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The Complexity of Being A20: From Biological Functions to Genetic Associations

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Abstract

A20, encoded by TNFAIP3, is a critical negative regulator of immune activation. A20 is a ubiquitin editing enzyme with multiple domains, each of which mediates or stabilizes a key ubiquitin modification. A20 targets diverse proteins that are involved in pleiotropic immunologic pathways. The complexity of A20-mediated immunomodulation is illustrated by the varied effects of A20 deletion in different cell types and disease models. Clinically, the importance of A20 is highlighted by its extensive associations with human disease. A20 germline variants are associated with a wide range of inflammatory diseases, while somatic mutations promote development of B cell lymphomas. More recently, the discovery of A20 haploinsufficiency (HA20) has provided real world evidence for the role of A20 in immune cell function. Originally described as an autosomal dominant form of Behcet’s disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes.

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Acknowledgements

Figures were prepared with Biorender. The authors would like to thank Natalie Deuitsch for critical revisions to the work.

Funding

There was no research funded in this manuscript. HA20 research at the University of Pittsburgh is funded in part by the Jeffrey Modell Foundation and by the Samuel and Emma Winters Foundation.

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  1. Urekha Karri and Magdalena Harasimowicz contributed equally.

Authors and Affiliations

  1. Departments of Medicine and Immunology, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA, 15213, USA

    Urekha Karri, Magdalena Harasimowicz, Manuel Carpio Tumba & Daniella M. Schwartz

  2. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Urekha Karri

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  1. Urekha Karri
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  2. Magdalena Harasimowicz
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  3. Manuel Carpio Tumba
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  4. Daniella M. Schwartz
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Contributions

UK, MH wrote the main manuscript and prepared figures and tables. MCT generated figures and tables. DMS supervised, edited, and wrote the main manuscript text. All authors reviewed the manuscript.

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Correspondence to Daniella M. Schwartz.

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DMS is a consultant for Sobi Pharmaceuticals and receives research funding from Eli Lilly.

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Karri, U., Harasimowicz, M., Carpio Tumba, M. et al. The Complexity of Being A20: From Biological Functions to Genetic Associations. J Clin Immunol 44, 76 (2024). https://doi.org/10.1007/s10875-024-01681-1

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