Abstract
Autoimmunity can be triggered by microbial infection. In this context, the discovery of Toll-like receptors (TLRs) provides new insights and research perspectives. TLRs induce innate and adaptive antimicrobial immune responses upon exposure to common pathogen-associated molecules, including lipopeptides, lipopolysaccharides, and nucleic acids. They also have the potential, however, to trigger autoimmune disease, as has been revealed by an increasing number of experimental reports. This review summarizes important facts about TLR biology, available data on their role in autoimmunity, and potential consequences for the management of patients with autoimmune disease.
Highlights
Autoimmunity is believed to develop from genetic predispositions while the onset of autoimmune tissue injury or disease flare is often triggered by microbial infection
Patients with chronic forms of autoimmunity may experience symptomatic disease flares following infections. These clinical observations raise a set of questions: what classes of receptors recognize microbes or vaccine adjuvants in the host? What molecular mechanisms induce immune activation upon recognition of the pathogen? And how does antimicrobial immunity modulate tolerance? Answers to these questions are expected from the recent discovery of Toll-like receptors (TLRs)
TLRs have been identified as a new family of innate receptors that recognize a set of microbial molecules known as pathogen-associated molecular patterns (PAMPs)
Summary
Autoimmunity is believed to develop from genetic predispositions while the onset of autoimmune tissue injury or disease flare is often triggered by microbial infection. Autoreactive B cells from these mice recognize the IgG part of the immune complex by their surface B cell receptor, internalize immune complexes, which exposes CpG-DNA to TLR9 in the endosomal compartment [32] These mechanisms may apply in vivo, because autoimmune MRLlpr/lpr mice injected with bacterial CpG-DNA produce large amounts of DNA autoantibodies [56] in association with increased MHC II expression on B cells isolated from spleens of these mice 220 [14]. Experimental studies that exposed rodents with lupus to TLR agonists, for example, experimental autoimmune encephalomyelitis, collagen-induced arthritis, immune complex glomerulonephritis and other types of autoimmune tissue injury, raise considerable concern about the safety of TLR agonists in patients with autoimmune disease [55,56,57,92] These studies reported disease aggravation after repeated injections with, for example, CpG-ODN, but side effects of TLR ligands may relate to the dose, treatment intervals, and route of administration [29,93]. Developing specific small molecule TLR9 antagonists may represent a new approach as a preventive therapy for systemic lupus erythematosus
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