What caused the increase of autoimmune and allergic diseases:A decreased or an increased exposure to luminal microbial components?

The dramatic increase of allergic and autoimmune diseases such as asthma, atopic dermatitis （eczema）, allergic rhinitis, inflammatory bowel disease （IBD, including both Crohn＇s disease and ulcerative colitis）, multiple sclerosis, and insulin-dependent diabetes mellitus （type Ⅰ diabetes） in the developed countries in the last century is a big puzle. ＂Hygiene Hypothesis＂ was proposed more than two decades ago and it suggested that the increase in these allergic and autoimmune diseases is caused by the aberrant development and response of the immune system due to a reduced exposure to microorganisms along with the improved hygiene. Interestingly, recent studies revealed that these allergic and autoimmune diseases are closely related to the microbes in the gut. For instance, even asthma, an allergic reaction of the lung to inhaled antigens, is closely related to a reduced exposure to foodborne and orofaecal microbes, rather than the amount of allergens in the air or the exposure to airborne microbes. It is known that bacteria in the gut could be 10 times in number of the eukaryotic cells of the body. Therefore, it would be not too surprising that microbes in the gut may have a great impact on these autoimmune and allergic diseases.

Regulation of interleukin 33/ST2 signaling of human corneal epithelium in allergic diseases

AIM:To identify the function of ST2 and explore the role of IL-33/ST2 signaling in regulating the pro-allergic cytokine production in human corneal epithelial cells (HCECs). METHODS:Human corneal tissues and cultured primary HCECs were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of pro-allergic cytokine and chemokine. The expression of mRNA was determined by reverse transcription and real time PCR, and protein production was measured by enzyme-linked immunosorbent assay (ELISA), immunohistochemical and immunofluorescent staining. ST2 protein was detected in donor corneal epithelium, and ST2 signal was enhanced by exposure to IL-33. ·RESULTS:IL-33 significantly stimulated production of pro-allergic cytokines thymic stromal lymphopoietin (TSLP) and chemokine (CCL2, CCL20, CCL22) in HCECs at both mRNA and protein levels. These stimulated productions of pro-allergic mediators by IL-33 were blocked by ST2 antibody or soluble ST2 protein(P 【0.05). Interestingly, the IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked NF-κB p65 protein nuclear translocation, and also suppressed the productions of these pro-allergic cytokines and chemokine induced by IL-33. CONCLUSION:These findings demonstrate that IL-33/ ST2 signaling plays an important role in regulating IL-33 induced pro-allergic responses. IL-33 and ST2 could become novel molecular targets for the intervention ofallergic diseases in ocular surface.

Current State of Monoclonal Antibody Therapy for Allergic Diseases

Allergic disease is one of the most common chronic diseases,which can affect both children and adults,be often caused by allergen-induced unfavorable immune responses,and initiate various symptoms in different organs,including up-/low-airways and skin,such as asthma,atopic dermatitis,and rhinosinusitis.With increasing prevalence of allergic disease worldwide and their impact on the quality of life,new biological therapeutic approaches for these disorders become hot areas of intensive research.Multiple factors are involved and play important role in the pathogenesis of allergic disease,which can promote or trigger T helper 2(Th2)-type immune responses,leading to production of the type 2 cytokines and immunoglobulin E(IgE),the two critical events in the allergic diseases.Using monoclonal antibodies to target these molecules,therefore,might provide possible benefits for the patients suffered from these diseases.Apart of those having approved biologics for allergic diseases,some potential targets such as epithelial-derived alarmins thymic stromal lymphopoietin(TSLP)and interleukin 33(IL-33)have been also described and proposed to develop monoclonal antibodies against either these cytokines,their receptors,or both.These new and potential targets have substantially enriched the therapeutic opportunities in the field of allergic diseases.The present review aims to briefly outline the role of monoclonal antibodies targeting the cytokines and immunoglobulin involved in the development of allergic diseases,and to discuss the clinical effects of these antibodies.

Association between maternal gestational diabetes and allergic diseases in offspring:a birth cohort study

Background Previous studies have linked gestational diabetes(GDM)with allergies in offspring.However,the effect of specific glucose metabolism metrics was not well characterized,and the role of polyunsaturated fatty acids(PUFAs),a modifier of metabolism and the immune system,was understudied.We aimed to investigate the association between maternal GDM and allergic diseases in children and the interaction between glucose metabolism and PUFAs on allergic outcomes.Methods This prospective cohort study included 706 mother–child dyads from Guangzhou,China.Maternal GDM was diagnosed via a 75-g oral glucose tolerance test(OGTT),and dietary PUFAs were assessed using a validated food frequency questionnaire.Allergic disease diagnoses and the age of onset were obtained from medical records of children within three years old.Results Approximately 19.4%of women had GDM,and 51.3%of children had any allergic diseases.GDM was positively associated with any allergic diseases(hazard ratio[HR]1.40;95%confidence interval(CI)1.05–1.88)and eczema(HR 1.44;95%CI 1.02–1.97).A unit increase in OGTT after two hours(OGTT-2 h)glucose was associated with an 11%(95%CI 2%–21%)higher risk of any allergic diseases and a 17%(95%CI 1–36%)higher risk of food allergy.The positive associations between OGTT-2 h glucose and any allergic diseases were strengthened with decreased dietary a-linolenic acid(ALA)and increased n-6 PUFAs,linoleic acid(LA),LA/ALA ratio,and n-6/n-3 PUFA ratio.Conclusions Maternal GDM was adversely associated with early-life allergic diseases,especially eczema.We were the first to identify OGTT-2 h glucose to be more sensitive in inducing allergy risk and that dietary PUFAs might modify the associations.

Environmental exposure during pregnancy and the risk of childhood allergic diseases

Background Allergic diseases are one of the most common and important diseases that can exert hazardous effects on chil-dren's health.The prevalence of allergic diseases in childhood is gradually increasing all over the world in recent decades.Known causes of these diseases include anomalous immune responses and allergic inflammatory reactions,but the causes of allergic diseases in childhood are complex.Data sources PubMed,Cochrane Library,Embase and Web of Science were searched for articles focusing on environmen-tal exposure during pregnancy and the risk of childhood allergic diseases,including asthma and atopic dermatitis,and the possible underlying mechanism.Results In terms of environmental factors,allergice diseases in childhood are closely related to environmental chemical expo-sure during pregnancy,including bisphenols,phthalates acid esters,perfuorochemicals,polybrominated diphenyl ethers,and polychlorinated biphenyls.However,allergic diseases in childhood are also closely associated with maternal dietary nutrition,maternal intake of drugs,such as acetylsalicylic acid(aspirin),paracetamol and antibiotics,and maternal lifestyle.Conclusions Several harmful environmental factors during pregnancy can result in the interruption of the function of helper T cells(Th1/Th2),cytokines and immunoglobulins and may activate allergice reactions,which can lead to allergic diseases during childhood.

Roles of histamine and its receptors in allergic and inflammatory bowel diseases

Mast cell has a long history of being recognized as an important mediator-secreting cell in allergic diseases, and has been discovered to be involved in IBD in last two decades. Histamine is a major mediator in allergic diseases, and has multiple effects that are mediated by specific surface receptors on target cells. Four types of histamine receptors have now been recognized pharmacologically and the first three are located in the gut. The ability of histamine receptor antagonists to inhibit mast cell degranulation suggests that they might be developed as a group of mast cell stabilizers. Recently, a series of experiments with dispersed colon mast cells suggested that there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. In a word, histamine is an important mediator in allergic diseases and IBD, its antagonists may be developed as a group of mast cell stabilizers to treat these diseases.

Comparative acetylome analysis reveals the potential mechanism of high fat diet function in allergic disease

Modern technological lifestyles promote allergic diseases,especially food allergies.The underlying molecular mechanisms remain to be uncovered.Protein acetylation is one of the most important post-translational modifications,and it is involved in regulating multiple body metabolic processes.This study aimed to clarify the effects of a high-fat diet(HFD)on allergy risk and the underlying mechanisms.Four-week-old male C57 BL/6 J mice were randomly divided into two groups and fed a normal fat diet(NFD)or HFD for 24 weeks.Then,serum lipids were measured,and skeletal muscle was collected for acetylome analysis.Compared with the findings in the NFD group,HFD-fed mice were obese and hyperlipidemic.Acetylome analysis also revealed 32 differentially expressed proteins between the HFD and NFD groups.Among these,eight acetylated proteins were upregulated in the HFD group.In addition,13 and 11 proteins were acetylated only in the HFD group and NFD group,respectively.These proteins were mainly involved in regulating energy metabolism and mitochondrial function.This study provides information regarding the underlying molecular mechanisms by which HFD promotes allergy.

Helicobacter pylori infection and atopic diseases:Is there a relationship? A systematic review and meta-analysis

AIM: To review and conduct a meta-analysis of the existing literature on the relationship between Helicobacter pylori (H. pylori), atopy and allergic diseases.

Mechanisms of preventative and therapeutic role of probiotics in different allergic and autoimmune disorders

The prevalence of allergic and autoimmune diseases has been increasing from the last decades of 20th century. Intestinal microflora contributes to antigen exposure in early life and is one of the most abundant sources of early immune stimulation as well as adaptation. Because allergic and autoimmune responses manifest early in life, there has been obvious interest in the potential benefits of modifying the gastrointestinal flora by using probiotic supplementation. So far, there have been several studies to address the role of probiotics in primary prevention and therapy, with a reported suspicious reduction in the incidence of atopic and autoimmune diseases. Here, our aim is to evaluate the available knowledge of mechanisms of preventative and therapeutic role of probiotics in different allergic and autoimmune disorders. Promising mechanisms of probiotic effects may be categorized as local and systemic effects. Local influences of probiotics potentially include reduction of gut permeability and systemic penetration of antigens, increased local immunoglobulin A production, and alteration of local inflammation or tolerance induction. Some possible systemic effects consist of anti-inflammatory effects mediated by Th17 cells and Toll-like receptors, Th1 skewing of responses to allergens, activation of tolerogenic dendritic cells, in addition to T-regulatory cell production.

Analysis of Serum Antibody Level after COVID-19 Vaccine and Side Effects after Vaccine

Background: COVID-19 has caused a large number of deaths, in the elderly. In this situation, vaccines have been considered the main strategy to combat COVID-19 and were developed worldwide in 2020. One problem with COVID-19 vaccination is side effects after vaccination. In this report, we identify the relationship between side effects and elevation of antibodies as determined by monitoring several kinds of antibodies against COVID-19. Objective: We investigated whether the antibody level changed depending on side effects after COVID-19 vaccination. Methods: Healthy volunteers, who received two vaccinations between 10 March and 7 May 2021, were collected for this study. Information including age, gender, smoking history, medical history including allergies and side reactions after vaccination was obtained by questionnaire. Serum levels of antibodies of IgG and IgM against each S1, SP, and NP antigens of COVID-19 were evaluated frequently for 3 - 4 months after the first vaccination. Result: Ten employees working at Iwate Medical University were evaluated in this study. Side effects were observed in 7 of 10 patients, and grade 2 side effects in all 3 patients with a history of allergic disease. Serum S1 and SP IgG were elevated sufficiently in all patients. In all patients, IgG antibody titers fell below the cutoff point in approximately 3 months. No cases had elevated NP antibodies. SP IgM was elevated in three cases;all three cases with elevated IgM had allergic disease and the degree of side effects was relatively higher. Subjects with long-lasting elevated SPIgM were observed. Conclusion: S1 IgG and SP IgG exceeded the cutoff in all subjects after vaccination but decreased below the cutoff in all subjects within 4 months, regardless of side effects or allergic history. On the other hand, elevated SPIgM was suspected to be related to side effects and history of allergies, and cases with persistent elevation of SPIgM were observed.

Multi-Omics Analysis Provides Insight into the Possible Molecular Mechanism of Hay Fever Based on Gut Microbiota

Due to the worldwide epidemic of allergic disease and a cure nowhere in sight,there is a crucial need to explore its pathophysiological mechanisms.As allergic disease has been associated with gut dysbiosis,we searched for a possible mechanism from the perspective of the molecular interface between host and microbiota with concurrent metabolomics and microbiome composition analysis.Sprague-Dawley rats were injected with Artemisia pollen extract to stimulate a hyper reaction to pollen.This hyper reaction decreased the circulation of valine,isoleucine,aspartate,glutamate,glutamine,indole-propionate(IPA),and myo-inositol,and reduced short-chain fatty acids(SCFAs)in feces.Several beneficial genera belonging to Ruminococcaceae,Lachnospiraceae,and Clostridiales declined in the model group,whereas Helicobacter and Akkermansia were only expressed in the model group.Furthermore,the expression of intestinal claudin-3 and liver fatty acid binding protein was downregulated in the model group and associated with metabolic changes and bacteria.Our results suggest that alterations in amino acids as well as their derivatives(especially valine,and IPA which is the reductive product of tryptophan),SCFAs,and the gut microbiome(specifically Akkermansia and Helicobacter)may disrupt the intestinal barrier function by inhibiting the expression of claudin proteins and affecting the mucus layer,which further results in hay fever.

Potential Role of Interleukin-25/Interleukin-33/Thymic Stromal Lymphopoietin-Fibrocyte Axis in the Pathogenesis of Allergic Airway Diseases

Objective： Allergic airway diseases （AADs） are a group of heterogeneous disease mediated by T-helper type 2 （Th2） immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs. Data Sources： Articles referred in this review were collected from the database of PubMed published in English up to January 2018. Study Selection： We had done a literature search using the following terms ＂allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte＂. Related original or review articles were included and carefully analyzed. Results： It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin （IL）-25, IL-33, and thymic stromal lymphopoietin （TSLP）, are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling. Conclusions： In view of the redundancy ofcytokines and ＂united airway＂ theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

Transgenic plants for allergen-specific immunotherapy

Allergen-specific immunotherapy （IT） is an effective treatment for allergic diseases. Although subcutane-ous and sublingual ITs are currently used, safer, easier, and more effective IT is under development. Induction of immune tolerance by oral administration of allergen has been proven, though oral IT has not been applied clinically. It is mainly because a large amount of puri-fied allergen is required to induce oral tolerance. To overcome this problem, plants, peculiarly rice, have been investigated as allergen vehicles for oral IT. Rice can store a considerable amount of expressed allergen in its seeds and the accumulated allergen is stable and resistant to gastrointestinal digestion. Therefore, we have developed transgenic rice seeds （Tg rice） in which major epitopes of cedar pollen or house dust mites are expressed. We are establishing Tg rice with dem-onstrated effcacy in murine models of allergic rhinitis and bronchial asthma by oral administration at practical doses. In addition, the amount, distribution, and aller-genicity of the expressed allergen have been improved in our Tg rice. Rice-based oral IT is a promising new concept in IT for the treatment of allergic diseases.

Chemical composition-based characterization of the anti-allergic effect of Guominkang Formula on IgE-mediated mast cells activation and passive cutaneous anaphylaxis

Guominkang(GMK),a Chinese medicine formula,has been used to treat allergic diseases in clinical settings for many years.To evaluate the antiallergic effect and molecular mechanism of action of GMK extract,RBL-2H3 cell models and passive cutaneous anaphylaxis(PCA)mouse models were established.High performance liquid chromatography(HPLC)and ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS)analyses were performed to characterize the chemical composition of GMK.A total of 94 compounds were identified or tentatively identified from GMK.Three of them,emodin,ursolic acid,and hamaudol,were identified for the first time as potential active compounds in GMK,since they inhibited the degranulation of mast cells.The anti-allergic effect of hamaudol was the first to be discovered.GMK could markedly mitigate the shade of Evans Blue extravasation and ear incrassation in PCA mouse models.Additionally,GMK significantly inhibited the degranulation of mast cells,suppressed mast cell degranulation by reducing Ca2+influx and the levels of TNF-α,IL-4,and histamine,and markedly inhibited the phosphorylation of Lyn,Syk,PLCγ1,IκBα,and NF-κB p65.Molecular docking results indicated that hamaudol and emodin had strong interaction with FcεRI and NF-κB related proteins,while ursolic acid only interacted with NF-κB associated proteins.These results suggest GMK suppresses the activation of MCs both in vivo and in vitro.The underlying mechanism of its anti-allergic activity is associated with the inhibition of FcεRI and NF-κB activation.

Recent Highlights of Chinese Herbs in Treatment of Allergic Disease：Acting via Mitogen-activated Protein Kinase Signal Pathway

The histamine receptor antagonists in the treatment of allergic disease have limitations.The treatments of Chinese herbs have some curative effects on allergic skin lesions.Present research indicates that the mitogen-activated protein kinase（MAPK）signaling pathway might be equally important in allergic reactions.It was found that the inhibition of MAPK signaling pathways might relieve allergy symptoms,and some herbs can inhibit the MAPK pathway,which yields anti-allergy effects.Chinese medicines（CMs）have immense potential in the development of treatments for allergic disease.

IL-10-Producing Type 1 Regulatory T Cells and Allergy

As an important subset of regulatory T （Treg） cells, IL-10-producing type 1 regulatory T cells （Trl）, have some different features to thymic-derived naturally occurring CD4^＋CD25^＋Foxp3^＋ Treg cells（nTreg cells）. Similar to nTreg cells, Trl also play important roles in the control of allergic inflammation in several ways. There is a fine balance between Trl and Th2 responses in healthy subjects. Skewing of allergic-specific effctor T cells to a Trl phenotype appears to be a critical event in successful allergen-specific immunotherapy and glucocorticoids and β2-agonists treatment. Trl suppress Th2 cells and effector cells of allergic inflammation, such as eosinophils, mast cells, basophils, through producing IL-10, and perhaps TGF-β. Understanding of Trl may be helpful in developing new strategies for treatment of allergic diseases.