What is ovalbumin allergy

An allergy involves an excessive TH2 helper cell response. TH2 helper cells are a specialised group of lymphocytes of the immune system. During an allergic reaction, these cells reply to generally harmless antigens such as pollen, but also antigens in peanuts, hen’s eggs, etc. Specific immunotherapy intends to re-establish the immune balance in favour of a TH1 helper response. In the above-described novel approach of immunotherapy, the modified virus Ankara not only serves as a transport vehicle of genetic information of the allergen but is also an effective immune modulator, since it creates a strong TH1 helper cell response against antigens.

This process involves induction of allergen specific IgG2a antibodies, which can act as blocking antibodies, as well as cytokines (interferon-gamma) which counteract allergic reactions. This helps to restore a normal immune response.

What is ovalbumin allergy


Literature

[1] Albrecht M, Suezer Y, Staib C, Sutter G, Vieths S, Reese G (): Vaccination with a Modified Vaccinia Virus Ankara-based vaccine protects mice from allergic sensitization. J Gene Med Online-Abstract.

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ORIGINAL ARTICLE
Year : | Volume : 28 | Issue : 3 | Page :

Schistosoma mansoni infection or soluble egg antigen immunization can reduce allergic airway diseases

Nashaat E Nassef, Wafaa M El-Kersh, Nadia S El-Nahas, Salwa A Shams El-Din, Shaimaa A Sharaf El-Deen
Department of Parasitology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission Apr
Date of Acceptance May
Date of Web Publication Oct

Correspondence Address:
Salwa A Shams El-Din
Department of Parasitology, Faculty of Medicine, Shibin El-Kom-YassinAbd El-Ghaffar Highway
Egypt

Source of Support: None, Conflict of Interest: None

[SCOPUS][CROSSREF][PUBMED]

DOI:/

Abstract

Objective
The purpose of the study was to investigate the impact of Schistosoma mansoni infection and soluble egg antigen (SEA) immunization on allergic airway diseases and to study the involved immune-modulation mechanisms.
Background
Schistosomiasis and allergic airway diseases are common health problems that affect a wide range of population.

Numerous studies showed that there is an inverse relationship between prevalence of Schistosoma and allergic airway diseases.
Materials and methods
The mice groups were either infected with S. mansoni or SEA immunized or noninfected. Airway allergy was induced in laboratory mice by ovalbumin. Thereafter, the degree of lung inflammation was sure by histopathology. Immune response was studied by immune-histochemical examination of regulatory T (T-reg), CD4+ and CD8+ cells, and serum antiovalbumin IgE level was sure by ELISA.
Results
The infected and immunized groups showed significant reduction in lung pathology, CD4+ cell infiltration of lungs and serum antiovalbumin IgE level than the control group.

This was associated with a significant increase in the immune-suppressor T-reg cells and CD8+ cells infiltration of lungs.
Conclusion
S. mansoni infection or SEA immunization own downregulating effects on ovalbumin-induced experimental allergic airway diseases. These effects could be attributed to increased activation of T-reg cells and CD8+ cells, which downregulate the immune response.

Keywords:Immune response, immunization, ovalbumin, Schistosoma mansoni, soluble egg antigen, T-reg cells

How to cite this article:
Nassef NE, El-Kersh WM, El-Nahas NS, Shams El-Din SA, Sharaf El-Deen SA.

Schistosoma mansoni infection or soluble egg antigen immunization can reduce allergic airway diseases. Menoufia Med J ;

How to cite this URL:
Nassef NE, El-Kersh WM, El-Nahas NS, Shams El-Din SA, Sharaf El-Deen SA. Schistosoma mansoni infection or soluble egg antigen immunization can reduce allergic airway diseases. Menoufia Med J [serial online] [cited Jan 30]; Available from:?/28/3//
Introduction

Schistosomiasis is the third most frequent parasitic disease affecting mankind.

It ranks immediately after malaria and amoebiasis [1]. Numerous control programs were directed against Schistosoma and led to a general decline in its prevalence. For example, Egyptian prevalence has declined from over 50% by the year to 12% by the year [2],[3].

Allergic airway diseases are also common. They happen because of an exaggerated immune response (hypersensitivity) to diverse antigens leading to activation of diverse cells responsible for immune response, mainly Th2 cells. Immune response to airway allergen begins with recognition by its specific IgE bound to mast cells and basophils.

This recognition is followed by early-phase and late-phase responses, which lead to secretion of numerous cytokines that activate numerous immune cells [4],[5].

In contrast to Schistosoma, the prevalence of allergic airway diseases has increased over the past decades, especially in developed areas. It was noticed that this increased prevalence was associated with a general decline in bacterial and parasitic infections in these areas [6],[7]. This was reported in numerous epidemiological and clinical studies, which showed an inverse correlation between allergic airway diseases and infections. These findings lead to development of ‘hygiene hypothesis’, which suggested that exposure to certain infections may own an inhibitory effect on the development of allergy and asthma [8],[9],[10].

Some experimental studies showed a protective effect of some chronic helminth infections including Schistosomamansoni on the development of allergic airway inflammation [11],[12].

The influence of parasitic infections on the development of allergy has been less well studied.

Some epidemiological and clinical studies own suggested that chronic helminth infections may inhibit allergy, although it is also controlled by Th2 response [13],[14]. Although allergy and helminth infections are controlled by Th2 responses, they are functionally diverse. Allergic Th2 response is an abnormality in human, whereas Th2 responses to helminth infections are significant protective mechanism against these parasitic infections. Numerous immune-modulatory effects of helminth infection also own been identified during immune reaction of the host against them [15].

Acute schistosomiasis is mainly controlled by Th1 response and its related cytokines [16],[17].

However, Th2 response increases as the infection moves toward chronicity, especially after onset of egg deposition [18]. This Th2 response is regulated by numerous cells and cytokines, mainly regulatory T (T-reg) cells and its cytokines interleukin (IL) and transforming growth factor (TGF)-b [19]. T-reg cells were found to be deficient in asthmatic patients, and it was also reported that numerous antiasthmatic drugs increase T-reg cells as a part of their action [20].

The purpose of the present work was to study the effect of experimental S. mansoni infection on induced allergic airway diseases.

The study also aimed to study the effect of immunization by S. mansoni soluble egg antigen (SEA) on the same disease through histopathological detection of cellular immune response of T-reg, CD4+ and CD8+ cells and through estimation of humoral immune response by serum antiovalbumin IgE level.

Materials and methods

Experimental animals

Sixty BALB/c mice (week-old) were obtained from the Schistosome Biological Supply Program, Theodor Bilharz Research Institute (Giza, Egypt) and kept under standard housing conditions in their animal home.

Every procedures met the International Guiding Principles for Biomedical Research Involving Animals as issued by the International Organizations of Medical Sciences ().

Study design

Mice were divided into six groups. Each group consisted of 10 mice. Group I (GI) was sensitized by ovalbumin. Group II (GII) was infected with S. mansoni then sensitized by ovalbumin after onset of egg deposition as detected by stool examination. Group III (GIII) received SEA immunization then sensitized by ovalbumin after the fourth dose of SEA.

Group IV (GIV) was infected with S. mansoni cercariae only. Group V (GV) was immunized by SEA, whereas group VI (GVI) was the nonovalbumin sensitized nonimmunized non-S. mansoni-infected group (the negative control group).

Infection of mice with Schistosoma mansoni[21]

Mice (GII and GIV) were infected with S. mansoni cercariae (Egyptian strain) by subcutaneous injection. Stool examination from the day 45 postinfection was performed to ensure completion of the cycle and onset of the chronic stage by presence of S.

mansoni eggs in stool of mice.

Immunization by Schistosoma mansoni soluble egg antigen

S. mansoni SEA was purchased from Schistosome Biological Supply Program, Theodor Bilharz Research Institute. The crude SEA preparation was purified, sterilized by filtration through m filters (Nalgene Brand Product; Sybran Corp., Rochester, New York, USA) and the protein content was estimated using the Bio-Rad Kit (Bio-Rad Laboratories, Hercules, California, USA) [22]. The immunized groups (GIII and GV) were intraperitoneally injected with four doses (10 g of the SEA each in 10 l PBS) given with 2 days separation between each dose [22].

Sensitization of mice by ovalbumin allergen [23]

To induce allergic airway inflammation, mice (GI, GII and GIII) were sensitized with ovalbumin (Worthington Biochemical Cooperation, Lakewood, New Jersey, USA) using 20 g of ovalbumin in 2 mg of aluminium hydroxide gel adjuvant in a entire volume of l by intraperitoneal injection (days 60 and 75).

On days , they were challenged with intranasal ovalbumin (50 g ovalbumin in 50 l PBS). Negative control animals were injected with aluminium hydroxide in PBS intraperitoneally and intranasally challenged with PBS instead of ovalbumin. S. mansoni infection (GII and GIV) and SEA immunization (GIII and GV) were totally completed before ovalbumin sensitization. Every mice were killed on the day 90 of the experiment.

Histopathological examination of lung tissue [24]

Lung tissue of mice from every groups was preserved in formalin 10% and stained with haematoxylin and eosin.

Stained slides were microscopically examined to determine the degree of lung inflammation as free, mild, moderate or severe. The degree of inflammation was categorized into four levels: free (no inflammation), mild ( foci of inflammation/section), moderate ( foci of inflammation/section) and severe (> 6 foci of inflammation/section). Three slides were evaluated for each mouse. The mean of every the individual scores was calculated and used for analysis [25].

Immunohistochemistry for Foxp3+ T-reg cells, CD4+ cells and CD8+ cells [26]

Lung tissue sections of 4-m thickness were deparaffinized, rehydrated and then incubated with rabbit monoclonal antimouse Foxp3+ monoclonal antibodies (Aviva Systems Biology, San Diego, California, USA), rabbit monoclonal antimouse antibodies against CD4+ cells (Abcam, Cambridge, Massachusetts, USA), or rabbit monoclonal antimouse antibodies against CD8+ cells (Abcam).

This step was followed by incubation with biotinylated goat antipolyvalent secondary antibody. Enzyme conjugate streptavidin peroxidase was applied before enzyme substrate chromogen solution. Counter staining was performed using Mayers hematoxylin. Positivity was considered when any cell showed brown membranous or membranocytoplasmic staining. Stained cells of lung tissues were counted from 10 randomly chosen high power field (h.p.f.).

Estimation of antiovalbumin IgE levels [27]

The levels of antiovalbumin IgE in serum were estimated by ELISA (Mouse Serum Antiovalbumin IgE Antibody Assay Kit; Chondrex Inc., Redmond, Washington, USA).

The assays were performed according to the manufacturer’s protocol.

Statistical analysis

The collected data were tabulated and analyzed by SPSS statistical package (version 13; SPSS Inc., Chicago, Illinois, USA). The Kruskal-Wallis test for nonparametric data was used. P-values of less than were considered statistically significant.

Results

Data in [Table 1] and [Figure 1] show that both S. mansoni infection and SEA immunization decreased incidence of severe lung inflammation, which was of the most prevalent degree in GI.

Severe inflammation was totally absent in GII and only 20% in GIII. Free lungs prevailed in GIV, whereas GV and GVI were totally free of inflammation.

Figure 1: Lung tissue of ovalbumin sensitized group (group I) showing severe lung congestion (C) associated with thick chronic infl ammatory infiltrate (I) of lung tissue (haematoxylin and eosin, ).

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Table 1: Comparison of the degree of lung inflammation between the studied groups

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[Table 2] describes T-reg cells count/10 h.p.f.

in the studied groups. Both GII and GIII had significantly higher counts than GI. The difference between GII and GIII was insignificant (P > ) [Figure 2] and [Figure 4].

Figure 2: Lung tissue of Schistosoma mansoni-infected ovalbumin sensitized group (group II) showing moderate chronic inflammatory infiltrate (I) in peribronchial and interstitial tissue together with tissue congestion (C) (haematoxylin and eosin, ).

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Table 2: Comparison between mean T regulatory cell count/10 high power field among studied groups

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CD4+ cells count/10 h.p.f.

described in [Table 3] shows that lung tissue of both GII and GIII showed significant reduction in CD4+ cells infiltration than GI, which was the most infiltrated by CD4+ cells [Figure 3] and [Figure 5], whereas the difference between GII and GIII was insignificant (P > ).

Data in [Table 4] show that CD8+ cells count/10 h.p.f. in both GII and GIII was significantly higher than GI. The difference between GII and GIII was insignificant (P > ).

Figure 3: Lung tissue of soluble egg antigen immunized ovalbumin sensitized group (group III) showing congested lung tissue (C) together with mild peribronchial and interstitial chronic lymphoplasmacytic inflammation (I) (haematoxylin and eosin, ) .

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Figure 4: Membranous expression of Foxp3 in some cells (red arrows) in lung tissue of ovalbumin sensitized group (group I) (immune-stain reaction for Foxp3, ) .

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Figure 5: Lung tissue of ovalbumin sensitized group (group I) showing strong membranous CD4 expression in numerous cells (red arrows) in the interalveolar septae (immune-stain reaction for CD4, ).

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Table 3: Comparison between mean T helper (CD4+) cell count/10 high power fi eld among studied groups

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Table 4: Comparison between mean T cytotoxic (CD8+) cell count/10 high power fi eld among studied groups

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[Table 5] shows that the mean CD4+/CD8+ cell ratio in both GII and GIII was significantly lower than GI.

Both GII and GIII were insignificantly diverse (P > ).

Table 5: Comparison between the mean CD4+/CD8+ cell ratio among studied groups

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[Table 6] describes the mean worth of serum antiovalbumin IgE. Both GII and GIII had significantly lower worth than GI. Insignificant difference was found between GII and GIII (P > ).

Table 6: Comparison between mean serum antiovalbumin IgE level among studied groups

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Discussion

There is an evidence that decreased helminthic infections in diverse countries is associated with increased incidence of allergic diseases [6],[7].

The present study investigated whether S. mansoni infection could affect the pathogenesis of ovalbumin-induced allergic airway diseases and whether SEA immunization has the same effects as infection.

In the present study, the results showed that the infected group (GII) had significant reduction in the incidence of severe lung inflammation than the pure ovalbumin group (GI). This suggests immune-downregulating effect of S. mansoni infection on the immunological pathway of allergic airway diseases, which is more or less similar in infection and SEA immunization.

This reduction in inflammation correlates with significant increase in T-reg cells in the infected and immunized groups, which are known as significant immune-suppressor cells. They express the immune-suppressive cytokine TGF-b, which blocks IL-2 production by T helper cells. Blocking of IL-2 prevents differentiation and proliferation of T cells, natural killer cells, and other immune system cells [28],[29]. It increases activation of T-reg cells themselves and expression of Foxp3 protein, which controls the development and functions of T-reg cells.

The T-reg cells act also in a cytokine-independent manner through cell contact-dependent mechanisms [30].

Similar results were recorded in a study on Schistosoma japonicum in which lung inflammation was decreased in ovalbumin-induced bronchial asthma in the infected mice groups. These results were attributed to activation of T-reg cells by infection or the transferred dendritic cells [31].

Treatment of S. mansoni infection or depletion of T-reg cells lead also to aggravation of asthmatic symptoms in murine ovalbumin-induced bronchial asthma.

This supported the significant role of T-reg cells in downregulation of the asthmatic pathway [32].

In contrast, a recent study [33] reported potent lung inflammation following intravenous injection of S. mansoni eggs in experimental mice. This inflammation was found to be caused by egg emboli that were carried to the lungs through the pulmonary vessels and trapped in the lung parenchyma.

In the present study lung T-reg cells showed significant increase in the infected and immunized asthmatic groups (GII and GIII) than the pure ovalbumin group (GI). This significant increase can explain the significant suppression of the immune response to ovalbumin allergen in both infected and immunized groups.

T-reg cells are normally activated in S. mansoni infection as a part of the immune response that limits the damage and excessive fibrosis, which can happen with exaggerated Th2 response [34]. The nonsignificant difference detected between GII and GIII clarifies similar effects of both whole infection and SEA immunization on T-reg cells stimulation.

Similarly, S. japonicum infection was reported to own an upregulating effect on T-reg cells.

Authors related this increase to immune evasion of S. japonicum. They proved their view by the decrease in worm load in T-reg cells-depleted mice [35].

The immune suppressive role of T-reg cells on bronchial asthma was also reported by Choi et al.[36], who proved that bee venom treatment suppressed the production of IL-2, IL-4, and IL and augmented the production of IL by T-reg cells.

The present study showed significant reduction in CD4+ lymphocytes infiltrating the lung in both GII and GIII.

These results can be due to the downregulating effects of both S. mansoni infection and SEA immunization. These results are confirmed by the fact that CD4+ lymphocytes frolic an significant role in allergic immune response especially the tardy phase, and their reduction denotes lesser inflammation [37].

Similarly, another study reported that proportion of CD4+ T helper cells with honor to T-reg cells in the spleens and mesenteric lymph nodes decreases gradually as the S.

japonicum infection becomes more chronic. This was explained by the suppressive role of T-reg cells [38].

S. mansoni infection and SEA immunization also had upregulating effects on CD8 + cells, which was significantly increased in both groups (GII and GIII) than the pure ovalbumin group (GI). These findings could be attributed to increased T-reg cells in the infected or immunized groups, which produce TGF-b that stimulates proliferation and immune-suppressive functions of CD8+ cells [30].

Similarly, Du et al.[39] reported that the mice groups infected with S.

japonicum or immunized with SEA showed significantly higher percentage of CD8+ cells.

Mulu et al.[40] also reported increased CD8+ cells in the peripheral blood of intestinal helminthes-infected AIDS patients (Ascaris lumbricoides, hook worms, Strongyloides stercoralis, Trichuris trichiura, and S. mansoni) than nonhelminth-infected ones.

In the present work, comparison of the mean CD4+/CD8+ cell ratio was significantly higher in the ovalbumin group (GI) than in the ovalbumin infected (GII) or immunized (GIII) groups, which may be explained by the separate downregulation of CD4+ and upregulation of CD8+ in those groups.

These data were supported by Du et al.[39] and De Vos et al.[41].

The present results showed a significant reduction in serum level of specific antiovalbumin IgE in both S. mansoni-infected (GII) and SEA-immunized (GIII) asthmatic groups compared with the pure ovalbumin group (GI). Both GII and GIII were found to own similar effects on serum antiovalbumin IgE levels. Antigen-specific IgE is known to own an significant role in the pathogenesis of asthma by binding to mast cells, basophils, and eosinophils, which release inflammatory mediators upon contact with the allergen [42].

Similarly, Trichinella spiralis infection, Heligmosomoides polygyrus excretory secretory antigens (HES), and S.

mansoni infection were associated with significant reduction in antiovalbumin IgE in murine experimental bronchial asthma. This was related to the immune-suppressive effects of T-reg cells, which were significantly increased with infection [32],[43],[44].

Conclusion

All data of the present study can give a conclusion that S. mansoni infection or SEA immunization own downregulating effects on ovalbumin-induced experimental allergic airway diseases.

These effects are noticed in decreasing inflammation of lung tissue, decreasing lung infiltration by CD4+cells, and decreasing allergic antibody response in the S. mansoni-infected or SEA-immunized asthmatic groups. These effects could be attributed to increased activation of T-reg cells and CD8+ cells, which downregulate the immune response.

Acknowledgements

The authors expresses their acknowledgement to Dr Noha Mohammad El Kady, Lecturer of Pathology, Faculty of Medicine, Menoufiya University, for her helpful assist in interpretation of pathological results.

Conflicts of interest

There are no conflicts of interest.

Authors contribution

Shimaa A.

Sharaf sharing in study thought maintainence of laboratory animals, infection of mice, immunization and performance of laboratory work.

Salwa A. Shams El-Din sharing in study thought, putting protocol, sharing in laboratory work, writing, editoing and citation of the work.

Nadia S. El-Nahas, sharing in study thought, revising and editing the study.

Wafaa M. El-Kersh, sharing in study thought, revising and editing the study.

Nashaat A.

Nassef, sharing in study thought, revising and editing the study.

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Figures

[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

Tables

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1 Masahiro Seike, Department of Food and Nutrition Science, Sagami Women’s Junior College, Bunkyo Minamiku Sagamihara Kanagawa, , Japan.

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.

It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on diverse terms, provided the original work is properly cited and the use is non-commercial. See: http: //

Correspondence to: Masahiro Seike, Department of Food and Nutrition Science, Sagami Women’s Junior College, Bunkyo Minamiku Sagamihara Kanagawa, , Japan.
Email: [email protected]
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Received: April 25,
Revised: April 28,
Accepted: April 30,
Published online: May 13,

Regulatory T cells (Tregs) are crucial in preventing excessive immune responses and autoimmunity.

Tregs elicit a direct or indirect response on target cells (such as lymphocytes, dendritic cells, monocytes, and mast cells). In allergic contact dermatitis and its animal model contact hypersensitivity, Tregs suppress sensitization and elicitation of delayed-type hypersensitivity responses to allergens. Chronic allergic contact dermatitis (CACD) induced by repeated exposure of the skin to the same allergen bears clinical, histological and immunological similarities with those of atopic dermatitis. Allergic responses of CACD are ameliorated as a result of infiltration of Tregs and elevation of IL and transforming growth factor-beta1 (TGF-β1) levels.

In CACD, histamine suppresses Tregs infiltration and IL production by decreasing the TGF-β1 levels through histamine H1 and H4 receptors. As a result, histamine amplifies eczema and maintains allergic reactions in CACD.

Key words: Regulatory T cell; Chronic allergic contact dermatitis; Histamine; IL; Transforming growth factor-beta1

© The Author(s). Published by ACT Publishing Group Ltd. Every rights reserved.

Seike M. Regulatory T Cells and Histamine in Allergic Contact Dermatitis. Journal of Dermatological Research ; 4(1): Available from: URL:

Regulatory T cells (Tregs) frolic an significant role in the immune system. Tregs are involved in the prevention of autoimmune diseases, allergies, infection-induced organ pathology, transplant rejection and graft versus host disease via suppression of effector T cells and other immune cells[1].

In certain conditions, Tregs protect against cancer by controlling cancer-associated inflammation[2]. Conversely, they also decrease immune responses against various types of cancer[3, 4]. Therefore, Tregs are a subject of intense investigations.

Tregs are divided into natural Tregs (nTregs) and induced Tregs (iTregs)[5]. nTregs are known as thymus-derived Tregs (tTregs), and they express the transcription factor forkhead box P3 (FoxP3).

nTregs acquire stable phenotypic and genetic characteristics during thymus selection and maturation and mainly induce immune tolerance to autoantigens[6]. nTregs express CD4, CD25, and FoxP3, with low CD expression[7]. CD4+CD25+Tregs account for 5%% of mature human or mouse CD4+T cells[6]. iTregs are derived from the peripheral lymphoid tissue. Naïve conventional T cells are transformed after coming in contact with an antigen and in the presence of immature transforming growth factor (TGF)-dendritic cells, IL, and interferon (IFN)-γ[8]. There are three types of iTregs: CD4+CD25+FoxP3+iTregs, expressing FoxP3; CD4+CD25lowFoxP3+Th3 cells, mainly secreting TGF-β; and CD4+CD25lowFoxP3-type1 regulatory T (Tr1) cells, secreting high level of IL[5].

The iTregs suppress the immune response induced by autoantigens and regulate the immune response induced by external antigens[5]. Th3 cells secrete TGF-β and IL to mediate the suppression mechanism, while Tr1 cells secrete IL to suppress T cell proliferation[6].

Tregs exist in every lymphoid tissues and include approximately 10% of every T cells in the normal skin, with a high proportion remaining in a resting state, especially in pilous follicles[9]. Few can be found in the interfollicular dermis, while majority is located near the follicular epithelium[10].

Tregs show two diverse mechanisms of suppressing immune cells.

They can either elicit a direct response on target cells or an indirect effects, in which third party cells or molecules are triggered and in turn suppress the target cells[11].

T-lymphocytes

Tregs suppress CD4+ T cell activation and proliferation through contact-dependent and contact-independent mechanisms[12]. They generate immunosuppressive adenosine or transfer cAMP to T lymphocytes. Tregs rapidly suppress T lymphocyte receptor-induced Ca2+, nuclear factor of activated T cells, and nuclear factor kuppa-B (NF-κB) signaling. In addition, they produce immunosuppressive cytokines (IL, IL, TGF-β), suppress target cells through IL-2 consumption or induce effector cell death via granzyme and perforin[12].

Furthermore, Tregs suppress T lymphocyte indirectly by downregulating co-stimulatory molecules on dendritic cells via cytotoxic T-lymphocyte antigen 4 (CTLA-4)[12]. Tregs also influence proliferation, activation and apoptosis of CD8+ T cells[13, 14]. As a result, the induction of effector and memory CD8+ T cells is reduced[15].

Figure 1 Suppressive mechanisms of regulatory T cells. Regulatory T cells (Tregs) suppress T lymphocyte activation and proliferation.

Tregs also generate immunosuppressive cytokines and induce T lymphocyte death via granzyme and perforin. Tregs prevent the production of antibodies through PD-1/PD ligands. Dendritic cells reduce the capacity to capture the antigens through CD80/86/CTLA-4 and LAG-3/MHC-II. M2 macrophages decrease the production of IL-6 and TNF-α, and the activation of NF-κB. Neutrophils produce more IL and TGF-β, and decrease IL Furthermore, Tregs induce the expression of heme oxygenase-1 (HO-1), indoleamine 2,3-dioxygenase (IDO), and the suppression of cytokine signaling molecule (SOCS3). Natural killer cells suppress the proliferation and secretion of IFN-γ via TGF-β.

Innate lymphoid cell 2 decreases the secretion of IL-5 and IL via ICOS/ICOSL. Mast cells inhibit degranulation and the secretion of histamine via OX40/OX40L.


B-lymphocytes

Tregs own the potential to suppress autoreactive B cells in an antigen-specific manner and to prevent the production of harmful autoantibodies. This suppression requires PD-1 expression on autoreactive B cells and expression of the two PD ligands on Treg[16]. Furthermore, Tregs destroy B cells by releasing granzyme B and perforin[17].

Dendritic cells

Tregs interact with dendritic cells in a leukocyte function-associated antigen-1 dependent manner[18] and down-regulate the expression of CD80/86 on target cells through CTLA-4[15].

Tregs express LAG3, a homolog of CD4 receptor. It binds to MHC-II with a higher affinity than CD4, and mediate the activation of PI3K/AKT, p42/44ERK, and p38MAPK pathways[19]. As a result, dendritic cells exhibit an increased expression of co-stimulatory molecules and reduced capacity to capture the antigens[15]. Tregs disrupt the microenvironment of the immunological synapse provided by dendritic cells, which are essential for T cells proliferation. In detail, Tregs function either by reducing the limiting enzyme for glutathione synthesis or by consuming extracellular cysteine[20, 21].

Monocytes

Tregs act on monocytes by inhibiting their cytokine secretion, differentiation and antigen presenting function. Monocytes exhibit classical features of M2 macrophages such as increased expression of CD and CD They reduce the capacity to reply to pro-inflammatory stimuli as demonstrated by decreased production of IL-6 and tumor necrosis factor-α (TNF-α) and decreased NF-κB activation, following co-culture with Tregs[22]. In addition, monocytes co-cultured with expanded Tregs reduce their capacity to increase detrimental IL producing T-cells when compared to freshly isolated Tregs[23].

Granulocytes

Tregs limit granulocytes accumulation by decreasing the expression of chemoattractant, CXCL1 and CXCL2, thus preventing aberrant skin infiltration[24].

Neutrophils co-cultured with Tregs produce more IL and TGF-β and decrease IL-6 production[25]. Moreover, Tregs induce the expression of heme oxygenase-1, indoleamine 2,3-dioxygenase and the suppressor of cytokine signaling 3 molecules[25]. Conversely, recent studies show that Tregs are capable to activate resting basophils by inducing their expression of CD69, CDc, and CD In addition, activated basophils are capable to release IL-4, IL-8 and IL[26].

Innate lymphoid cells

During pregnancy, Tregs suppress natural killer cells to create a tolerable environment favoring implantation[27], while in tumors, Tregs own the potential to block natural killer cells, thereby generating an immune-suppressive environment, which favors cancer cell survival[28].

Tregs prevent natural killer cells from proliferating, secreting IFN-γ and enhancing missing self-recognition[28]. They suppress natural killer cells via membrane bound TGF-β[29].

Induced Tregs, but not thymus-derived Tregs, own the ability to suppress innate lymphoid cell 2 function by preventing the secretion of both IL-5 and IL in an ICOS/ICOSL dependent manner[30]

.

Mast cells

Tregs also negatively regulate mast cells by suppressing their degranulation and anaphylactic response[31, 32]. The induction of allergen-specific tolerant T cells in a murine model of bronchial asthma causes a decrease in circulating histamine after challenge[33]. In mast cells, Tregs directly inhibit degranulation in vitro and in vivo through OX40/OX40L reverse signaling[32].

What is ovalbumin allergy

Allergic contact dermatitis, one of the most common skin diseases, is affecting % of the general population worldwide[34]. Allergic hypersensitivity is associated with both immunoglobulin (Ig) E and T helper 2 (Th2) responses to environmental allergens. In allergic individuals, priming of allergen-specific CD4+Th2 cells by antigen-presenting cells results in the production of Th2 cytokines, which are responsible for initiating B cell production of allergen-specific IgE. IgE binds to the high-affinity IgE receptor on mast cells and basophils. Allergen cross-linking of the cell surface-bound allergen-specific IgE leads to the release of allergic mediators such as histamine, which are stored in granules, as well as to the secretion of de novo synthesized prostaglandins, cysteinyl leukotrienes, cytokines and chemokines[32].

Granule stored-allergic mediators are the key to immediate allergic reactions such as wheal and flare responses of the skin[35], whereas de novo synthesized mediators are more significant for the tardy phase of allergic response[32].

Allergic contact dermatitis and its animal model contact hypersensitivity (CHS) are T cell-mediated skin inflammatory diseases caused by delayed-type hypersensitivity responses to environmental allergens[]. Little organic compounds that rapidly penetrate the skin and bind to proteins in the dermis comprise an significant group of contact allergens[39].

Little organic compounds activate keratinocytes and mast cells directly or indirectly through the innate immune system. The activated keratinocytes and mast cells produce various chemical mediators, which activate dendritic cells. The activated dendritic cells capture antigens, mature, and migrate to the draining lymph nodes via afferent lymphatics. The migrated dendritic cells present antigens to naïve T cells in the draining lymph nodes. Antigen-specific clones differentiate and proliferate into effector T cells[40].

During this sensitization process, the transfer of Tregs suppresses CHS. Tregs in lymph nodes acquire an activated phenotype through ATP. The activated Tregs establish gap junctions with dendritic cells in the lymph nodes, which causes a reduction in the capacity of dendritic cells to stimulate CD8+ T cells[41]. When Tregs are depleted during sensitization, it causes higher effector CD4+ and CD8+ T cell induction and leads to enhanced and prolonged ear swelling. The results indicate that endogenous Tregs contribute to the control of sensitization[42].

Upon re-exposure to antigens, keratinocytes and mast cells are activated and produce various chemical mediators, which activate endothelial cells and cause inflammatory cell infiltration, including antigen-specific T cells. The infiltrated antigen-specific effector T cells are activated and produce pro-inflammatory cytokines and chemokines, which activate keratinocytes and cause further inflammatory cell infiltration[40]. Re-exposure of the skin to the same allergen leads to the development of a delayed-type hypersensitivity reaction mediated by T cells[38].

Neutrophils[43], natural killer cells[44], and innate lymphoid cells[45] influence the magnitude and duration of CHS responses. When Tregs are depleted during elicitation, it leads to an enhanced and prolonged ear swelling response. The results indicate that Tregs are significant in the termination of inflammation[46]. The number of Tregs on the skin increases during the skin inflammation process, suggesting that Tregs own a suppressive role at the inflammatory sites[40]. Skin infiltrating T cells move from the skin to the draining lymph nodes in both steady and inflammatory conditions[46]. Additionally, Tregs migrate selectively under inflammatory conditions compared to under steady conditions.

Moreover, Tregs that migrate to the draining lymph nodes own the potential to re-migrate into the skin. The skin-derived Tregs exhibit an activated phenotype with high expression of CTLA-4 and IL, and they show more potent suppressive activities compared to the resident Tregs in the draining lymph nodes. This suggests that skin Tregs exert their potent suppressive activities not only on the skin but also on the draining lymph nodes via circulation[40].

In addition to Tregs, regulatory B cells (Bregs) own been proposed as other regulators involved in CHS. Bregs are identified as the CD1bhighCD5+ B cell population[47]. Bregs represent 1%~2% of spleen B+ cells, and they produce abundant quantity of IL[48]. CDdeficient mice exhibit augmented CHS responses, and the transfer of Bregs into CDdeficient mice normalizes the extent of inflammation in CHS[49].

In addition, repeated exposure of the skin to the same allergen induces chronic allergic contact dermatitis (CACD). Atopic dermatitis bears clinical, histological, and immunological similarities with CACD[50, 51].

In CACD, a large number of Tregs infiltrate eczematous lesions, induced by repeated exposure to sensitizing agents. Interestingly, allergic responses of CACD (epidermal hyperplasia, thick infiltration of inflammatory cells, and elevated levels of inflammatory cytokines and IgE) are ameliorated during excessive, repeated exposure to the same allergen[52]. As the levels of TGF-β and IL are elevated in CACD[52, 53], allergic responses are considered to be suppressed by Tregs.

Mast cells are widely deployed to the skin and serve as powerful sentinels of the immune system. Mast cells are stimulated via high-affinity receptors for IgE, and by multiple other mechanisms, including activation by cytokines, which lead to the release a diverse spectrum of biologically athletic mediators, including some with pro- or anti-inflammatory functions[54,55].

Therefore, mast cells can own potentially significant effector or immunoregulatory functions during inflammatory processes, such as during the sensitization and effector phases of CHS responses[39]. During the sensitization phase, mast cells are activated directly or indirectly by haptens to release a diverse spectrum of mediators including histamine and TNF. IgE amplifies mast cell activation through antigen-independent cytokinergic effects. Direct cell-to-cell contacts between mast cells and dendritic cells and mast cell-derived TNF amplify dendritic cell migration to the draining lymph nodes, where these cells prime naïve T cells to become effector cells via antigen presentation.

In moderate CHS responses, mast cells and mast cell-derived TNF amplify ear swelling, leukocyte recruitment (mainly neutrophils and CD8+ T cells), and epidermal hyperplasia. In more severe and chronic CHS responses, mast cells act as an early source of IL in the skin, amplifying the recruitment of Tregs and limiting ear swelling and epidermal hyperplasia. Additionally, mast cells migrate to the draining lymph nodes and the spleen in an IgE-dependent manner, where they produce IL-2, which helps in maintaining the effector T cell: Treg ratio at the site of inflammation, and thereby contributes to limiting the severity of CHS responses[39].

However, mast cells sustain inflammatory signals that locally inhibit Treg suppression.

The cytokine IL-6, released by innate and adaptive cells on activation, is known to inhibit Treg anergy and suppression[56]. Among mast cell-associated membrane molecules, the co-stimulatory receptor OX40L can prevent de novo differentiation of Tregs and block their function[57, 58]. Tregs directly inhibit mast cell degranulation through OX40/OX40L[32] and suppress the release of histamine[59].

Histidine decarboxylase (HDC) (-/-) mice lack the ability of synthesize histamine from histidine and show histamine deficiency[60]. In HDC (-/-) mice, no plasma extravasation reaction is observed after passive cutaneous anaphylaxis test[60].

In contrast to immediate-type response, there is no difference observed in CHS (delayed-type responses, observed as thickening of ear skin) between HDC (+/+) and HDC (-/-) mice[60, 61]. However, in CACD models, induced by sensitization and subsequent repeated challenge to a hapten, allergic responses of HDC (-/-) mice are moderate compared to those of HDC (+/+) mice[61, 62]. Histamine appears to be one of the mediators of CACD[62, 63]. HDC (+/+) mice own a lower number of FoxP3 (+) and CTLA-4 (+) cells and lower levels of IL compared to in HDC (-/-) mice with CACD.

Treatment with histamine H1 or H4 receptor antagonist increases the number of FoxP3+ cells, and the levels of IL in HDC (+/+) mice. Histamine leads to the development of CACD by suppressing Tregs through histamine H1 and H4 receptors[53]. The transcription factor FoxP3 is an significant regulator of inflammation because loss-of-function mutations result in an intense multi-organ inflammatory response associated with allergic airway inflammation, striking hyperimmunoglobulinemia E, eosinophilia, and dysregulated Th1 and Th2 cytokine production[64]. Injection of Tregs into animals with established CHS suppresses infiltration and functions of mast cells, and leads to decreased production of inflammatory cytokines at the contact site[65].

Assuming the role of Tregs in CHS as a reaction suppressor is similar to CACD, an increase in Treg activity will appear to suppress the infiltration of mast cells and decrease IL-4 levels in CACD eczematous lesions[53].

TGF-β is reported to increase Tregs through FoxP3 induction[66]. Tregs inhibit established CHS by suppressing the activity of effector T cells in mice[67]. The suppressive effect of Tregs is transmitted through the cell surface molecule CTLA-4, because effector T cell proliferation is suppressed by anti-CTLA-4 treatment in mice[68]. In humans, Tregs are capable to inhibit effector T cells activation in individuals who are not allergic to nickel, while allergic individuals are unable to suppress nickel-specific effector T cell activation in vitro.

This supports the conclusion that Tregs are involved in allergic contact dermatitis suppression and hapten tolerance[69]. Histamine decreases the levels of TGF-β1 in CACD eczematous lesions. istration of TGF-β1 increases the number of Foxp3 (+) cells and the levels of IL in CACD eczematous lesions, while istration of an anti-TGF-β1 antibody decreases IL levels. Treatment with histamine H1 or H4 receptor antagonist increases IL levels in HDC (+/+) mice. Therefore, histamine suppresses the number of Tregs and IL production by decreasing the levels of TGF-β1 through histamine H1 and H4 receptors[53]. Since Tregs suppress Th2 cell-driven allergic reactions through IL production in bronchial allergic reactions[70], histamine might reduce Th2 cytokines by reducing IL in CACD[53].

Several studies propose shut relationship between histamine and Tregs.

A mixture of lactic acid bacteria and sodium butyrate increases Treg differentiation in the mesenteric lymph nodes and the spleen tissues, and the serum IL levels in atopic dermatitis murine model. However, it reduces serum histamine levels[71]. Oral istration of ferulic acid rutinoside suppresses serum levels of histamine in ovalbumin-sensitized mice and triggers the differentiation of Tregs[72]. Histamine levels in allergic rhinitis murine models sensitized with Derp1 and treated with Derp1-modified dendritic cells are lower, and Treg percentage is higher, than in control models[73].

What is ovalbumin allergy

Eucheuma cottonii sulfated oligosaccharide decreases the levels of histamine and up-regulates Tregs in murine models[74]. Glycation of allergens via Maillard reaction or chemical conjugation influences the susceptibility to food-induced allergies. The ovalbumin-mannose treated mice own less histamine and more Tregs than the control mice[75]. These studies support the hypothesis that histamine levels are inversely correlated with the activity of Tregs. However, mice incubated with Echinococcosis granulosus and sensitized own higher histamine levels compared to healthy controls. However, there was no difference observed in the numbers of Tregs in peripheral lymph nodes between the two groups[76].

Further studies are needed to clarify the relationship between histamine and Tregs.

Tregs are significant in the regulation and amelioration of allergic dermatitis. Mast cells are one of the inflammatory cells involved in allergic dermatitis regulated by Tregs. Since histamine, which is mainly secreted from mast cells, results in the development of allergic dermatitis by suppressing Tregs, understanding the effects of histamine against Tregs would assist improve treatment of allergic dermatitis.

I would love to thank Editage () for English language editing.

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What is ovalbumin allergy

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What is ovalbumin allergy

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Part Descriptions

LP Ovalbumin
An albumin obtained from the white of eggs. It is a member of the serpin superfamily. Copyright Text is available under the Creative Commons Attribution/Share-Alike License. See for details.Source: National Library of Medicine, MeSH , Immunoglobulin E

LP Ovalbumin
Gal d 2, also known as Ovalbumin and Albumin, is a 44 kDa phosphoglycoprotein.

Ovalbumin is a major allergen of Hen’s egg white and is the most abundant of Egg white proteins, comprising 54% of the entire proteins and a fivefold greater quantity than Ovomucoid.

Ovalbumin was previously considered to be the most significant allergen of Egg white.

But its importance was over-estimated due to frequent contamination of commercial preparations with Ovomucoid. In spite of a difference in the molecular weights of Ovomucoid and Ovalbumin, they cannot be completely separated by some processes, which has lead to the erroneous assumption of cross-reactions. Copyright Copyright © Phadia AB.Source: ImmunoCap, ImmunoCap

Combating food allergies with vaccine viruses

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Researchers of the Paul-Ehrlich-Institut own succeeded in preventing food allergy against chicken protein using a modified vaccine virus.

The viruses serve a dual function: They transfer genetic information of the allergen into the target cell of the immune system and they own an inherent immunomodulatory effect. The research results own been published in the online edition of the journal Allergy of 30 July

Food allergies are on the increase in every industrialised countries, affecting around five per cent of every children and four per cent of every adults.

Allergen avoidance is currently the only established treatment of choice. Specific immunotherapy using allergen extracts, which is common in the treatment of pollen allergies, has not yet been established for food allergies. Moreover, there is an inherent risk of serious adverse reactions including anaphylactic shock.

Researchers of the Paul-Ehrlich-Institut own therefore taken a completely novel approach towards immunotherapy of food allergy, which is based on modified vaccinia virus Ankara (MVA). MVA is a modified vaccine virus which has been found to be safe in several clinical trials in infection medicine.

MVA facilitates transfer of the genetic information of the allergen to antigen presenting cells of the body. Cells infected with the virus start to produce the allergen and present it to the immune system. Unlike the established immunotherapy of pollen or home dust mite allergy where allergen extracts are applied directly, the new method ascertains that the immune system does not come into contact with the allergen before allergen fragments are presented on the surface of antigen presenting cells.

Serious allergic reactions as in the case of direct allergen uptake via food consumption can be ruled out. Researchers in the Allergology and Virology Divisions at the Paul-Ehrlich-Institut had already been capable to show that «vaccination» of mice with MVA carrying the gene for the chicken protein ovalbumin (MVA-OVA) prevented the generally considerable increase in allergy inducing IgE antibodies in response to exposure to the allergen [1].

Which clinical significance do these changes imply? To establish this, Dr Masako Toda, head of the Temporary Research Group «Experimental Allergy Models» at the PEI, and her co-workers developed a model of intestinal food allergy in mice.

Sensitisation of mice to ovalbumin led to clinical symptoms such as diarrhoea, loss of bodyweight, and drop of body temperature. The researchers of the PEI were capable to show that allergic symptoms could be prevented by vaccination with MVA-OVA and, what’s more, in collaboration with researchers of Tokyo University, Japan, they were capable to establish that the vaccination could prevent inflammatory changes of the intestinal mucosa (see figure).

Inflammation of intestinal mucosa in allergic mice (on the left; e.g. thickened basal layer) as compared to MVA-OVA-vaccinated mice with unimpaired intestinal mucosa (on the correct side).Source: PEI

When examining the local immune response in the little intestine, the researchers were also capable to prove – based on the modified release of the cytokines (inhibition of interleukin-4 and stimulation of interferon-gamma release) – that the adverse (allergic) response of TH2 helper cells was inhibited and the desired TH1 helper cell response was stimulated.

, Dr Stephan Scheurer explained the success of this approach. Dr Scheurer is the head of the Section «Recombinant Allergen Therapeutics» at the PEI.

The next steps to be taken by the researchers of the PEI will be to test how endless this allergy protection will final and whether the therapy approach can be used to treat fully established allergies. , explained Dr Scheurer.


Original publication

Bohnen C, Wangorsch A, Schülke S, Nakajima-Adachi H, Hachimura S, Burggraf M, Süzer Y, Schwantes A, Sutter G, Waibler Z, Reese G, Toda M, Scheurer S, Vieths S (): Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice.
Allergy
Online-Abstract


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