A Novel Heterozygous Variant in AICDA Impairs Ig Class Switching and Somatic Hypermutation in Human B Cells and is Associated with Autosomal Dominant HIGM2 Syndrome.

Autor: Della Mina E; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia., Jackson KJL; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., Crawford AJI; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., Faulks ML; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia., Pathmanandavel K; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia., Acquarola N; Department of Clinical Immunology and PathWest, Fiona Stanley Hospital, Murdoch, WA, Australia., O'Sullivan M; Department of Clinical Immunology and PathWest, Fiona Stanley Hospital, Murdoch, WA, Australia.; Department of Immunology, Perth Children's Hospital, Perth, WA, Australia., Kerre T; Department of Hematology, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.; Center for Primary Immunodeficiency Ghent (CPIG), Jeffrey Modell Diagnosis and Research Center, ERN Rita Network Center, Ghent University Hospital, Ghent, Belgium., Naesens L; Center for Primary Immunodeficiency Ghent (CPIG), Jeffrey Modell Diagnosis and Research Center, ERN Rita Network Center, Ghent University Hospital, Ghent, Belgium.; Primary Immunodeficiency Research Lab, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Claes K; Center for Primary Immunodeficiency Ghent (CPIG), Jeffrey Modell Diagnosis and Research Center, ERN Rita Network Center, Ghent University Hospital, Ghent, Belgium.; Primary Immunodeficiency Research Lab, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Goodnow CC; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia., Haerynck F; Center for Primary Immunodeficiency Ghent (CPIG), Jeffrey Modell Diagnosis and Research Center, ERN Rita Network Center, Ghent University Hospital, Ghent, Belgium.; Primary Immunodeficiency Research Lab, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Kracker S; Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, 75015, Paris, France.; Université Paris Cité, 75015, Paris, France., Meyts I; Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Louvain, Belgium.; Pediatric Immunodeficiency, Department of Pediatrics, University Hospitals Leuven, Louvain, Belgium., D'Orsogna LJ; Department of Clinical Immunology and PathWest, Fiona Stanley Hospital, Murdoch, WA, Australia.; School of Medicine, University of Western Australia, Nedlands, WA, Australia., Ma CS; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia., Tangye SG; Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia. s.tangye@garvan.org.au.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia. s.tangye@garvan.org.au.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2024 Feb 16; Vol. 44 (3), pp. 66. Date of Electronic Publication: 2024 Feb 16.
DOI: 10.1007/s10875-024-01665-1
Abstrakt: B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders.
(© 2024. The Author(s).)
Databáze: MEDLINE
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