Focus on Inflammatory Disease

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

Journal name:
Nature Medicine
Year published:
Published online


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.

At a glance


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

    Altered immune function antedates disease presentation across autoimmune diseases. In some cases, most notably for type 1 diabetes, substantial structural damage has already occurred by the time of disease presentation. In such cases, therapeutic options are restricted to symptomatic treatment, such as hormone replacement (insulin, thyroid hormones). For many other autoimmune diseases, therapeutic paradigms involve earlier treatment, control of inflammation and prevention of structural damage. In the future, induction of immune tolerance, and normalization of immune function may be accomplished, guided by genetic stratification for both treatment and prevention of disease.

  2. Levels of therapeutic targeting across autoimmunity.
    Figure 2: Levels of therapeutic targeting across autoimmunity.

    Targetable pathways of rheumatoid arthritis and psoriasis are shown. Therapies that are effective in rheumatoid arthritis are shown in red, and therapies effective in psoriasis are shown in blue. The broad efficacy of anti-TNF therapy across many diseases reflects its central role in the cytokine network. In contrast, a more limited range of diseases have demonstrated positive results to blockade with anti–IL-12/23. IL-23 perpetuates and stabilizes IL23R-expressing pathogenic cells, including CD4+ TH17 cells. IL-17, as produced by TH17 cells, promotes neutrophilia, as well as enhances antimicrobial defense and tissue repair. Antagonism of IL6R and CTLA4 fusion proteins preventing CD28 co-stimulation are effective in the treatment of rheumatoid arthritis, as are B cell ablation approaches, such as by CD20-specific antibody administration, which are approved for the treatment of rheumatoid arthritis.


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  1. Department of Genetics, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Judy H Cho
  2. Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Judy H Cho
  3. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

    • Marc Feldman

Competing financial interests

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

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