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Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.217 Figure 3 Ectopic germinal centres sustain antigen-specific and disease-specific autoimmune responses Figure 3 | Ectopic germinal centres sustain antigen-specific and disease-specific autoimmune responses. Ectopic lymphoid structures (ELSs) arising in the salivary glands of Sjögren syndrome (part a) and in the synovium of rheumatoid arthritis (RA; part b) are depicted. Although ELSs in RA and Sjögren syndrome display overlapping architecture and are regulated by similar mechanisms, they favour the affinity maturation and differentiation of plasma cells reactive against disease-specific autoantigens. These autoantigens are exposed as a result of the chronic inflammatory process and can be presented by both professional antigen-presenting cells (APCs) and B cells to T cells. The left side of parts a and b are representative schematics of the potential source of autoantigens driving the formation of ELSs. Briefly, in Sjögren's syndrome (part a), after an initial unknown trigger (that is, viral infection), necrotic or apoptotic epithelial cells release autoantigens. In the RA synovium (part b), breach of self-tolerance to citrullinated antigens precedes ELS onset. Circulating anticitrullinated protein antibodies (ACPAs) (that is, as immune complexes, IC) may enter the RA synovium due to increased vascular permeabilization (for example following injury or infection). Once inflammation is established, citrullinated antigens can be locally released by several cell types, including neutrophil extracellular traps (NET). The right side of parts a and b shows double immunofluorescence microscopy demonstrating that perifollicular CD138+ plasma cells (depicted in green) in Sjögren syndrome salivary glands (part a) react against the Sjögren syndrome-associated autoantigen Ro52 (stained in red) but not against Cit-fibrinogen (cFb); conversely, CD138+ plasma cells in the RA synovium (part b) display strong reactivity to cFb (in red), but not Ro52. Original magnification: ×400 for CD138/Ro52 and CD138/cFb. Permission to use microscopy images obtained from Wiley © Croia, C. et al. Arthritis Rheumatol. 66, 2545–2557 (2014). Permission to use microscopy images obtained from Wiley © Croia, C. et al. Arthritis Rheumatol. 66, 2545–2557 (2014). Bombardieri, M. et al. (2017) Ectopic lymphoid neogenesis in rheumatic autoimmune diseases Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.217