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The multiple pathways to autoimmunity

Abstract

Efforts to understand autoimmunity have been pursued relentlessly for several decades. It has become apparent that the immune system evolved multiple mechanisms for controlling self-reactivity, and defects in one or more of these mechanisms can lead to a breakdown of tolerance. Among the multitude of lesions associated with disease, the most common seem to affect peripheral tolerance rather than central tolerance. The initial trigger for both systemic autoimmune disorders and organ-specific autoimmune disorders probably involves the recognition of self or foreign molecules, especially nucleic acids, by innate sensors. Such recognition, in turn, triggers inflammatory responses and the engagement of previously quiescent autoreactive T cells and B cells. Here we summarize the most prominent autoimmune pathways and identify key issues that require resolution for full understanding of pathogenic autoimmunity.

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Figure 1: Escape of autoreactive T cells and B cells from central tolerance and engagement in the periphery.
Figure 2: Engagement of endosomal or cytosolic nucleic-acid sensors as central events in inflammatory responses.
Figure 3: Pathways by which sensors of self and foreign nucleic acids promote autoimmunity.
Figure 4: The multiple pathways to autoimmunity.

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Acknowledgements

We thank B. Beutler, D. Burton, L. Teyton and D. Nemazee for manuscript review and advice. Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR065919 and AR068910 to A.N.T.), the National Heart, Lung and Blood Institute (HL114408 to D.H.K.) and the National Institute of Allergy and Infectious Diseases (AI121525 and AI117563 to R.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Argyrios N Theofilopoulos or Roberto Baccala.

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Theofilopoulos, A., Kono, D. & Baccala, R. The multiple pathways to autoimmunity. Nat Immunol 18, 716–724 (2017). https://doi.org/10.1038/ni.3731

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