General autoimmunity

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Immunoediting Through Somatic Loss of Hla Class I Alleles Uncovers the Role of Hla Class I-mediated Autoimmunity in Acquired Aplastic Anemia

Friday, June 16
6:15 PM - 7:30 PM

Acquired aplastic anemia (aAA) is an acquired bone marrow failure syndrome associated with predisposition to myelodysplastic syndrome and leukemia. Although its exact pathogenesis is unknown, aAA is believed to be immune-mediated. Recently, copy number-neutral loss of heterozygosity of chromosome arm 6p (6p CN-LOH), the site of the Major Histocompatibility Complex and Human Leukocyte Antigen (HLA) genes—was identified as a recurrent somatic change in aAA, thought to emerge due to immune escape of cells lacking certain HLA alleles. However, the linkage disequilibrium between HLA loci as well as other genes in the region made it difficult to pinpoint the etiologic driver of acquired 6p CN-LOH. Recently, we identified two aAA patients with somatic loss-of-function mutations in HLA class I genes. This led us to hypothesize that inactivating HLA gene mutations represent another mechanism of immune escape in aAA and may enable a more precise characterization of aAA immune specificity. To screen for HLA mutations, we performed targeted next-generation sequencing of HLA class I genes in 66 aAA patients. Eleven patients (17%) had somatic HLA loss, with recurrent loss-of-function mutations in HLA-A*33:03, HLA-A*68:01, HLA-B*14:02 and HLA-B*40:02 alleles. Patients who inherited these four HLA alleles had a more severe disease course with more clonal complications as assessed by whole exome sequencing (WES), SNP-array genotyping, and metaphase cytogenetics, and were also more likely to develop myelodysplastic syndrome. Our results demonstrate the role of HLA class I-driven autoimmunity in aAA, and establish a novel link between aAA patients' immunogenetics and risk of hematologic malignancies.

Daria Babushok

Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania

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    Jamie Duke

    Children's Hospital of Philadelphia

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      Hongbo Xie

      Children's Hospital of Philadelphia

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        Natasha Stanley

        Children's Hospital of Philadelphia

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          Jamie Atienza

          Children's Hospital of Philadelphia

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            Nieves Perdigones

            Children's Hospital of Philadelphia

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              Peter Nicholas

              Children's Hospital of Philadelphia

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                Deborah Ferriola

                Children's Hospital of Philadelphia

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                  Yimei Li

                  Children's Hospital of Philadelphia

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                    Hugh Huang

                    Children's Hospital of Philadelphia

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                      Wenda Ye

                      Children's Hospital of Philadelphia

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                        Jennifer Morrissette

                        Hospital of University of Pennsylvania

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                          Gregory Podsakoff

                          Children's Hospital of Philadelphia

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                            Laurence Eisenlohr

                            Children's Hospital of Philadelphia

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                              Jaclyn Biegel

                              Children's Hospital of Philadelphia

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                                Stella Chou

                                Children's Hospital of Philadelphia

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                                  Dimitrios Monos

                                  Children's Hospital of Philadelphia

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                                    Monica Bessler

                                    Children's Hospital of Philadelphia

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                                      Timothy Olson

                                      Children's Hospital of Philadelphia

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                                        Immunoediting Through Somatic Loss of Hla Class I Alleles Uncovers the Role of Hla Class I-mediated Autoimmunity in Acquired Aplastic Anemia



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