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Although food allergy has emerged as a major health problem, the mechanisms that are decisive in the development of sensitization to dietary Ag remain largely unknown. CTLA-4 signaling negatively regulates immune activation, and may play a crucial role in preventing induction and/or progression of sensitization to food Ag. To elucidate the role of CTLA-4 signaling in responses to food allergens, a murine model of peanut allergy was used. During oral exposure to peanut protein extract (PPE) together with the mucosal adjuvant cholera toxin (CT), which induces peanut allergy, CTLA-4 ligation was prevented using a CTLA-4 mAb. Additionally, the effect of inhibition of the CTLA-4 pathway on oral exposure to PPE in the absence of CT, which leads to unresponsiveness to peanut Ag, was explored. During sensitization, anti-CTLA-4 treatment considerably enhanced IgE responses to PPE and the peanut allergens, Ara h 1, Ara h 3, and Ara h 6, resulting in elevated mast cell degranulation upon an oral challenge. Remarkably, antagonizing CTLA-4 during exposure to PPE in the absence of CT resulted in significant induction of Th2 cytokines and an elevation in total serum IgE levels, but failed to induce allergen-specific IgE responses and mast cell degranulation upon a PPE challenge. These results indicate that CTLA-4 signaling is not the crucial factor in preventing sensitization to food allergens, but plays a pivotal role in regulating the intensity of a food allergic sensitization response. Furthermore, these data indicate that a profoundly Th2-biased cytokine environment is insufficient to induce allergic responses against dietary Ag.

ABSTRACT:Evidence is increasing for a role of polymorphisms in maternal or fetal innate immune response genes in preterm birth. Toll-like receptors (TLRs) are important receptors in the innate immunity. The genotype distribution of two TLR2 single nucleotide polymorphisms (SNPs) and one TLR4 SNP were determined among 524 neonates and associated with gestational age (GA). Genomic DNA was isolated from prospectively collected blood samples and polymorphisms in TLR2 (T-16934A, RS4696480 and Arg753Gln, RS5743708) and TLR4 (Thr399Ile, RS4986791) were determined using sequence specific primers by PCR. Allele frequencies of two TLR2 SNPs and one TLR4 SNP were analyzed according to prematurity. Analysis among 305 infants, after exclusion of infants born after multiple pregnancy or because of preeclampsia, revealed significantly shorter GAs for infants carrying two polymorphic TLR2 alleles (-16934TA/AA and 753ArgGln/GlnGln) compared with infants carrying one polymorphic and one wild-type allele or two wild-type alleles (median GA 30.6 wk versus 34.1-36.8 wk, respectively, p Ͻ 0.02). Carriage of two variant TLR2 alleles potentially leads to aberrant innate immune responses, which may have contributed to very preterm birth. (Pediatr Res 62: 474-476, 2007) P reterm birth remains a major public health concern because of its associated perinatal morbidity and mortality (1). Evidence is increasing of an important role of polymorphisms in maternal or fetal immune response genes in preterm birth (2,3). Several single nucleotide polymorphisms (SNPs) in immune response genes, particularly in proinflammatory cytokine genes, have been investigated for their contribution to the etiology of preterm birth (2-5). The innate immune system's rapid recognition of pathogens is mediated through toll-like receptors (TLRs) and binding of a microbe to a TLR leads to activation of several inflammatory pathways (6 -9). SNPs in TLR genes may affect TLR function, contributing to a modulated inflammatory response. Up-regulation of TLRs may be one of the mechanisms by which intrauterine inflammation signals parturition and triggers preterm labor (10). This is supported by the fact that the majority of pregnancies that end with very preterm birth are more likely to be complicated by chorioamnionitis and/or neonatal infection acquired by vertical transmission from the mother (11,12). Moreover, an increased frequency of two TLR4 polymorphisms has been found in a population of preterm Finnish infants when compared with term control infants (5). The most important TLR4 ligand is LPS from Gram-negative microorganisms.We hypothesize that polymorphisms in the TLR2 and TLR4 genes result in modulation of fetal inflammatory responses, which trigger preterm birth. To address this issue, we determined the genotype distribution of two common TLR2 (T-16934A, Arg753Gln) and two cosegregating TLR4 (Asp299Gly and Thr399Ile) SNPs among 524 infants admitted to the neonatal intensive care unit of our hospital and associated this with gestational age (GA). METHODS Patient...

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