Functional Relevance of CTLA4 Variants: an Upgraded Approach to Assess CTLA4-Dependent Transendocytosis by Flow Cytometry.

التفاصيل البيبلوغرافية
العنوان:	Functional Relevance of CTLA4 Variants: an Upgraded Approach to Assess CTLA4-Dependent Transendocytosis by Flow Cytometry.
المؤلفون:	Rojas-Restrepo J; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany., Sindram E; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany., Zenke S; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Matterhorn Biosciences GmbH, Basel, Switzerland., Haberstroh H; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Mitsuiki N; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Gabrysch A; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Huebscher K; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Posadas-Cantera S; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Krausz M; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany., Kobbe R; Institute for Infection Research and Vaccine Development (IIRVD), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany., Rohr JC; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Novartis Institutes for Biomedical Research (NIBR), Novartis Pharma AG, Basel, Switzerland., Grimbacher B; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.; Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.; German Center for Infection Research (DZIF), Satellite Center Freiburg, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.; CIBSS - Center for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de., Gámez-Díaz L; Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. laura.gamez@uniklinik-freiburg.de.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. laura.gamez@uniklinik-freiburg.de.
المصدر:	Journal of clinical immunology [J Clin Immunol] 2023 Nov; Vol. 43 (8), pp. 2076-2089. Date of Electronic Publication: 2023 Sep 23.
نوع المنشور:	Journal Article; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: Springer Country of Publication: Netherlands NLM ID: 8102137 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2592 (Electronic) Linking ISSN: 02719142 NLM ISO Abbreviation: J Clin Immunol Subsets: MEDLINE
أسماء مطبوعة:	Publication: Amsterdam : Springer Original Publication: New York : Plenum, c1981-
مواضيع طبية MeSH:	Antigen-Presenting Cells* , Autoimmunity*, Humans ; CTLA-4 Antigen/genetics ; Flow Cytometry ; Reproducibility of Results
مستخلص:	Variants of uncertain significance (VUS) in CTLA4 are frequently identified in patients with antibody deficiency or immune dysregulation syndromes including, but not limited to, patients with multi-organ autoimmunity and autoinflammation. However, to ascertain the diagnosis of CTLA4 insufficiency, the functional relevance of each variant needs to be determined. Currently, various assays have been proposed to assess the functionality of CTLA4 VUS, including the analysis of transendocytosis, the biological function of CTLA4 to capture CD80 molecules from antigen presenting cells. Challenges of this assay include weak fluorescence intensity of the internalized ligand, poor reproducibility, and poor performance upon analyzing thawed cells. In addition, the distinction of pathogenic from non-pathogenic variants and from wild-type CTLA4, and the classification of the different VUS according to its level of CTLA4 dysfunction, would be desirable. We developed a novel CD80-expressing cell line for the evaluation of CD80-transendocytosis and compared it to the published transendocytosis assay. Our approach showed lower inter-assay variability and better robustness regardless the type of starting material (fresh or thawed peripheral mononuclear cells). In addition, receiver operating characteristic analysis showed 100% specificity, avoiding false positive results and allowing for a clear distinction between pathogenic and non-pathogenic variants in CTLA4-variant carriers. With our transendocytosis assay, we assessed the pathogenicity of 24 distinct CTLA4 variants from patients submitted to our diagnostic unit. Significantly impaired transendocytosis was demonstrated for 17 CTLA4 variants, whereas seven variants tested normal. In conclusion, our upgraded transendocytosis assay allows a reliable assessment of newly identified variants in CTLA4. (© 2023. The Author(s).)
التعليقات:	Erratum in: J Clin Immunol. 2023 Oct 9;:. (PMID: 37812314)
References:	Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev. 2019;287(1):33–49. https://doi.org/10.1111/imr.12721 . (PMID: 10.1111/imr.1272130565239) Qureshi OS, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3. https://doi.org/10.1126/science.1202947 . (PMID: 10.1126/science.1202947214747133198051) Kuehn HS, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623–7. https://doi.org/10.1126/science.1255904 . (PMID: 10.1126/science.1255904252133774371526) Schubert D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6. https://doi.org/10.1038/nm.3746 . (PMID: 10.1038/nm.3746253293294668597) Schwab C, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932–46. https://doi.org/10.1016/j.jaci.2018.02.055 . (PMID: 10.1016/j.jaci.2018.02.055297299436215742) Egg D, et al. Increased risk for malignancies in 131 affected CTLA4 mutation carriers. Front Immunol. 2018;9:2012. https://doi.org/10.3389/fimmu.2018.02012 . (PMID: 10.3389/fimmu.2018.02012302504676140401) Hou TZ, et al. A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells. J Immunol. 2015;194(5):2148–59. https://doi.org/10.4049/jimmunol.1401876 . (PMID: 10.4049/jimmunol.140187625632005) Hou TZ, et al. Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood. 2017;129(11):1458–68. https://doi.org/10.1182/blood-2016-10-745174 . (PMID: 10.1182/blood-2016-10-745174281597335438243) Egg D, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022;149(2):736–46. https://doi.org/10.1016/j.jaci.2021.04.039 . (PMID: 10.1016/j.jaci.2021.04.03934111452) Sic H, et al. An activating janus kinase-3 mutation is associated with cytotoxic T lymphocyte antigen-4-dependent immune dysregulation syndrome. Front Immunol. 2017;8:1824. https://doi.org/10.3389/fimmu.2017.01824 . (PMID: 10.3389/fimmu.2017.01824293755475770691) Catak MC, et al. Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency. Allergy. 2022;77(10):3108–23. https://doi.org/10.1111/all.15331 . (PMID: 10.1111/all.1533135491430) Rojas-Restrepo J, et al. Establishing the molecular diagnoses in a cohort of 291 patients with predominantly antibody deficiency by targeted next-generation sequencing: experience from a monocentric study. Front Immunol. 2021;12:786516. https://doi.org/10.3389/fimmu.2021.786516 . (PMID: 10.3389/fimmu.2021.786516349758788718408) Lo B, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40. https://doi.org/10.1126/science.aaa1663 . (PMID: 10.1126/science.aaa166326206937) Krausz M, et al. The ABACHAI clinical trial protocol: safety and efficacy of abatacept (s.c.) in patients with CTLA-4 insufficiency or LRBA deficiency: a non controlled phase 2 clinical trial. Contemp Clin Trials Commun. 2022;30:101008. https://doi.org/10.1016/j.conctc.2022.101008 . (PMID: 10.1016/j.conctc.2022.101008362628019573884) Collins AV, et al. The interaction properties of costimulatory molecules revisited. Immunity. 2002;17(2):201–10. https://doi.org/10.1016/s1074-7613(02)00362-x . (PMID: 10.1016/s1074-7613(02)00362-x12196291) Sansom DM. IMMUNOLOGY. Moving CTLA-4 from the trash to recycling. Science. 2015;349(6246):377–8. https://doi.org/10.1126/science.aac7888 . (PMID: 10.1126/science.aac788826206917) Shinoda H, Shannon M, Nagai T. Fluorescent proteins for investigating biological events in acidic environments. Int J Mol Sci. 2018;19(6) https://doi.org/10.3390/ijms19061548 . Kennedy A, et al. Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nat Immunol. 2022;23(9):1365–78. https://doi.org/10.1038/s41590-022-01289-w . (PMID: 10.1038/s41590-022-01289-w359993949477731) Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol. 2006;24:65–97. https://doi.org/10.1146/annurev.immunol.24.021605.090535 . (PMID: 10.1146/annurev.immunol.24.021605.09053516551244) Gamez-Diaz L, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223–30. https://doi.org/10.1016/j.jaci.2015.09.025 . (PMID: 10.1016/j.jaci.2015.09.02526768763) Lorenzini T, et al. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J Allergy Clin Immunol. 2020;146(4):901–11. https://doi.org/10.1016/j.jaci.2019.11.051 . (PMID: 10.1016/j.jaci.2019.11.051322787908246418) Bergbreiter A, et al. Recurrent necrotizing cellulitis, multi-organ autoimmune disease and humoral immunodeficiency due to a novel NFKB1 frameshift mutation. Eur J Med Genet. 2021;64(3):104144. https://doi.org/10.1016/j.ejmg.2021.104144 . (PMID: 10.1016/j.ejmg.2021.10414433486103)
فهرسة مساهمة:	Keywords: CTLA4; LRBA; diagnostics; inborn errors of immunity; transendocytosis
المشرفين على المادة:	0 (CTLA-4 Antigen) 0 (CTLA4 protein, human)
تواريخ الأحداث:	Date Created: 20230922 Date Completed: 20231121 Latest Revision: 20240221
رمز التحديث:	20240221
مُعرف محوري في PubMed:	PMC10661720
DOI:	10.1007/s10875-023-01582-9
PMID:	37740092
قاعدة البيانات:	MEDLINE

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تدمد:	1573-2592
DOI:	10.1007/s10875-023-01582-9