TLR4 Asp299Gly and Thr399Ile Polymorphisms: No Impact on Human Immune Responsiveness to LPS or Respiratory Syncytial Virus

A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV)--driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction.To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7-9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV.In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with "at risk" clinical phenotypes.Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma

Pathophysiological classification of chronic rhinosinusitis

BACKGROUND: Recent consensus statements demonstrate the breadth of the chronic rhinosinusitis (CRS) differential diagnosis. However, the classification and mechanisms of different CRS phenotypes remains problematic. METHOD: Statistical patterns of subjective and objective findings were assessed by retrospective chart review. RESULTS: CRS patients were readily divided into those with (50/99) and without (49/99) polyposis. Aspirin sensitivity was limited to 17/50 polyp subjects. They had peripheral blood eosinophilia and small airways obstruction. Allergy skin tests were positive in 71% of the remaining polyp subjects. IgE was<10 IU/ml in 8/38 polyp and 20/45 nonpolyp subjects (p = 0.015, Fisher's Exact test). CT scans of the CRS without polyp group showed sinus mucosal thickening (probable glandular hypertrophy) in 28/49, and nasal osteomeatal disease in 21/49. Immunoglobulin isotype deficiencies were more prevalent in nonpolyp than polyp subjects (p < 0.05). CONCLUSION: CRS subjects were retrospectively classified in to 4 categories using the algorithm of (1) polyp vs. nonpolyp disease, (2) aspirin sensitivity in polyposis, and (3) sinus mucosal thickening vs. nasal osteomeatal disease (CT scan extent of disease) for nonpolypoid subjects. We propose that the pathogenic mechanisms responsible for polyposis, aspirin sensitivity, humoral immunodeficiency, glandular hypertrophy, eosinophilia and atopy are primary mechanisms underlying these CRS phenotypes. The influence of microbial disease and other factors remain to be examined in this framework. We predict that future clinical studies and treatment decisions will be more logical when these interactive disease mechanisms are used to stratify CRS patients

Impaired Toll-like receptor 2 signalling in monocytes from 5-year-old allergic children

The relative composition of the two major monocytic subsets CD14+CD16− and CD14+CD16+ is altered in some allergic diseases. These two subsets display different patterns of Toll-like receptor levels, which could have implications for activation of innate immunity leading to reduced immunoglobulin E-specific adaptive immune responses. This study aimed to investigate if allergic status at the age of 5 years is linked to differences in monocytic subset composition and their Toll-like receptor levels, and further, to determine if Toll-like receptor regulation and cytokine production upon microbial stimuli is influenced by the allergic phenotype. Peripheral blood mononuclear cells from 5-year-old allergic and non-allergic children were stimulated in vitro with lipopolysaccharide and peptidoglycan. Cells were analysed with flow cytometry for expression of CD14, Toll-like receptors 2 and 4 and p38-mitogen-activated protein kinase (MAPK). The release of cytokines and chemokines [tumour necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70] into culture supernatants was measured with cytometric bead array. For unstimulated cells there were no differences in frequency of the monocytic subsets or their Toll-like receptor levels between allergic and non-allergic children. However, monocytes from allergic children had a significantly lower up-regulation of Toll-like receptor 2 upon peptidoglycan stimulation. Further, monocytes from allergic children had a higher spontaneous production of IL-6, but there were no differences between the two groups regarding p38-MAPK activity or cytokine and chemokine production upon stimulation. The allergic subjects in this study have a monocytic population that seems to display a hyporesponsive state as implicated by impaired regulation of Toll-like receptor 2 upon peptidoglycan stimulation

Does the relationship between IgE and the CD14 gene depend on ethnicity?

This review considers the data from studies analysing associations between the CD14C-159T single nucleotide polymorphism (SNP) and asthmatic phenotypes and discusses the variability of the conclusions. By searching PubMed and EMBASE for articles on CD14C-159T -related population or family-based association studies, 47 were identified up till September 2007. Collectively, the studies reviewed herein consistently showed population differences in frequencies of the alleles of the SNP, with African descent having the highest C allele frequencies, followed by Caucasians and Asians. The T allele of the SNP was associated with increased sCD14 in some studies but not in others. Inconsistently, the C allele, or even occasionally the T allele, was associated with atopic phenotypes in a population subgroup. There are several explanations for these inconsistencies, including lack of power, linkage disequilibrium, gene-gene interactions, population admixture and gene-environment interactions. If the SNP was associated with functional changes to the coded protein and thus modulating susceptibility to allergic disease, its effect may be modest and dependent on other co-existent, ethnicity-specific, genetic or environmental risk factors. © 2008 The Authors