IgE synthesis in man. II. Comparison of tetanus and diphtheria IgE antibody in allergic and nonallergic children.

Specific IgE and IgG antibodies were quantitated in 91 allergic and 80 nonallergic age- and sex-matched children between 4 and 17 yr of age. Statistically significant increased antidiphtheria and antitetanus IgE antibodies (p < 0.01) measured by the radioallergosorbent test (RAST) were noted in allergic compared with nonallergic subjects. Of the allergic children with total serum IgE >500 U/ml, 19 of 52 (37%) and 25 of 52 (48%) had elevations (>2 SD above nonallergic control mean) of serum antitetanus or antidiphtheria IgE antibody, respectively, whereas only 2 of 35 allergic children with serum IgE <500 U/ml had elevation (>2 SD) of these antibodies. Antitetanus and antidiphtheria IgG antibodies were measured by passive sheep red blood cell (SRBC) hemagglutination. Geometric mean antitetanus IgG antibodies were higher in allergic (4.9 AU/ml) as compared to nonallergic (1.7 AU/ml) children (p < 0.001). Geometric mean antidiphtheria IgG antibodies were higher (0.31 AU/ml) in nonallergic and lower in allergic (0.10 AU/ml) subjects (p < 0.01). These data suggest that allergic individuals with markedly elevated total serum IgE have unique antibody responses following routine immunization with tetanus-diphtheria (Td) toxoids and tetanus-pertussis-diphtheria (DPT) which are manifest by enhanced specific IgE synthesis.     

Elevated immunoglobulin E against recombinant Brugia malayi gamma-glutamyl transpeptidase in patients with bancroftian filariasis: association with tropical pulmonary eosinophilia or putative immunity

A major allergen of the lymphatic filarial nematode Brugia malayi, a homologue of gamma-glutamyl transpeptidase (gamma-GT), is involved in the pathology of tropical pulmonary eosinophilia (TPE) through its potent allergenicity and the induction of antibodies against the host pulmonary epithelium. To investigate the immunoglobulin G (IgG) subclass and IgE responses to recombinant B. malayi gamma-GT, we analyzed the results obtained from 51 patients with differing clinical manifestations of bancroftian filariasis. gamma-GT-specific IgG1, rather than IgG4, was the predominant IgG subclass, particularly in patients with TPE (geomean, 6,321 ng/ml; range, 78 to 354,867 ng/ml) and was 75 times higher than in patients with elephantiasis (CP) (P < 0.003) and 185 times higher than in endemic normal individuals (ENL) (P < 0.010). IgG2 responses were low and IgG3 was almost absent, with no significant differences among the groups. gamma-GT-specific IgG4 responses were significantly elevated in those with subclinical microfilaremia (MF) compared to the CP and ENL groups and correlated with the presence of circulating filarial antigen (CAg). More significantly, gamma-GT-specific IgE antibody levels were strikingly elevated in patients with TPE (geomean, 681 ng/ml; range, 61 to 23,841 ng/ml) and in the ENL group (geomean, 106 ng/ml; range, 13 to 1,405 ng/ml) whereas the gamma-GT-specific IgE level was 44 and 61 times lower in those with MF and CP, respectively (P < 0.001). Elevated gamma-GT-specific IgE/IgG4 ratios were demonstrated in patients with TPE (ratio, 45) and ENL (ratio, 107). Because expression of gamma-GT in Brugia infective third-stage larvae (L3) was demonstrated by immunoblot analysis, the elevated gamma-GT-specific IgE antibodies appear to be associated not only with pulmonary pathology but also with possible resistance to infection in lymphatic filariasis.     

Determination of IgG subclass antibodies against wheat flour antigens by an ELISA technique

We describe the assay conditions for an enzyme-linked immunoassay for the determination of IgG and IgG subclass antibodies in serum to water-soluble wheat flour antigens. The optimal antigen coating concentration was 5 micrograms/ml for total IgG, IgG1, IgG4 and 100 micrograms/ml for IgG2. Serial dilutions of test sera were used and commercially available monoclonal mouse anti-human IgG isotype antibodies (as ascites fluid) were diluted 1:500-1:1000. Specific wheat flour antibodies belonging to the IgG1, IgG2 and IgG4 subclasses were detected. Despite the lack of standardized isotype-specific second mouse monoclonal antibodies, the subclass antibody levels between flour-exposed bakers and controls could be compared. We observed significantly higher IgG1, IgG2, and IgG4 subclass antibodies among 23 bakers than among 12 non-exposed controls, but no IgG3 antibodies were detected. The differences in biological activities of the IgG subclass antibodies may explain the clinical and pathophysiological features for fluor-induced occupational allergic diseases among bakers.     

Humoral Immunity to Dietary Antigens in Atopic Dermatitis

IgG subclass antibodies to two dietary antigens, ovalbumin (OA) and beta-lactoglobulin (BLG) were measured with quantitative ELISA-techniques in 16 patients with atopic dermatitis (AD) (6-21 years old) and closely matched controls. In addition, IgE-antibodies to OA, BLG and milk were determined with RAST. IgG subclass antibodies were frequently detected in IgG1 and IgG4 for both AD-patients and controls, quantitatively dominated by IgG4. The IgG4 anti-BLG antibody levels were significantly higher (P less than 0.001) in AD-patients (median: 1.1 microgram/ml, range: 0-24.0 microgram/ml) than in controls (median: 0.05 microgram/ml, range: 0-1.05 microgram/ml). No relation was found between IgG4 anti-BLG antibody levels, levels of IgE antibodies to milk or BLG, or severity of disease.     

Studies on IgG subclass antibodies in adult asthma. 2. Changes in serum antigen specific IgG subclass antibodies for aging and intractability in asthmatics]

To clarify the factors which induce intractable asthma, the level of serum IgG subclass antibodies to mite (Dermatophagoides farinae) and Candida antigens (Candida albicans) for aging and severity was investigated in 230 bronchial asthmatics (Male: 117, Female: 113) aged 6-81 years old (mean age = 40). Total IgE level and IgE antibodies to mite and Candida antigens were measured by radioimmunosorbent test (RIST) and radioallergosorbent test (RAST), respectively. The serum level of IgG and IgG1 antibodies to the antigens were measured by enzyme-linked immunosorbent assay (ELISA). The results were as follows: 1) The incidence of severe asthma in aged and late onset asthmatics, especially late onset intractable asthma (LOIA), was higher than that in young and early onset asthmatics. 2) The serum level of total IgE and IgE antibodies to mite in aged and late onset asthmatics was lower than that in young and early onset asthmatics. 3) The incidence of severe and intractable asthmatics in the group of low IgE levels (less than 300 IU/ml) was higher than that in the group of high IgE levels (over 500 IU/ml). The incidence of positive IgE (RAST) score to mite in severe and intractable asthmatics was lower than that in mild and moderate asthmatics. 4) Considering aging, the serum levels of IgG and IgG1 antibodies to mite and Candida in severe and intractable asthmatics was higher than those in mild asthmatics. These data indicate that the aged and late onset asthmatics may produce dominantly the IgG (IgG1) antibody to the antigens, and have severe asthma attacks caused by IgG (IgG1) rather than IgE antibody.     

Clinical significance of IgG subclass antibodies to wheat flour antigens in bakers

We measured the IgG subclass antibody levels to wheat flour in 42 bakers and 20 controls with an enzyme immunoassay. The levels of total IgG, IgG1 IgG2 and IgG4 antibodies were significantly higher in the bakers than in the unexposed controls. The presence of anti-wheat flour IgG subclass antibodies in the bakers was correlated with various clinical variables including IgE levels, duration of asthmatic or rhinitis symptoms, skin prick test response, peripheral blood eosinophil levels, bronchial histamine reactivity and responses to nasal challenge with wheat flour. The IgG subclass antibody levels of the total cohort of bakers did not correlate with any of the measured clinical variables. However, among men specific IgG4 and IgG1 antibody levels correlated negatively with total IgE levels and duration of rhinitis, respectively. We conclude that IgG and IgG subclass levels to wheat flour in bakers reflect exposure, but that it is not related to any specific clinical situation. The exact pathogenic role of these antibodies in the development of occupational asthma and rhinitis is thus not clear.     

Allergenicity of major cow's milk and peanut proteins determined by IgE and IgG immunoblotting

BACKGROUND: Specific IgG antibodies are frequently observed in food-allergic patients. However, the allergen-fraction specificity of IgG antibodies in relation to IgE antibodies is not well defined. Our aim was to determine the IgE and IgG antibody profile to major cow's milk and peanut-antigen fractions in food-allergic patients and tolerant individuals. METHODS: Sera were collected from 10 patients allergic to cow's milk and 10 patients allergic to peanuts, as well as from 20 control subjects. Cow's milk and peanut proteins were migrated on SDS-PAGE and immunoblotted for IgE, IgG, and IgG4 antibodies. Food-specific IgE concentrations were measured by CAP System FEIA, and IgG and IgG4 concentrations by ELISA. RESULTS: In food-allergic children, similar fraction-specific IgE, IgG, and IgG4 antibody-binding profiles to the major cow's milk or peanut antigens were found. In nonallergics, the presence of fraction-specific IgG antibodies was mostly dependent on regular ingestion of the food. The presence of specific antibody on immunoblots correlated with their quantitative measurement. The mean value for specific IgE in cow's milk-allergic patients was 450 +/- 1,326 IU/ml, and 337 +/- 423 IU/ml in peanut-allergic patients. Specific IgG antibody values in milk-allergic patients were not different (median OD 1.5, range 0.3-2.3) from controls (median OD 1, range 0.2-1.8). However, in peanut-allergic patients, IgG concentrations were significantly higher than in controls (OD 1.2 [0.5-1.3] vs 0.5 [0.3-0.7]; P< 0.01). CONCLUSIONS: Similar fraction-specific IgE and IgG antibody profiles in allergic individuals suggest a common switching trigger involving both isotypes. Intrinsic allergenicity might explain identical IgG antibody fraction specificity in nonallergics and in allergics. The presence of IgG antibodies in nonallergics was related to regular ingestion of the food.     

Effect of praziquantel on certain immune responses of schistosomal egyptian patients

Specific antischistosomal IgG, IgM, and IgE were estimated by ELISA in 117 rural school students before specific treatment with praziquantel monthly for 3-4 months thereafter. IgG and IgM were estimated as percentage of bound antibodies. IgE was estimated by avidin-biotin ELISA (AB-ELISA) as IU/ml using a panel of known IgE standards. Soluble surface Schistosoma mansoni adult worm antigen was used for all estimates. Total IgE was estimated in a smaller group by an ELISA kit. The percentage of specific IgE was calculated. A group of endemic controls (22 students) and non-endemic controls (17 cases) were included. Statistical analysis of results showed the specific immunoglobulins to be significantly reduced 2 months after treatment of the schistosomal cases. These reduced levels, however, were still significantly higher than those of controls. The presence of early hepatosplenomegaly and the co-existence of other parasites had no significant influence on the results. No correlation could be established between the levels of specific antischistosomal IgG, M and E and the intensity of infection. The significance of these results is discussed.     

Immunoglobulin G subclass response of localized juvenile periodontitis patients to Actinobacillus actinomycetemcomitans Y4 lipopolysaccharide.

Sera from patients with localized juvenile periodontitis (LJP) often contain markedly elevated immunoglobulin G (IgG) antibody titers to serospecific determinants of the lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans. The objective of the present study was to define the subclass distribution of the IgG antibody response of LJP patients to this key cell envelope antigen. IgG subclass antibody responses to A. actinomycetemcomitans LPS were quantified in an enzyme-linked immunosorbent assay with human IgG subclass-restricted monoclonal antibodies. Serum antibody concentrations were calculated by heterologous interpolation of a dose-response curve constructed by using human-mouse chimeric antibodies. Sixteen of 17 LJP serum samples tested contained significantly greater concentrations of IgG2 than IgG1 antibodies reactive toward A. actinomycetemcomitans LPS. Geometric mean antibody concentrations of IgG1 and IgG2 were 7.8 and 136.5 micrograms/ml, respectively, among LJP patients with elevated IgG titers to LPS (94% of whom were black). However, both IgG1 and IgG2 antibody concentrations were significantly greater than the corresponding values obtained from sera from LJP patients with low IgG titers to LPS. Among LJP patients with elevated IgG titers to A. actinomycetemcomitans LPS, serum IgG2 concentration and total IgG concentration were also significantly elevated compared with both low-titered LJP sera and sera from periodontally healthy race-matched controls. The results of this study indicate that the humoral response of a predominantly black population of LJP patients to A. actinomycetemcomitans includes the production of LPS-reactive IgG antibodies which are primarily of the IgG2 subclass.     

Immunoglobulin G subclass restriction of antibodies against hepatitis B surface antigen.

Immunoglobulin G (IgG) antibodies against hepatitis B surface antigen were found to be restricted to subclasses IgG1 and IgG3 in serum samples of 17 individuals. Quantitative determinations showed that in 10 samples the minor serum subclass IgG3 contained more antibodies than the predominant subclass IgG1. Ranges of concentrations were between 0.72 and 16.50 micrograms/ml for IgG3 antibodies and between 0.55 and 6.19 micrograms/ml for antibodies of subclass IgG1.     

Humoral and cellular responses to gliadin in wheat-dependent, exercise-induced anaphylaxis

BACKGROUND: Wheat-dependent, exercise-induced anaphylaxis (WDEIA) is a severe allergy where wheat ingestion together with physical exercise induces anaphylaxis. We have previously shown that patients with WDEIA have IgE antibodies against gliadin proteins and identified omega-5 gliadin (Tri a 19) as a major allergen. OBJECTIVE: The aim of this study was to examine gliadin-specific IgG subclass, IgA and IgE antibodies, basophil histamine release and cell-mediated responses in WDEIA. METHODS: Sera and peripheral blood mononuclear cells (PBMC) were obtained from patients with WDEIA and from controls without wheat allergy. Serum antibodies to crude gliadin extract (CGE) and purified omega-5 gliadin were measured by ELISA and basophil reactivity by histamine-release test. Gliadin-induced cell-mediated responses were assessed by lymphocyte proliferation assay, and cytokine mRNA expression with real-time quantitative PCR. RESULTS: All patients with WDEIA, but none of the controls, had IgE antibodies to CGE and omega-5 gliadin. Both allergens released high levels of histamine from the basophils of patients with WDEIA. Levels of IgA antibodies to CGE and omega-5 gliadin were significantly elevated in the patients, but the distribution of IgG subclass antibodies showed no statistically significant differences between the two groups. Proliferative responses of PBMC to CGE were increased in patients with WDEIA, and stimulation of PBMC with CGE caused, both in patients and in controls, a clear induction of IL-10 mRNA. Compared with the controls, induction of IL-10 mRNA expression in patients with WDEIA was significantly (P < 0.01) suppressed. CONCLUSION: These results suggest that, in addition to IgE antibodies against omega-5 gliadin, specific IgA antibodies may be involved in the pathogenesis of WDEIA. Decreased expression of IL-10 mRNA in PBMC during gliadin stimulation may facilitate the development of gliadin-specific T cell responses.     

Immunosuppressant effect of gold on IgG subclasses and IgE; evidence for sparing of Th2 responses

We set out to examine the effect of gold treatment on the Th2-dependent antibodies IgG4 and IgE in relation to other IgG subclasses in patients with rheumatoid arthritis (RA). Eighty-five gold-treated RA patients and 82 RA controls were studied. Serum IgG subclass concentrations were measured by ELISA, IgE was measured by automated enzyme immunoassay. Samples were studied serially in 13 gold-treated patients and in 11 patients with gold-induced adverse events. There was a significant reduction in the concentration of IgG1, IgG2 and IgG3 in gold-treated RA patients compared with RA controls (P 0.004-0.019), whereas IgG4 was less significantly reduced in gold-treated patients (P = 0.044) and there was no difference in IgE. In serial samples there was a significant fall in the concentration of IgG1 (P = 0.001), IgG2 (P = 0.001) and IgG3 (P = 0.026) with time but no change in IgG4 and IgE. The development of gold-induced adverse events was not associated with any change in the concentration of each IgG subclass or IgE. Deficiencies of IgG subclasses were found in 30% of gold-treated RA patients and 8.5% of RA controls, and were associated in gold-treated patients with a longer disease duration (P = 0.003) and with erosive disease (P = 0. 03). IgG2 was affected most frequently and in the majority of these cases subnormal specific IgG2 binding to widespread polysaccharide antigens (Pneumovax II) was found. Gold induces an overall immunosuppressant effect on IgG subclasses, with a deficiency in 21. 5%, adjusted for controls. The effect on the Th2-dependent antibodies IgG4 and IgE is less marked, suggesting a sparing of Th2 responses.     

The IgG subclasses of antibodies to grass pollen allergens produced in hay fever patients during hyposensitization

Total IgG, IgG subclass and IgE antibodies specific for grass pollen allergens were measured by the red cell linked antigen-antiglobulin reaction (RCLAAR) in serum samples from nineteen patients who had undergone a course of hyposensitization. Increases in both specific IgG and IgE antibodies were seen after treatment in most patients. In the IgG subclasses the predominant response was for IgG1 and IgG4 antibodies. Attempts were made to correlate the antibody responses with the clinical response and the results are discussed with reference to the possible mechanisms of hyposensitization.     

Differences in titres of IgE, IgG4 and other IgG subclass anti- Der p 2 antibodies in allergic and non-allergic patients measured with recombinant allergen

Background The mite allergens are recognized as major causes of allergic disease such as bronchial asthma, allergic rhinitis and atopic dermatitis. The functions of allergen-specific IgG subclass antibodies are not defined.
Objective In order to clarify the relationship between IgE and IgG subclasses, we examined scrum levels of the Dermatophagoides pteronyssisus group 2 (Der p 2)-specific antibodies of IgH. IgG total and IgG subclasses in children with mite allergy.
Methods We prepared a recombinant Der p 2 fusion protein and examined serum levels of Der p 2 antigen-specific antibodies by enzyme-linked immunosorbent assay (FLISA) systems developed in our laboratory using a recombinant Der p 2 as target antigen. Sera from 240 children with mite allergy and 25 controls were measured.
Results The serum levels of specific IgE and, to lesser degree, lgG4 were higher in allergic children than non-allergic controls, while in the levels of the other IgG subclasses there was no difference between the two groups. There was no correlation between levels of specific IgF and IgG4 or in those between specific IgG4 and other IgG subclasses.
Conclusion Results indicate that the induction of Der p 2-specific lgG4 in allergic diseases is independent to IgE as well as other IgG subclasses.     

IgE production in vitro by peripheral blood mononuclear cells of patients with parasitic helminth infections.

Helminth parasites induce production of high levels of IgE antibodies but the immunoregulatory mechanisms determining this IgE biosynthesis are poorly understood. To investigate these mechanisms, peripheral blood mononuclear cells were obtained from six normal controls, six atopic patients and eight patients with parasitic helminth infections (three with schistosomiasis, two with loiasis, three with onchocerciasis). Cells were cultured at 1 X 10(6) cells/ml for 8 days in the presence of media alone or media supplemented with pokeweed mitogen (PWM) or cycloheximide; the supernatant fluids from these cultures were then assayed quantitatively for total and parasite specific IgE and IgG using an avidin-biotin amplified (for IgE) or standard (for IgG) microelisa assay. The geometric mean spontaneous IgE production was markedly elevated in peripheral blood mononuclear cells from parasitized individuals (2,487 pg/ml) when compared to those from atopics (358 pg/ml) or normals (152 pg/ml). Spontaneous IgG synthesis was equivalent in all three groups (range 140-420 ng/ml). PWM did not induce IgE production in any group and in the parasitized group even caused significant suppression of total IgE synthesis. Antigen specific antibody production (both IgE and IgG) paralleled total immunoglobulin synthesis. These findings demonstrate for the first time spontaneously enhanced IgE production in vitro in patients with helminth infections and provide a model system for studying the suppressive and regulatory mechanisms controlling IgE secretion.     

Immunoglobulin subclass distribution of specific antibodies in allergic patients

The IgG and IgA subclass distribution of specific antibodies against a variety of protein and polysaccharide antigens was determined in sera from individuals with high levels of IgE. No shift of the antibody pattern could be observed, suggesting that the aberrant regulation of responses against allergens noted in these patients is limited, encompassing selected antigens only. Antibodies against protein antigens are mainly of the IgG1 subclass. In addition, low levels of specific IgG3 or IgG4 antibodies may be formed. Our data suggest that a given antigen induces either IgG3 or IgG4 and that potential allergens, in addition to IgG1 and IgE, elicit a response restricted to IgG4.     

Evolution of the subclass of IgG antibody to type 3 pneumococcal polysaccharide during childhood

Human antibodies to bacterial polysaccharides consist primarily of IgG and are largely restricted to the IgG2 subclass in adults. We examined the ontogeny of the IgG subclass response to pneumococcal polysaccharide type 3 to determine if the poor response of infants to immunization with polysaccharide antigens is due to a diminished capacity to form this subclass of antibodies. Sera from 33 patients aged 2 months to 25 years who had previously been shown to respond to polyvalent pneumococcal polysaccharide vaccine by producing IgG antibodies, were assayed for pneumococcal type 3 specific antibodies of the IgG1, IgG2, IgG3, or IgG4 subclass. IgG1 antibodies to pneumococcal polysaccharide type 3 were uniformly low in all age groups. In contrast, IgG2 antibody activity was lowest in children less than the age of 2 years (170 +/- 20 ng/ml), but rose progressively in the age group 2-5 years (210 +/- 40 ng/ml), 5-10 years (330 +/- 30 ng/ml), and over the age of 10 (390 +/- 30 ng/ml) (differences significant at P less than 0.0005 by ANOVA). Thus, even in infants, pneumococcal polysaccharide responses are confined largely to the IgG2 subclass. Our findings are consistent with the hypothesis that purified bacterial capsular polysaccharide antigens preferentially activate IgG2-committed B cell clones at all ages.     

C3-containing IgE immune complexes in asthmatic patients.

Higher levels of IgE-containing immune complexes (IC) have been reported in sera from patients with allergic diseases than in sera from controls. To evaluate the possibility of an IC-mediated mechanism in the pathogenesis of bronchial asthma, we measured circulating C3-containing IgE IC (C3-IgE IC) using anti-C3 ELISA from 20 house dust mite (HDM)-sensitive asthmatics, 20 non-atopic asthmatics, and 14 non-atopic controls. C3-IgE IC levels were significantly higher in HDM-sensitive asthmatics (mean +/- S.D.: 12.2 +/- 7.8 AU/ml) than in non-atopic asthmatics (6.5 +/- 7.5 AU/ml) or controls (5.8 +/- 4.4 AU/ml). C3-IgE IC levels were significantly correlated with HDM-specific IgE levels (r = 0.50, p < 0.05), but not with total IgE levels (r = 0.36, p > 0.05) in HDM-sensitive atopic asthmatics. C3-IgE IC levels in sera did not significantly change during HDM-bronchoprovocation test in six HDM-sensitive asthmatics who showed positive reaction. Part of C3-IgE IC could be precipitated by protein G coupled beads. In conclusion, C3-IgE IC levels were elevated in sera from HDM-sensitive asthmatics; moreover IgG antibodies might be a component of C3-IgE IC. Our results suggest that an IgE IC-mediated mechanism could be involved in the pathogenesis of atopic asthma.     

Immunogenicity and antigenicity of a partially hydrolyzed cow's milk infant formula

We evaluated the immunogenicity and antigenicity of a formula based on partially hydrolyzed cow's milk whey protein in infants at risk of atopy and in controls. Total IgE and specific IgE, IgG, and IgG4 subclass antibodies against egg albumin and cow's milk α-lactalbumin, casein, and β-lactoglobulin were measured by radioimmunoassay of cord blood and of peripheral blood at 5 days and 6 months of life in five groups of infants: 16 breast-fed infants at risk of atopy (group 1), 21 partially hydrolyzed whey formula-fed infants at risk of atopy (group 2), 14 formula-fed infants at risk of atopy (group 3), 10 breast-fed control infants (group 4), and 13 formula-fed control infants (group 5). Total IgE concentration was significantly lower in group 2 at 6 months than in groups 3 and 5 infants and similar to that observed in groups 1 and 4 infants. The concentration of specific antiegg and anti-cow's milk protein IgG and of specific anti-cow's milk α-lactalbumin and β-lactoglobulin IgG4 subclass antibodies was significantly reduced in group 2 as compared to group 3 infants and similar to that found in breastfed infants. In conclusion, the partially hydrolyzed formula was less immunogenic and antigenic than a traditional formula and was as immunogenic and antigenic as breast milk.     

Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID)

Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n =?354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (<?2 IU/ml) occurs in only 3.3% (95% CI, 1.9–5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6–85.7%) of patients with CVID. Conversely, a high IgE (>?180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is >?2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.