Nucleic acid recognition receptors in autoimmunity.
Recent studies in mouse models of systemic autoimmune diseases have drawn attention to the involvement of Toll-like receptors (TLRs) in the generation of autoreactive immune responses. The endosomally localized TLRs7 and 9 are activated by autoimmune complexes containing self DNA and RNA in B lymphocytes and dendritic cells. These endogenous TLR ligands act as autoadjuvants providing a stimulatory signal together with the autoantigen and thus contribute to break peripheral tolerance against self antigens in systemic lupus erythematosus (SLE), for example. In vivo studies in SLE mouse models demonstrate an essential role for TLR7 in the generation of RNA-containing antinuclear antibodies and deposition of pathogenic immune complexes in the kidney. TLR9, however, appears to have immunostimulatory as well as regulatory functions in SLE mouse models. Type I Interferon, which is produced by plasmacytoid dendritic cells in response to autoimmune complexes containing RNA and DNA recognized by TLR7 and 9 acts as a potent amplifier of the autoimmune response. TLR-independent recognition of self nucleic acids by cytosolic RNA and DNA sensors may also play a role in the generation of autoimmune responses. Defects in protective mechanisms, which normally prevent immunostimulation by self nucleic acids in healthy individuals, promote the development of autoimmune diseases. For example, defects in nucleases that clear nucleic acids derived from apoptotic material, changes in the level and localization of TLR expression, defects in negative regulators of TLR signaling, or changes in the posttranscriptional modification of mammalian DNA and RNA may contribute to autoreactive responses. A better understanding of the exact function of different nucleic acid recognition receptors in the development of systemic autoimmunity will allow targeting of these innate immune receptors for the therapy of patients with systemic autoimmune diseases.
Krug
Anne
A
II. Medizinische Klinik, Klinkum Rechts der Isar, Technische Universität München, Trogerstr. 32, D-81675, München, Germany. anne.krug@lrz.tum.de
D000818:Animals; D015551:Autoimmunity / Q000276:immunology / Q000502:physiology*; D006801:Humans; D051379:Mice; D009696:Nucleic Acids / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000187:drug effects / Q000276:immunology / Q000502:physiology
D009696:Nucleic Acids; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors