Toll-like receptors, transduction-effector pathways, and disease diversity: evidence of an immunobiological paradigm explaining all human illness?

Membrane-bound Toll-like receptors (TLRs) are frontline guardians in the mammalian innate immune system. They primarily function to recognize pathogen-associated molecular patterns (PAMPs) of invading microorganisms and on activation mount rapid, nonspecific innate responses and trigger sequential delayed specific adaptive cellular responses, which are mediated by complex signal transduction pathways involving adaptor molecules, costimulatory ligands and receptors, kinases, transcription factors, and modulated gene expression. Increasing evidence of multiple functionality and diversity suggests TLRs play critical roles in noninfective medical conditions such as cardiovascular, gastrointestinal, neurologic, musculoskeletal, obstetric, renal, liver, and dermatologic diseases, allergy, autoimmunity, and tissue regeneration. The significance of TLR heterogeneity underscores the possibility for establishing a universal immunobiological model to explain all human disease. Novel immunomodulatory therapies targeting specific or multiple TLRs may in the future offer new tools to combat or eradicate pathogenesis potentially transforming the landscape of current medical treatments.