IgE autoantibodies in atopic dermatitis -occurrence of different antibodies against the CH3 and the CH4 epitopes of IgE

Levels of "free" anti-IgE autoantibodies and IgE/anti-IgE immune complexes were measured in the sera of patients with atopic dermatitis before and after treatment, psoriasis patients, and nonatopic controls. In this measurement, we used two monoclonal antibodies with distinct in vitro functions (LE 27, BSW 17), directed against the epsilon CH3 and CH4 domains of the IgE Fc-fragment, in a novel immunobinding assay. In patients with atopic dermatitis, elevated levels of "free" anti-IgE antibodies and IgE/anti-IgE immune complexes were detected in comparison to psoriasis patients and controls. In addition, there was a positive correlation between total IgE and the amount of IgE/anti-IgE complexes detected by LE 27 ( r =0.7; P < 0.001) or BSW 17 ( r = 0.64; P < 0.001) in patients with atopic dermatitis. In contrast, an inverse correlation was observed between total IgE and "free" anti-IgE antibodies ( r =−0.34; P < 0.05) in atopic dermatitis. However, serum levels of anti-IgE autoantibodies before and after therapy in patients with atopic dermatitis did not differ, and levels of anti-IgE antibodies did not correlate with clinical severity, as evaluated by an established clinical scoring system. Our data clearly indicate that significantly elevated amounts of anti-IgE antibodies could be observed in patients with atopic dermatitis, which are directed against different epitopes on the IgE molecule. It is tempting to speculate that these autoantibodies exert different effects on IgE-receptor-bearing effector cells and may play an important role in IgE regulation.     

Monitoring of serologic immune parameters in inflammatory skin diseases

This paper deals with the correlation of clinical scoring and serologic markers of inflammation in atopic dermatitis and psoriasis. Serum eosinophil cationic protein (ECP), soluble inlerleukin-2 receptor (sIL-2R), total serum IgE, IgG and IgM anti-IgE antibodies, and IgE immune complexes were evaluated in monitoring inflammatory skin diseases such as atopic dermatitis and psoriasis. Well-established clinical activity scores were used as standards in recording skin improvement under treatment in a clinical setting. Serum ECP was found to be increased in both atopic dermatitis and psoriasis patients compared to normal controls; sIL-2R and IgE immune complexes were increased only in atopies with increased serum IgE. Anti-IgE antibodies did not show any deviation in both groups of patients. There was a significant elevation of sIL-2R and IgE immune complexes and a nonsignificant elevation of ECP in high-IgE atopics in comparison to those with normal serum IgE. In both groups of patients, there was a significant reduction of ECP and sIL-2R accompanying the improving skin condition. Serum IgE and the other immune parameters failed to respond. In contrast to other studies, serum ECP failed to correspond significantly with disease activity in our study. Our results showed measurable changes of ECP and sIL-2R for atopic dermatitis and/or psoriasis under treatment, but comparison to clinical scores remains difficult due to the different basis of the two systems. The only significant correlation was established for relative changes in sIL-2R and psoriasis area and intensity (PASI), a correlation which might be a useful approach in psoriasis.     

Evidence for IgE immune complexes and distribution of IgG subclasses with anti-IgE activity in patients with atopic dermatitis

The anti-IgE autoantibody was detected, using a radioimmunoassay, in 17 out of 35 (48.6%) of patients with atopic dermatitis. Significant increased levels of IgG-anti-IgE were seen in the patients studied compared with the control group. The specificity of the anti-IgE autoantibody was confirmed by competitive inhibition assay using IgG, IgM, IgE myeloma. A correlation was observed between the levels of IgG-anti-IgE and serum IgE but not between the IgG subclasses with anti-IgE activity and the clinical status. These data demonstrate that the IgG subclass distribution with anti-IgE activity belongs mostly to the IgG1 and IgG4 subclasses compared with the controls. Moreover, ultracentrifugation analysis indicated that the IgG-anti-IgE in the serum samples from the patients with atopic dermatitis was present in the form of an immune complex with self-IgE. These observations may suggest that the anti-IgE complexes may play a broader role in the modulation of the immune response and that this autoantibody may mask recognition of IgE in conventional assays.     

Fc epsilon receptor II/CD23-positive lymphocytes in atopic dermatitis. I. The proportion of Fc epsilon RII+ lymphocytes correlates with the extent of skin lesion.

Cells expressing Fc receptors for IgE (Fc epsilon RII) were identified in the peripheral blood from patients with atopic dermatitis and with eczematous dermatitis, and normal non-atopic subjects by using monoclonal antibodies to human lymphocyte Fc epsilon RII, and to lymphoid cell-surface antigens by immunofluorescence staining. Based on the extent of the dermatitis patients were classified as severe (greater than 50% skin surface involved), moderate (50-10%) and mild (less than 10%). Patients with severe and moderate atopic dermatitis had 5.9% and 5.7% Fc epsilon RII+ peripheral blood mononuclear cells (PBMC), respectively, that were significantly higher than percentages in mild atopic dermatitis patients (2.6%), severe to moderate eczematous dermatitis patients (2.3%), mild eczematous dermatitis patients (2.2%) and normal individuals (1.7%)(0.05 greater than P). In severe and moderate atopic dermatitis patients, 10% of Fc epsilon RII+ PBMC were T cells that preferentially expressed CD8, and the remainder B cells and monocytes. Fc epsilon RII+ T cells comprised 1% of peripheral T cells, while half or more of peripheral B cells expressed Fc epsilon RII. In mild atopic dermatitis patients, eczematous dermatitis patients and normal subjects. Fc epsilon RII were expressed exclusively on 25-35% of peripheral B cells. Short-term treatment and long-term follow-up of atopic dermatitis patients revealed that changes in the skin condition were related closely to fluctuations in the proportion of Fc epsilon RII+ PBMC. Total serum IgE levels and atopic respiratory allergy did not influence the percentage of Fc epsilon RII+ PBMC. These findings suggest that the percentage of Fc epsilon RII+ PBMC reflects the extent of atopic dermatitis.     

Basic and clinical aspects of atopic dermatitis

The history of atopic dermatitis is replete with many disparate theories. The most enduring is the allergic causation theory but definitive, convincing evidence remains elusive. Elevated IgE synthesis is well established and reflects abnormal immune regulation. The basic mechanism for the regulatory defect remains conjectural. Cellular immune functions, including delayed cutaneous hypersensitivity, in vitro lymphocyte transformation and chemotaxis are reduced in atopic dermatitis. However, these abnormalities fluctuate with the clinical condition and may be secondary phenomena. A number of physiologic and pharmacologic abnormalities in atopic dermatitis are not clearly understood. Recent studies of patients leukocytes have shown that the diminished cyclic AMP responses are a consequence of increased catabolism by elevated cyclic AMP-specific phosphodiesterase. This high enzyme activity correlates well with elevated IgE synthesis and histamine release by cultured leukocytes. Both of these functions can be reduced by phosphodiesterase inhibitors in vitro. These new investigations provide fresh insight into the pathogenesis of atopic dermatitis and offer possible new therapeutic approaches. Basic studies of biochemical abnormalities may help define the defective molecular site that accounts for the many immune and physiologic abnormalities that have been described in atopic dermatitis and the other atopic conditions.     

A rare variant in CYP27A1 and its association with atopic dermatitis with high serum total IgE

This study investigated rare variants associated with atopic dermatitis. We performed exome analyses on 37 patients who were diagnosed with atopic dermatitis by board‐certified dermatologists and had total serum IgE levels greater than 1000 IU/ml. The exome analysis identified seven variants with <1% allele frequency in Asian (ASN) population of 1000 Genomes Project phase 1 data and >5% allele frequency in the atopic dermatitis exome samples. We then conducted a replication study using 469 atopic dermatitis patients with total serum IgE ≥1000 IU/ml and 935 Japanese controls to assess the presence of these 7 candidate variants. The replication study confirmed that CYP27A1 rs199691576 (A/G) was associated with atopic dermatitis with high serum IgE levels (P = 0.012, odds ratio = 2.1). CYP27A1 is involved in the metabolism of vitamin D3, which plays important roles in modulating immune function. Previous studies have reported polymorphisms in vitamin D pathway genes that are associated with allergy‐related phenotypes. Our data confirm the importance of genes regulating the vitamin D pathway in the development of atopic dermatitis.     

Analysis of IgE reactivities of purified allergens from Candida albicans and Malassezia furfur among patients with atopic dermatitis]

We analyzed the reactivities of a series of purified allergens from Candida albicans (C. albicans) and Malassezia furfur (M. furfur) with IgE antibodies in sera from patients with atopic dermatitis. We compared the specific IgE antibody levels to manganese superoxide dismutase (Mn SOD), cyclophilin, enolase, secretory aspartic protease (SAP 2) and type A mannan from C. albicans and Mn SOD, cyclophilin and Mal f 2 from M. furfur in 21 sera from patients with atopic dermatitis and 20 sera from patients with asthma without atopic dermatitis. The prevalence of IgE antibodies and the mean IgE antibody levels to all of the allergens tested were higher among patients with atopic dermatitis than among those with asthma without atopic dermatitis. More than 50% of patients with atopic dermatitis were IgE antibody-positive to Mn SOD, cyclophilin and type A mannan from C. albicans, and Mn SOD and cyclophilin from M. furfur. The availability of these purified allergens will facilitate studies on the contribution of fungal allergens to the development of atopic dermatitis.     

Serum IgE concentration in atopic dermatitis. Relationship to severity of disease and presence of atopic respiratory disease

A survey was conducted to evaluate the serum IgE concentrations of 58 patients with atopic dermatitis of varying severity and activity. The determination of serum IgE concentrations does not provide a diagnostic criterion for atopic dermatitis because 57% of the patients had levels of IgE considered to be within a normal range. When serum IgE concentrations are elevated in atopic dermatitis, this is associated with an increased severity of the disease, with coexistent atopic respiratory disease or with both. This association may have relevance to the pathogenesis of the respiratory disease, which is IgE-mediated, the severity of the dermatitis, or both. The manner in which this may occur, if there is more than a coincidental relationship, is uncertain.     

Intravenous immune globulin (i.v.IG) therapy in steroid-resistant atopic dermatitis

Many trials have been done on steroid-resistant atopic dermatitis. Recently, intravenous immune globulin (i.v.IG) was reported to be effective in the treatment of steroid-dependent atopic dermatitis. The aim of this study was to clarify whether i.v.IG therapy is effective in steroid-resistant atopic dermatitis. Forty-one steroid-resistant atopic dermatitis patients were tested in this study. Patients who weighed less than 30 kg were administered 500 mg/kg of i.v.IG. Patients who weighed 30 kg or more were administered 15 g of i.v.IG. Patient evaluations and laboratory tests with peripheral bloods such as eosinophil percentages and serum IgE levels were performed at days 0, 1, 7, and 21. In the present study, patients who responded to i.v.IG therapy were classified as Group A. Twelve patients who showed transient effects with lower clinical significance were classified as Group B (29.3%). Remaining 12 patients (29.3%) in Group C showed no improvement at all. Serum IgE levels and blood eosinophil percentages were markedly decreased in Group A. I.v.IG therapy may be recommended in the treatment of atopic dermatitis with extremely high serum IgE levels.     

Recognition of pathogenically relevant house dust mite hypersensitivity in adults with atopic dermatitis: a new approach?

BACKGROUND: The pathogenic importance of the ubiquitous house dust mite, Dermatophagoides pteronyssinus (Dp), in atopic dermatitis is unclear. OBJECTIVE: We aimed to explore the relevance of Dp hypersensitivity in adult patients with atopic dermatitis by using an in vivo topical challenge method and in vitro assays for T-cell reactivity. METHODS: Dp and control skin prick test solutions were applied to the cubital fossae of 20 patients twice daily for 4 days; the severity of dermatitis and pruritus in the challenge sites were determined before and after testing. The same solutions were used in PBMC proliferation assays that included 10% fresh, autologous serum, the latter aimed at maximizing IgE facilitated allergen presentation. RESULTS: Although most patients had markedly elevated Dp-specific serum IgE levels, only 6 of 20 patients developed increases in cubital fossa dermatitis severity and pruritus scores that were greater at sites of application of Dp solution than at control sites. In addition, PBMC proliferation in response to Dp solution in the presence of autologous serum was significantly greater in the in vivo challenge-positive patients than in those who did not respond to challenge. A subgroup of patients (7/20) also developed transient but pronounced contact urticaria at sites of Dp application. CONCLUSION: These findings suggest that hypersensitivity to Dp might be clinically relevant in approximately one third of the adult atopic dermatitis population studied. They also point to methods of identifying patients who might respond to house dust avoidance measures.     

Autoimmunity and atopic dermatitis

PURPOSE OF REVIEW: It has been demonstrated that a considerable percentage of patients suffering from atopic dermatitis mount IgE autoantibodies against a broad variety of human proteins. This review summarizes evidence for autoimmune mechanisms in atopic dermatitis and suggests novel pathomechanisms that may be involved in this disease. RECENT FINDINGS: It has been shown that patients suffering from atopic dermatitis exhibit IgE autoreactivity to human proteins. These autoantigens are expressed in a variety of cell and tissue types. Complementary DNAs coding for IgE autoantigens have been identified, cloned and characterized at the molecular level. Using purified recombinant IgE autoantigens, it has been shown in paradigmatic models that IgE autoimmunity may be a pathogenetic mechanism in atopic dermatitis. Moreover, it has been shown that the levels of IgE autoantibodies are associated with severity of disease. SUMMARY: Patients suffering from severe manifestations of atopy mount IgE autoantibodies against a variety of human proteins. The levels of IgE autoantibodies correspond with disease severity. Several mechanisms of IgE autoimmunity may contribute to the pathogenesis of atopic dermatitis.     

The profiles of interleukin (IL)-2, IL-6, and interferon-gamma production by peripheral blood mononuclear cells from house-dust-mite-allergic patients: a role for IL-6 in allergic disease

We have developed a model to measure cytokine production by peripheral blood mononuclear cells (PBMC) in vitro. In this report, we examine the production of interleukin-2 (IL-2), IL-6, and interferon-gamma (IFN-γ) by PBMC of house-dust-mite ( Dermatophagoides pteronyssinus )-allergic subjects. When stimulated with specific allergen ( D. pteronyssinus ), PBMC of patients produced significant levels of IL-2 and high levels of IL-6, but little or no IFN-γ. Nonatopic control PBMC also produced IL-6, although at lower levels, but no IL-2 or IFN-γ. A ubiquitous antigen, streptokinase/streptodornase (SKSD), induced high levels of IL-2 in patients, but only low levels of IFN-γ and IL-6. Nonatopic controls produced similar levels of IL-2 and IL-6, but high levels of IFN-γ to SKSD. IL-2 and IFN-γ levels induced by the T-cell mitogen phytohaemagglutinin (PHA) were similar in patient and control groups, but IL-6 levels were significantly lower in the patients. IgE synthesis in vitro was shown only in atopic PBMC cultures stimulated with specific allergen. The major points can be summarized as 1) IL-2 production by atopic patients in response to allergen; 2) IL-6 production to allergen by both atopic and nonatopic patients, but significantly increased in atopic patients; and 3) defective IFN-γ production by atopic patients to both allergen and antigen. These findings suggest that IL-6 may be important in the immune response to inhalent allergens such as D. pteronyssinus , possibly by creating a cytokine environment favourable to a T^H2 response, and that atopic patients exhibit a generalized defect of IFN-γ production, not related to the response to allergen.     

Serum IgE in atopic dermatitis

Serum IgE concentrations were determined according to the radioimmunosorbent technique (RIST, Phadebas) on 116 adult patients with atopic dermatitis of varying severity and activity. Geometric mean IgE levels of patients with atopic dermatitis were significantly higher compared with the mean level of ninety-three non-atopic adult subjects without parasitic infestation. Severity of the atopic dermatitis was highly correlated to the levels of serum IgE. Severe chronic cases with ever-recurrent exacerbations show the most extreme values. In the moderate forms of atopic dermatitis, coexistent bronchial asthma causes a greater increase in the IgE values. Among the mild or abortive forms, higher IgE levels were found in cases with allergic rhinitis than in the cases with‘pure’atopic dermatitis. Other findings in connection with IgE in atopic dermatitis are summarized. The pathogenetic significance of IgE in the cutaneous changes is briefly discussed.     

Prevalence of atopic dermatitis and serum IgE of Yusho patients born before 1967

Dioxins may have an impact on the human immunological system, which would increase the risk to develop allergic diseases, such as atopic dermatitis. In order to determine the lifetime prevalence of atopic dermatitis in Yusho patients, a questionnaire-based survey was conducted in 2008. One thousand and seventy-one out of 1430 certified yusho patients who were born before Yusho accident answered the questionnaires, and the prevalence of atopic dermatitis in Yusho patients was 5.5%. We also measured serum IgE in 515 Yusho patients who attended annual medical check-ups from 2007 to 2009 and in 172 control subjects. Serum levels of IgE in Yusho patients were 250.7 +/- 663.4 IU/ml, whereas those in control subjects were 265.0 +/- 602.0 IU/ml. There was no significant difference in serum levels of IgE between Yusho patients and control subjects. In addition, no significant correlation was observed between serum levels of IgE and blood levels of dioxins in Yusho patients.     

Essential fatty acids in serum lecithin of children with atopic dermatitis and in umbilical cord serum of infants with high or low IgE levels

The fatty acid composition of serum lecithin from children with atopic dermatitis (AD) was found to be abnormal, characterized by significantly increased proportion of linoleic acid and reduced levels of metabolites of this fatty acid. The levels of linoleic acid in umbilical cord serum lecithin were significantly higher in babies with high serum IgE than in those with low or non-demonstrable serum IgE. Since elevated cord serum IgE is strongly associated with development of atopic disease the results suggest that fatty acid changes may be a basic feature of AD. Immunologic dysfunction in patients with AD may possibly partly be a consequence of the fatty acid abnormality.     

Children with atopic dermatitis who carry toxin-positive Staphylococcus aureus strains have an expansion of blood CD5- B lymphocytes without an increase in disease severity

Toxin-positive strains of Staphylococcus aureus (T + S. aureus) are present on the skin of some but not all patients with atopic dermatitis. Many staphylococcal toxins are superantigens, which can stimulate the immune response and thus may potentially lead to the very high levels of IgE characteristic of this condition, as well as exacerbating the clinical disease. The aim of this study was to determine whether the presence of T + S. aureus on the skin of children with atopic dermatitis was associated with in vivo evidence of a heightened humoral immune response, higher IgE levels and more severe clinical disease. Toxin gene expression in S. aureus isolated from the eczematous lesions of 28 children with atopic dermatitis was assessed by PCR. Clinical and immune data were also collected from this cohort. Thirteen of the 28 children (46%) were colonized with T + S. aureus strains. The presence of T + S. aureus was associated with a significant expansion in peripheral blood CD5- B cells (P = 0.01), and the more toxin types identified the greater the B-cell expansion (P = 0.002). However, in this cohort of children with atopic dermatitis, despite th in vivo expansion of B cells in children harbouring T + S. aureus, there was no associated increase in IgE levels or in clinical disease severity scores.     

Milk whey-specific immune complexes in allergic and non-allergic subjects

We developed an antigen- and isotype-specific ELISA for the rapid detection of native serum immune complexes (IC). It is a sandwich assay, in which a solid phase antigen-specific capture antibody selectively binds the antigen-specific IC via the antigen. The isotype of the bound IC is then identified using an enzyme-labelled indicator antibody. Using this sensitive assay system, we were able to detect native serum milk whey-specific immune complexes (SMIC) of the IgG, IgE and IgA isotypes. Detectable amounts of native serum SMIC of all three isotypes were found in sera of the majority of both atopic and non-atopic subjects. The ELISA was then used to compare the levels of native IgE SMIC in sera of milk RAST positive atopic patients with those found in milk RAST negative atopic patient sera. Milk RAST positive patient sera were found to have significantly higher mean levels (P less than or equal to 0.005) of native IgE SMIC than milk RAST negative sera. Sera of other atopic individuals were also found to contain significantly higher mean levels (P less than or equal to 0.005) of native IgG and IgA SMIC than non-atopic donors. IgE IC may specifically be involved in adverse symptoms seen in milk allergic patients.     

Immunoglobulin E, a pathogenic factor in Plasmodium falciparum malaria.

Most children and adults living in areas where the endemicity of Plasmodium falciparum malaria is high have significantly elevated levels of both total immunoglobulin E (IgE) and IgE antimalarial antibodies in blood. This elevation is highest in patients with cerebral malaria, suggesting a pathogenic role for this immunoglobulin isotype. In this study, we show that IgE elevation may also be seen in severe malaria without cerebral involvement and parallels an elevation of tumor necrosis factor alpha (TNF). IgE-containing serum from malaria immune donors was added to tissue culture plates coated with rabbit anti-human IgE antibodies or with P. falciparum antigen. IgE-anti-IgE complexes as well as antigen-binding IgE antibodies induced TNF release from peripheral blood mononuclear cells (PBMC). Nonmalaria control sera with no IgE elevation induced significantly less of this cytokine, and the TNF-inducing capacity of malaria sera was also strongly reduced by passing them over anti-IgE Sepharose columns. The cells giving rise to TNF were adherent PBMC. The release of this cytokine probably reflects cross-linking of their low-affinity receptors for IgE (CD23) by IgE-containing immune complexes known to give rise to monocyte activation via the NO transduction pathway. In line with this, adherent monocytic cells exposed to IgE complexes displayed increased expression of CD23. As the malaria sera contained IgG anti-IgE antibodies, such complexes probably also play a role in the induction of TNF in vivo. Overproduction of TNF is considered a major pathogenic mechanism responsible for fever and tissue lesions in P. falciparum malaria. This overproduction is generally assumed to reflect a direct stimulation of effector cells by certain parasite-derived toxins. Our results suggest that IgE elevation constitutes yet another important mechanism involved in excessive TNF induction in this disease.