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      Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease

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          Abstract

          TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel mutations in TLR7, F507S and L528I. While the L528I substitution arose de novo, the F507S mutation was present in three individuals from the same family, including a severely affected male, notably given that the TLR7 gene is situated on the X chromosome and that all other cases so far described have been female. The observation of mutations at residues 507 and 528 of TLR7 indicates the importance of the TLR7 dimerization interface in maintaining immune homeostasis, where we predict that altered homo-dimerization enhances TLR7 signaling. Finally, while mutations in TLR7 can result in SLE-like disease, our data suggest a broader phenotypic spectrum associated with TLR7 gain-of-function, including significant neurological involvement.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s10875-024-01660-6.

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          The Protein Data Bank.

          The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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            Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication.

            Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased toward nucleolar antigens because of increased expression of TLR7, a single-stranded RNA-binding innate immune receptor. The TLR7 gene is duplicated in Yaa mice because of a 4-Megabase expansion of the pseudoautosomal region. These results reveal high divergence in mouse Y chromosomes and represent a good example of gene copy number qualitatively altering a polygenic disease manifestation.
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              Novel paradigms in systemic lupus erythematosus

              The heterogeneity of systemic lupus erythematosus (SLE), long recognised by clinicians, is now challenging the entire lupus community, from geneticists to clinical investigators. Although the outlook for patients with SLE has greatly improved, many unmet needs remain, chief of which is the development of safer and more efficacious therapies. To develop innovative therapies, a far better understanding of SLE pathogenesis as it relates to the array of clinical phenotypes is needed. Additionally, to efficiently achieve these goals, the lupus community needs to refine existing clinical research tools and better adapt them to overcome the obstacles created by the heterogeneity of manifestations. Here, we review progress towards the ultimate goal of safely reducing disease activity and preventing damage accrual and death. We discuss the new classification criteria from the European League Against Rheumatism and American College of Rheumatology, novel definitions of remission and low lupus disease activity, and new proposals for the histological classification of lupus nephritis. Recommendations for the treatment of SLE and novel approaches to drug development hold much promise to further enhance SLE outcomes.
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                Author and article information

                Contributors
                yanickcrow@mac.com
                Journal
                J Clin Immunol
                J Clin Immunol
                Journal of Clinical Immunology
                Springer US (New York )
                0271-9142
                1573-2592
                7 February 2024
                7 February 2024
                2024
                : 44
                : 2
                : 60
                Affiliations
                [1 ]GRID grid.7429.8, ISNI 0000000121866389, Laboratory of Neurogenetics and NeuroinflammationImagine Institute, , INSERM UMR1163, ; Paris, France
                [2 ]GRID grid.518206.8, ISNI 0000 0004 0605 7892, MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, ; Edinburgh, UK
                [3 ]Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, ( https://ror.org/05tr67282) Paris, France
                [4 ]Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, ( https://ror.org/02sy42d13) Rome, Italy
                [5 ]Pediatric Haematology/Oncology, Fondazione IRCCS Policlinico San Matteo, ( https://ror.org/05w1q1c88) Pavia, Italy
                [6 ]Department of Brain and Behavioural Sciences, University of Pavia, ( https://ror.org/00s6t1f81) Pavia, Italy
                [7 ]GRID grid.419416.f, ISNI 0000 0004 1760 3107, Child Neurology and Psychiatry Unit, , IRCCS Mondino Foundation, ; Pavia, Italy
                [8 ]Neuroradiology Unit, Fondazione IRCCS Policlinico San Matteo, ( https://ror.org/05w1q1c88) Pavia, Italy
                [9 ]Cell Factory, Fondazione IRCCS Policlinico San Matteo, ( https://ror.org/05w1q1c88) Pavia, Italy
                [10 ]GRID grid.419504.d, ISNI 0000 0004 1760 0109, UOC Reumatologia E Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, ; Genoa, Italy
                [11 ]Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, ( https://ror.org/02sy42d13) Rome, Italy
                [12 ]Department of Molecular Medicine, University of Pavia, ( https://ror.org/00s6t1f81) Pavia, Italy
                [13 ]GRID grid.419416.f, ISNI 0000 0004 1760 3107, Medical Genetics Unit, IRCCS Mondino Foundation, ; Pavia, Italy
                [14 ]Laboratory of Immuno-Rheumatology, Bambino Gesù Children’s Hospital, IRCCS, ( https://ror.org/02sy42d13) Rome, Italy
                [15 ]Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università Degli Studi Di Genova, ( https://ror.org/0107c5v14) Genoa, Italy
                [16 ]GRID grid.7429.8, ISNI 0000000121866389, Bioinformatics Core Facility, , Paris-Cité University-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, ; Paris, France
                [17 ]GRID grid.5379.8, ISNI 0000000121662407, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, , University of Manchester, Manchester Academic Health Science Centre, ; Manchester, UK
                [18 ]Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Paris, France
                [19 ]University Paris Cité, ( https://ror.org/05f82e368) Paris, France
                Article
                1660
                10.1007/s10875-024-01660-6
                10850255
                38324161
                2ce84b09-432b-4ad9-a771-f8068a97ee80
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 December 2023
                : 17 January 2024
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002915, Fondation pour la Recherche Médicale;
                Award ID: FDM202106013329
                Award Recipient :
                Funded by: Italian Ministry of Heath
                Award ID: Ricerca Corrente 08045818
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MC_UU_00035/11
                Award Recipient :
                Categories
                Research
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2024

                Immunology
                tlr7,systemic lupus erythematosus,stem cell transplantation
                Immunology
                tlr7, systemic lupus erythematosus, stem cell transplantation

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