Cardiac ectopic lymphoid follicle formation in viral myocarditis involving the regulation of podoplanin in Th17 cell differentiation

Autoimmunity contributes to the pathogenesis of viral myocarditis (VMC), which is characterized by the production of anti-heart autoantibodies (AHA) from lymphoid follicles. Recently, the formation of ectopic lymphoid follicles (ELFs) was reported in heart grafts. However, the existence and role of ELFs in myocardial tissues of VMC remain unclear. This study aimed to explore whether and how cardiac ELFs with germinal centers (GCs) could be generated during the development of VMC. We identified the existence of ELFs and explored the underlying mechanism. In a BALB/c mouse model of VMC, the dynamic myocardial infiltrations of lymphocytic aggregates and expressions of associated lymphorganogenic factors were investigated, accompanied by the detection of the production and location of myocardial AHA. The data indicated ELFs formation in myocardial tissues of VMC, and the number of ELFs was in accordance with the severity of VMC. Moreover, the functional ELFs with GCs were capable of facilitating the production of local AHA. Blocking IL-17 or podoplanin (PDPN) could inhibit cardiac ELFs generation, perhaps due to the negative regulation of PDPN neutralization in Th17 cell proliferation and differentiation. The presence of cardiac ELFs and AHA might offer new opportunities for stratification and early identification of VMC patients.