Increased IgE Production Research Articles

Upregulation of B7.2, but not B7.1, on B cells from patients with allergic asthma

Background: Allergic asthma is associated with T H2-like cell responses and increased IgE production. Recent studies in mice have suggested that the costimulatory molecule B7.2 (CD86) may influence the development of T H2 cells. Objective: We sought to determine the potential role of B7.2 in patients with asthma. Methods: We performed an analysis of B cells from patients with allergic asthma and healthy control subjects for expression of B7.1 and B7.2 on B cells using five-parameter flow cytometry. Results: We report that atopic patients with asthma who are exposed to allergens have significantly ( p < 0.005) higher levels of B7.2 expression on B cells than atopic asthmatic subjects not exposed to allergen in vivo or nonatopic control subjects. In contrast, there were no differences in B7.1 (CD80) expression among the three study subject groups. When peripheral blood mononuclear cells from asthmatic patients or normal control subjects were stimulated with IL-4 or IL-13, the expression of B7.2, but not B7.1, was significantly increased ( p < 0.005) on B cells. Interferon-γ or IL-12 did not affect the expression of either molecule. The functional significance of B7.2 induction by IL-4 in allergic disease was suggested by the increased expression of this molecule on CD23+, but not CD23−, B cells. Conclusion: These results indicate that the same B cell involved in allergen presentation also expresses the costimulatory molecule B7.2 and support the hypothesis that this molecule is an important costimulatory molecule in allergic responses, the expression of which can be modulated by T H2-like cytokines. (J Allergy Clin Immunol 1998;101:96-102.)

Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography.

To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated increased pulmonary resistance responses to aerosolized methacholine when measured using an invasive technique the following day in the same animals. The increases in Penh values were inhibited by pretreatment of the mice with a beta 2-agonist. These data indicate that measurement of AR to inhaled methacholine by barometric whole-body plethysmography is a valid indicator of airway hyperresponsiveness after allergic sensitization in mice. The measurement of AR in unrestrained, conscious animals provides new opportunities to evaluate the mechanisms and kinetics underlying the development and maintenance of airway hyperresponsiveness and to assess various therapeutic interventions.

Plasma IgE levels, activation marker expression, and cytokine production in non-atopic individuals.

Since human IgE serum levels are very low compared with the other immunoglobulin isotypes, most studies have examined the regulation of IgE production in severely atopic individuals where serum IgE levels are increased. Since atopy is a pathologic consequence of increased IgE production, this disease state could have other influences that result in abnormal expression of these parameters and may not reflect normal IgE regulatory mechanisms. To study nonatopic individuals to examine the expression of IgE regulatory cytokines as well as additional cell surface activation markers in relation to serum IgE levels. We selected ten individuals at both the lower and higher end of a spectrum of plasma IgE concentrations from 29 nonatopic individuals and compared the differences in cytokine and activation marker expression in relation to IgE production. We found that even upon extensive examination of activation markers on T, B, and NK cell subsets, there are no significant differences in the cell populations or surface marker expression between the high IgE and low IgE groups. Messenger RNA expression in peripheral blood mononuclear cells (PBMCs) of the cytokines IL-4 and IL-6 was significantly higher, whereas IL-10 was lower in the high IgE group. In addition upon in vitro polyclonal stimulation of peripheral blood mononuclear cells, individuals of the high IgE group produced lower levels of IL-2, IFN gamma and IL-10 compared to the low IgE donors. Since our results differ from studies using atopic individuals, this study demonstrates the importance of using nonatopic individuals for examining associations between various immune parameters and IgE.

Immune responses to a Nippostrongylus brasiliensis infection in athymic and euthymic rats: surface expression of IgE receptors, IgE occupancy and secretory ability of mast cells.

The significance of T cells in an allergy-related immune response was investigated. Athymic, nude (Lewis rnu/rnu) rats lacking T lymphocytes and euthymic (Lewis+/+) rats were infected with the nematode Nippostrongylus brasiliensis. The density and occupancy of IgE receptors on peritoneal mast cells were quantified using a cytofluorometric method. The secretory ability of the mast cells as a function of anti-IgE challenge was evaluated in terms of histamine releasability in vitro. It was found that the IgE receptors were markedly up-regulated and the IgE occupancy increased on the mast cells of both athymic and euthymic rats during the parasite infection. However, at its peak, IgE occupancy was significantly higher in euthymic rats than in athymic ones. To our knowledge, this is the first proof of the possibility of a T-cell-independent IgE response in vivo. The IgE-mediated histamine releasability of mast cells was significantly enhanced 1 week after the infection in euthymic rats but not in athymic ones. These results thus indicate that the IgE immune response can occur in the absence of, but is augmented by, T cells. They also suggest that the concept of the IgE response should be widened to comprise not only increased IgE production but also an up-regulation of Ig receptors and an increase in IgE occupancy on mast cells, as well as an increase in the secretory ability of these cells. The latter is T cell dependent, although it is not directly related to the density of IgE-receptor complexes on the mast cells but is more likely due to a stimulation of the post-receptor signal transduction mechanism.

IL-4 induces germ-line IgE heavy chain gene transcription in human fetal pre-B cells. Evidence for differential expression of functional IL-4 and IL-13 receptors during B cell ontogeny.

The present study demonstrates that IL-4 induces germ-line IgE heavy chain (epsilon) gene transcription in human fetal splenic mononuclear cells; fetal bone marrow cells; highly purified sorted surface (s) mu+, CD10+, CD19+ immature B cells; and s mu-, cytoplasmic mu+, CD10+, CD19+ pre-B cells derived from human fetal bone marrow. Similar to observations in normal adult B cells, TGF-beta and IFN-gamma inhibited IL-4-induced germ-line epsilon RNA synthesis in fetal pre-B cells, whereas anti-CD40 mAbs and TNF-alpha had enhancing effects, suggesting that the general mechanisms regulating germ-line epsilon transcription in adult B cells and pre-B cells are similar. IL-13 also induced germ-line epsilon RNA synthesis in s mu+, CD10+, CD19+ immature B cells, but the level of transcription induced by IL-13 was significantly less than that induced by IL-4. Anti-CD40 mAbs strongly synergized with both IL-4 and IL-13 in inducing germ-line epsilon RNA synthesis by fetal immature B cells. Interestingly, IL-13 failed to induce germ-line epsilon RNA synthesis in s mu- pre-B cells even in the presence of anti-CD40 mAbs. These distinct effects of IL-4 and IL-13 suggest that functional IL-13R are expressed at a later stage of B cell ontogeny than IL-4R, and that IL-13, in contrast to IL-4, does not regulate pre-B cell differentiation. Given the fact that IL-4 production appears to be enhanced in atopic individuals, the capacity of IL-4 to induce germ-line epsilon transcription in human fetal immature B cells and pre-B cells suggests that commitment of B cell precursors to IgE-producing cells may occur during intrauterine life and may explain the increased IgE production in neonates with a family history of atopy.

Enhanced human IgE production results from exposure to the aromatic hydrocarbons from diesel exhaust: Direct effects on B-cell IgE production

Epidemiologic and experimental studies suggest that air pollution, and particularly diesel exhaust particles (DEPs) may play a role in the increasing prevalence and severity of airway allergic disease. We show that the extract of polyaromatic hydrocarbons (PAHs) from DEPs (PAH-DEP) enhances human IgE production from purified B cells. Interleukin-4 plus CD40 monoclonal antibody–stimulated IgE production was enhanced 20% to 360% by the addition of PAH-DEP over a period of 10 to 14 days. This effect was increased when PAH-DEP was added 2 to 5 days after cultures were initiated. PAH-DEP itself did not induce IgE production or synergize with interleukin-4 alone to induce IgE from purified B cells, suggesting that it was enhancing ongoing IgE production rather than inducing germline transcription or isotype switching. The prototype nonmetabolized aromatic hydrocarbon 2,3,7,8 tetracholorodibenzo- p-dioxin, which functions solely through activation of the cytosolic aromatic hydrocarbon receptor complex, also increased IgE production. Additionally, the pattern of mRNAs coding for distinct isoforms of the ϵ chain was altered by PAH-DEP, and B-cell expression of the low-affinity IgE receptor was upregulated by PAH-DEP. Enhanced IgE production in the human airway, resulting from exposure to PAH-DEP, may be an important factor in the increase in airway allergic disease. (J A LLERGY C LIN I MMUNOL 1995;95:103-115)

Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia.

Increasing evidence suggests an important role for cytokines in the regulation of eosinophilic inflammation. In the present study we investigated the distribution of leukocytes, lymphocyte subsets, their activation state, and the cytokine profile present in BAL fluid from patients with various lung diseases associated with eosinophilia. For this purpose, we analyzed the levels of IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, as well as soluble IL-2 and TNF receptors, in concentrated bronchoalveolar lavage (BAL) fluid obtained from clearly defined patients with allergic and nonallergic asthma, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis (ABPA), hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. BAL fluid from normal individuals and sarcoidosis patients was analyzed as noneosinophilic controls. BAL cytokine levels were compared with the cellular infiltrate and the activation state of CD4+ and CD8+ T cells as measured by the expression of IL-2 receptors (CD25), HLA-DR, and the very late activation antigen VLA-1. Beside the characteristic leukocyte infiltrate in the various lung diseases, all patients demonstrated significantly increased numbers of activated CD4 and CD8 T cells compared with normal individuals. The analysis of the cytokine profile present in BAL fluid revealed a T helper type 2 (Th2) cell cytokine pattern, with elevated IL-4 and IL-5 but normal levels of IL-2 or IFN-gamma in allergic asthma. ABPA patients demonstrated significantly increased levels of IL-4 and IL-5, with low but significantly elevated concentrations of IL-2 and IFN-gamma. In contrast, the analysis of the cytokine profile in sarcoidosis patients revealed a Th1 cell cytokine pattern characterized by increased concentrations of IL-2 and IFN-gamma but normal levels of IL-4 or IL-5. All other patient groups showed a cytokine pattern incompatible with a pure Th1 or Th2 cell response, because IL-5, IL-2, and IFN-gamma were found to be significantly increased. The BAL fluid analysis of the other, mainly non-T cell-derived cytokines and soluble receptors showed increased levels in all patients compared with normal individuals and may represent the ongoing inflammatory responses. In conclusion, whereas increased IL-4 levels were found only in diseases characterized by increased IgE production, IL-5 was elevated in all patients with increased numbers of eosinophils. The close correlation between IL-5 levels, number of eosinophils, and activated T cells further supports a role for IL-5 in causing tissue eosinophilia.

Leukotriene B 4 Enhances IL-4-Induced IgE Production from Normal Human Lymphocytes

Interleukin 4 (IL-4)-induced IgE production by normal peripheral blood mononuclear cells (PBMC) and E - cells (PBMC partially depleted of T cells) was significantly enhanced by leukotriene B 4 (LTB 4) in a dose-dependent manner, whereas LTB 4 by itself was not effective for IgE production. The potentiating effect of LTB 4 was strictly dependent on IL-4. When PBMC or E - cells were primed with IL-4 (300 U/ml) for 48 hr, then recultured with LTB 4 alone (10 -10 to 10 -8 M), increased IgE production was observed. Maximum enhancement of IgE production after IL-4 priming was achieved using a combination of IL-4 and LTB 4, acting additively. Moreover, the potentiating effect of LTB 4 on IL-4-induced IgE production was completely dependent on the presence of a monocyte/macrophage population. This effect of LTB 4 was completely abolished by depletion of monocytes and recovered by reconstitution with autologous monocytes. From the study of IL-4 receptor (IL-4R) expression determined by flow cytometry, IL-4 was found to upregulate the biotinylated-IL-4 (B-IL-4)/streptavidin binding to both T- and B-cell populations. A further increase of B-IL-4 binding was obtained when the cells were incubated with IL-4 and LTB 4. Finally. LTB 4 can induce soluble CD23 (sCD23) release by E - cells tested either alone or in the presence of IL-4. Taken together, these data suggest that LTB 4 can influence the IL-4-induced IgE production through, at least, a bimodal action, i.e., increase of IL-4R positive cells and release of sCD23. These findings may be a specific feature of LTB 4 which provides a crucial role in IL-4-linked allergic inflammatory process.

Enhancement of IgE production by anti-CD40 antibody in atopic dermatitis

It has been recently recognized that the obligate requirement for T cells in the development of IgE responses can be substituted for by anti-CD40 antibody. In this study of patients with atopic dermatitis and high IgE levels, we have analyzed the role of the CD40 molecule in IgE production. Costimulation of peripheral blood mononuclear cells (PBMCs) from normal donors with interleukin-4 (IL-4) and anti-CD40 monoclonal antibody resulted in a selective increase in IgE production; either reagent alone, however, was ineffective. In contrast, addition of anti-CD40 monoclonal antibody alone to PBMCs or B cells from patients with atopic dermatitis markedly increased IgE production, even in the absence of exogenous IL-4. With the use of an ELISA spot assay, this increase in IgE production was attributed to an expansion of IgE-secreting B cells. In anti-IgM–stimulated lymphocyte cultures from patients with atopic dermatitis the costimulation with anti-CD40 induced strong lymphocyte proliferation. Similar results were observed with anti-IgM plus IL-4. The augmentation induced by anti-CD40 was inhibited by addition of anti-IL4 to anti-CD40–treated atopic dermatitis cells. In normal subjects the effects of anti-CD40 alone on IgE production could be observed after pretreatment of normal PBMCs with IL-4 for 3 days. The effects of anti-CD40 in atopic dermatitis may be explained in part by differences in CD40 expression. In freshly isolated PBMCs from patients with atopic dermatitis, the mean fluorescence intensity of CD40 expression on B cells was increased when compared with PBMCs from nonatopic donors, and stimulation of normal or atopic dermatitis PBMCs with IL-4 increased the intensity of CD40 staining of cells. (J A LLERGY C LIN I MMUNOL 1994;93:658-68.)

Normal and atopic IgE responses.

"Isotype switch", the capacity of B lymphocytes to change expression from one to another class of immunoglobulin (Ig) molecule while retaining the same antigen specificity, has been known to exist for a long time. However, it was not known whether this D N A rearrangement in the Ig constant region gene cluster is simply a random event or a response to a specific exogenous signal. The IgE switch now stands out as a paradigm, both for (1) Ig class expression in response to a defined signal [interleukin(IL)-4 binding to its specific receptor] [6, 10, 14, 42] and (2) for a biological response which in a rather unique manner depends on one particular cytokine; mice with two deleted IL-4 genes make no IgE [20]. However, IL-4 leads to IgE switch only in conjunction with other B cell activation signals. In murine B cells, the stimulation with lipopolysaccharide (LPS) and IL-4 is sufficient for the induction o f an IgE response [6]. Human B cells are more demanding in that they require cell contact with helper T cells in addition to IL-4 [13, 28, 38]. The recently cloned ligand on T cells [2, 3] for the CD40 cell surface molecule on B cells can act as a potent co-signal for IgE switch [31], as well as for B cell activation in general [30]. For our own studies on the regulation of the human B cell response, we have used a culture system in which the direct contact with cells of a mutagenized subclone of the mouse EL4 thymoma cell line, in conjunction with either human T cell supernatant (T-SN) or phorbol myristate acetate (PMA), induces a particularly potent, polyclonal human B cell response [41, 45]. Our EL4 ceils are now known also to express the CD40 ligand, which reacts with human CD40 [2, 3], and this may at least in part explain their antigenand lectin-independent, "universal" B cell stimulatory activity. The questions which were addressed with regard to the IgE response are (1) how much IgE can B cells maximally produce, how do various parameters of this response (switch frequency, amount of Ig produced per clone, cellular Ig secretion rate, cytokine dependence) compare with IgG and IgA responses, and (2) is increased IgE production in atopic individuals related to an

Immunopathology of atopic dermatitis.

In summary, AD is a chronic inflammatory skin disease associated with increased IgE production, eosinophilia, increased mast cell number and increased expression of the CD23 low-affinity IgE receptor on mononuclear cells. The basis of these immunologic defects appear to be the result of increased numbers of IL-4-, IL-5-producing Th2 cells. This results in an overstimulation of their IL-4-IL-4 receptor pathway that is accompanied by a relative deficiency of IFN-γ production.

Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse

Inhalation of an antigen, ovalbumin (OVA), in the absence of adjuvant has been demonstrated to induce an immune response that is associated with increased airway responsiveness. Determination of OVA-specific serum IgE and IgG antibody responses revealed an early increase in antibody titers that were initially restricted to the IgE class. Subsequently, IgG antibody titers increased and IgE antibody plateaued. Furthermore, we observed a tenfold increase in the number of lymphocytes caused by a predominant expansion of CD3 + T cells in thn peribronchial-associated lymph modes (PBLNs) of sensitized animals compared with the numbers of cells in control animals or in the gut-associated lymphoid tissue. The sensitized animals demonstrated an increase in airway responsiveness to intravenous methacholine challenge. Analysis of in vitro immunoglobulin production by spleen mononuclear cells revealed increased spontaneous IgE production that was more than fourfold enhanced in the presence of OVA, but IgG production was not increased. Spleen and PBLN lymphocytes, but not lymphocytes from gut-draining lymp nodes, demonstrated a proliferative response to OVA. Control animals exhibited no proliferative response to OVA. Histopathologic examination of the sensitized lung revealed an absence of acute inflammatory cells (e.g., neutrophils and macrophages), lymphocytes, or monocytes at the time of the increased airway hyperresponsiveness. These data indicate that, after sensitization of mice by inhalation of antigen, the animals develop a specific IgE antibody response, expansion of PBLN lymphocyte numbers, and increased airway hyperresponsiveness in the absence of signs of airway inflammation.

CD4+ Memory T Cells in Peripheral Blood Are Not Decreased in Patients with Atopic Dermatitis

Atopic dermatitis (AD) is a severe and chronic eczematous skin disease, to which increased IgE levels and imbalances of CD4+ T cells are related. CD4+ T cells, however, are heterogeneous and include at least two subpopulations being designated as CD4+ naive and memory T cells. They represent sequential maturational stages (naive into memory) in CD4+ T cell development differing in function and phenotype. Of these two subpopulations the CD4+ memory T cell compartment is a potent producer of gamma-interferon which suppresses IgE synthesis in B cells. Therefore, we speculated whether an inborn maturation defect of CD4+ memory T cells causes the increased IgE production in AD. In patients with AD and age- and sex-matched controls (both n = 10) we analyzed the distribution of both subpopulations in peripheral blood by two-color flow cytometry using monoclonal antibodies against the CD4, CD45RA and CD29 antigen. We provide evidence that the numerical values of CD4+ memory T cells and CD4+ naive T cells are equivalent in both groups. This supports the view that functional disturbances of lymphocytes or lymphocyte subsets are responsible for IgE excess and the pathogenesis of AD.

In vitro generation of IFN-gamma in relationship to in vivo concentration of IgE and IgG subclasses and Fc epsilon Rl/CD23 positive circulating lymphocytes in patients with severe atopic dermatitis (AD).

In fifteen patients with severe atopic dermatitis (AD) and ten healthy controls we investigated the in vitro generation of IFN-gamma and analysed the number of Fc epsilon RL/CD23 (low affinity Fc receptor for IgE) positive lymphocytes. We found a significantly impaired capacity to secrete IFN-gamma after PHA-stimulation compared to controls in a significant proportion of patients. Serum IgG4 levels in patients were higher compared to controls. A significant portion of lymphocytes bearing the low affinity Fc receptor for IgE (CD23) was observed with the moab Tü1 in patients. Lymphocytes from healthy donors were completely negative or less than 2% positive for Tü1. Despite small numbers of patients a significant correlation was found between IFN-gamma generation in vitro and IgE serum concentration in patients, whereas the IFN-gamma generation and IgG4 concentration were negatively correlated in the patient group. The number of Fc epsilon RL/CD23 positive lymphocytes in patients was positive correlated with the serum IgG4 and IgE concentration and negative correlated with IFN-gamma generation in vitro. Our data suggest that a possible dysregulation of IFN-gamma, Interleukin 4 or other lymphokine production may be related to increased IgE and IgG4 production.

Cytophilic IgE on human blood and tissue eosinophils: detection by flow microfluorometry.

Flow microfluorometry (FMF) was used to investigate the presence of cytophilic Ig (IgE or IgG) and the proportion of Fc receptor (Fc epsilon R or Fc gamma R)-bearing eosinophils among eosinophils from 21 hypereosinophilic patients. In a large majority of the cases, it was possible to detect cytophilic IgE significantly associated with serum IgE levels. Moreover, when lung and blood eosinophils were compared, the proportion of occupied Fc epsilon R was significantly increased on lung eosinophils, whereas very few cells had cytophilic IgG. This work provides further evidence that cytophilic IgE is not restricted to cells with high affinity Fc epsilon R, but can also be detected on the cell populations with low affinity IgE receptors. These findings support the view that eosinophils can act as effector cells in immediate hypersensitivity reactions and in diseases associated with increased IgE production and hypereosinophilia.

Cytophilic IgE on Human Blood and Tissue Eosinophils

Flow microfluorometry (FMF) was used to investigate the presence of cytophilic Ig (IgE or IgG) and the proportion of Fc receptor (Fc epsilon R or Fc gamma R)-bearing eosinophils among eosinophils from 21 hypereosinophilic patients. In 75% of the cases, it was possible to detect cytophilic IgE, significantly associated with serum IgE levels. Moreover, when lung and blood eosinophils were compared, the proportion of occupied Fc epsilon R was significantly increased on lung eosinophils, whereas very few cells had cytophilic IgG. This work provides further evidence that cytophilic IgE is not restricted to cells with high-affinity Fc epsilon R but can also be detected on the cell populations with low-affinity IgE receptors. These findings support the view that eosinophils can act as effector cells in immediate hypersensitivity reactions and in diseases associated with increased IgE production and hypereosinophilia.

Effects of a beta-receptor blocking agent (propranolol) on synthesis of IgE in vitro by peripheral blood lymphocytes from atopic patients.

Peripheral blood lymphocytes from patients with atopy were studied for IgE production in vitro. Addition of a beta-receptor blocking agent (propranolol) to lymphocytes from 9 of 10 patients with low spontaneous IgE production in vitro caused increased IgE production. In 10 tests with lymphocytes from patients, who were undergoing hyposensitization treatment for cat epithelium and/or birch pollen allergy, no spontaneous in vitro production of the relevant antigen-specific IgE antibodies was detected. However, when propranolol was added to the lymphocyte cultures in vitro, production of antigen-specific IgE antibodies was found. No such production was found when lymphocytes from patients who were not allergic to either of these antigens were studied. Szentivanyi's theory of a partial blockade of beta-adrenergic receptors in atopy and a possible linkage between this theory and the hypotheses of disturbed regulatory functions in the immune system of patients with atopy is discussed.

An in vitro study of IgE production in severe atopic dermatitis

Peripheral blood lymphocytes from 4 patients with severe atopic dermatitis and with high serum IgE levels produced measurable amounts of IgE in vitro in repeated tests. These patients had increased numbers of IgE-bearing peripheral blood lymphocytes on at least one test occasion. No measurable IgE production in vitro was found in 6 other patients with atopic dermatitis and in 3 healthy controls. Inhibition of the IgE production was observed following treatment with PHA, Con A, PWM, mixed lymphocyte culture and radiation. LPS and histamine induced neither definite stimulation nor inhibition of IgE production. Supernatants from Con A stimulated cells were used in tests for suppressor factors. The hypothesis that depressed suppressor function of the T cells might be responsible for the tendency to increased IgE production in atopic dermatitis is discussed.

Defective T cell function in atopic dermatitis

The cellular immune system of 37 patients with atopic dermatitis (AD) was assessed by measuring peripheral blood T and B cells and the in vitro lymphocyte response to graded doses of phytohemagglutinin (PHA) (background and 6 concentrations of PHA from 100 to 1.6 μg). These were then correlated with clinical severity, eosinophil counts, and serum IgE levels. The IgE levels (1,482 IU ± 252 SEM), eosinophil counts (977 ± 143), and absolute number of B cells (958 ± 123) were significantly (p < 0.05) higher than in age-matched controls (70 IU ± 28, 182 ± 79, and 480 ± 60, respectively), and each significantly (p < 0.05) correlated with the clinical severity. By contrast, percent B lymphocytes (20 ± 1), percent (51 ± 2) and total (2,357 ± 217) T cells did not differ from controls. Eleven patients had low percent T cells (<40%); clinical and laboratory evaluation in these patients did not differ from the remaining 26. Lymphocytes from AD patients had higher background deoxyribonucleic acid (DNA) synthesis than controls (suggestive of increased number of B cells) and significantly depressed responses at the low PHA concentrations (6.3, 3.1, and 1.6 μg), which significantly correlated (p < 0.05) inversely with IgE levels. These studies suggest a subtle defect in T lymphocyte function leading to increased B cells and increased IgE production.

EXTREME HYPERIMMUNOGLOBULINEMIA E AND UNDUE SUSCEPTIBILITY TO INFECTION

The clinical and immunologic features of two adolescent boys who had recurrent pyogenic infections are judged to constitute a new syndrome. Its characteristics include: recurrent cutaneous, pulmonary, and joint abscesses; growth retardation; coarse facies; chronic dermatitis; exquisite immediate hypersensitivity associated with exceptionally high serum concentrations of IgE and eosinophilia; and depressed in vivo cellular immunity and antibody formation. These patients lacked evidence of respiratory allergy or parasitism. Atopic dermatitis was not present in one boy and the physical characteristics of the other boy's dermatitis were not typical for that entity. Concentrations of immumnoglobulins G, A, M, D and the various IgG subtypes were normal, as were natural antibody titers to red cell antigens. Nevertheless, depressed anamnestic antibody responses were noted to diphtheria and tetanus antigens and neither patient demonstrated responses to primary immunization with KLH, typhoid, and DNCB antigens. Complement and polymorphonuclear functions were normal. In vitro lymphocyte studies done demonstrated normal DNA synthesis in phytohemagglutinin and staphylococcal antigen-stimulated cultures and MIF production by some antigen-stimulated cultures from each. The explanation for the undue susceptibility to infection, increased IgE production, subnormal antibody formation, and impaired in vivo cell-mediated immunity in these patients remains conjectural.