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Mendelian Causes of Autoimmunity: the Lupus Phenotype

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Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.

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Acknowledgements

We thank the patients and families. We also thank Véréna Landel for her help proofreading the manuscripts.

Funding

This research was funded by ANR (ANR-21-CE17-0064 [SOCSIMMUNITY]]), ANR-21-RHUS-08 [COVIFERON]) from the ANR–Recherche Hospitalo Universitaire Program; by the Horizon Europe (01057100 [UNDINE]) from the HORIZON-HLTH-2021-DISEASE-04; le Centre de référence des rhumatismes inflammatoires, des interféronopathies et des maladies autoimmunes (RAISE).

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  1. Maud Tusseau

    Present address: National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children, European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center, Hospices Civils de Lyon, Lyon, France

Authors and Affiliations

  1. Centre International de Recherche en Infectiologie, Inserm, U1111, University Claude Bernard, Lyon 1, Centre National de La Recherche Scientifique, UMR5308, ENS de Lyon, Lyon, France

    Maud Tusseau, Jade Cognard, Sebastien Viel, Liliane Khoryati, Sarah Benezech, Anne-Laure Mathieu & Alexandre Belot

  2. National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children, European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center, Hospices Civils de Lyon, Lyon, France

    Samira Khaldi-Plassart, Brigitte Bader-Meunier & Alexandre Belot

  3. Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France

    Fréderic Rieux-Laucat & Brigitte Bader-Meunier

  4. Department for Immunology, Hematology and Pediatric Rheumatology, Necker Hospital, APHP, Institut IMAGINE, Paris, France

    Brigitte Bader-Meunier

  5. Pediatric Nephrology, Rheumatology, Dermatology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France

    Samira Khaldi-Plassart, Jade Cognard & Alexandre Belot

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Contributions

M.T: Wrote the initial draft and contribute to the conceptualisation of the manuscript. S.K-P: made all the figures and did critical review of the manuscript, J.C, S.V, L.K, S.B, AL. M: did critical review of manuscript, F.R-L, B.B-M: made critically revised the manuscript and contribute to the conceptualisation of the manuscript, A.B: conceptualized the work, critically revised the manuscript and approved the version to be published.

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Correspondence to Alexandre Belot.

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Competing Interests

AB reports consulting fees from Kabi, Roche Chugai, GlaxoSmithKline, AbbVie, Novartis, and Boehringer Ingelheim; research grants from Boehringer Ingelheim, ANR, and Horizon Europe outside the scope of this comment; and is an unpaid co-chair of the French National Network on Rare Autoimmune and Autoinflammatory Diseases. All other authors declare no competing interests.

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Tusseau, M., Khaldi-Plassart, S., Cognard, J. et al. Mendelian Causes of Autoimmunity: the Lupus Phenotype. J Clin Immunol 44, 99 (2024). https://doi.org/10.1007/s10875-024-01696-8

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