From the Th1/Th2 paradigm towards a Toll-like receptor/T-helper bias.

An efficient defense against invading pathogenic microorganisms is achieved through coordination of a complex network of both innate and acquired immune responses. The first step for the elimination of a pathogenic bacterium or virus is reliable detection, a complex task due to both variation and evolution of the pathogenic microorganisms. In order to achieve this goal, the innate immune system has developed a strategy of recognizing conserved structures of microbes which are not present in mammalian cells, called pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are the major class of signaling receptors, first described for Drosophila (26), which recognize PAMPs and signal the presence of an invading pathogen (24, 51). The specificity of TLR recognition has been established for several important PAMPs: lipoteichoic acid, bacterial lipoproteins, and zymosan are recognized by TLR2, double-stranded RNA by TLR3, lipopolysaccharide and heat shock proteins by TLR4, flagellin by TLR5, and CpG motifs of bacterial DNA by TLR9 (3). Additional microbial ligands for TLRs have been found, as reviewed elsewhere (3, 48). Ligation of TLRs by PAMPs leads to induction of cytokine production, and at first glance, the pathways involved are rather similar and seem to be inherently redundant. Hirschfeld and colleagues were the first to suggest that differential cytokine patterns are released when various TLRs are engaged by lipopolysaccharides (LPS) from different species: stimulation with Escherichia coli LPS, a ligand for TLR4, led to release of large amounts of tumor necrosis factor (TNF), interleukin-1 (IL-1 ), IL-12p40, and IP-10 (gamma-interferon-inducible protein 10), whereas Porphyromonas gingivalis LPS, a TLR2 ligand, induced moderate amounts of TNF and IL-1 and no production of IL-12p40 or IP-10 (16). These results were later confirmed and extended by the observation that the specific effect of TLR4 on IL-12p40 and IP-10 release is mediated through intermediary production of endogenous beta interferon (IFN) (50). These and additional studies reviewed below showed that TLRs not only enable the innate immune system to recognize specific PAMPs, but by inducing specific cytokine profiles, bring a certain degree of specificity to the innate immune system and influence the nature of the adaptive immune responses.