Genetic and Immunological Investigation of ABCF1 in Celiac Disease and Autoimmunity

Genetic and Immunological Investigation of ABCF1 in Celiac Disease and Autoimmunity Abstract: Inborn Errors of Immunity are Mendelian disorders caused by rare pathogenic variants in genes with critical immunological functions. Clinically, they manifest as increased susceptibility to infections or autoimmune diseases. Celiac disease (CeD) is a chronic autoimmune disorder triggered by dietary gluten, characterized by increased epithelial lymphocytes and villous atrophy in the small intestine. Familial clustering occurs in approximately 10% of affected individuals, providing an opportunity to identify rare causative variants that contribute to immune dysregulation. In our pilot study, we enrolled 42 families with two or more CeD-affected members to identify potential disease-causing genes. Whole exome sequencing (WES) identified ABCF1 (ATP- binding cassette sub-family F member 1) as a strong candidate. ABCF1 is an essential cytosolic protein with pleiotropic functions, including E2 ubiquitin-conjugating activity and ribosomal regulation. Our preliminary data confirmed an association between rare ABCF1 variants and CeD, as well as inflammatory bowel disease, by integrating data from All of Us and UK Biobank. We demonstrated that peripheral blood mononuclear cells from individuals with a heterozygous loss-of-function ABCF1 mutation exhibit significantly increased baseline expression of interferon-stimulated genes (ISGs). Furthermore, ABCF1 regulates IFN-α induced STAT1 phosphorylation and interacts with key proteins such as RIG-I and TRIM25, which are involved in pathogen- associated molecular pattern (PAMP)-mediated innate immune responses. Additionally, using a conditional Abcf1-deficient mouse model, we observed increased susceptibility to dextran sodium sulfate (DSS)-induced colitis. To further characterize this novel genetic disorder, we will determine how ABCF1 regulates type I IFN production and responses, assess the pathogenicity and domain-specific impacts of naturally occurring ABCF1 mutations, and investigate how ABCF1 deficiency promotes the development of DSS-induced and Il-10⁻/⁻ colitis in Abcf1-deficient mice. These studies will elucidate novel molecular mechanisms underlying JAK-STAT activation and innate immune regulation, paving the way for precision treatments for CeD and other autoimmune diseases. Project Number: 1R01AI189502-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Xiao-Fei Kong | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $661,009 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 KUDS-T (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18950201A1