Modulation of in vivo and in vitro cytokine production over the course of pregnancy in allergic and non-allergic mothers.

Cytokines secreted during pregnancy may influence immune development of the foetus. This study aimed to determine if maternal allergy alters patterns of systemic cytokine production throughout and after pregnancy. Maternal plasma cytokines and allergen-specific production of interleukin (IL)-10, IL-13 and interferon (IFN)-gamma were measured in allergic (n = 63) and non-allergic (n = 70) pregnant women who had a full set of sequential peripheral blood samples collected at 20-, 30-, 36-wk gestation and 6-wk post-partum. Maternal allergy was strictly defined by both allergen sensitization and doctor-diagnosed asthma, eczema or rhinitis. IL-13 responses to allergen were higher for allergic mothers at all time-points (20 wk: p < 0.001; 30 wk: p = 0.001; 36 wk: p < 0.001; post-partum: p < 0.001). For the non-allergic group, IL-13 levels to house dust mite decreased from 20- to 36-wk gestation (Friedman ANOVA p = 0.012) and were significantly lower at 36 wk compared with post-partum (p = 0.002). In contrast, IL-13 production by allergic mothers did not change from 20 wk through to post-partum. For both allergic and non-allergic mothers, in vitro IFN-gamma production was lower at all pregnancy time-points compared with post-partum levels. Allergic women had an increased propensity for peripheral blood allergen-specific T helper-2 responses during pregnancy, and failed to downregulate these responses in comparison with non-allergic women. This may be a factor that contributes to the increased risk of atopy in infants born to allergic mothers.

Presymptomatic differences in Toll-like receptor function in infants who have allergy.

BACKGROUND: Microbial exposure might play a key role in allergy development, but little is known about the role of Toll-like receptors (TLRs). OBJECTIVE: This study explored the association between neonatal TLR microbial recognition/function, allergy risk (maternal allergy), and prospective allergy development. METHODS: Cord blood mononuclear cells (n = 111) were cultured either alone or with optimal concentrations of TLR ligands: lipoteichoic acid (TLR2), polyinosinicpolycytidylic acid (TLR3), LPS with IFN-gamma (TLR4), flagellin (TLR5), imiquimod R837 (TLR7), or CpG (TLR9). Cytokine responses were assessed in relation to allergy risk (maternal allergy) and allergy outcomes (sensitization, food allergy, and atopic dermatitis) at 12 months of age. RESULTS: Maternal allergy (n = 59) was associated with significantly higher neonatal IL-12 and IFN-gamma responses to TLR2, TLR3, and TLR4 activation, whereas TNF-alpha and IL-6 responses to TLR2, TLR4, and TLR5 activation were significantly higher in newborns who subsequently had allergic disease (n = 32). Notably, consistent with previous reports, newborns who had disease had lower T(H)1 IFN-gamma response to mitogens (PHA). CONCLUSION: Allergic disease was associated with increased (rather than decreased) perinatal TLR responses. Further studies are needed to determine how these responses track in the postnatal period and whether this relative hyperresponsiveness is a product of intrauterine influences, including maternal atopy, functional genetic polymorphisms, or both.

The effects of maternal smoking on early mucosal immunity and sensitization at 12 months of age.

With the dramatic rise in asthma and respiratory disease, there is an urgent need to determine the effects of common environmental exposures on early immune development. In this study, we examined the effects of maternal smoking as a major adverse exposure in early life, on mucosal immune function and allergen sensitization in the first year of life. A cohort of 60 smokers and 62 non-smokers was recruited in pregnancy, and followed prospectively at 3 and 12 months of age for saliva collection [for immunoglobulin (Ig) A measurements], urine collection (for cotinine levels) and clinical assessments (for allergy and infection history). Allergen skin-prick tests were also performed at 12 months of age. Specific IgA to common colonizing bacteria was measured on saliva samples, including pneumococcal polysaccharide (PS) serotype 14 and non-typeable Haemophilus influenza (NTHI) outer membrane protein 6 (OMP6). Eighty-two mothers and their infants completed the 12-month follow-up period--56 in the maternal non-smoking group and 26 in the maternal smoking group. Maternal smoking was associated with significantly higher total infant salivary IgA at 12 months of age (p = 0.026), and more chronic upper respiratory tract symptoms (p = 0.012). However, there were no differences in the level of specific IgA antibodies to common colonizing bacteria (pneumococcal PS serotype 14 and NTHI OMP6). In general, the IgA levels at 12 months were higher in children who had more chest infections in the first year (Kendall's tau b, 0.282; p = 0.003). There was also a trend of lower respiratory tract symptoms (wheeze) (p = 0.142) in infants of smokers. There were no effects of maternal smoking on the rates of allergen sensitization, atopic dermatitis and food allergy at 12 months of age. In conclusion, maternal smoking did not inhibit the production of anti-microbial IgA, suggesting that other factors are responsible for the increased susceptibility to infection in these infants. The increased mucosal inflammation in these children was not associated with effects on early allergy propensity.

Anti-tissue factor pathway inhibitor activity in subjects with antiphospholipid syndrome is associated with increased thrombin generation.

BACKGROUND AND OBJECTIVES: Immunoglobulin G (IgG) fractions from subjects with antiphospholipid syndrome (aPS) have previously been demonstrated to have inhibitory activity against tissue factor pathway inhibitor (TFPI). This may contribute to the development of a prothrombotic state by impaired regulation of the tissue factor (TF) pathway. This study investigated the effect that IgG fractions from aPS subjects containing anti-TFPI activity have on in vitro TF-induced thrombin generation. DESIGN AND METHODS: TFPI and anti-TFPI activities were determined in normal controls (n=29) and aPS subjects (n=57). TFPI activity was determined using an amidolytic assay based on the generation of factor Xa. Anti-TFPI activity was determined after incubating IgG isolated from a control or subject plasma with pooled normal plasma, using the TFPI activity assay. The influence of IgG fractions from controls (n=10) and subjects (n=23) on TF-induced in vitro thrombin generation was determined using a chromogenic assay of thrombin activity. RESULTS: TFPI activity in controls (1.13+/-0.25 U/mL) was significantly lower than in subjects (1.30+/-0.42 U/mL) (p < 0.05). Anti-TFPI activity was significantly higher in subjects than controls (p = 0.0001). TF-induced thrombin generation was positively associated with anti-TFPI activity (r = 0.356; p > 0.05), with increased levels of each demonstrated in 5 subjects. INTERPRETATION AND CONCLUSIONS: Anti-TFPI activity was confirmed in 65% of aPS subjects. IgG fractions demonstrated a variable ability to interfere with TFPI function and TF-induced thrombin generation. Cross-reacting antiphospholipid antibodies and/or other entities may interfere with TFPI function, resulting in a net increase in thrombin generation and an increased thrombotic risk.