Allergen-specific IgE Responses Research Articles

Immunothérapies épicutanées et sublinguales : efficacité, tolérance et place dans la prise en charge de l’allergie alimentaire

Oral immunotherapy (OIT) is the only treatment usable in practice for inducing tolerance in food-allergic patients. However, adverse events often lead to OIT refusal or discontinuation. Epicutaneous (EPIT) and sublingual (SLIT) immunotherapies are protocols developed concurrently with OIT, mainly for peanut allergy. They share immunological principles, capitalizing on Langerhans cells found in oral and cutaneous tissues to induce regulatory T lymphocytes and produce allergen-specific immunoglobulin G4 (IgG4). However, both EPIT and SLIT expose patients to smaller amounts of allergen compared to OIT. EPIT and SLIT are usually well tolerated, and have a lower risk of anaphylaxis when compared to OIT. Despite the lack of studies offering direct comparison, the ability of EPIT and SLIT to increase the tolerance threshold while on treatment seems lower compared to OIT. However, it appears that they have similar potential to OIT in terms of adjusting allergen-specific IgE and IgG4 serological responses as well as disease progression, especially in the age group of 1–4. EPIT and SLIT appear as complementary treatments to OIT, promoting medium- to long-term tolerance in peanut-allergic patients. These treatments could have an indication in patients who are ineligible, have failed, or refused OIT, or even as a first-line treatment to rescue a primary prevention failure in early childhood.

Serum Allergen-Specific Immunoglobulin E in Cats with Inflammatory Bronchial Disease.

The etiology of feline inflammatory bronchial disease is poorly understood. This study compares the degree of allergen-specific serum IgE responses between cats with feline asthma, chronic bronchitis, mixed inflammation, and clinically healthy cats (HCs). The retrospective case-control study used serum from eighteen cats with eosinophilic inflammation (EI), ten with neutrophilic inflammation (NI), six with mixed inflammation (MI), and fourteen HCs. Affected cats were categorized into groups based on bronchoalveolar lavage cytology. The measurement of IgE for 34 different allergens including fungal organisms, weeds, grasses, trees, mites, and insects was performed using an indirect ELISA. Positive reactions to allergens were detected in the serum of 17/18 cats with EI, 8/10 with NI, 6/6 with MI, and 11/14 HCs (p = 0.364). When overall positive reactions were compared between groups, cats with MI (p = <0.01) had significantly more positive reactions against mite allergens than HCs. Blood eosinophils inversely correlated with the absolute amount of allergen-specific serum IgE expressed in ELISA absorbance units (EAs) (p = 0.014). Sensitization against dust mites seems to be more prevalent in cats with MI. However, positive IgE reactions can be observed in healthy and diseased cats, and, therefore, need to be interpreted in the light of clinical findings and environmental conditions of individual patients.

Long-term IgE immunological tolerance to peanut allergens: An alternative to Noon’s daily desensitization paradigm

Herein, we show that profound afferent long-term peanut-allergen-specific IgE immunological tolerance for 3 to 9 months induced sustained unresponsiveness (SU) in naïve or peanut-sensitized rodents after peanut allergen immunization. Rodents were vaccinated sublingually with a peanut allergen extract or recombinant peanut allergen in chenodeoxycholate (CDCA), a fanesoid X receptor (FXR, NR1H4) agonist that downregulates SREBP-1c (sterol regulatory element binding protein-1c) and upregulates SHP in bone marrow-derived tolerogenic dendritic cells (DCs). Approximately 90 ∼ 95 % of the total circulating PE-potentiated IgE and Ara h1, Ara h 2, and Ara h 6 peanut allergen-specific IgE responses were suppressed by recombinant peanut allergen-conjugated solid magnetic beads (sensitivity of 0.2 IU/ml). In contrast, peanut allergen-specific IgG production was not affected. Similarly, oleoylethanolamine (OEA), a peroxisome proliferator-activator receptor alpha (PPARα) agonist, and GW9662, a PPARγ antagonist, induced long-term peanut-specific IgE tolerance when administered via the sublingual, oral or i.p. route. Prophylactic Ara h2 DNA immunization with caNRF2 and IL-35 coexpression induced Ara h2 IgE tolerance. In summary, peanut allergen vaccination with select natural molecular ligands of nuclear receptors induced long-term peanut allergen-specific IgE tolerance via the afferent limb, which indicates that vaccination is an immune tolerance-promoting strategy that is effective at the DC level and that differs from Noon’s daily desensitization program, which is effective at the mast cell level.

Paneth cells regulate allergic sensitization in the gastrointestinal tract

Abstract The gut immune homeostasis plays a major role in controlling sensitization to food allergens and the development of allergic responses in the gastrointestinal tract, but also to skin or lung. Epithelial cells sensing of commensal microbes is crucial for the maturation of the gut immune system and antibiotic treatment during early life is believed to have contributed to the increased incidence of food allergy. Paneth cells secrete antimicrobial products and cytokines in the crypts of the small intestine, but their role in food allergy remains elusive. We found that SOX9ΔIEC mice, which lack Paneth cells, display dysbiosis with increased microbial diversity. Interestingly, Paneth cell deficiency increased the of numbers of ILC2 in intestinal lymphoid tissues. Upon oral sensitization with a model food antigen in the presence of cholera toxin, SOX9ΔIEC mice developed significantly higher allergen-specific serum IgE responses, and enhanced signs of allergic responses (i.e., swelling, hypothermia, impairment of lung functions) after nasal allergen challenge. Transplantation of fecal materials from SOX9ΔIEC mice was able to transfer the hyper-allergenic phenotype to control wild-type mice. In addition, bacteria-free fecal extract from SOX9ΔIEC mice increased the number of IgE producing B cells than fecal extract from control mice with treatment of anti-CD40 and IL-4 in vitro. Ongoing studies are assessing the metabolites present in the intestinal lumen of SOX9ΔIEC mice and their effect of intestinal epithelial cells and myeloid cells to elucidate the mechanisms by which impaired or defective anti-microbial functions of Paneth cells regulate allergic sensitization of the GI tract. Supported by Ohio State Univerisity NIH

HLA-G in Allergy: Does It Play an Immunoregulatory Role?

Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.

Allergen skin test reactivity and asthma are inversely associated with ratios of IgG4/IgE and total IgE/allergen-specific IgE in Ugandan communities.

SummaryBackgroundSerum inhibition of allergen‐specific IgE has been associated with competing IgG4 and non‐specific polyclonal IgE. In allergen immunotherapy, beneficial responses have been associated with high IgG4/IgE ratios. Helminths potentiate antibody class switching to IgG4 and stimulate polyclonal IgE synthesis; therefore, we hypothesized a role for helminth‐associated IgG4 and total IgE in protection against atopic sensitization and clinical allergy (asthma) in tropical low‐income countries.MethodsAmong community residents of Ugandan rural Schistosoma mansoni (Sm)–endemic islands and a mainland urban setting with lower helminth exposure, and among urban asthmatic schoolchildren and non‐asthmatic controls, we measured total, Schistosoma adult worm antigen (SWA)–specific, Schistosoma egg antigen (SEA)–specific and allergen (house dust mite [HDM] and German cockroach)–specific IgE and IgG4 by ImmunoCAP® and/or ELISA. We assessed associations between these antibody profiles and current Sm infection, the rural‐urban environment, HDM and cockroach skin prick test (SPT) reactivity, and asthma.ResultsTotal IgE, total IgG4 and SWA‐, SEA‐ and allergen‐specific IgE and IgG4 levels were significantly higher in the rural, compared to the urban setting. In both community settings, both Sm infection and SPT reactivity were positively associated with allergen‐specific and total IgE responses. SPT reactivity was inversely associated with Schistosoma‐specific IgG4, allergen‐specific IgG4/IgE ratios and total IgE/allergen‐specific IgE ratios. Asthmatic schoolchildren, compared with non‐asthmatic controls, had significantly higher levels of total and allergen‐specific IgE, but lower ratios of allergen‐specific IgG4/IgE and total IgE/allergen‐specific IgE.Conclusions and clinical relevanceOur immuno‐epidemiological data support the hypothesis that the IgG4–IgE balance and the total IgE–allergen‐specific IgE balance are more important than absolute total, helminth‐ or allergen‐specific antibody levels in inhibition of allergies in the tropics.

Biology and dynamics of B cells in the context of IgE-mediated food allergy.

An increasing number of people suffer from IgE-mediated food allergies. The immunological mechanisms that cause IgE-mediated food allergy have been extensively studied. B cells play a key role in the development of IgE-mediated food allergies through the production of allergen-specific antibodies. While this particular function of B cells has been known for many years, we still do not fully understand the mechanisms that regulate the induction and maintenance of allergen-specific IgE production. It is still not fully understood where in the body IgE class switch recombination of food allergen-specific B cells occurs, and what processes are involved in the immunological memory of allergen-specific IgE responses. B cells can also contribute to the regulation of allergen-specific immune responses through other mechanisms such as antigen presentation and cytokine production. Recent technological advances have enabled highly detailed analysis of small subsets of B cells down to the single-cell level. In this review, we provide an overview of the current knowledge on the biology of B cells in relation to IgE-mediated food allergies.

Genetically engineered fusion of allergen and viral-like particle induces a more effective allergen-specific immune response than a combination of them.

Chimeric virus-like particles (VLPs) were developed as a candidate for allergen-specific immunotherapy. In this study, hepatitis B core antigen (HBcAg) that genetically fused to Chenopodium album polcalcin (Che a 3)-derived peptide was expressed in E. coli BL21, purified, and VLP formation was evaluated using native agarose gel electrophoresis (NAGE) and transmission electron microscopy (TEM). Chimeric HBc VLPs were characterized in terms of their reactivity to IgE, the induction of blocking IgG and allergen-specific IgE, basophil-activating capacity, and Th1-type immune responses. Results from IgE reactivity and basophil activation test showed that chimeric HBc VLPs lack IgE-binding capacity and basophil degranulation activity. Although chimeric HBc VLPs induced the highest level of efficient polcalcin-specific IgG antibody in comparison to those induced by recombinant Che a 3 (rChe a 3) mixed either with HBc VLPs or alum, they triggered the lowest level of polcalcin-specific IgE in mice following immunization. Furthermore, in comparison to the other antigens, chimeric HBc VLPs produced a polcalcin-specific Th1 cell response. Taken together, genetically fusion of allergen derivatives to HBc VLPs, in comparison to a mix of them, may be a more effective way to induce appropriate immune responses in allergen-specific immunotherapy. KEY POINTS: • The insertion of allergen-derived peptide into major insertion region (MIR) of hepatitis B virus core (HBc) antigen resulted in nanoparticles displaying allergen-derived peptide upon its expression in prokaryotic host. • The resultant VLPs (chimeric HBc VLPs) did not exhibit IgE reactivity with allergic patients' sera and were not able to degranulate basophils. • Chimeric HBc VLPs dramatically improved protective IgG antibody response compared with those induced by allergen mixed either with HBc VLPs or alum. • Chimeric HBc VLPs induced Th1 responses that were counterparts of Th2 responses (allergic). • Chimeric HBc VLPs increased IgG2a/ IgG1 ratio and the level of IFN-γ compared to those induced by allergen mixed with either HBc VLPs or alum. Graphical Abstract.

Modeling the conversion between specific IgE test platforms for nut allergens in children and adolescents.

Multiplex tests allow for measurement of allergen-specific IgE responses to multiple extracts and molecular allergens and have several advantages for large cohort studies. Due to significant methodological differences, test systems are difficult to integrate in meta-analyses/systematic reviews since there is a lack of datasets with direct comparison. We aimed to create models for statistical integration of allergen-specific IgE to peanut/tree nut allergens from three IgE test platforms. Plasma from Canadian and Austrian children/adolescents with peanut/tree nut sensitization and a cohort of sensitized, high-risk, pre-school asthmatics (total n=166) were measured with three R&D multiplex IgE test platforms: Allergy Explorer version 1 (ALEX) (Macro Array Dx), MeDALL-chip (Mechanisms of Development of Allergy) (Thermo Fisher), and EUROLINE (EUROIMMUN). Skin prick test (n=51) and ImmunoCAP (Thermo Fisher) (n=62) results for extracts were available in a subset. Regression models (Multivariate Adaptive Regression Splines, local polynomial regression) were applied if >30% of samples were positive to the allergen. Intra-test correlations between PR-10 and nsLTP allergens were assessed. Using two regression methods, we demonstrated the ability to model allergen-specific relationships with acceptable measures of fit (r2 =94%-56%) for peanut and tree nut sIgE testing at the extract and molecular-level, in order from highest to lowest: Ara h 2, Ara h 6, Jug r 1, Ana o 3, Ara h 1, Jug r 2, and Cor a 9. Our models support the notion that quantitative conversion is possible between sIgE multiplex platforms for extracts and molecular allergens and may provide options to aggregate data for future meta-analysis.

Cul o 2 specific IgG3/5 antibodies predicted Culicoides hypersensitivity in a group imported Icelandic horses

BackgroundCulicoides hypersensitivity (CH) is induced in horses by salivary allergens of Culicoides midges. In Iceland, the causal Culicoides species for CH are not present. Previous epidemiological data indicated that Icelandic horses are more susceptible to CH when they are exported from Iceland and first exposed to Culicoides at adult age. Horses born in countries where Culicoides is endemic, develop the disease less frequently. Here, we established a longitudinal allergy model to identify predictive and diagnostic serological biomarkers of CH.ResultsSixteen adult Icelandic horses from Iceland were imported to the Northeastern United States (US) during the winter and were kept in the same environment with natural Culicoides exposure for the next two years. None of the horses showed clinical allergy during the first summer of Culicoides exposure. In the second summer, 9/16 horses (56%) developed CH. Allergen specific IgE and IgG isotype responses in serum samples were analysed using nine potential Culicoides allergens in a fluorescent bead-based multiplex assay. During the first summer of Culicoides exposure, while all horses were still clinically healthy, Cul o 2 specific IgG3/5 antibodies were higher in horses that developed the allergic disease in the second summer compared to those that did not become allergic (p = 0.043). The difference in Cul o 2 specific IgG3/5 antibodies between the two groups continued to be detectable through fall (p = 0.035) and winter of the first year. During the second summer, clinical signs first appeared and Cul o 3 specific IgG3/5 isotypes were elevated in allergic horses (p = 0.041). Cul o 2 specific IgG5 (p = 0.035), and Cul o 3 specific IgG3/5 (p = 0.043) were increased in late fall of year two when clinical signs started to improve again.ConclusionsOur results identified IgG5 and IgG3/5 antibodies against Cul o 2 and Cul o 3, respectively, as markers for CH during and shortly after the allergy season in the Northeastern US. In addition, Cul o 2 specific IgG3/5 antibodies may be valuable as a predictive biomarker of CH in horses that have been exposed to Culicoides but did not yet develop clinical signs.

Transfer and loss of allergen-specific responses via stem cell transplantation: A prospective observational study.

Currently, no estimates can be made on the impact of hematopoietic stem cell transplantation on allergy transfer or cure of the disease. By using component-resolved diagnosis, we prospectively investigated 50 donor-recipient pairs undergoing allogeneic stem cell transplantation. This allowed calculating the rate of transfer or maintenance of allergen-specific responses in the context of stem cell transplantation. Allergen-specific IgE and IgG to 156 allergens was measured pretransplantation in 50 donors and recipients and at 6, 12 and 24months in recipients post-transplantation by allergen microarray. Based on a mixed effects model, we determined risks of transfer of allergen-specific IgE or IgG responses 24months post-transplantation. After undergoing stem cell transplantation, 94% of allergen-specific IgE responses were lost. Two years post-transplantation, recipients' allergen-specific IgE was significantly linked to the pretransplantation donor or recipient status. The estimated risk to transfer and maintain individual IgE responses to allergens by stem cell transplantation was 1.7% and 2.3%, respectively. Allergen-specific IgG, which served as a surrogate marker of maintaining protective IgG responses, was highly associated with the donor's (31.6%) or the recipient's (28%) pretransplantation response. Hematopoietic stem cell transplantation profoundly reduces allergen-specific IgE responses but also comes with a considerable risk to transfer allergen-specific immune responses. These findings facilitate clinical decision-making regarding allergic diseases in the context of hematopoietic stem cell transplantation. In addition, it provides prospective data to estimate the risk of transmitting allergen-specific responses via hematopoietic stem cell transplantation.

Paneth cells regulate allergic sensitization in the gastrointestinal tract

Abstract The gut immune homeostasis plays a major role in controlling sensitization to food allergens and the development of allergic responses in the gastrointestinal tract, but also to skin or lung. Epithelial cells sensing of commensal microbes is crucial for the maturation of the gut immune system and antibiotic treatment during early life is believed to have contributed to the increased incidence of food allergy. Paneth cells secrete antimicrobial products and cytokines in the crypts of the small intestine, but their role in food allergy remains elusive. We found that SOX9ΔIEC mice, which lack of Paneth cells, display dysbiosis with increased microbial diversity. Interestingly, Paneth cell deficiency have increased numbers of ILC2 in the intestinal lymphoid tissues. Upon oral sensitization with a model food antigen in the presence of cholera toxin, SOX9ΔIEC mice developed significantly higher allergen-specific serum IgE responses, and enhanced signs of allergic responses (i.e., swelling, hypothermia, impairment of lung functions) after nasal allergen challenge. Transplantation of fecal materials from SOX9ΔIEC mice was able to transfer the hyper-allergenic phenotype to control wild-type mice and bacteria-free fecal extract from SOX9ΔIEC mice increased the number of IgE producing B cells than fecal extract from control mice with treatment of anti-CD40 and IL-4 in vitro. Ongoing studies are assessing the metabolites present in the intestinal lumen of SOX9ΔIEC mice and their effect of intestinal epithelial cells and myeloid cells to elucidate the mechanisms by which impaired or defective anti-microbial functions of Paneth cells regulate allergic sensitization of the GI tract.

Ragweed SLIT-Tablets Induce Similar Patterns of Allergen-Specific IgE and IgG4 Responses in Children and Adults with Allergic Rhinoconjunctivitis

Ragweed SLIT-Tablets Induce Similar Patterns of Allergen-Specific IgE and IgG4 Responses in Children and Adults with Allergic Rhinoconjunctivitis

Two years of treatment with the recombinant grass pollen allergy vaccine BM32 induces a continuously increasing allergen-specific IgG4 response.

BackgroundBM32, a grass pollen allergy vaccine containing four recombinant fusion proteins consisting of hepatitis B-derived PreS and hypoallergenic peptides from the major timothy grass pollen allergens adsorbed on aluminium hydroxide has been shown to be safe and to improve clinical symptoms of grass pollen allergy upon allergen-specific immunotherapy (AIT). We have investigated the immune responses in patients from a two years double-blind, placebo-controlled AIT field trial with BM32.MethodsBlood samples from patients treated with BM32 (n = 27) or placebo (Aluminium hydroxide) (n = 13) were obtained to study the effects of vaccination and natural allergen exposure on allergen-specific antibody, T cell and cytokine responses. Allergen-specific IgE, IgG, IgG1 and IgG4 levels were determined by ImmunoCAP and ELISA, respectively. Allergen-specific lymphocyte proliferation by 3H thymidine incorporation and multiple cytokine responses with a human 17-plex cytokine assay were studied in cultured peripheral blood mononuclear cells (PBMCs).FindingsTwo years AIT comprising two courses of 3 pre-seasonal injections of BM32 and a single booster after the first pollen season induced a continuously increasing (year 2 > year 1) allergen-specific IgG4 response without boosting allergen-specific IgE responses. Specific IgG4 responses were accompanied by low stimulation of allergen-specific PBMC responses. Increases of allergen-specific pro-inflammatory cytokine responses were absent. The rise of allergen-specific IgE induced by seasonal grass pollen exposure was partially blunted in BM32-treated patients.InterpretationAIT with BM32 is characterised by the induction of a non-inflammatory, continuously increasing allergen-specific IgG4 response (year 2 > year1) which may explain that clinical efficacy was higher in year 2 than in year 1. The good safety profile of BM32 may be explained by lack of IgE reactivity and low stimulation of allergen-specific T cell and cytokine responses.FundingsGrants F4605, F4613 and DK 1248-B13 of the Austrian Science Fund (FWF).

Maternal allergen-specific IgG might protect the child against allergic sensitization

BackgroundAnalysis of allergen-specific IgE responses in birth cohorts with microarrayed allergens has provided detailed information regarding the evolution of specific IgE responses in children. High-resolution data regarding early development of allergen-specific IgG are needed.ObjectiveWe sought to analyze IgG reactivity to microarrayed allergens in mothers during pregnancy, in cord blood samples, in breast milk, and in infants in the first years of life with the aim to investigate whether maternal allergen-specific IgG can protect against IgE sensitization in the offspring.MethodsPlasma samples from mothers during the third trimester, cord blood, breast milk collected 2 months after delivery, and plasma samples from children at 6, 12, and 60 months of age were analyzed for IgG reactivity to 164 microarrayed allergens (ImmunoCAP ISAC technology) in 99 families of the Swedish birth cohort Assessment of Lifestyle and Allergic Disease During Infancy (ALADDIN). IgE sensitizations to microarrayed allergens were determined at 5 years of age in the children.ResultsAllergen-specific IgG reactivity profiles in mothers, cord blood, and breast milk were highly correlated. Maternal allergen-specific IgG persisted in some children at 6 months. Children’s allergen-specific IgG production occurred at 6 months and reflected allergen exposure. Children who were IgE sensitized against an allergen at 5 years of age had significantly higher allergen-specific IgG levels than nonsensitized children. For all 164 tested allergens, children from mothers with increased (>30 ISAC standardized units) specific plasma IgG levels against an allergen had no IgE sensitizations against that allergen at 5 years of age.ConclusionThis is the first detailed analysis of the molecular IgG recognition profile in mothers and their children in early life. High allergen-specific IgG reactivity in the mother’s plasma and breast milk and in cord blood seemed to protect against allergic sensitization at 5 years of age.

Paneth cells regulate allergic sensitization in the gastrointestinal tract

Abstract The gut immune homeostasis plays a major role in controlling sensitization to food allergens and the development of allergic responses in the gastrointestinal tract, but also to skin or lung. Epithelial cells sensing of commensal microbes is crucial for the maturation of the gut immune system and antibiotic treatment during early life is believed to have contributed to the increased incidence of food allergy. Paneth cells secrete antimicrobial products in the crypts of the small intestine, but their role in food allergic remains elusive. We found that SOX9ΔIEC mice, which lack of Paneth cells, display dysbiosis with increased microbial diversity and the presence of a large number of unclassified bacterial species. Upon oral sensitization with OVA as a model of food antigen in the presence of cholera toxin, SOX9ΔIEC mice developed similar levels of allergen-specific serum IgA and IgG responses to control wild-type mice with the exception of IgG3 responses, which were elevated in SOX9ΔIEC mice. Interestingly, SOX9ΔIEC mice exhibited significantly increased allergen-specific serum IgE responses, and exacerbated signs of allergic responses (i.e., swelling, hypothermia, impairment of lung functions) after nasal allergen challenge. Transplantation of fecal materials from SOX9ΔIEC mice was able to transfer the hyper-allergenic phenotype to control wild-type mice. Ongoing studies are assessing the metabolites present in the intestinal lumen of SOX9ΔIEC mice and their effect on intestinal epithelial cells and myeloid cells to elucidate the mechanisms by which impaired or defective anti-microbial functions of Paneth cells regulate allergic sensitization of the GI tract.

Issue Highlights

Issue Highlights

Differential role of oxidative stress pathways and microbiota in the development of allergen specific IgE following chronic ingestion of low doses of cadmium

Abstract Chronic ingestion of low doses of cadmium is becoming a major public health issue due to the presence of this heavy metal in contaminated water and its accumulation in leafy vegetables, fish and grains. Environmental pollutants are believed to contribute to the increased incidence of allergy diseases, but underlying mechanisms remain poorly understood. We found that C57BL/6 mice chronically exposed to low doses of cadmium through drinking water develop higher titer of antigen-specific IgE responses upon oral sensitization. Cadmium-treated mice also exhibited higher IL-17 and Th1 responses in the airways and displayed more severe signs of airway allergic responses, upon nasal antigen challenge. Analysis of innate responses in the intestine revealed that ingestion of low doses of cadmium activated both the canonical and the non-canonical NF-κB pathway and promoted proinflammatory cytokine and antimicrobial responses through activation of oxidative signaling pathways including Duox2 and Nrf2. Chronic ingestion of low doses of cadmium also resulted in a dysbiosis of the intestinal microbial community, which persisted long after exposure was interrupted. Germ-free C57BL/6 mice exposed to cadmium and sensitized under the same conditions failed to develop elevated allergen-specific IgE responses. Finally, when transferred into untreated mice, the fecal microbe of cadmium-treated mice increased the allergen-specific IgE responses in the recipients confirming the central role the dysbiosis in the induction of allergic responses. Microbial products mediating the allergy-promoting effect of cadmium are being identified in ongoing studies.

A B Cell Epitope Peptide Derived from the Major Grass Pollen Allergen Phl p 1 Boosts Allergen-Specific Secondary Antibody Responses without Allergen-Specific T Cell Help.

More than 40% of allergic patients suffer from grass pollen allergy. Phl p 1, the major timothy grass pollen allergen, belongs to the cross-reactive group 1 grass pollen allergens that are thought to initiate allergic sensitization to grass pollen. Repeated allergen encounter boosts allergen-specific IgE production and enhances clinical sensitivity in patients. To investigate immunological mechanisms underlying the boosting of allergen-specific secondary IgE Ab responses and the allergen epitopes involved, a murine model for Phl p 1 was established. A B cell epitope–derived peptide of Phl p 1 devoid of allergen-specific T cell epitopes, as recognized by BALB/c mice, was fused to an allergen-unrelated carrier in the form of a recombinant fusion protein and used for sensitization. This fusion protein allowed the induction of allergen-specific IgE Ab responses without allergen-specific T cell help. Allergen-specific Ab responses were subsequently boosted with molecules containing the B cell epitope–derived peptide without carrier or linked to other allergen-unrelated carriers. Oligomeric peptide bound to a carrier different from that which had been used for sensitization boosted allergen-specific secondary IgE responses without a detectable allergen-specific T cell response. Our results indicate that allergen-specific secondary IgE Ab responses can be boosted by repetitive B cell epitopes without allergen-specific T cell help by cross-linking of the B cell epitope receptor. This finding has important implications for the design of new allergy vaccines.

P062 Modulation of allergen specific IgE and IgG4 responses after sublingual immunotherapy in respiratory allergic patients

P062 Modulation of allergen specific IgE and IgG4 responses after sublingual immunotherapy in respiratory allergic patients