Inhibition of Erythroid Progenitor Cells by Anti-Kell Antibodies in Fetal Alloimmune Anemia

Vaughan, Janet; Maiming, M.; Warwick, Ruth M.; Letsky, Elizabeth A.; Murray, Neil A; Roberts, I

doi:10.1097/00006254-199808000-00006

Cited by 87 publications

(121 citation statements)

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“…99 The mechanisms include suppressing fetal erythropoiesis in the marrow and hemolysis. 100 As to function, the K2 gene encodes a zinc endoproteinase that cleaves big endothelin-1 and -3; K1, which has a point mutation that deletes an N-glycosylation site and likely changes its tertiary structure, is inactive. 26,101 Whether and/or how this might be relevant to the role of endothelin in the pathogenesis of preeclampsia 102 remains to be determined, as does the potential of certain combinations of mismatched KELL antigens to evoke a maternal immune response.…”

Section: Research Implicationsmentioning

confidence: 99%

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Gormley

Ona

Kapidzic

et al. 2017

American Journal of Obstetrics and Gynecology

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BACKGROUND:The maternal signs of preeclampsia, which include the new onset of high blood pressure, can occur because of faulty placentation. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would lend new insights into the role of these cells in preeclampsia pathogenesis. OBJECTIVE: Our goal was to enrich syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts from the placentas of severe preeclampsia cases. Total RNA was subjected to global transcriptional profiling to identify RNAs that were misexpressed compared with controls. STUDY DESIGN: This was a cross-sectional analysis of placentas from women who had been diagnosed with severe preeclampsia. Gestational age-matched controls were placentas from women who had a preterm birth with no signs of infection. Laser microdissection enabled enrichment of syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts. After RNA isolation, a microarray approach was used for global transcriptional profiling. Immunolocalization identified changes in messenger RNA expression that carried over to the protein level. Differential expression of noneprotein-coding RNAs was confirmed by in situ hybridization. A 2-way analysis of variance of non-coding RNA expression identified particular classes that distinguished trophoblasts in cases vs controls. Cajal body foci were visualized by coilin immunolocalization. RESULTS: Comparison of the trophoblast subtype data within each group (severe preeclampsia or noninfected preterm birth) identified many highly differentially expressed genes. They included molecules that are known to be expressed by each subpopulation, which is evidence that the method worked. Genes that were expressed differentially between the 2 groups, in a cell-typeespecific manner, encoded a combination of molecules that previous studies associated with severe preeclampsia and those that were not known to be dysregulated in this pregnancy

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Section: Research Implicationsmentioning

confidence: 99%

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Gormley

Ona

Kapidzic

et al. 2017

American Journal of Obstetrics and Gynecology

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“…Today, KEL alloantibodies are a leading cause of antibody-mediated transfusion and pregnancy-associated morbidity/mortality. 5,[14][15][16][17][18] To our knowledge, no animal model to date has been generated in which pregnancy-associated RBC alloantibodies lead to adverse fetal outcomes. Limited knowledge of the RBC antigen systems of animals, in combination with lack of clinical significance of alloantibodies against these antigens, has contributed to the lack of model development.…”

Section: Introductionmentioning

confidence: 99%

Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model

Stowell

Henry

Smith

et al. 2013

Blood

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• Anti-KEL alloantibodies generated after exposure to paternally derived RBC antigens during pregnancy result in fetal anemia.• This is the first animal model of pregnancy associated HDFN, with transfusion and pregnancy resulting in boostable anti-KEL alloantibodies.Exposure to nonself red blood cell (RBC) antigens, either from transfusion or pregnancy, may result in alloimmunization and incompatible RBC clearance. First described as a pregnancy complication 80 years ago, hemolytic disease of the fetus and newborn (HDFN) is caused by alloimmunization to paternally derived RBC antigens. Despite the morbidity/mortality of HDFN, women at risk for RBC alloimmunization have few therapeutic options. Given that alloantibodies to antigens in the KEL family are among the most clinically significant, we developed a murine model with RBC-specific expression of the human KEL antigen to evaluate the impact of maternal/fetal KEL incompatibility. After exposure to fetal KEL RBCs during successive pregnancies with KEL-positive males, 21 of 21 wild-type female mice developed anti-KEL alloantibodies; intrauterine fetal anemia and/or demise occurred in a subset of KEL-positive pups born to wild type, but not agammaglobulinemic mothers. Similar to previous observations in humans, pregnancy-associated alloantibodies were detrimental in a transfusion setting, and transfusion-associated alloantibodies were detrimental in a pregnancy setting. This is the first pregnancy-associated HDFN model described to date, which will serve as a platform to develop targeted therapies to prevent and/or mitigate the dangers of RBC alloantibodies to fetuses and newborns. (Blood. 2013;122(8):1494-1504

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“…1 Maternal anti-K Abs that cross the placenta during an incompatible pregnancy can suppress fetal erythropoiesis and cause hemolytic disease of the newborn (HDN). 2,3 Unlike the RhD blood group Ag, which was the most frequent blood group targeted in HDN until the advent of effective prophylaxis with anti-D Ab, there are no specific immune-based treatments to prevent or control K alloimmunization in K-negative women. The management of pregnancies affected by anti-K Abs therefore remains unsatisfactory and reliant on invasive procedures such as fetal blood sampling and transfusion.…”

Section: Introductionmentioning

confidence: 99%

Identification, immunomodulatory activity, and immunogenicity of the major helper T-cell epitope on the K blood group antigen

Stephen

Cairns

Pickford

et al. 2012

Blood

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Inhibition of Erythroid Progenitor Cells by Anti-Kell Antibodies in Fetal Alloimmune Anemia

Cited by 87 publications

References 0 publications

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model

Identification, immunomodulatory activity, and immunogenicity of the major helper T-cell epitope on the K blood group antigen

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