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  • Review Article
  • Published:

Ectopic lymphoid neogenesis in rheumatic autoimmune diseases

Nature Reviews Rheumatology volume 13, pages 141–154 (2017)Cite this article

Subjects

Key Points

  • Ectopic lymphoid structures (ELSs) develop in the target organs of a subset of patients with rheumatic autoimmune diseases and recapitulate key cellular and molecular features normally present in secondary lymphoid organs

  • ELSs in rheumatic autoimmune diseases can function as germinal centres, favouring B cell selection and plasma cell differentiation

  • B cells and plasma cells associated with ELSs in rheumatic autoimmune diseases frequently display an autoreactive phenotype towards disease-specific autoantigens

  • Ectopic germinal centres in patients with Sjögren syndrome have been associated with more severe systemic manifestations and a higher risk of B cell lymphoma

  • In rheumatoid arthritis, emerging but as-yet-inconclusive evidence suggests a role for ELSs in influencing disease evolution and the response to conventional and biologic treatments

  • Several candidate therapeutic agents that target ELS-associated pathways are currently in clinical trials for rheumatic autoimmune diseases

Abstract

Ectopic lymphoid neogenesis often occurs in the target tissues of patients with chronic rheumatic autoimmune diseases such as rheumatoid arthritis, Sjögren syndrome and other connective tissue disorders, including systemic lupus erythematosus and myositis. However, the mechanisms of ectopic lymphoid-like structure (ELS) formation and function are not entirely understood. For example, it is unclear whether ELSs indicate distinct disease phenotypes or whether they are evolutionary manifestations of chronic inflammation. Also unclear is why ELSs form in some patients but not in others. Nonetheless, ELSs frequently display functional features of ectopic germinal centres and can actively contribute to the maintenance of autoimmunity through the production of disease-specific autoantibodies; furthermore, they seem to influence disease severity and response to both synthetic and biologic DMARDs. In this Review, we discuss current knowledge and gaps in understanding of ELS formation and function including their prevalence in the above rheumatic autoimmune diseases; the mechanisms underlying their formation, maintenance and function, including positive and negative regulatory pathways; their functional relevance in the perpetuation of autoimmunity; their relationship with disease phenotypes, clinical outcomes and response to treatment; and the potential for specific targeting of ELSs through novel therapeutic modalities.

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Figure 1: Ectopic lymphoid structures (ELSs) that form in rheumatic autoimmune diseases share features of secondary lymphoid organs.
Figure 2: Schematic representation illustrating the journey of T follicular helper (TFH) cells from the T-cell rich area of the ectopic lymphoid structure (ELS) to the B cell follicles, where TFH cells initiate and sustain germinal centre responses.
Figure 3: Ectopic germinal centres sustain antigen-specific and disease-specific autoimmune responses.

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Authors and Affiliations

  1. Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    Michele Bombardieri, Myles Lewis & Costantino Pitzalis

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  1. Michele Bombardieri
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  2. Myles Lewis
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  3. Costantino Pitzalis
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M.B. and M.L. researched data for the article. All authors made a substantial contribution to discussion of the content, and writing, reviewing and editing the manuscript before submission.

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Correspondence to Costantino Pitzalis.

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Bombardieri, M., Lewis, M. & Pitzalis, C. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol 13, 141–154 (2017). https://doi.org/10.1038/nrrheum.2016.217

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