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Maintenance therapy upon discontinuation of AIT may be used in order to prolong the achieved tolerance in patients with FA, but the maintenance doses vary greatly. A rapid decrease in the number of mast cells and basophils in skin, as determined by SPT, has been observed in immunotherapy for both aeroallergens 73 and food allergens Mast Cell and Basophil Activation Test Mast cells and basophils play an important role in allergies as major effector cells.

Both cells have intracellular granules, in which biologically active mediators and cytokines are stored, which are released after activation Mast cells are generally present in the skin, gastrointestinal and respiratory tracts. In the tissue, they reside as tissue resident cells and play a major role in the first defense against invading pathogens Once activated, mast cells and basophils degranulate and release different mediators and cytokines, playing a role in defense against parasitic and bacterial infections 75 , 77 , Some of these are present in the pre-formed granules and can be released within seconds or minutes after their activation, whereas others are de novo synthesized 81 , These mediators can be divided into different classes such as biogenic amines e.

Besides secreted mediators also the expression of CDc identification marker and CD63 marker for anaphylactic degranulation , and phosphorylation of certain intracellular molecules MAPK and STAT5 can be measured to assess basophil or mast cell activation Basophils can also be enriched from the PBMC fraction by negative selection using magnetic beads.

When the basophil is activated, different activation markers CD63, CDc, histamine can be measured using flow-cytometry or fluorescent labelling The whole blood assay is considered to be more physiologically relevant, because factors that are naturally present in the blood, such as blocking antibodies, may play a role in phenotype of allergic or non-allergic individuals However, both tests need further improvement, are still technically challenging 89 , 90 , 92 and not used in routine clinical practice.

Basophils are more accessible than mast cells for ex vivo studies, which explains why most studies apply BAT. However, in only seven studies the BAT was one of the main outcome parameters 36 , 93 — Furthermore, correlation with the clinical outcome was only assessed in five studies 63 , 94 , 98 — A significant reduction in allergen-induced CD63 expression was observed in the majority of AIT studies including peanut 36 , 53 , 98 , — , CM 94 , , and egg 95 , 96 , , AIT.

A single center study with 28 egg allergic children 5—10 years showed that OIT with egg white was effective. Twenty-seven out of 28 children became tolerant to egg and showed a significant decrease in CD63 expression to egg white, ovalbumin and ovomucoid The CD63 expression increased during SLIT build-up phase in those who did not become tolerant, and CD63 expression decreased after de second phase in those who became tolerant.

On the contrary, six studies showed no clear effect on basophil activation during AIT; three peanut 42 , 54 , 57 , 2 CM , , and one apple Importantly, five of these studies also showed no clinical effect as which correlates with little change in BAT. In some cases basophil markers at baseline were excellent predictors for a higher tolerated dose in DPFC and sustained unresponsiveness after OIT 63 , In subjects who became tolerant, CD63 expression was decreased, but the CDc expression did not change.

Overall, it seems that the amount and duration of the maintenance dose as well as the type of IT OIT vs. SLIT could influence the basophil reactivity and subsequently the probability of sustained unresponsiveness. Basophil Marker CDc Thirteen studies also assessed the basophil marker CDc, including studies on peanut 36 , 57 , 98 , 99 , , , , , egg , , and CM 95 , , Only four studies showed a significant decrease in CDc expression upon allergen stimulation during or after the AIT protocol 36 , 99 , , A multicenter randomized egg AIT study with 45 egg allergic children showed that the duration of the OIT is crucial for an effect on CDc expression.

No effect was found after 3 months of OIT, but after 12 months a reduction in CDc expression and tolerance was encountered The remaining nine studies did not show a significant reduction of CDc expression. The four remaining studies only included the marker CDc in their gating strategy while using CD63 as the primary marker for basophil activation , , , Histamine Release Three studies measured histamine release; two with CM 94 , and one with peanut The use of whole blood is preferred because the physiological in vivo conditions, such as the presence of blood components e.

Moreover, the cells are less activated due to centrifugation and other handling steps Also, in this study the histamine release was measured in a basophil enriched fraction However, after the maintenance dose or off dose, the levels increased and where no longer significantly decreased in the OIT group. This study also used basophil enriched mononuclear cell fraction The OIT egg study with 28 egg-allergic patients 5—9 years showed no significant differences in basophil activation levels after stimulation with anti-IgE before or after OIT, while 27 patients became tolerant to egg after the AIT Summary of Findings Related to Basophil Activation Tests CD63 is expressed in several cell types, such as basophils, mast cells, macrophages and platelets, while CDc is solely expressed in basophils.

Moreover, basophils are primed with IL-3 to increase the sensitivity of CDbased assays. In CDc based assays, priming with IL-3 causes a non-specific increase in the test result. This might also explain the contradictory results on CDc and CD63 expression. The difference in CD63 expression and histamine release might be related to the measurement of CD63 in a whole blood assay, while histamine release was assessed in the enriched basophil fraction.

The use of whole blood mimics physiological in vivo conditions, such as the presence of blood components e. Overall, CD63 expression could be a suitable marker for basophil activation and for determining the efficacy of the AIT. However, the results were not always comparable, probably due to differences in the study design of the AIT, BAT, and blood collection. In summary, BAT may be a suitable objective measure of desensitization in AIT trials if the following factors are harmonized: type of allergen extract or recombinant protein , concentration of allergen, use of IL-3 priming, type of biological sample whole blood vs.

Humoral Responses IgE Since the discovery of the novel class of antibodies in , IgE have been a hallmark of allergic disease In vitro diagnosis relies on the specific binding of IgE sIgE to allergen molecules in order to determine the allergen source. However, the presence of IgE and the titers of sIgE do not normally correlate with the severity of the clinical reaction but rather represent reaction probability.

Several factors related to IgE, such as antibody affinity, the ratio of sIgE to total IgE, the degree of antibody polyclonality, the number of epitopes recognized in one allergen as well as the number of allergens recognized in an allergen source, may all contribute to clinical reactivity in the patient.

This observation seems to be independent of the administration route: oral, sublingual or epicutaneous. In a peanut OIT with 24 patients 1—16 years , sIgE to single components was shown to follow the same increase and decrease during the trial as sIgE to whole peanut extract In addition, patients with a successful OIT i.

Markedly, this ratio was significantly higher for food challenges related to more persistent allergies, such as peanut, tree nuts, shellfish, and seeds. Two studies reported no changes in total IgE during AIT 70 , , and one found an increase at the end of therapy More recently, a study of OIT for CM allergy in 24 children 13—22 years also looked at potential biomarkers that could predict long-term outcome of OIT. They showed that total IgE measured at baseline and after 6 months of OIT proved to be not useful to determine responsiveness to this intervention The role of specific IgE-binding epitopes has not yet been thoroughly evaluated in the context of AIT.

In a longitudinal study comparing 35 children 3—68 months with persistent CM allergy to children that had naturally outgrown their allergy, it was shown that children with persistent allergy had greater intensity and broader diversity of IgE and IgG4 binding epitopes than children with transient CM allergy. Ara h1, Ara h 2 and Ara h 3 peptide epitopes have been analyzed during a peanut OIT study including 22 patients 1—16 years.

IgE peptide repertoire was broad at baseline and tended to diminish during therapy. Although sIgE levels decreased, some patients developed novel IgE specificities Recently, a peanut OIT trail in toddlers revealed that IgE-binding to specific Ara h 2 epitopes, in addition to testing peanut extract, is useful for stratifying patients, both in regard to food challenge sensitivity prior to OIT and to prediction of OIT outcome The study suggests that the analysis of peptide binding epitopes at baseline could be used to predict therapy outcome Overall, most AIT studies investigating sIgE have shown an increase in sIgE level in the beginning of therapy, followed by a decrease during prolonged therapy.

Peptide epitopes repertoire and binding seem to be modified during AIT, and this is an area of great interest to understand and predict therapy outcome. It has been extensively studied in the context of AIT because of its potential protective effect against allergies.

IgG4 is considered an anti-inflammatory antibody isotype because, unlike IgG1, IgG2 and IgG3, it cannot activate the classical complement pathway , In addition, IgG4 can undergo a process called Fab arm exchange, during which Fab arms are exchanged between different IgG4 molecules by swapping a heavy chain and attached a light chain This results in the formation of functionally monovalent IgG4 antibodies that are bispecific because they are made up of the heavy chains derived from two different IgG4 antibodies that contain the variable regions.

As a result, these antibodies have a severely impaired capacity to form immune complexes and may inhibit the immune complex formation by other isotypes. The production of allergen-specific IgG4 is strongly induced in response to prolonged exposure to high doses of soluble protein antigens Mechanistic studies on the regulation of IgG4 production are hampered by the fact that no functional analog of IgG4 exists in mice.

Changes in concentrations of specific IgG4 have been assessed during OIT with CM 72 , , peanut 38 , 52 , 58 , 63 , 99 , , , — , egg 69 , , , — , and wheat 49 , Increases in specific IgG4 concentrations were directly associated to successfully consumed dose 49 and SU 69 , and IgG blocking activity was correlated with SU All but one study demonstrated that allergen-specific IgG antibodies with new antigen specificities developed during AIT No direct correlation between IgG4 concentrations and allergen induced basophil activation has been found This could indicate that other inhibitory factors are involved such as IgG1, IgA , and also that the inhibitory activity of OIT-induced IgG may be more important than their absolute quantities It should be noted that the effect of IgG blocking activity is dependent on the epitopes that are targeted by these antibodies.

IgG that target the same epitopes as IgE are more likely to prevent IgE binding than IgG that target other epitopes, especially if they have a higher affinity for their target than IgE Assessment of the blocking activity using in vitro models of facilitated antigen presentation and BAT 91 , 99 , , , may greatly improve the outcomes values of this immunological parameter in relation to clinical response to OIT.

IgA IgA is an antibody that plays a crucial role in the immune function of mucous membranes The monomeric molecules are predominantly of the IgA1 subclass, being produced mainly in the bone marrow, while in external secretions most of the IgA, produced locally in mucosal tissues, occurs in the polymeric configuration with a relatively increased proportion of IgA2 molecules The major difference between IgA1 and IgA2 resides in the hinge region that lies between the two Fab arms and the Fc region Our current knowledge suggests a regulatory role of IgA responses in allergy and it has been proposed as a biomarker to assess the effectiveness of food AIT Several studies using peanut , CM , , and egg , , have assessed allergen-specific IgA before, during and after OIT.

In another study, the levels of specific IgA and sIgA from saliva and serum were investigated in 17 patients 1—11 years undergoing either peanut SLIT or placebo, at baseline and at the time of the challenge. Salivary and serum levels of peanut-specific IgA increased significantly for subjects receiving SLIT, but not for placebo The same study suggested that salivary IgA could be a prospective biomarker to follow throughout therapy, being potentially useful in defining the efficacy of therapy and in monitoring the progress of the treatment Most of the available literature suggests that increasing IgA levels might be indicative of a positive response to AIT treatments.

In general, IgA levels of food allergic patients are lower compared to control groups. However, there is a lack of data with respect to the clinical value of IgA assessments for predicting treatment response and SU. T Cell Responses T cells play a key role for the immune response of the host upon ingestion of foods both in the context of obtaining normal homeostasis in a healthy host, i.

In line with this, decreased numbers, lower rate of activated Tregs and dysfunctional Tregs with subsequent limited host immune suppressive capability upon ingestion of foods, seem of importance for failure in immune tolerance and susceptibility to develop food allergy Due to the key roles of Tregs and TH2 cells in immune tolerance to foods, it is plausible that the number, phenotype and effector functions of these T cell subsets may serve as biomarkers of FA-AIT treatment response and aid the clinician to predict SU, which would be valuable for the food allergic patient undergoing AIT as it is a long-term treatment with a substantial risk of adverse events and anaphylactic reactions Tregs Despite the expectation that Tregs could be of importance for predicting response to FA-AIT, there has only been few studies addressing this topic.

These studies were mostly peanut OIT studies with low numbers of patients and a short follow up in which Treg were analyzed quantitatively and not in terms of suppressive capacity. These results of increased Treg numbers were subsequently replicated in a similarly small numbered open-label randomized trial of peanut OIT with 1 year of treatment among 22 patients 7—15 years Changes in immune suppressive functions of Tregs during and after cessation of food AIT has rarely been studied, but one study investigated this via demethylation of FOXP3 CpG sites in Tregs of 23 peanut allergic patients 5—45 years undergoing OIT compared to 20 age-matched controls on peanut avoidance diet Three months after cessation of peanut OIT the patients developing tolerance, i.

However, this increase in immune suppressive functions of Tregs was transient as four of seven initially peanut tolerant patients were no longer peanut tolerant on an OFC and showed increased FOXP3 methylation after an additional 3 months of peanut OIT One double-blind, placebo-controlled peanut SLIT study of 18 patients 1—11 years showed no changes in numbers of Tregs or IL production after 1 year of therapy, although a significant proportion of the SLIT-treated children had a positive treatment response and were tolerant to an OFC However, only few immunotherapy studies have reported on numbers of TH2 cells, which may be important as a mechanism of successful AIT may include apoptosis of highly differentiated CD allergen-specific TH2 cells that was first demonstrated in studies of grass AIT This specific T cell population may be re-activated upon peanut exposure and thus serve as a biomarker of the durability of SU following peanut OIT Overall, most AIT studies investigating Tregs have shown an increase in numbers of Tregs and enhanced, but transient, immunosuppressive Treg functions during therapy.

However, there is a lack of data with respect to the clinical value of Treg assessments for predicting treatment response, particularly SU, that is the most important from a patient perspective. Responses of Other Cell Types B Cells B cells play a critical role both in the development and persistence of allergies as well as in the induction of allergen tolerance. The contribution of B cells to these processes is primarily related to their unique capacity to produce antibodies.

As discussed above, the heavy chain isotype, specificity, and affinity of these antibodies determine their function. The frequencies of circulating Ara h 1- and Ara h 2-specific B cells were found to increase in response to OIT , Interestingly, one study reported that the increase of Ara h 2-binding memory B cells peaked after 7 weeks of peanut OIT and then started to decline to levels that were lower than before OIT While the role of regulatory B cells has been studied in the context of autoimmune diseases, cancer, transplantation, infections and several allergies , no human studies have been performed that focused on the cellular B cell responses in food allergy immunotherapy.

While both qualitative cell characteristics such as cytokine production and cell surface markers and quantitative frequencies of allergen-specific B cells features of B cells have a potential to be developed as future biomarkers, there are currently no data available that indicate B cell-associated biomarkers that can be used for as biomarkers of food immunotherapy. Dendritic Cells DCs play a key role in initiation of immune responses to food allergens through antigen presentation and driving T cell differentiation.

Several mouse studies have been performed to determine the role of DCs in the induction of tolerance to food allergens. Nevertheless, most data on the role of DCs in relation to food allergy is derived from mouse models and immunophenotyping of circulating no distinct DC subsets. So far, this has not led to identification of applicable biomarkers for the use in food OIT. Innate Lymphoid Cells Innate lymphoid cells ILCs are subgroups of lymphocytes lacking lineage markers and antigen specific receptors for B and T cells.

ILCs have crucial roles in immune defense, regulation of inflammation and tissue remodeling Group-2 ILCs are highly relevant in the context of allergic inflammation, as they share many functional similarities with TH2 cells — IL promotes food anaphylaxis in sensitized mice by targeting mast cells but it also synergizes with intestinal IL production to drive the expansion and activation of ILC2s, which promotes food anaphylaxis Besides, IL stimulates IL production after repeated intragastric allergen challenges It has been postulated that food allergy can be promoted as a result of allergen-specific Treg blockage by stimulated ILC2s Cytokines and Other Potential Soluble Biomarkers Analysis of cytokine production in response to in vitro re-stimulation of PBMCs with allergens has also been performed in many studies.

OIT studies using peanut, CM, and egg have been reported, in which soluble biomarkers and cytokine measurements were performed in serum or stimulated PMBCs. Similarly, a study of 20 egg allergic patients 5—15 years showed that, at baseline, OVA-re-stimulated PBMCs from allergic patients produced significantly lower levels of IL than healthy controls. Another study of 20 patients 4—18 years undergoing peanut OIT showed that the changes in cytokine production were based on extended therapy and that pathogenic cytokine producing T cells persisted despite clinical success However, serum adipsin was significantly higher in the group who failed OIT, which prompted the suggestion that high serum adipsin after 6 months of increasing OIT doses might predict poor outcome.

A downregulation of the angiogenesis factors platelet-derived growth factor and the vascular endothelial growth factor was found after rapid desensitization and oral immunotherapy in children with CM allergy. Baseline levels of platelet-derived growth factor and vascular endothelial growth factor in the CM allergic patients were already different compared to non-allergic subjects and a significant increase of platelet-derived growth factor and vascular endothelial growth factor was seen in children with a history of anaphylaxis IgE-associated food allergy mechanisms of pathogenesis include cross-linking of mast cell- and basophil-bound IgE and immediate release of inflammatory mediators.

Histamine-releasing factor interacts with a subset of IgE molecules and the histamine-releasing factor dimer activates mast cells in a histamine-releasing factor-reactive IgE-dependent manner. Besides using biomarkers from sera and ex vivo stimulation, there are some metabolites found in the urine, which have potential as soluble biomarkers for FA-AIT. As it remains unclear whether these markers are predictive of efficacy, computational approaches have been attempted to compare mechanistic features of food allergies during OIT to determine the biological relevance of biomarkers and have led to promising clusters of biomarkers Control: Healthy male or female subjects with no history of atopy.

Outcomes: A measure of SPT results. Types of studies: Any observational study including case control trials, retrospective chart reviews, cross-sectional studies, and case series. Outcomes: A measure of tIgE levels. Types of studies: Any observational study including case control trials, cross-sectional studies, and case series. Types of studies: Any observational study including case control trials, cross-sectional studies, retrospective chart reviews and case series.

Articles describing acute urticaria or inducible urticaria were excluded. Non-full text publications, letters to the editor, case reports, as well as articles that were not published in the English language were also excluded. Finally, abstract-only publications were not considered due to lack of detailed raw data. Data collection and quality assessment Two reviewers independently assessed the titles and abstracts of all retrieved publications to identify eligible and relevant studies.

Full texts of selected publications were then retrieved if necessary and eligibility criteria was considered. Any discrepancies that were raised during data collection were resolved through consensus. Should the publication have met all eligibility criteria, information regarding the first author, year of publication, country that the study was conducted in, definition of CSU, indication of treatment provided, and the: 1. We used Review Manager version 5.

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PMID: Abstract Probiotic microorganisms have been shown to be effective in the treatment of allergic inflammation and food allergy, but their efficacy remains controversial. This study tested the effect of a yogurt supplemented with a probiotic strain Bifidobacterium longum BB in the treatment of Japanese cedar pollinosis JCPsis.

Forty subjects with a clinical history of JCPsis were given yoghurt either containing BB BB yoghurt or without BB placebo yoghurt at 2 X g per day for 14 weeks, in a randomized, double-blind, placebo-controlled trial. Subjective symptoms and self-care measures were recorded daily and blood samples were taken before and during the intervention at weeks 4, 9, and 14 to measure the blood parameter levels related to JCPsis. Yoghurt supplemented with BB significantly alleviated eye symptoms compared with placebo yoghurt odds ratio 0.

Binding of AECAs to endothelial cells would cause endothelial activation or damage, with proinflammatory cytokine release, thus fostering a hypercoagulable state resulting from leukocyte activation by proinflammatory cytokines. This, in turn, would lead to coronary artery lesions. KD vasculitis might be initiated upon binding of AECAs to the vasa vasorum and progress to panvasculitis and a vulnerable vessel wall, resulting in an aneurysm.

The aneurysm would cause flow recirculation and alteration of wall shear stress. Consequently, platelets activated by shear stress, along with ultralarge von Willebrand factor VWF released by endothelial cells, would cause platelet-driven arterial thrombosis. Autoimmunity-associated thrombosis initiated by binding of AECAs to endothelial cells might play a major role in the pathogenesis of certain subtypes of KD.