Novel pathogenic variants in CTLA4 and LRBA immune dysregulation: Reduced CTLA-4 expression with normal expression of co-stimulatory surface molecules

• Published in: Clinical immunology (Orlando, Fla.) Vol. 280; p. 110565
• Main Authors: Tromp, Samantha A.M., van Leeuwen, Ester M.M., Jansen, Machiel H., Kwakernaak, Arjan J., Bomers, Marije K., Jonkers, René E., van Spaendonk, Resie M.L., Kuijpers, Taco W., de Bree, Godelieve J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2025
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Adult; B-Lymphocytes - immunology; Co-stimulation; Common variable immunodeficiency (CVID); Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; CTLA-4; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; Exome Sequencing; Female; Humans; Inborn error of immunity (IEI); LRBA; Male; Middle Aged; Pedigree; Whole-exome sequencing (WES); Whole-exome sequencing (WES); TCR; Co-stimulation; WES; Common variable immunodeficiency (CVID); Tconv; IMDM; CVID; BSA; Tfh; geoMFI; CTLA-4; PBS; CR2; PMA; LRBA; anti-TPO; Treg; IVIG; CFSE; IEI; Inborn error of immunity (IEI); PBMC; mAb; GLILD; CCV; FCS; HD
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2025.110565

Genetic variants in Cytotoxic T-Lymphocyte-associated protein 4 (CTLA4) and LPS responsive beige-like anchor protein (LRBA), involved in the same biological pathways, are implicated as monogenic causes of Common Variable Immunodeficiency Disorder (CVID). The pitfall in the recognition of CVID possibly related to CTLA-4 haploinsufficiency or LRBA deficiency is a clinical picture that is very heterogeneous. In the present study, we illustrate this challenge by means of clinical and immunological analysis of five patients with novel genetic variants in CTLA4 and LRBA. Whole-exome sequencing (WES) was performed to identify genetic variants in the currently known immune genes in patients. Extensive immunophenotyping, lymphocyte proliferation assays and expression of CTLA-4 and a panel of 17 co-stimulatory molecules, both in rest and upon activation, were performed to gain insight into the impact of the genetic variants on B and T cell phenotype and function. A novel heterozygous variant in CTLA4 (c.457 + 5G > A) was identified in three members of a single family, all presenting with different clinical manifestations. In two additional patients, two genetic variants in LRBA (c.1771 T > C; c.2450-3C > A) were found, of which one is novel as well. The B cell phenotype was naïve with absence of non-switched and switched memory B cells in all patients except of the genetically affected elderly woman without any clinical manifestations. CD4 and CD8 T cell numbers and phenotype were normal. Differentiation of B cells into antibody secreting cells in vitro was reduced, especially in response to T cell-independent stimulation. The T cells showed impaired upregulation of CTLA-4 expression, which was most pronounced in CD4+CD25+FoxP3+ regulatory T cells, which helped to biologically support the genetic diagnosis. The described novel genetic variants in CTLA4 and LRBA show immunological impact and are therefore likely to underly an immune dysregulation syndrome with a highly variable clinical presentation. Apart from the immunophenotypic abnormal findings in activated T cells, the intrinsic B cell defect aids in the interpretation of novel genetic variants in these two genes in the context of a highly suspected clinical presentation. Created in BioRender. van Leeuwen, E. (2025) https://BioRender.com/t4edfpo. [Display omitted] •Novel pathogenic variants in CTLA4 and LRBA identified by WES expand the genetic spectrum associated with CVID.•Clinical heterogeneity ranged from asymptomatic to autoimmunity and recurrent infections, illustrating variable penetrance.•Immunophenotypes included low CTLA-4, absent memory B cells, andpoor B cell proliferation to T cell-independent stimuli.•CTLA-4 expression assays help interpret novel variants and guide precision diagnosis in immune dysregulation syndromes.