Toll-like receptors (TLRs) play a crucial role in the early detection of pathogen-associated molecular patterns and the subsequent activation of the adaptive immune response. However, their role in recognizing endogenous ligands has been more controversial. Recent studies have shown that TLRs can also recognize and respond to endogenous ligands, such as DNA and RNA, which are often associated with systemic autoimmune diseases like systemic lupus erythematosus (SLE), scleroderma, and Sjögren's syndrome. These endogenous ligands can activate plasmacytoid dendritic cells (pDCs) and other immune cells, leading to the production of type I interferons (IFNs) and the activation of TLRs, which are key events in the development and progression of autoimmune diseases. IFNα, a cytokine with pleiotropic functions, is particularly important in SLE. It promotes many clinical features of SLE, including the differentiation of monocytes into myeloid dendritic cells, the activation of autoreactive T cells and B cells, and the production of autoantibodies. pDCs, which are highly efficient producers of IFNα, can be activated by both microbial and endogenous ligands, including DNA- and RNA-containing immune complexes. These complexes bind to FcγRs on pDCs and are then transported to the cytoplasmic compartments containing TLR7 and TLR9, where they activate these receptors. In vivo studies in mouse models of SLE have further supported the role of TLRs in autoantibody production and disease progression. Mice deficient in TLR9 or MyD88, a TLR adaptor protein, show reduced autoantibody production and less severe clinical disease. Additionally, inhibitors of TLR7 and TLR9, such as antimalarial drugs and inhibitory oligonucleotides, have shown therapeutic potential in treating SLE. Genetic studies have also linked SNPs in genes involved in the type-1-IFN signalling pathway, such as IRF5, to increased susceptibility to SLE, further connecting TLR signalling to the development of autoimmune diseases. Overall, the identification and characterization of endogenous ligands for TLRs provide new insights into the pathogenesis of autoimmune diseases and suggest that therapeutic strategies targeting TLRs may be effective in treating these conditions.Toll-like receptors (TLRs) play a crucial role in the early detection of pathogen-associated molecular patterns and the subsequent activation of the adaptive immune response. However, their role in recognizing endogenous ligands has been more controversial. Recent studies have shown that TLRs can also recognize and respond to endogenous ligands, such as DNA and RNA, which are often associated with systemic autoimmune diseases like systemic lupus erythematosus (SLE), scleroderma, and Sjögren's syndrome. These endogenous ligands can activate plasmacytoid dendritic cells (pDCs) and other immune cells, leading to the production of type I interferons (IFNs) and the activation of TLRs, which are key events in the development and progression of autoimmune diseases. IFNα, a cytokine with pleiotropic functions, is particularly important in SLE. It promotes many clinical features of SLE, including the differentiation of monocytes into myeloid dendritic cells, the activation of autoreactive T cells and B cells, and the production of autoantibodies. pDCs, which are highly efficient producers of IFNα, can be activated by both microbial and endogenous ligands, including DNA- and RNA-containing immune complexes. These complexes bind to FcγRs on pDCs and are then transported to the cytoplasmic compartments containing TLR7 and TLR9, where they activate these receptors. In vivo studies in mouse models of SLE have further supported the role of TLRs in autoantibody production and disease progression. Mice deficient in TLR9 or MyD88, a TLR adaptor protein, show reduced autoantibody production and less severe clinical disease. Additionally, inhibitors of TLR7 and TLR9, such as antimalarial drugs and inhibitory oligonucleotides, have shown therapeutic potential in treating SLE. Genetic studies have also linked SNPs in genes involved in the type-1-IFN signalling pathway, such as IRF5, to increased susceptibility to SLE, further connecting TLR signalling to the development of autoimmune diseases. Overall, the identification and characterization of endogenous ligands for TLRs provide new insights into the pathogenesis of autoimmune diseases and suggest that therapeutic strategies targeting TLRs may be effective in treating these conditions.