The effects of somatic HLA class I allele mutations on antigen presentation in acquired aplastic anemia

体细胞 HLA I 类等位基因突变对获得性再生障碍性贫血抗原呈递的影响

• 批准号: 10545024
• 负责人: Daria Babushok
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545024
• 关键词: Address; Affect; Alleles; Amino Acid Substitution; Amino Acids; Antigen Presentation; Aplastic Anemia; Autoantigens; Autoimmune; Autoimmunity; Award; Binding; Bone Marrow; Bone marrow failure; Cell Line; Cell surface; Cells; Cellular Assay; Characteristics; Complex; Data; Development; Disease; Endoplasmic Reticulum; Foundations; Future; HLA Antigens; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Histocompatibility Antigens Class I; Immune; Immunologics; Immunoprecipitation; Individual; Induced Mutation; Life; Loss of Heterozygosity; Mediating; Missense Mutation; Molecular; Mutate; Mutation; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Property; Proteins; Proteomics; Recurrence; Role; Somatic Mutation; Surface; Surface Antigens; T-Lymphocyte; Therapeutic immunosuppression; Work; antigen processing; autoimmune pathogenesis; candidate validation; cohort; cytopenia; effective therapy; mutant; peptide I; prevent; protein folding; protein structure; rational design; risk variant; tapasin; therapy design; therapy development

PROJECT SUMMARY The aim of this proposal is to explore the functional significance of somatic mutations in peptide-binding domains of Human Leukocyte Antigen (HLA) class I alleles in surviving hematopoietic cells of patients with acquired aplastic anemia (AA). AA is an autoimmune bone marrow aplasia that occurs in previously healthy individuals causing life-threatening cytopenias. Multiple lines of evidence, most notably the efficacy of T-cell directed immu- nosuppressive therapy in AA, implicate T lymphocytes in autoimmune destruction of hematopoietic stem and progenitor cells (HSPCs) in AA. Despite some progress, AA patients’ outcomes remain poor, and there is a critical need to develop more effective therapies for AA. The main barrier to progress has been the poor under- standing of specific mechanisms of autoimmunity in AA. Neither the antigenic target nor the causes of autoim- munity have been identified. Understanding the immune pathogenesis of AA is essential for developing therapies that can more effectively treat AA and prevent its complications. In previous studies of acquired mutations in AA, we identified recurrent mutations in HLA class I alleles in surviving hematopoietic cells of AA patients. The en- hanced survival of HLA class I-mutant cells underscored the critical role of HLA class I in mediating the autoim- mune recognition of HSPCs in AA. HLA alleles disrupted by somatic mutations are thought to be responsible for autoantigen presentation in the affected patients (function as “risk alleles”). Their somatic inactivation allows mutant HSPCs to evade the autoimmune attack. While 80% of the identified mutations led to the loss of mutant HLA alleles’ expression, 20% of mutations were predicted to form a functional HLA protein. Notably, eight muta- tions were amino acid changes located in the alpha (α)-1 and α-2 domains of the HLA peptide-binding pocket, which could be especially informative about residues critical for AA autoantigen binding. These data support our central hypothesis that autoimmune attack in AA is directed against AA autoantigen(s) presented by specific HLA class I alleles, and somatic HLA mutations can disrupt autoantigen presentation in AA by abrogating HLA risk allele expression or its autoantigen binding. To address our hypothesis, we will evaluate the functional con- sequences of mutations in peptide-binding domains of HLA alleles in AA patients in two integrated aims. Aim 1 will use cellular assays to determine the effects of HLA missense mutations on HLA processing and surface stability. Aim 2 will use proteomics to define the HLA class I immunopeptidome of cells expressing wild-type and mutant HLA alleles. Our results will define structural features of AA HLA risk alleles necessary for autoanti- gen binding, forming the foundation for future studies of candidate AA autoantigens. AA is a devastating disease, yet its underlying immunological mechanisms remain unknown. Our studies will fill this critical need, opening the door to future in-depth mechanistic studies and the future development of more effective, rationally-designed therapies for AA.

项目总结

项目成果

Severe aplastic anaemia after serial vaccinations for SARS-CoV-2, pneumococcus and seasonal influenza.

• DOI: 10.1002/jha2.443
• 发表时间: 2022-08
• 期刊: EJHaem
• 作者: Wang, Xiao;Laczko, Dorottya;Caponetti, Gabriel C;Rabatin, Susan;Babushok, Daria V
• 通讯作者: Babushok, Daria V