TLRs and interferons: a central paradigm in autoimmunity

Abstract

Investigations into the pathogenesis of lupus have largely focused on abnormalities in components of the adaptive immune system. Despite important advances, however, the question about the origin of the pathogenic process, the primary disease trigger, and the dominance of autoantibodies against nuclear components, remained unanswered. Discoveries in the last decade have provided some resolution to these questions by elucidating the central role of nucleic acid-sensing TLRs and the attendant inflammatory response, particularly the production of type I interferons. These priming events are responsible for initiating the adaptive responses that ultimately mediate the pathogenic process.

Figure 1

Role of nucleic acid TLRs and type I IFN to the pathogenesis of autoantibody production in lupus. Antinuclear autoantibody production in lupus is thought to involve several steps. (1) Secretion of IgG autoantibodies by plasma cells (or B cells). (2) Formation of IgG immune complexes containing nucleic acid material, immune complexes with apoptotic material is depicted as an example. (3) Engulfment of these immune complexes via FCGR2A (FcγRIIa) by macrophages (Mac), pDCs, and, immature DCs (3a–c) into endosomes where released nucleic acids bind to the corresponding TLR resulting in cell activation. Each of these cell types can promote inflammation, immune responses, and autoimmunity by different mechanisms including release of proinflammatory factors and BAFF, and maturation into potent antigen presenting cells. Importantly, pDCs produce copious amounts of IFN-I, which drives multiple processes that enhance the development of autoimmiunity (red arrows, see text for details). (4) Activated DCs can present self-antigen to autoreactive CD4⁺ T cells. (5) Autoreactive B engage corresponding helper T cells. (6) Activated B cells differentiate into plasma cells or enter germinal centers (GCs) where higher affinity autoreactive plasma cells and memory B cells are generated. Plasma cells then produce more IgG autoantibodies resulting in promulgation and amplification of this process. The nucleic acid-sensing TLR-dependent steps are circled in red.