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Upregulation of HLA-Class I and II in Placentas Diagnosed with Villitis of Unknown Etiology

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Abstract

The placenta utilizes many mechanisms to protect the haploidentical fetus from recognition by the maternal immune system. However, in cases of villitis of unknown etiology (VUE), maternal lymphocytes gain access into the placenta, causing significant health risks for the fetus. Evidence suggests that VUE is a rejection response between the mother and the haploidentical fetus. Therefore, we profiled human leukocyte antigen (HLA), an important predictor of transplant rejection, in VUE using placental tissue from ten patients with VUE and ten gestational age matched controls. Placentas were stained using novel multiplexed immunofluorescence (MxIF) to investigate morphology and HLA classes I and II. Gene expression was evaluated by microarray, and where available, tissue typing of mother/baby pairs was completed to determine HLA type. MxIF demonstrated strong CD8+ T cell infiltration and HLA class I staining both the distal and stem villi of VUE placentas. Compared to controls, VUE cases had significantly higher expression of HLA class II mRNA and pathway analysis demonstrated that 40% of the differentially expressed genes in VUE are related to tissue rejection. The data suggest that VUE resembles a rejection response between the mother and the fetus. It remains unknown what initiates immune recognition and why some mothers appear to be at higher risk for developing this condition than others. Understanding this etiology will be critical for developing effective interventions or prevention strategies during pregnancy.

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Acknowledgments

The authors would like to acknowledge Wendy Nevala, MS, for her excellent training in the MxIF technique.

Funding

Financial support for this project was provided by Mayo Clinic Division of Anatomic Pathology (SEK) and NICHD K12 HD065987 (EALE).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Elizabeth Ann L. Enninga, Bohdana Fedyshyn & Rodrigo Ruano

  2. Department of Health Science Research, Mayo Clinic, Rochester, MN, USA

    Alexey A. Leontovich

  3. Department of Transfusion Medicine, Mayo Clinic, Rochester, MN, USA

    Laurie Wakefield & Manish Gandhi

  4. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Svetomir N. Markovic

  5. Department of Laboratory Pathology, Mayo Clinic, Rochester, MN, USA

    Sarah E. Kerr

Authors
  1. Elizabeth Ann L. Enninga
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  2. Alexey A. Leontovich
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  3. Bohdana Fedyshyn
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  4. Laurie Wakefield
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  5. Manish Gandhi
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Correspondence to Elizabeth Ann L. Enninga.

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Enninga, E.A.L., Leontovich, A.A., Fedyshyn, B. et al. Upregulation of HLA-Class I and II in Placentas Diagnosed with Villitis of Unknown Etiology. Reprod. Sci. 27, 1129–1138 (2020). https://doi.org/10.1007/s43032-019-00101-9

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  • DOI: https://doi.org/10.1007/s43032-019-00101-9

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