Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases.

Histamine plays an important role in the development of symptoms in allergic, infectious, neoplastic and other diseases. Empirical findings have suggested beneficial effects of ascorbic acid supplementation in those diseases, and these effects are assumed to be related to a possible decrease in systemic histamine concentration. In the present study, we systematically investigated for the first time the effect of 7.5 g of intravenously administered ascorbic acid on serum histamine levels (as detected by ELISA) in 89 patients (19 with allergic and 70 with infectious diseases). When all patients were grouped together, there was a significant decline in histamine concentration from 0.83 to 0.57 ng/ml×m2 body surface area (BSA, p<0.0001). The decrease in serum histamine concentration in patients with allergic diseases (1.36 to 0.69 ng/ml×m2 BSA, p=0.0007) was greater than that in patients with infectious diseases (0.73 to 0.56 ng/ml×m2 BSA, p=0.01). Furthermore, the decline in histamine concentration after ascorbic acid administration was positively correlated with the basal, i.e. pre-therapeutic, histamine concentration. Intravenous infusion of ascorbic acid clearly reduced histamine concentrations in serum, and may represent a therapeutic option in patients presenting with symptoms and diseases associated with pathologically increased histamine concentration.

Entropy-favored human antibody binding reactions with a non-infectious antigen.

Little is known about the thermodynamic properties of human antibodies directed against 'natural' antigen surfaces, possibly due to the complex interactions that are involved. Using an affinity distribution method, we have previously characterized the binding reactions between a major allergen from ragweed, Amb a 1, and serum Amb a 1-specific IgE as a model system. We determined the temperature dependence of these interactions using serum samples from people with established allergic sensitivity to ragweed pollen. Each sample provided evidence for three epitope-specific IgE reactions with extremely high equilibrium binding affinities @ 37 degrees C (10(8) to 10(11)M(-1)). Determining the affinities over a range of temperatures (4-41 degrees C) revealed a favorable exothermic Gibbs free energy change, DeltaG approximately -17.59 (+/- 5.04)kcal/M, comparable to previous reports using monoclonal antibodies produced against well-defined artificial antigens. In contrast to previous studies, in this system there was minimal input from enthalpy: DeltaH approximately -2.41 (+/- 2.32)kcal/M. However, a significant contribution was found from entropic changes: DeltaS approximately 48.98 (+/- 9.20)cal/KM. Human 'secondary antibodies' such as IgE, produced after exposure to 'natural' antigens, are optimized in terms of their high equilibrium binding constants with the antigen (allergen) that induced their production. Thermodynamically this is exemplified by minimal enthalpic (bond formation) concomitant with significant entropic (alignment) contributions to the total free energy change of reaction. These results suggest a high degree of 'complementarity' between the antibody and antigen surfaces in this experimental system, and may be a general guiding principle in the evolution of antibody repertoires by the adaptive immune system.

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.

Evidence for two independent distributions of serum immunoglobulin E in atopic families: cognate and non-cognate IgE.

Genetic studies of IgE-mediated atopic disease have produced conflicting results, due largely to variable phenotype definitions. Total IgE concentrations and 14 allergen skin prick tests (SPT) were determined in 1099 members of families with history of atopy. Log10 [Total IgE] values were normally distributed in both atopic (SPT [+]) and non-atopic (SPT [-]) groups. The mean Log10 [Total IgE] value was higher in the atopic group, although the standard deviations of the distributions were the same. The mean Log10 [Total IgE] value of the non-atopic distribution was subtracted from the individual Log10 [Total IgE] values of the atopic group giving an allergen-specific fraction. There was a strong positive correlation between the specific IgE fraction and the number (#) SPT [+] results, defined as Cognate IgE. Among the atopics, subtracting the Cognate IgE value from total IgE yielded Non-Cognate IgE. The Cognate and Non-Cognate IgE distributions were statistically uncorrelated. Evidence is presented for two serum IgE fractions that are statistically and physiologically independent of one another in atopic families; a Cognate IgE fraction associated with atopic sensitization and a Non-Cognate IgE fraction unrelated to atopic disease. Elevated serum IgE is a consequence, not a predisposing cause, of allergen sensitization.

Robustness into advanced age of atopy-specific mechanisms in atopy-prone families.

We evaluated atopy-associated parameters in 1,099 people (aged 6-84 years) from families with history for atopy. All were tested for serum total immunoglobulin E (IgE) and allergen sensitivity by skin prick test. Specific IgE tests were done in randomly selected families. There was a decline with age in serum total IgE values, and relative atopy "incidence rates" were slightly lower among those older than 60 years. However, there was no change with age in sensitivity or severity of atopy. Among those sensitized to ragweed (Ambrosia artemisilfolia), there was no age-associated change in IgE levels specific to Amb a 1, a major allergen extracted from ragweed, and no change in the binding affinity of IgE for the Amb a 1 allergen. Among families with atopic histories, the underlying atopic mechanisms are particularly robust, and the atopic propensity remains into advanced age. In addition, established atopic responses may be focused in an immune system compartment either independent of or minimally influenced by T-cell activity.

Allergen skin test reaction patterns in children (

BACKGROUND: Genetic studies of atopy rely upon evidence of abnormal IgE production, usually elevated total IgE or skin prick test (SPT) reactions. However, these measures may change with subject age. METHODS: We screened 1,099 members of atopic families (aged 6-87 years) by serum total IgE and SPT for 14 allergens. For those SPT negative, we screened for Amb a 1- and Der p 1-specific IgE. Der p 1 IgE-Der p 1 allergen binding affinities were done on randomly selected subjects. RESULTS: There were significantly fewer atopics 10 years old (75.8%) based upon any SPT-positive result. Children 10 years old = 82.3%). Among those SPT-positive for house dust mite extract, there was a positive correlation between Der p 1 binding affinity and the wheal area of the house dust mite extract. There was a positive correlation between the number of SPT-positive reactions and total IgE for both age groups. However, there was only a significant relationship between SPT-positive wheal area and total IgE for those >10 years old and no apparent relationship between wheal area and total IgE for those

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.