Ectopic lymphoid neogenesis in rheumatic autoimmune diseases

Ectopic lymphoid structures have been identified in the target organs of a subset of patients with rheumatic autoimmune diseases. This Review describes these structures and summarizes our current understanding of how they form, function and contribute to autoimmunity. 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.