Role of the innate and adaptive immune responses in the pathogenesis of systemic lupus erythematosus

Summary Dendritic cells (DC) are a class of bone‐marrow‐derived cells arising from lympho‐myeloid haematopoiesis that form an essential interface between the innate sensing of pathogens and the activation of adaptive immunity. This task requires a wide range of mechanisms and responses, which are divided between three major DC subsets: plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2). Each DC subset develops under the control of a specific repertoire of transcription factors involving differential levels of IRF8 and IRF4 in collaboration with PU.1, ID2, E2‐2, ZEB2, KLF4, IKZF1 and BATF3. DC haematopoiesis is conserved between mammalian species and is distinct from monocyte development. Although monocytes can differentiate into DC, especially during inflammation, most quiescent tissues contain significant resident populations of DC lineage cells. An extended range of surface markers facilitates the identification of specific DC subsets although it remains difficult to dissociate cDC2 from monocyte‐derived DC in some settings. Recent studies based on an increasing level of resolution of phenotype and gene expression have identified pre‐DC in human blood and heterogeneity among cDC2. These advances facilitate the integration of mouse and human immunology, support efforts to unravel human DC function in vivo and continue to present new translational opportunities to medicine.

The aetiology of systemic lupus erythematosus (SLE) is multifactorial, and includes contributions from the environment, stochastic factors, and genetic susceptibility. Great gains have been made in understanding SLE through the use of genetic variant identification, mouse models, gene expression studies, and epigenetic analyses. Collectively, these studies support the concept that defective clearance of immune complexes and biological waste (such as apoptotic cells), neutrophil extracellular traps, nucleic acid sensing, lymphocyte signalling, and interferon production pathways are all central to loss of tolerance and tissue damage. Increased understanding of the pathogenesis of SLE is driving a renewed interest in targeted therapy, and researchers are now on the verge of developing targeted immunotherapy directed at treating either specific organ system involvement or specific subsets of patients with SLE. Accordingly, this Review places these insights within the context of our current understanding of the pathogenesis of SLE and highlights pathways that are ripe for therapeutic targeting.

Key Points Stimulator of interferon genes (STING) is activated by binding to cyclic dinucleotides (CDNs), which results in potent cytokine production. CDNs are produced by certain intracellular bacteria and are generated by the cyclic GMP–AMP synthase (cGAS) following binding to cytosolic DNA species, such as viral DNA. STING-inducible innate immune molecules are essential for protection of the host against pathogens and are important for the stimulation of adaptive immunity. Self-DNA, for example from the nucleus or mitochondria, can leak into the cytosolic compartment and stimulate STING activity to cause autoinflammatory disease. Certain mutations in the gene encoding STING can cause the protein to become permanently active and similarly induce autoinflammatory responses. STING can be activated in phagocytes by DNA released from engulfed tumour cells and drive the production of cytokines necessary for generating robust antitumour T cell responses. DNA-damaging agents can cause the release of nuclear DNA into the cytosol that stimulates STING-dependent cytokine production and phagocyte infiltration. This may be essential for eliminating damaged cells and generating antitumour T cell responses, but chronic stimulation may also promote inflammation-aggravated cancer. STING agonists exert potent antitumour activity and may be effective, novel adjuvants in vaccine formulations. In contrast, inhibitors of STING signalling may be beneficial for the treatment of autoinflammatory disease, such as systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI). Supplementary information The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.