Figure 3

Model for the development of systemic lupus erythematosus and its inflammatory manifestations. In systemic lupus erythematosus (SLE), aberrant apoptosis or insufficient clearance of apoptotic cells leads to the local or systemic presence of high amounts of apoptotic blebs and nucleosomes, which are modified during apoptosis. These are then taken up by immature myeloid dendritic cells (mDCs). After ingestion of apoptotic blebs or nucleosomes, mDCs gain a mature phenotype with increased expression of costimulatory molecules (for example, CD40 and CD86), and production of proinflammatory cytokines, such as IL-6. Mature mDCs can induce activation of Th1 or Th2 cells and, in the presence of TGF-β, IL-6 and/or other proinflammatory cytokines, also support the development of Th17 cells. Next to its role in Th17 development, IL-6 inhibits the development and activity of regulatory T cells (Tregs). After activation by T helper (Th) cells, autoreactive B cells produce autoantibodies, which can form immune complexes with apoptotic material. Plasmacytoid dendritic cells (pDCs) preferentially take up these immune complexes and subsequently produce high amounts of IFN-a, which enhances autoantibody production and isotype switching. This results in increasing concentrations of immune complexes, which can associate with the (glomerular) basement membrane. The resulting influx of immune cells ultimately gives rise to multiple disease manifestations, including lupus nephritis, and local tissue damage, thereby inducing an increase in apoptotic cells, which 'feeds' mDCs with immunogenic material. ACB, apoptotic cell body ("late apoptotic cell"); Blebs, apoptotic blebs; EAC, early apoptotic cell; MF, macrophage; mDC, myeloid dendritic cell; Nucleosomes, apoptosis-induced hyper acetylated nucleosomes; pDC, plasmacytoid dendritic cell; Th, T helper cell; Treg, regulatory T cell.