Search for quantitative trait loci of atopy-associated immune responses using allergen-specific IgG1 as an "endophenotype".

Inherited atopic diseases of humans arise from adverse adaptive humoral responses to noninfectious environmental allergens. We previously reported that allergen-specific IgG1 provides more reliable heritability estimates for responses to allergens than total IgE. Genome scans were done for 91 Caucasian nuclear families with history of atopy for total IgE and IgG1 produced against a common major allergen from house dust mite, Der p 1. Suggestive associations for Der p 1-IgG1 production were found at 7 quantitative trait loci (QTL) (logarithm of the odds, LOD > or = 1.23; p < or = 0.009) with QTL-specific heritabilities of 73%-80%. Scans using total IgE found suggestive associations for 12 QTLs (LOD > or = 1.44; p < or = 0.004), but QTL-specific heritabilities only in the range of 30%-35%. Allergen-specific IgG1 is a suitable "endophenotype" to be used in searches for genes associated with atopy-associated humoral immune responses to common aeroallergens.

Allergen-specific IgG1 provides parsimonious heritability estimates for atopy-associated immune responses to allergens.

Although serum total immunoglobulin E (IgE) is generally elevated in atopic conditions, it is an unreliable trait for dissecting the genetic and environmental components contributing to atopic immune responses, because it can be significantly confounded by demographic factors (age, gender, and race) and clinical status (atopic vs nonatopic). Allergen-specific IgE is a discontinuous trait present only in those with sensitivity to allergens. However, all people will produce allergen-specific immunoglobulin G1 (IgG1), which is elevated among those atopically sensitized to specific allergens. We screened 91 Caucasian nuclear families (N = 367) with medical histories of atopic diseases and used variance components analysis to compare heritability estimates for total IgE and IgG1 produced against the common major allergen from house dust mite Dermatophagoides pteronyssinus (Der p 1). An estimate of total IgE heritability was about 48%, although this was significantly confounded by age, gender, and clinical atopic status. In contrast, Der p 1-IgG1 demonstrated a significant inherited component of about 62% that was not influenced by age, gender, or clinical status. For genetic studies of atopic humoral responses, allergen-specific IgG1 may be a more reliable quantitative trait than serum IgE. Moreover, atopy is an inherited deregulation of immune responses to noninfectious antigens, involving antibody isotypes other than IgE.

CD14 promoter polymorphisms in atopic families: implications for modulated allergen-specific immunoglobulin E and G1 responses.

BACKGROUND: CD14 promoter DNA sequence polymorphisms for the endotoxin receptor gene have been implicated in modulating allergen-specific immunoglobulin (Ig)E responses in randomly selected individuals with atopy. We sought to determine if a single nucleotide polymorphism in the CD14 promoter region is associated with atopy in atopic families, and to assess its influence on serum levels of CD14 and allergen-specific IgE and IgG1 responses. METHODS: We screened 367 members of 91 Caucasian nuclear families with a history of asthma for pulmonary function by spirometry, including methacholine challenge to detect bronchial hyperreactivity, and atopy by serum total IgE and skin prick test to 14 allergens. The CD14 promoter single nucleotide polymorphism was analyzed in DNA isolated from peripheral blood mononuclear cells to identify C/C, C/T and T/T genotypes. Serum tests were done for soluble CD14 (sCD14) and dust mite-specific antibody (Der p 1-IgG1). RESULTS: Serum sCD14 levels were not associated with clinical phenotypes (asthma, bronchial hyperreactivity or atopy). However, sCD14 levels were inversely related to both allergen-specific IgE and Der p 1-IgG1 production, but only among those with evidence of atopic sensitization. Linear regression analysis, accounting for random family effects, demonstrated a higher production of allergen-specific IgE or Der p 1-IgG1 associated with the T/T genotype and a lower level of specific IgE and IgG1 production associated with sCD14 levels. CONCLUSIONS: An element of the innate immune system (CD14) has profound effects upon modulating the acquired allergen-specific immunoglobulin responses among those with an inherited atopic predisposition.

Evidence that negative feedback between antibody concentration and affinity regulates humoral response consolidation to a non-infectious antigen in infants.

The dynamics of human antigen-specific immunoglobulin (Ig) responses in early life are not well characterized. We have previously observed an inverse relationship between allergen-specific Ig concentration and allergen-Ig-binding affinity in allergen-sensitive atopic adults, suggesting a possible feedback relationship between these variables. We prospectively studied children (6 months to 6 years) with and without atopic sensitization to the Der p 1 major allergen. Experimental results showed the following trends. (1) In both study groups, there was little change with age in average Der p 1-specific Ig (IgG1 or IgE) concentrations or allergen-Ig-binding affinities, and concentrations and affinities were independent. (2) Among individuals, however, there was a negative correlation between Ig concentration changes and affinity changes with age. (3) The rate of increase with age of the non-atopic Der p 1-IgG1 total binding capacity (Ig concentration x Ig affinity) paralleled that for the atopic Der p 1-IgE total binding capacity, and there was a comparable 'consolidation' of responses with age reflected by a narrowing of the variance of total binding capacity values. Except for the Ig classes involved, development of a humoral response to a non-infectious allergen is similarly regulated in atopic and non-atopic children, with Ig total binding capacity as the key regulatory variable. These results also suggest that there is a time-dependent feedback relationship between Ig concentrations and affinities that establishes an optimal Ig total binding capacity for a given environmental 'antigen load'. A theoretical model is proposed to account for this relationship.

Variable binding affinities for allergen suggest a 'selective competition' among immunoglobulins in atopic and non-atopic humans.

Atopy is a persistent, aberrant humoral response to certain classes of proteins (allergens) characterized by the presence of allergen-specific IgE. Yet, in both atopic and non-atopic individuals, allergen-specific responses involving the IgA and IgG subclasses have been observed, which evidence does not support models suggesting inherited differences in sensitivity to certain protein classes. Using the major ragweed component Amb a 1 as a model allergen, we assessed the humoral responses in three groups of unrelated donors: (A) atopic, ragweed sensitive; (B) atopic, but not ragweed sensitive; (C) non-atopic. As expected, Amb a 1-specific IgE was present in group A only. However, there were essentially no differences in the relative proportions of Amb a 1-specific IgA(1,2) and IgG(1-4) among the groups. We also determined the Amb a 1 binding affinities for IgG(1) and IgG(4) in the three groups, and compared these to Amb a 1-specific IgE binding affinities in group A. Group A donors' Amb a 1-IgE had extremely high affinities (10(8) to 10(11)M(-1)), but their Amb a 1-IgG(1) and Amb a 1-IgG(4) affinities were significantly lower (10(7) to 10(10)M(-1)). The average IgG(4) binding affinities in groups B and C were slightly higher than that of IgG(4) in group A, although not statistically significant. However, the IgG(1) affinity for Amb a 1 among group C, non-atopic donors was significantly elevated and comparable to the IgE affinity observed in group A, ragweed atopics. Inhibition studies with allergen-specific IgE-free serum showed that all isotypes recognized the major epitopes seen by IgE. These results suggest that there may be a "selective competition" among isotypes for allergens that is driven by the ability to produce high affinity, allergen-specific immunoglobulins.