The role of innate immunity in asthma: leads and lessons from mouse models.

According to the Hygiene Hypothesis, respiratory infections should protect individuals from allergic diseases including asthma, but epidemiologic data on the role of infections or exposure to microbial compounds in asthma are contradictory. Meanwhile, a number of murine models of airway sensitization are available facilitating the elucidation of pathways involved in asthma pathogenesis. Such studies have linked antigen presentation by activated pulmonary dendritic cells (DCs) with airway sensitization. Toll-like receptors (TLRs), which play a major role in innate immunity by sensing various microbial compounds, are expressed on DCs, as well as on mast cells (MCs). Activation of TLRs by administration of specific bacterial ligands, in particular lipopolysaccharide, can augment airway sensitization in mice, and there is evidence that this process involves TLR-dependent activation of DCs. Intriguingly, viral infection has been shown to increase airway inflammation in a murine asthma model via activation of DCs as well. TLR-4-dependent stimulation of MCs may also play a role in allergic sensitization in mice, and in vitro studies in murine cells show that ligation of TLRs expressed on MCs enhances degranulation. Therefore, evidence obtained from studies on mice indicates that innate immune responses may promote, rather than protect from, the development as well as the exacerbation of asthma.

Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria.

Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.

Chronic periodontal disease is associated with single-nucleotide polymorphisms of the human TLR-4 gene.

Periodontitis is an inflammatory disease affecting the connective tissue surrounding the teeth leading to tooth loss. Pathogens associated with periodontitis interact with Toll-like receptors (TLRs) to induce cytokines causing and aggravating disease. We screened 197 individuals suffering from generalized periodontitis for the presence of Asp299Gly and Thr399Ile of TLR-4 as well as Arg753Gln of TLR-2 in comparison to matched controls. Single-nucleotide polymorphisms (SNPs) of TLR-4 were elevated among patients (odd's ratio 3.650, 95% CI 1.573-8.467, P < or = 0.0001), while no difference was observed for TLR-2. TLR-4 SNPs were correlated with chronic periodontitis (odd's ratio 5.562, 95% CI 2.199-14.04, P < or = 0.0001), but not with aggressive periodontitis. This observation was confirmed employing a group of periodontally healthy probands over 60 years of age. These data demonstrate that genetic variants of TLR-4 may act as risk factors for the development of generalized chronic periodontitis in humans.