Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies


Recent advances in genome-wide association studies (GWAS) across autoimmune and immune-mediated diseases have augmented our understanding of pathogenic mechanisms underlying these diseases. This has further highlighted their heterogeneous nature, both within and between diseases. Furthermore, varying responses to therapy have also served to underline the importance of this heterogeneity in the manner in which these diseases are diagnosed and treated. Here we discuss our current understanding of the shared pathways of autoimmunity, including the tumor necrosis factor (TNF), major histocompatibility complex (MHC), interleukin 23 receptor (IL23R) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) pathways. In addition, we summarize effective specific therapies tested across major autoimmune diseases, highlighting the insight they have provided into disease mechanisms and their implications for potential future improvements.

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Figure 1: Timeline of pathogenicity and therapeutic interventions in autoimmune diseases.

Debbie Maizels/Nature Publishing Group

Figure 2: Levels of therapeutic targeting across autoimmunity.

Debbie Maizels/Nature Publishing Group


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J.H.C. is supported by US National Institutes of Health grants U01 DK62429, U01 DK062422, R01 DK092235, SUCCESS, by he Helmsley Charitable Trust and by the Sanford J. Grossman Charitable Trust.

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Correspondence to Judy H Cho.

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The Kennedy Institute and M.F. receive royalties on patents using combination therapies of methotrexate plus anti-TNF.

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Cho, J., Feldman, M. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nat Med 21, 730–738 (2015). https://doi.org/10.1038/nm.3897

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