Figure 10. Activation and pathogenesis in systemic autoimmunity.

(1) Autoreactive B cells, such as those specific for DNA, become activated through engagement of their BCR and TLRs in a MyD88-dependent manner. (2) Activated autoreactive B cells present antigen on MHCII and upregulate costimulatory molecules, resulting in the activation of cognate autoreactive CD4 T cells. (3) B cells and DCs promote subsequent differentation into T_H1 and T_EF cells. (4) Cognate activated T cells provide help such as CD40 ligation and cytokines, resulting in significant expansion and isotype switch of the plasmablasts. (5) Activated autoreactive B cells promote epitope spreading and expansion of the anti-self response. B cells have the potential to present anything that is endocytosed through their BCR, not only the protein sequences recognized by the CDR3 region. (6) Activated T cells migrate and infiltrate target tissues, such as the kidneys, in a DC-dependent manner. These T cells may activate resident or migratory DCs through CD40-CD40L ligation which induces ICOSL expression on the DCs. DC-expressed ICOSL promotes kidney damage.