Toll-like receptors (TLRs) play a crucial role in detecting pathogen-associated molecular patterns and activating the adaptive immune response. Recent studies suggest that TLRs may also recognize endogenous ligands, contributing to the initiation or progression of systemic autoimmune diseases. Autoantibodies in diseases like systemic lupus erythematosus (SLE), scleroderma, and Sjögren's syndrome often bind DNA, RNA, or macromolecular complexes containing these molecules. These autoantigens may become visible to the immune system during apoptosis, leading to loss of tolerance or the creation of neo-epitopes. TLRs, particularly TLR7 and TLR9, detect nucleic acid-containing immune complexes, which can activate plasmacytoid dendritic cells (pDCs) and promote the production of type I interferons (IFNs), such as IFNα, which contribute to autoimmune disease. IFNα is a key player in SLE, with evidence showing its role in disease pathogenesis through various mechanisms, including activation of APCs, T cells, and B cells. pDCs are the main source of IFNα and respond to immune complexes, especially those containing DNA or RNA. These immune complexes can be activated by FcγR-mediated uptake of IgG or by apoptotic/necrotic cell debris. TLR7 and TLR9 are expressed in pDCs and detect nucleic acids, leading to IFNα production and further immune activation. Autoantigens can act as autoadjuvants, activating TLRs and promoting autoantibody production. Endogenous TLR ligands, such as DNA and RNA, may contribute to autoantibody production through mechanisms involving TLR7 and TLR9. In vivo studies in mouse models of SLE show that TLR7 and TLR9 are involved in autoantibody production and disease progression. TLR9 deficiency reduces autoantibody production, while TLR7 deficiency affects RNA-specific autoantibodies. Inhibitors of TLR7 and TLR9, such as antimalarial agents and inhibitory oligodeoxynucleotides, can reduce SLE severity in mouse models. TLR7 and TLR9 are critical in the recognition of nucleic acid-containing immune complexes, which can activate pDCs and lead to the production of IFNα, contributing to autoimmune disease. The role of TLRs in autoimmune disease is increasingly recognized, highlighting their importance in both the initiation and progression of systemic autoimmune conditions.Toll-like receptors (TLRs) play a crucial role in detecting pathogen-associated molecular patterns and activating the adaptive immune response. Recent studies suggest that TLRs may also recognize endogenous ligands, contributing to the initiation or progression of systemic autoimmune diseases. Autoantibodies in diseases like systemic lupus erythematosus (SLE), scleroderma, and Sjögren's syndrome often bind DNA, RNA, or macromolecular complexes containing these molecules. These autoantigens may become visible to the immune system during apoptosis, leading to loss of tolerance or the creation of neo-epitopes. TLRs, particularly TLR7 and TLR9, detect nucleic acid-containing immune complexes, which can activate plasmacytoid dendritic cells (pDCs) and promote the production of type I interferons (IFNs), such as IFNα, which contribute to autoimmune disease. IFNα is a key player in SLE, with evidence showing its role in disease pathogenesis through various mechanisms, including activation of APCs, T cells, and B cells. pDCs are the main source of IFNα and respond to immune complexes, especially those containing DNA or RNA. These immune complexes can be activated by FcγR-mediated uptake of IgG or by apoptotic/necrotic cell debris. TLR7 and TLR9 are expressed in pDCs and detect nucleic acids, leading to IFNα production and further immune activation. Autoantigens can act as autoadjuvants, activating TLRs and promoting autoantibody production. Endogenous TLR ligands, such as DNA and RNA, may contribute to autoantibody production through mechanisms involving TLR7 and TLR9. In vivo studies in mouse models of SLE show that TLR7 and TLR9 are involved in autoantibody production and disease progression. TLR9 deficiency reduces autoantibody production, while TLR7 deficiency affects RNA-specific autoantibodies. Inhibitors of TLR7 and TLR9, such as antimalarial agents and inhibitory oligodeoxynucleotides, can reduce SLE severity in mouse models. TLR7 and TLR9 are critical in the recognition of nucleic acid-containing immune complexes, which can activate pDCs and lead to the production of IFNα, contributing to autoimmune disease. The role of TLRs in autoimmune disease is increasingly recognized, highlighting their importance in both the initiation and progression of systemic autoimmune conditions.