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland
| | - Nandor Gabor Than
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | | | - Olav Lapaire
- Department of Obstetrics, University Women's Hospital Basel, Basel, Switzerland
| | - Simona W Rossi
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland
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Arese V, Murabito P, Ribero S, Panzone M, Tonella L, Fierro MT, Papini M, Quaglino P. Autoimmune connective tissue diseases and pregnancy. GIORN ITAL DERMAT V 2019; 154:263-276. [PMID: 30650958 DOI: 10.23736/s0392-0488.18.06252-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Autoimmune connective tissue-diseases are more frequent in women and deserve a multidisciplinary approach in which the dermatologist play a major role together with other physicians. Pregnancy in these patients has to be considered a high-risk situation, because of possible worsening of the mother's disease and increased morbility and mortality for the fetus; also, therapies have to be chosen carefully because some drugs cannot be used during pregnancy. For all these reasons, the decision to become pregnant needs to consider the type of disease, stage of disease, age and clinical condition, and requires a multidisciplinary approach. A correct counselling, a close monitoring, a specific approach based on the risks involved and the use of appropriate therapies are the keys to obtain optimal pregnancy outcomes.
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Affiliation(s)
- Veronica Arese
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Pierangela Murabito
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Simone Ribero
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Michele Panzone
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Luca Tonella
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Maria T Fierro
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Manuela Papini
- Department of Surgical and Biomedical Sciences, Dermatologic Clinic of Terni, University of Perugia, Perugia, Italy
| | - Pietro Quaglino
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy -
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30
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Cruz GI, Shao X, Quach H, Quach D, Ho KA, Sterba K, Noble JA, Patsopoulos NA, Busch MP, Triulzi DJ, Ladas N, Blasczyk R, Wong WSW, Solomon BD, Niederhuber JE, Criswell LA, Barcellos LF. Mother-child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythematosus among mothers. Genes Immun 2019; 21:27-36. [PMID: 30635658 PMCID: PMC7039805 DOI: 10.1038/s41435-018-0055-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 10/20/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022]
Abstract
The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.
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Affiliation(s)
- Giovanna I Cruz
- Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA, 94720-3220, USA
| | - Xiaorong Shao
- Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA, 94720-3220, USA
| | - Hong Quach
- Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA, 94720-3220, USA
| | - Diana Quach
- Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA, 94720-3220, USA
| | - Kimberly A Ho
- Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kirsten Sterba
- Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Janelle A Noble
- Children's Hospital Oakland Research Institute, 5700 M.L.K. Jr. Way, Oakland, CA, 94609, USA
| | - Nikolaos A Patsopoulos
- Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.,Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.,Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA, 02142, USA
| | - Michael P Busch
- Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA, 94118-4417, USA
| | - Darrell J Triulzi
- Institute for Transfusion Medicine, Department of Pathology, University of Pittsburgh, 3636 Blvd. of the Allies, Pittsburgh, PA, 15213, USA
| | - Nektarios Ladas
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Wendy S W Wong
- Division of Medical Genomics, Inova Translational Medicine Institute, 8110 Gatehouse Road, Falls Church, VA, 22042, USA
| | - Benjamin D Solomon
- Division of Medical Genomics, Inova Translational Medicine Institute, 8110 Gatehouse Road, Falls Church, VA, 22042, USA
| | - John E Niederhuber
- Division of Medical Genomics, Inova Translational Medicine Institute, 8110 Gatehouse Road, Falls Church, VA, 22042, USA.,School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Lindsey A Criswell
- Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Lisa F Barcellos
- Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA, 94720-3220, USA. .,California Institute for Quantitative Biosciences (QB3), University of California Berkeley, 174 Stanley Hall, Berkeley, CA, 94720-3220, USA.
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31
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Shree R, Harrington WE, Kanaan SB, Forsyth A, Cousin E, Lopez A, Nelson JL, Gammill HS. Fetal microchimerism by mode of delivery: a prospective cohort study. BJOG 2019; 126:24-31. [PMID: 30102819 PMCID: PMC6294652 DOI: 10.1111/1471-0528.15432] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2018] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To compare fetal microchimerism (FMc) in pregnancies with uncomplicated vaginal delivery (VD) versus caesarean delivery (CD). DESIGN Prospective cohort study. SETTING University of Washington and Fred Hutchinson Cancer Research Center, USA. POPULATION Women delivering singleton pregnancies without pertinent antenatal complications with uncomplicated deliveries (n = 36). METHODS We collected maternal predelivery, postdelivery and umbilical cord blood for each mother-baby pair. Following maternal and fetal genotyping, FMc was measured with quantitative polymerase chain reaction assays targeting fetus-specific polymorphisms. Quantification of FMc is expressed as genome equivalents (gEq) of fetal DNA/100 000 total gEq tested. FMc detection was evaluated by logistic regression while controlling for total number of cell equivalents tested and clinically relevant covariates. FMc concentrations were compared using negative binomial regression while controlling for the same covariates and predelivery FMc positivity. MAIN OUTCOME MEASURE Detection and concentration of FMc by mode of delivery. RESULTS Twenty-four mother-baby pairs had a VD and 12 had a CD. Postdelivery FMc detection was higher following CD than after VD (58.3% versus 16.7%, P = 0.02). After controlling for covariates, the likelihood of postdelivery FMc detection was almost nine-fold higher after CD than VD (odds ratio 8.8, 95% CI 1.6-47.6; P = 0.01). With respect to postdelivery FMc concentration, the detection rate ratio for CD versus VD in the adjusted negative binomial regression model was 14.7 (95% CI 3.2-66.8; P = 0.001). CONCLUSION Postdelivery peripheral FMc detection and concentration are significantly higher after CD than after VD. As FMc is associated with long-term maternal health, our findings suggest that the mode of delivery may impact this risk. TWEETABLE ABSTRACT Greater fetal microchimerism found in maternal blood following caesarean delivery compared with vaginal delivery.
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Affiliation(s)
- R Shree
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
| | - W E Harrington
- Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
| | - S B Kanaan
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - A Forsyth
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - E Cousin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - A Lopez
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
| | - J L Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - H S Gammill
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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32
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Gerussi A, Cristoferi L, Carbone M, Asselta R, Invernizzi P. The immunobiology of female predominance in primary biliary cholangitis. J Autoimmun 2018; 95:124-132. [DOI: 10.1016/j.jaut.2018.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022]
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34
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Aydın MŞ, Yiğit EN, Vatandaşlar E, Erdoğan E, Öztürk G. Transfer and Integration of Breast Milk Stem Cells to the Brain of Suckling Pups. Sci Rep 2018; 8:14289. [PMID: 30250150 PMCID: PMC6155265 DOI: 10.1038/s41598-018-32715-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 09/12/2018] [Indexed: 01/19/2023] Open
Abstract
Beside its unique nutritional content breast milk also contains live cells from the mother. Fate of these cells in the offspring has not been adequately described. In this study, we aimed to detect and identify maternal cells in the suckling’s blood and the brain. Green fluorescent protein expressing transgenic female mice (GFP+) were used as foster mothers to breastfeed wildtype newborn pups. One week and two months after the birth, blood samples and brains of the sucklings were analyzed to detect presence of GFP+ cells by fluorescence activated cell sorting, polymerase chain reaction and immunohistochemistry on the brain sections and optically cleared brains. The tests confirmed that maternal cells were detectable in the blood and the brain of the pups and that they differentiated into both neuronal and glial cell types in the brain. This phenomenon represents breastfeeding – induced microchimerism in the brain with functional implications remain to be understood.
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Affiliation(s)
- Mehmet Şerif Aydın
- Regenerative and Restorative Medicine Research Center, Istanbul Medipol University, Istanbul, 34810, Turkey
| | - Esra Nur Yiğit
- Regenerative and Restorative Medicine Research Center, Istanbul Medipol University, Istanbul, 34810, Turkey
| | - Emre Vatandaşlar
- Regenerative and Restorative Medicine Research Center, Istanbul Medipol University, Istanbul, 34810, Turkey
| | - Ender Erdoğan
- Department of Histology and Embryology, Faculty of Medicine, Selcuk University, Konya, 42030, Turkey
| | - Gürkan Öztürk
- Regenerative and Restorative Medicine Research Center, Istanbul Medipol University, Istanbul, 34810, Turkey. .,Department of Physiology, International School of Medicine, Istanbul Medipol University, Istanbul, 34810, Turkey.
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35
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Taneja V. Sex Hormones Determine Immune Response. Front Immunol 2018; 9:1931. [PMID: 30210492 PMCID: PMC6119719 DOI: 10.3389/fimmu.2018.01931] [Citation(s) in RCA: 367] [Impact Index Per Article: 52.4] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 08/06/2018] [Indexed: 12/19/2022] Open
Affiliation(s)
- Veena Taneja
- Department of Immunology and Rheumatology, Mayo Clinic, Rochester, MN, United States
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36
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Di Cristofaro J, Karlmark KR, Kanaan SB, Azzouz DF, El Haddad M, Hubert L, Farge-Bancel D, Granel B, Harlé JR, Hachulla E, Pardoux E, Roudier J, Picard C, Lambert NC. Soluble HLA-G Expression Inversely Correlates With Fetal Microchimerism Levels in Peripheral Blood From Women With Scleroderma. Front Immunol 2018; 9:1685. [PMID: 30158921 PMCID: PMC6104483 DOI: 10.3389/fimmu.2018.01685] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 07/09/2018] [Indexed: 01/22/2023] Open
Abstract
Women with scleroderma (SSc) maintain significantly higher quantities of persisting fetal microchimerism (FMc) from complete or incomplete pregnancies in their peripheral blood compared to healthy women. The non-classical class-I human leukocyte antigen (HLA) molecule HLA-G plays a pivotal role for the implantation and maintenance of pregnancy and has often been investigated in offspring from women with pregnancy complications. However data show that maternal HLA-G polymorphisms as well as maternal soluble HLA-G (sHLA-G) expression could influence pregnancy outcome. Here, we aimed to investigate the underlying role of maternal sHLA-G expression and HLA-G polymorphisms on the persistence of FMc. We measured sHLA-G levels by enzyme linked immunosorbent assay in plasma samples from 88 healthy women and 74 women with SSc. Male Mc was quantified by DYS14 real-time PCR in blood samples from 58 women who had previously given birth to at least one male child. Furthermore, eight HLA-G 5'URR/3'UTR polymorphisms, previously described as influencing HLA-G expression, were performed on DNA samples from 96 healthy women and 106 women with SSc. Peripheral sHLA-G was at lower concentration in plasma from SSc (76.2 ± 48.3 IU/mL) compared to healthy women (117.5 ± 60.1 IU/mL, p < 0.0001), independently of clinical subtypes, autoantibody profiles, disease duration, or treatments. Moreover, sHLA-G levels were inversely correlated to FMc quantities (Spearman correlation, p < 0.01). Finally, women with SSc had lower sHLA-G independently of the eight HLA-G 5'URR/3'UTR polymorphisms, although they were statistically more often homozygous than heterozygous for HLA-G polymorphism genotypes -716 (G/T), -201 (G/A), 14 bp (ins/del), and +3,142 (G/A) than healthy women. In conclusion, women with SSc display less sHLA-G expression independently of the eight HLA-G polymorphisms tested. This decreased production correlates with higher quantities of persisting FMc commonly observed in blood from SSc women. These results shed some lights on the contribution of the maternal HLA-G protein to long-term persistent fetal Mc and initiate new perspectives in this field.
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Affiliation(s)
- Julie Di Cristofaro
- Aix Marseille Univ, CNRS, EFS, ADES, "Biologie des Groupes Sanguins", Marseille, France
| | - Karlin R Karlmark
- Aix Marseille Univ, INSERM, Autoimmune Arthritis (AA), Marseille, France
| | - Sami B Kanaan
- Aix Marseille Univ, INSERM, Autoimmune Arthritis (AA), Marseille, France
| | - Doua F Azzouz
- Aix Marseille Univ, INSERM, Autoimmune Arthritis (AA), Marseille, France
| | - Marina El Haddad
- Aix Marseille Univ, INSERM, Autoimmune Arthritis (AA), Marseille, France
| | - Lucas Hubert
- Immunogenetics Laboratory, EFS-Alpes Méditerranée, Marseille, France.,Antibody Therapeutics and Immunotargeting, CRCM, INSERM U1068, Institut Paoli Calmettes, Aix-Marseille Université, Marseille, France.,UM 105, CNRS UMR7258, Marseille, France
| | - Dominique Farge-Bancel
- Unité de Médecine Interne Maladies Auto-immunes et Pathologie Vasculaire (UF 04) Hôpital Saint Louis, AP-HP, Centre de Référence des Maladies auto-immunes systémiques Rares d'Île-de-France, FAI2R, EA 3518, Institut Universitaire d'Hématologie, Paris, France
| | - Brigitte Granel
- UMR-S 1076 Endothélium, Pathologies Vasculaires et Cibles Thérapeutiques - Faculté de Pharmacie, Marseille, France.,AP-HM, Pôle de Médecine Interne, Centre de Compétence PACA Ouest pour la prise en charge des maladies autoimmunes systémiques, Marseille, France
| | - Jean Robert Harlé
- AP-HM, Pôle de Médecine Interne, Centre de Compétence PACA Ouest pour la prise en charge des maladies autoimmunes systémiques, Marseille, France
| | - Eric Hachulla
- Service de Médecine Interne, Centre National de Référence de la Sclérodermie Systémique, Hôpital Claude Huriez, Lille, France
| | - Etienne Pardoux
- Aix Marseille Univ, CNRS, Centrale Marseille, I2M, Marseille, France
| | - Jean Roudier
- Aix Marseille Univ, INSERM, Autoimmune Arthritis (AA), Marseille, France.,Rhumatologie, IML, AP-HM, Hôpital Sainte Marguerite, Marseille, France
| | - Christophe Picard
- Aix Marseille Univ, CNRS, EFS, ADES, "Biologie des Groupes Sanguins", Marseille, France.,Immunogenetics Laboratory, EFS-Alpes Méditerranée, Marseille, France
| | - Nathalie C Lambert
- Aix Marseille Univ, INSERM, Autoimmune Arthritis (AA), Marseille, France
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Ståhlberg A, El-Heliebi A, Sedlmayr P, Kroneis T. Unravelling the biological secrets of microchimerism by single-cell analysis. Brief Funct Genomics 2018; 17:255-264. [PMID: 29028900 PMCID: PMC6063264 DOI: 10.1093/bfgp/elx027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The presence of microchimeric cells is known for >100 years and well documented since decades. Earlier, microchimeric cells were mainly used for cell-based non-invasive prenatal diagnostics during early pregnancy. Microchimeric cells are also present beyond delivery and are associated to various autoimmune diseases, tissue repair, cancer and immune tolerance. All these findings were based on low complexity studies and occasionally accompanied by artefacts not allowing the biological functions of microchimerism to be determined. However, with the recent developments in single-cell analysis, new means to identify and characterize microchimeric cells are available. Cell labelling techniques in combination with single-cell analysis provide a new toolbox to decipher the biology of microchimeric cells at molecular and cellular level. In this review, we discuss how recent developments in single-cell analysis can be applied to determine the role and function of microchimeric cells.
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Affiliation(s)
- Anders Ståhlberg
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 1F, Gothenburg, Sweden
| | - Amin El-Heliebi
- Institute of Cell Biology, Histology & Embryology, Medical University of Graz, Harrachgasse 21, Graz, Austria
| | - Peter Sedlmayr
- Institute of Cell Biology, Histology & Embryology, Medical University of Graz, Harrachgasse 21, Graz, Austria
| | - Thomas Kroneis
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 1F, Gothenburg, Sweden
- Institute of Cell Biology, Histology & Embryology, Medical University of Graz, Harrachgasse 21, Graz, Austria
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38
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Abstract
Maternal microchimerism may arise in the offspring during pregnancy, and may be favorable or unfavorable. Additionally, maternal cells present in umbilical cord blood used for stem cell transplantation may affect the outcome after transplantation. The aim of this study was to evaluate the cellular subset and frequency of maternal cells in umbilical cord blood following vaginal deliveries and elective Cesarean sections where the umbilical cord clamping time was measured. A total of 44 healthy women with normal pregnancies were included in the study. Of these, 24 delivered vaginally and 20 by elective Cesarean sections. In the fresh umbilical cord blood, cellular subsets of CD3+ (T-cells), CD19+ (B-cells), CD33+ (myeloid cells), CD34+ (hematopoietic progenitor cells) and CD56+ (natural killer cells) cells were isolated and DNA extracted. A single-nucleotide polymorphism unique to the mother was identified and maternal microchimerism in the different cellular fractions was detected using quantitative real-time polymerase chain reaction with a sensitivity of 0.01%. Overall, 5 out of the 44 (11%) umbilical cord blood samples contained maternal microchimerism. The positive fractions were total DNA (whole blood, n = 3), CD34+ (n = 1), CD56+ (n = 1) and CD34+/CD56+ (n = 1). Overall, four of the five (80%) positive samples were from Cesarean sections and one was from a vaginal delivery. The conclusion from this study is that maternal microchimerism in umbilical cord blood is not a common phenomenon but includes both lymphoid and hematopoietic progenitor lineages.
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Affiliation(s)
- Anna Maria Jonsson Kanold
- Division of Obstetrics and Gynecology, Department of Clinical
Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Westgren
- Division of Obstetrics and Gynecology, Department of Clinical
Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Division of Obstetrics and Gynecology, Department of Clinical
Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Cecilia Götherström, Division of Obstetrics
and Gynecology, Karolinska Institutet, Department of Clinical Science,
Intervention and Technology, Alfred Nobels Allé 8, SE-141 52 Stockholm, Sweden.
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39
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HSCT-GAVE as a Manifestation of Chronic Graft versus Host Disease: A Case Report and Review of the Existing Literature. Case Rep Transplant 2018; 2018:2376483. [PMID: 29721346 PMCID: PMC5867646 DOI: 10.1155/2018/2376483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 02/05/2018] [Accepted: 02/08/2018] [Indexed: 11/17/2022] Open
Abstract
Gastric antral vascular ectasia or “watermelon stomach” is a significant cause of nonvariceal upper GI bleeding and is characterized by red, tortuous ectatic vessels along longitudinal folds in the gastric antrum. The existing literature links GAVE to patients with cirrhosis, scleroderma, bone marrow transplantation, and chronic renal failure among other associations, but its pathophysiology remains ill-defined. Over 30 cases of hematopoietic stem cell transplant-related GAVE (HSCT-GAVE) have been reported in the literature to date and there are likely many more that go undiagnosed or are attributed to another cause of upper gastrointestinal bleeding. Interestingly, a busulfan-containing conditioning regimen has been the primary factor implicated in the etiology of HSCT-GAVE because this was common to all cases in the literature to date. Here, we present the first case of HSCT-GAVE in a patient that was treated with a non-busulfan-containing conditioning regimen. We propose a link between chronic GVHD and the development of HSCT-GAVE that is supported by a similar development of GAVE in patients with systemic sclerosis.
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40
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Kamper-Jørgensen M, Gammill HS, Nelson JL. Preeclampsia and scleroderma: a prospective nationwide analysis. Acta Obstet Gynecol Scand 2018; 97:587-590. [PMID: 29344946 DOI: 10.1111/aogs.13296] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 01/10/2018] [Indexed: 12/31/2022]
Abstract
INTRODUCTION In a preliminary case-control study, women with scleroderma more frequently reported having had hypertensive complications during pregnancy compared with healthy women. MATERIAL AND METHODS To prospectively investigate this possible association, we conducted a nation-wide cohort analysis of a major hypertensive complication during pregnancy, namely preeclampsia, and later scleroderma. Analyses were based on Danish register-based birth and hospital contact data on preeclampsia and scleroderma. We followed 778,758 women from time of giving birth between 1978 and 2010 to end of follow-up, emigration, death, or scleroderma diagnosis, whichever occurred first. The association was evaluated by incidence rate ratios, obtained in Poisson regression models. RESULTS We report that preeclampsia is associated with a 69% significantly increased risk of later developing scleroderma. CONCLUSIONS Though these findings do not impact clinical care directly, the association of preeclampsia with scleroderma underscores the significant relation of preeclampsia and other adverse pregnancy outcomes with later disease in women and should be included in patient counseling and education.
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Affiliation(s)
| | - Hilary S Gammill
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - J Lee Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, Rheumatology, University of Washington, Seattle, WA, USA
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41
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42
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Zhong JF, Weiner LP. Role of Fetal Stem Cells in Maternal Tissue Regeneration. GENE REGULATION AND SYSTEMS BIOLOGY 2017. [DOI: 10.1177/117762500700100011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Microchimerism refers to the status of harboring cells from another individual at low levels. It is well known that cells traffic bidirectionally between fetus and mother during pregnancy. This situation resembles a naturally occurring long lasting fetal stem cell transplantation. The fetus acts as the donor and the mother acts as the recipient. To study the role of microchimerism in tissue regeneration, we constructed a murine microchimerism model with wild type C57BL/6J female mice carrying progenies which expressed green fluorescent proteins (GFP). Our data indicated that skin injuries in the female mice during pregnancy increased microchimerism of GFP expressing cells from the GFP transgenic progenies. The GFP positive cells also appeared at the site of spinal cord where injury occurred during pregnancy. Our study suggests that the amount of fetal cells in maternal mice significantly increased if injuries occurred during pregnancy. Fetal stem cells appear to respond to maternal injury signals and may play a role in maternal tissue regeneration during pregnancy.
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Affiliation(s)
- Jiang F. Zhong
- The Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, U.S.A
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, U.S.A
| | - Leslie P. Weiner
- The Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, U.S.A
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43
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Abstract
As chimeras transform from beasts of Greek mythology into tools of contemporary bioscience, secrets of developmental biology and evolutionary divergence are being revealed. Recent advances in stem cell biology and interspecies chimerism have generated new models with extensive basic and translational applications, including generation of transplantable, patient-specific organs.
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Affiliation(s)
- Fabian Suchy
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
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44
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Gammill HS, Harrington WE. Microchimerism: Defining and redefining the prepregnancy context - A review. Placenta 2017; 60:130-133. [PMID: 28911790 DOI: 10.1016/j.placenta.2017.08.071] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/27/2017] [Accepted: 08/29/2017] [Indexed: 12/14/2022]
Abstract
Bidirectional transplacental exchange characterizes human pregnancy. Cells exchanged between mother and fetus can durably persist as microchimerism and may have both short- and long-term consequences for the recipient. The amount, type, and persistence of microchimerism are influenced by obstetric characteristics, pregnancy complications, exposures to infection, and other factors. A reproductive-aged woman enters pregnancy harboring previously acquired microchimeric "grafts," which may influence her preconception health and her subsequent pregnancy outcomes. Many questions remain to be answered about microchimerism with broad-ranging implications. This review will summarize key aspects of this field of research and propose important questions to be addressed moving forward.
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Affiliation(s)
- H S Gammill
- Department of Obstetrics and Gynecology, University of Washington, United States; Clinical Research Division, Fred Hutchinson Cancer Research Center, United States.
| | - W E Harrington
- Department of Pediatrics, University of Washington and Seattle Children's Hospital, United States
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45
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Bloch EM, Reed WF, Lee TH, Montalvo L, Shiboski S, Custer B, Barcellos LF. Male microchimerism in peripheral blood leukocytes from women with multiple sclerosis. CHIMERISM 2017; 2:6-10. [PMID: 21547029 DOI: 10.4161/chim.2.1.15151] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Revised: 02/08/2011] [Accepted: 02/14/2011] [Indexed: 11/19/2022]
Abstract
BACKGROUND Fetal microchimerism (F-MC), the persistence of fetal cells in the mother, is frequently encountered following pregnancy. The high prevalence of F-MC in autoimmune disease prompts consideration of the role for immune tolerance and regulation. This study examines the association between F-MC and multiple sclerosis (MS), an autoimmune disorder, of undetermined etiology. RESULTS 21 out of 51 MS-positive subjects (41%) were classified as positive for F-MC; 4 of 22 (18%) of MS-negative sibling controls, were also positive for MC (p = 0.066). Unanticipated F-MC in controls lead to re-evaluation using 30 female singleton cord blood units (CBUs) as a biological control. Four CBUs were low-level positive. STUDY DESIGN AND METHODS Seventy-three female subjects were assigned to three groups according to disease status and pregnancy history: (1) MS positive (+) women with a history of one male pregnancy before symptom onset (n = 27); (2) MS negative (-) female siblings of MS(+) women with a history of one male pregnancy (n = 22); and (3) MS(+) women that reported never having been pregnant (n = 24). Ten micrograms of genomic DNA obtained from peripheral blood leukocytes of each subject were analyzed for F-MC using allele-specific real-time PCR targeting the SR-Y sequence on the Y-chromosome. MC classification was dichotomous (positive vs. negative) based on PCR results. CONCLUSION The association between F-MC and MS warrants further study to define this relationship. F-MC in women self-reporting as nulligravid, supports previous findings that a significant proportion of pregnancies go undetected. This lead to re-validation of a Y-chromosome based assay for F-MC detection.
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Affiliation(s)
- Evan M Bloch
- International Research and Training; Blood Systems Research Institute (BSRI); San Francisco, CA, USA
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46
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Sunku CC, Gadi VK, de Laval de Lacoste B, Guthrie KA, Nelson JL. Maternal and fetal microchimerism in granulocytes. CHIMERISM 2017; 1:11-4. [PMID: 21327147 DOI: 10.4161/chim.1.1.13098] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Revised: 07/19/2010] [Accepted: 07/21/2010] [Indexed: 12/25/2022]
Abstract
Cell trafficking during pregnancy may result in durable microchimerism, both fetal microchimerism in the mother and maternal microchimerism in her children. Whether microchimerism is continuously replenished has not been well-described. To address this question, we isolated granulocytes, cells with relatively short half-lives, from peripheral blood of healthy women. CD66b-positive cells were isolated by fluorescence activated cell sorting and a panel of polymorphism-specific quantitative pCR assays was employed to investigate fetal and maternal microchimerism. Overall 33% (10/30) of study subjects had at least one source of microchimerism in CD66b(+) cells. Interestingly, maternal microchimerism was more common than fetal microchimerism, 40% vs. 15%, respectively (p = 0.05) and was present at higher levels (p = 0.03). The identification of maternal and fetal origin CD66b(+) cells is strong evidence for an active microchimeric hematopoietic stem and progenitor cell niche. Furthermore, microchimeric CD66b(+) cells could have an impact on innate and adaptive immune responses.
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47
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de Bellefon LM, Heiman P, Kanaan SB, Azzouz DF, Rak JM, Martin M, Roudier J, Roufosse F, Lambert NC. Cells from a vanished twin as a source of microchimerism 40 years later. CHIMERISM 2017; 1:56-60. [PMID: 21327048 DOI: 10.4161/chim.1.2.14294] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Revised: 11/22/2010] [Accepted: 11/29/2010] [Indexed: 11/19/2022]
Abstract
We report the case of a 40-year-old man diagnosed with a scleroderma-like disease. Clinical similarities with graft versus host disease prompted initial testing for chimerism employing fluorescence in situ hybridization (FISH). Female cells were observed within peripheral blood mononuclear cells from the patient.Because maternal cells have been detected in healthy immunologically competent adults and patients with autoimmune conditions, we hypothesized that these cells were of maternal origin. Contrary to our expectations, HLA-specific quantitative PCR (QPCR) ruled out maternal microchimerism. However, HLA-specific QPCR testing was positive for the paternal HLA haplotype that the patient did not inherit. We reasoned that the most likely origin of chimerism with non-inherited paternal HLA alleles was from an unrecognized "vanished" twin. The patient had never received a blood transfusion.This report suggests that cells from a vanished twin are a possible source of chimerism. The frequency of chimerism from this source is not yet known and whether the scleroderma-like disease observed in the patient is anecdotal or implies a potential association with autoimmune disease remains to be elucidated.
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48
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Soulaidopoulos S, Triantafyllidou E, Garyfallos A, Kitas GD, Dimitroulas T. The role of nailfold capillaroscopy in the assessment of internal organ involvement in systemic sclerosis: A critical review. Autoimmun Rev 2017; 16:787-795. [DOI: 10.1016/j.autrev.2017.05.019] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 05/01/2017] [Indexed: 10/19/2022]
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49
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Kinder JM, Stelzer IA, Arck PC, Way SS. Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol 2017; 17:483-494. [PMID: 28480895 PMCID: PMC5532073 DOI: 10.1038/nri.2017.38] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immunological identity is traditionally defined by genetically encoded antigens, with equal maternal and paternal contributions as a result of Mendelian inheritance. However, vertically transferred maternal cells also persist in individuals at very low levels throughout postnatal development. Reciprocally, mothers are seeded during pregnancy with genetically foreign fetal cells that persist long after parturition. Recent findings suggest that these microchimeric cells expressing non-inherited, familially relevant antigenic traits are not accidental 'souvenirs' of pregnancy, but are purposefully retained within mothers and their offspring to promote genetic fitness by improving the outcome of future pregnancies. In this Review, we discuss the immunological implications, benefits and potential consequences of individuals being constitutively chimeric with a biologically active 'microchiome' of genetically foreign cells.
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Affiliation(s)
- Jeremy M. Kinder
- Division of Infectious Disease and Perinatal Institute, Cincinnati Children’s Hospital. Cincinnati, Ohio 45229 USA
| | - Ina A. Stelzer
- Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Prenatal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Petra C. Arck
- Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Prenatal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Sing Sing Way
- Division of Infectious Disease and Perinatal Institute, Cincinnati Children’s Hospital. Cincinnati, Ohio 45229 USA
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50
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Kanaan SB, Gammill HS, Harrington WE, De Rosa SC, Stevenson PA, Forsyth AM, Allen J, Cousin E, van Besien K, Delaney CS, Nelson JL. Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant. Oncoimmunology 2017. [PMID: 28638735 DOI: 10.1080/2162402x.2017.1311436] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Among reported advantages of umbilical cord blood (CB) in transplantation is lower leukemia relapse probability. Underlying cellular mechanisms of graft-vs.-leukemia (GVL) are thought to include a prominent role for T cells. Cells of the CB's mother, maternal microchimerism (MMc), were recently strongly, but indirectly, implicated in this GVL benefit. We assayed MMc directly and hypothesized benefit accrues from CB maternal T cells. MMc was quantified in 51 CBs and, within memory T, naïve T, B, NK cells, and monocytes in 27 CBs. Polymorphism-specific quantitative-PCR assays targeted maternal genotypes non-shared with CBs. Overall MMc was common and often at substantial levels. It was present in 52.9% of CB and in 33.3-55.6% of tested subsets. Remarkably, MMc quantities were greater in memory T cells than other subsets (p < 0.001). Expressed as genome equivalents (gEq) per 105 total gEq tested (gEq/105), memory T cell MMc averaged 850.2 gEq/105, while other subset mean quantities were 13.8-30.1 gEq/105. After adjustment for proportionality in CB, MMc remained 6-17 times greater in memory T, and 3-9 times greater in naïve T, vs. non-T-cell subsets. Further, CB-origin MMc was detected in vivo in a patient up to 6 mo post-transplantation, including among T cells. Overall, results revealed levels and phenotypes of CB MMc with potential relevance to CB transplantation and, more broadly, to offspring health.
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Affiliation(s)
- Sami B Kanaan
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hilary S Gammill
- Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
| | | | - Stephen C De Rosa
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Philip A Stevenson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Alexandra M Forsyth
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Judy Allen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Emma Cousin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Koen van Besien
- Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Colleen S Delaney
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
| | - J Lee Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
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