Cross-reactivity Patterns Research Articles

Detection of Multiple Sclerosis Biomarkers in Serum by Ganglioside Microarrays and Surface Plasmon Resonance Imaging.

Multiple sclerosis (MS) is an autoimmune disease that damages the myelin sheaths of nerve cells in the central nervous system. An individual suffering from MS produces increased levels of antibodies that target cell membrane components, such as phospholipids, gangliosides, and membrane proteins. Among them, anti-ganglioside antibodies are considered as important biomarkers to differentiate MS from other diseases that exhibit similar symptoms. We report here a label-free method for detecting a series of antibodies against gangliosides in serum by surface plasmon resonance imaging (SPRi) in combination with a carbohydrate microarray. The ganglioside array was fabricated with a plasmonically tuned, background-free biochip, and coated with a perfluorodecyltrichlorosilane (PFDTS) layer for antigen attachment as a self-assembled pseudo-myelin sheath. The chip was characterized with AFM and matrix-assisted laser desorption ionization mass spectrometry, demonstrating effective functionalization of the surface. SPRi measurements of patients' mimicking blood samples were conducted. A multiplexed detection of antibodies for anti-GT1b, anti-GM1, and anti-GA1 in serum was demonstrated, with a working range of 1 to 100 ng/mL, suggesting that it is well suited for clinical assessment of antibody abnormality in MS patients. Statistical analyses, including PLS-DA and PCA show the array allows comprehensive characterization of cross reactivity patterns between the MS specific antibodies and can generate a wide range of information compared to traditional end point assays. This work uses PFDTS surface functionalization and enables direct MS biomarker detection in serum, offering a powerful alternative for MS assessment and potentially improved patient care.

Validation and cross-reactivity pattern assessment of monoclonal antibodies used for the screening of donor-specific IgG antibody subclasses in transplant recipients

The screening for IgG subclass donor-specific antibodies (DSAs) in allograft recipients uses IgG1-4 subclass-specific monoclonal antibodies (mAbs) that should be mono-specific. The cross-reactivity discrepancies reported for IgG subclass-specific mAbs warranted a critical cross-reactivity pattern analysis of the IgG subclass-specific mAbs most commonly used to detect DSAs.We tested the reactivity of 2 anti-IgG1-, 3 anti-IgG2-, 1 anti-IgG3-, and 2 anti-IgG4-specific PE-conjugated mAbs against microbeads coated with IgG1-4 proteins separately. Each IgG subclass protein was coated at three densities on the beads (0.5, 1, and 2 μg of protein per 106 beads), and the PE-conjugated mAbs were titrated from 0.04 μg/mL to 5 μg/mL. The IgG subclass reactivity of the sample was acquired on the Luminex multiplex platform.Among the IgG subclass-specific mAbs, only the anti-IgG3 (clone: HP6050) mAb was mono-specific. All other mAbs tested were binding to IgG subclass proteins other than their respective immunogen, thereby being cross-reactive. IgG subclass cross-reactivity patterns were dependent on the concentration of both IgG subclass-specific mAbs and IgG1–4 protein targets coated onto the beads. With the current IgG subclass mAbs available, 3 of the 15 possible combinations of IgG1–4 subclass protein could be identified. While the remaining 12 unique combinations cannot be distinguished clearly, 6 groups that corresponded to two different unique combinations of IgG1–4 subclass protein could be identified.The dilution of serum samples and IgG subclass-specific mAbs, other than the anti-IgG3 (clone: HP6050), must be further optimized before their implementation in IgG subclass DSA screening in allograft recipients.

Pooling of monoclonal antibodies for the rapid detection of commercially important finfish

Fish are a valuable source of high-quality proteins, beneficial polyunsaturated fatty acids, and lipid-soluble vitamins in the human diet, but they also make up one of the “big eight” allergenic foods that are responsible for >90% of food allergy cases. A reliable and cost-effective analytical method is thus needed to detect fish protein in foods to protect fish-allergic individuals. Although immunoassays have been developed to detect many food allergens, there is no effective immunoassay capable of recognizing all common food fish species on the market. The selectivities of three monoclonal antibodies (mAbs), 8F5, 2G9 and 2F3, known to exhibit anti-finfish activity against cooked crude fish protein extract from red snapper, yellow fin tuna and swordfish, respectively, were each tested for 63 commercially important fish species using indirect enzyme-linked immunosorbent assays (iELISA). Based on the results, none of the mAbs showed cross-reactivity with all fish species tested; the cross reactivity patterns of these 3 mAbs complemented each other and none cross reacted with any non-fish samples. Pooling these mAbs (1:1:1) in an iELISA successfully detected a wide spectrum of commercially important fish species, including those subjected to various processing conditions. This pooled mAbs based iELISA exhibited high sensitivity, specificity and reproducibility, suggesting its potential utility as a qualitative assay for the regulatory enforcement of the food laws that protect fish sensitive consumers.

Testing Strategies and Predictors for Evaluating Immediate and Delayed Reactions to Cephalosporins

Although 1% to 2% of the general population carries a cephalosporin allergy label (CAL), we lack validated testing strategies and predictors of true allergy. To identify cross-reactivity patterns and predictors of skin test positive (STP) in geographically disparate patients with a CAL. A total of 780 adult patients labeled with a CAL or penicillin allergy label (PAL) with unknown tolerance of cephalosporins identified from the Austin Hospital (Melbourne, Australia) (n= 410) and Vanderbilt University Medical Center (Nashville, TN) (n= 370) between 2014 and 2018 underwent a standardized skin testing. Of 328 patients with a CAL, 29 (8.8%) tested STP to ≥1 cephalosporin(s). There were no cefazolin or ceftriaxone STP, 0 of 452 (0%), in patients with a PAL only. Of 328 patients with a CAL, 16 (4.8%) were ampicillin STP. Eleven of 16 of these patients had an initial allergy label to cephalexin. Twenty of 29 cephalosporin STP patients demonstrated tolerance to a cephalosporin with a different R1 side chain, and 8 of 14 ampicillin STP patients demonstrated tolerance to ≥1 non-amino R1 group cephalosporin. Eleven of 13 patients STP to cefazolin were skin and ingestion challenge negative to all other penicillins and cephalosporins predicted by its distinct R1/R2 groups. Seven of 15 ceftriaxone STP patients demonstrated cross-reactivity with R1-similar cephalosporins. Time since the original reaction predicted STP testing to both penicillins, adjusted odds ratio (aOR) per year 0.93 (95% confidence interval [CI]: 0.90, 0.97), and cephalosporins, aOR per year 0.71 (95% CI: 0.56, 0.90). Cephalosporin cross-reactivity is based on shared R1 groupings. Increasing time since the original reaction and the presence of a PAL with unknown cephalosporin tolerance predict a lower likelihood of cephalosporin STP.

Allergome-wide peptide microarrays enable epitope deconvolution in allergen-specific immunotherapy

The interaction of allergens and allergen-specific IgE initiates the allergic cascade after crosslinking of receptors on effector cells. Antibodies of other isotypes may modulate such a reaction. Receptor crosslinking requires binding of antibodies to multiple epitopes on the allergen. Limited information is available on the complexity of the epitope structure of most allergens. We sought to allow description of the complexity of IgE, IgG4, and IgG epitope recognition at a global, allergome-wide level during allergen-specific immunotherapy (AIT). We generated an allergome-wide microarray comprising 731 allergens in the form of more than 172,000 overlapping 16-mer peptides. Allergen recognition by IgE, IgG4, and IgG was examined in serum samples collected from subjects undergoing AIT against pollen allergy. Extensive induction of linear peptide-specific Phl p 1- and Bet v 1-specific humoral immunity was demonstrated in subjects undergoing a 3-year-long AIT against grass and birch pollen allergy, respectively. Epitope profiles differed between subjects but were largely established already after 1 year of AIT, suggesting that dominant allergen-specific antibody clones remained as important contributors to humoral immunity following their initial establishment during the early phase of AIT. Complex, subject-specific patterns of allergen isoform and group cross-reactivities in the repertoires were observed, patterns that may indicate different levels of protection against different allergen sources. The study highlights the complexity and subject-specific nature of allergen epitopes recognized following AIT. We envisage that epitope deconvolution will be an important aspect of future efforts to describe and analyze the outcomes of AIT in a personalized manner.

Immediate hypersensitivity reactions to steroids and steroid containing medications.

Although rare and counterintuitive, hypersensitivity reactions to corticosteroids have been reported since the 1950s. Delayed hypersensitivity reactions following cutaneous exposure (contact allergy) are well understood and principles of testing, as well as cross-reactivity patterns, have been established. In contrast, understanding of immediate hypersensitivity reactions and delayed hypersensitivity reactions after systemic exposure is evolving more slowly. However, progress has been made in the delineating of underlying pathogenic mechanisms and in the development of testing. IgE-mediated hypersensitivity reactions to corticosteroids have been described. It has been recognized that some, if not all of them, may be due to excipients in steroid formulations. Two excipients, polyethylene glycol and carboxymethylcellulose, seem of particular importance, but cases of reactions to polysorbate 80 and lactose have also been reported. The use of skin testing but also, increasingly, in-vitro methods such as basophil activation test is improving diagnostic accuracy. The recognition of the role of excipients is leading to a paradigm shift in our approach to immediate hypersensitivity to corticosteroids. Improved access to in-vivo and in-vitro testing will enhance our understanding of true corticosteroid immediate allergy.

Immunoglobulin E-Binding Pattern of Canadian Peanut Allergic Children and Cross-Reactivity with Almond, Hazelnut and Pistachio.

Peanut allergic individuals can be both co-sensitized and co-allergic to peanut and tree nuts. At the moment, standard diagnostic approaches do not always allow differentiation between clinically relevant sensitization and nonsignificant cross-reactions, and the responsibility of each allergen remains unclear. The objective of this study was therefore to determine a peanut sensitization profile in a cohort of Canadian peanut allergic children and assess the immunoglobulin E (IgE) molecular cross-reactivity between peanut, almond, hazelnut and pistachio. The specific IgE (sIgE) levels of each patient serum were determined by ImmunoCAP, indirect ELISA and immunoblot to examine their sIgE-binding levels and profiles to peanut proteins. Reciprocal inhibition ELISA and immunoblotting were used to study sIgE cross-reactions between peanut and the selected tree nuts using an adjusted and representative serum pool of the nine allergic patients. The results showed that the prepared peanut and tree nut protein extracts allowed for the detection of the majority of peanut and selected tree nut known allergens. The reciprocal inhibition ELISA experiments showed limited sIgE cross-reactivities between peanut and the studied tree nuts, with peanut being most likely the sensitizing allergen and tree nuts the cross-reactive ones. In the case of hazelnut and pistachio, a coexisting primary sensitization to hazelnut and pistachio was also demonstrated in the serum pool. Reciprocal inhibition immunoblotting further revealed that storage proteins (2S albumin, 7S vicilin and 11S legumin) could possibly account for the observed IgE-cross-reactions between peanut and the studied tree nuts in this cohort of allergic individuals. It also demonstrated the importance of conformational epitopes in the exhibited cross-reactions.

A Survey on Knowledge Gaps in Assessment and Management of Severe Drug Hypersensitivity Reactions: Multicenter Cross-Sectional Study of Australian Health Care Providers.

Severe drug hypersensitivity reactions (DHRs) are often encountered by health care professionals (HCPs). We evaluated knowledge of doctors and pharmacists in the assessment and management of severe DHRs using a structured questionnaire. A cross-sectional study was conducted in 4 metropolitan hospital networks in Melbourne, Australia. A 13-question, scenario-based multiple-choice questionnaire to assess specific knowledge domains in drug hypersensitivity syndrome recognition, causality attribution, cross-reactivity patterns, appropriate diagnostic tests, and therapy was administered to HCPs of various vocation and specialty groups. Data were analyzed according to profession, self-reported experience, and preparedness in managing severe DHRs. Two hundred thirty-eight participants (45.0% senior doctors, 24.4% junior doctors, and 30.7% pharmacists) across a range of subspecialties achieved an overall median score of 7 (IQR, 5-8)-overall 55.6% correct responses to all questions-with senior doctors outperforming junior doctors and pharmacists (P<.001). The best performance by all participants was in DHR syndrome recognition (60.9%), and the poorest was in diagnostics/therapy (52.0%). HCP group and experience level were significantly associated with better performance in the knowledge domains of cross-reactivity and diagnostics/therapy (P = .003 and <.001, respectively), but not in the domains of syndrome recognition and causality attribution (P >.05). Levels of self-reported preparedness in DHR management were not associated with performance rates in any of the knowledge domains. This study demonstrated significant knowledge gaps in the recognition and management of severe drug hypersensitivity reactions. Targeted multidisciplinary education of staff caring for these patients is needed to improve knowledge gaps.

Shellfish Tropomyosin IgE Cross-Reactivity Differs Among Edible Insect Species.

Insects are a potentially environmentally friendly alternative dietary protein source to supplement mammalian and fish sources, but potential allergenic risks are a concern. Consumption of insects may result in anaphylaxis and has been implicated in cross-reactivity with shellfish. Many allergenic proteins may be involved in cross-reactivity, including tropomyosin (TM). The uniformity of TM cross-reactivity among edible insects is unknown. Candidate edible insects for variability in shellfish IgE cross-reactivity are investigated. Selected insects and known related sources of allergens are extracted and probed by immunoblot with sera/plasma from patients sensitized to insects or shellfish. Quantification of TM in these extracts is performed using mass spectrometry. A comparison of the quantity of TM and the IgE reactivity of TM from these insects is performed. Distinct patterns of IgE cross-reactivity are observed with three insect species showing diminished reactivity. This pattern is not consistent with the amount of TM present in these insects, or with overall sequence homology. Insects display a diversity of TM-associated IgE reactivity. It is likely that minor sequence features and/or structural effects are primarily responsible. Additionally, it is demonstrated that some insect species may present significantly less IgE cross-reactivity to shrimp than do others.

Identifying Potential Co-Sensitization and Cross-Reactivity Patterns Based on Component-Resolved Diagnosis

Background: Component-Resolved diagnosis (CRD) can help to establish immunoglobulin E (IgE) sensitization profiles and potential risks and determines whether specific IgE is the result of primary sensitization or cross-reactivity, especially for those who are polysensitized. Methods: We recruited 432 patients with mite-sensitized respiratory allergic diseases to study the co-sensitization and cross-reactivity of the 17 allergen components in Guangdong Province, China, using the CRD method and to describe the potential association between allergen components. Results: Among the 432 patients, serum specific immunoglobulin E of the 17 components were tested by EUROIMMUN system. Der p 1 (81.48%), Der f 2 (77.78%), Der f 1 (74.07%), Der p 2 (66.20%) and Der p 23 (54.63%) were the main sensitized components in patients with mite-sensitized respiratory allergy, while the components of cockroach, crab, and shrimp had a lower positive rate. In the crude extract allergen-positive samples, Der f 2 (91.06%) and Der f 1 (86.72%) were the major sensitized components of Der f, while Der p 1 (94.52%), Der p 2 (78.36%), Der p 23 (63.29%) were the major sensitized components of Der p, And other components of Der p such as Der p 7 (34.25%), Der p 5 (17.81%), Der p 10 (12.05%), Der p 3 (1.92%) were all below 50.00%. Blo t 5 (54.55%) was one of the major components of Blo t. The positive rates of all Bla g components were as follows, rBla g 2 (15.56%) >rBla g 5 (8.89%) >rBla g 4 (4.44%) >rBla g 1 (1.11%). The positive rate of the only available pen a 1 component was 9.43%. Using hierarchical cluster and optimal scale analysis, 17 components can be roughly divided into 5 different sensitization clusters. Also, from the results of the Venn diagram, the allergen component in each cluster has a high proportion of co-sensitization and cross-reactivity. Regardless of age, total IgE levels, and disease type factors, similar sensitization profiles were observed for each component in the same category based on hierarchical clustering analysis. Conclusions: Epidemiological data on allergen components causing allergic symptoms can be further understood using CRD. Der p 1, Der p 2, Der p 23, Der f 1, Der f 2 as the primary sensitizing component of the study cohort. The positive rate for Blo t 5 was 28.01% for all populations and 54.45% for Blo t-positive samples. In addition, CRD allows us to identify more potential allergen associations such as common sensitivities and cross-reactions between component proteins. Based on these results, we suggest that when patients are identified as sensitized to a particular allergen, clinicians can pay more attention to other allergy components that are closely related to it.

Cross-Reactivity of Drug-Dependent Antibodies in Patients with Immune Thrombocytopenia Induced By Beta-Lactam Antibiotics

More than 50 beta lactam (BL) antibiotics are now in active use for treatment of a wide range of bacterial infections. BL antibiotics are among the most common drugs capable of inducing antibodies (DDAbs) that cause drug-induced immune thrombocytopenia (DITP). Most DDAbs are highly specific for the sensitizing drug but beta lactams all have a common core structure and many similarities among side groups that are added to augment potency and modify specificity, raising the possibility that a DDAb specific for one BL may cross-react with another. We studied DDAbs from 33 patients with DITP induced by 9 commonly used BL drugs to determine whether patterns of cross-reactivity exist that might influence the choice of an alternative antibiotic in a patient with BL-induced DITP. DDAbs were demonstrated in a flow cytometric assay considered to be "positive" when immunoglobulins in patient serum but not normal serum react with normal platelets in the presence, but not in the absence of drug (Blood 2018;131:1486). DDAbs detected in the 33 patients were specific for 9 different BL drugs that were divided into two groups, "penicillins" (Group 1) and cephalosporins (Group 2) on the basis of structural similarities (Figure 1). In Group 1 were 19 DDAbs specific for amoxicillin (2), nafcillin (4) and piperacillin (13). Structurally similar ampicillin and penicillin were also tested with these abs. In Group 2 were 14 DDAbs specific for cefadroxil (1), cefepime (2), ceftazidime (2), ceftizoxime (1), ceftriaxone (7) and cephalexin 1). Cross-reactions identified within these groups of DDAbs are shown in Tables 1 and 2. Cross-reactions, many quite strong (S) were observed among DDAbs specific for drugs in both structural groups (Tables 1 and 2). Particularly noteworthy were cross-reactions of the 19 Group 1 DDAbs with ampicillin (6) and penicillin (6) (Table 1) and of the 14 Group 2 DDAbs with cefepime (6), ceftizoxazole (6) and ceftriaxone (3) (Table 2). The findings show that platelet-specific DDAbs induced by beta lactam antibiotics, in contrast with those induced by medications like quinine, sulfamethoxazole and vancomycin, commonly cross-react with other antibiotics of this class. In patients with immune thrombocytopenia induced by a beta lactam antibiotic, it may be prudent to avoid switching to another beta lactam or, if this is necessary, to monitor platelet counts carefully. Disclosures No relevant conflicts of interest to declare.

Retrospective serological analysis reveals presence of the emerging lagovirus RHDV2 in Australia in wild rabbits at least five months prior to its first detection.

The lagovirus rabbit haemorrhagic disease virus (RHDV) has been circulating in Australia since the mid-1990s when it was released to control overabundant rabbit populations. In recent years, the viral diversity of different RHDVs in Australia has increased, and currently four different types of RHDV are known to be circulating. To allow for ongoing epidemiological studies and impact assessments of these viruses on Australian wild rabbit populations, it is essential that serological tools are updated. To this end, reference sera were produced against all four virulent RHDVs (RHDV, RHDV2 and two different strains of RHDVa) known to be present in Australia and tested in a series of available immunological assays originally developed for the prototype RHDV, to assess patterns of cross-reactivity and the usefulness of these assays to detect lagovirus antibodies, either in a generic or specific manner. Enzyme-linked immunosorbent assays (ELISAs) developed to detect antibody isotypes IgM, IgA and IgG were sufficiently cross-reactive to detect antibodies raised against all four virulent lagoviruses. For the more specific detection of antibodies to the antigenically more different RHDV2, a competition ELISA was adapted using RHDV2-specific monoclonal antibodies in combination with Australian viral antigen. Archival serum banks from a long-term rabbit monitoring site where rabbits were sampled quarterly over a period of 6years were re-screened using this assay and revealed serological evidence for the arrival of RHDV2 in this population at least 5months prior to its initial detection in Australia in a dead rabbit in May 2015. The serological methods and reference reagents described here will provide valuable tools to study presence, prevalence and impact of RHDV2 on Australian rabbit populations; however, the discrimination of different antigenic variants of RHDVs as well as mixed infections at the serological level remains challenging.

Filovirus-reactive antibodies in humans and bats in Northeast India imply zoonotic spillover.

Bats are reservoirs for several zoonotic pathogens, including filoviruses. Recent work highlights the diversity of bat borne filoviruses in Asia. High risk activities at the bat-human interface pose the threat of zoonotic virus transmission. We present evidence for prior exposure of bat harvesters and two resident fruit bat species to filovirus surface glycoproteins by screening sera in a multiplexed serological assay. Antibodies reactive to two antigenically distinct filoviruses were detected in human sera and to three individual filoviruses in bats in remote Northeast India. Sera obtained from Eonycteris spelaea bats showed similar patterns of cross-reactivity as human samples, suggesting them as the species responsible for the spillover. In contrast, sera from Rousettus leschenaultii bats reacted to two different virus glycoproteins. Our results indicate circulation of several filoviruses in bats and the possibility for filovirus transmission from bats to humans.

Providing an Antibiotic Allergy Service

Approximately 10% of patients report an allergy to ≥1 antibiotics, most commonly penicillins. Having a label of penicillin allergy has important health consequences for the individual, as well as health and economic impact at the population level. Despite this, only a minority of patients have the opportunity to have suspected antibiotic allergies confirmed. Busy clinicians seldom have time to explore the history of suspected antibiotic allergies in detail; an important role of the antibiotic allergy service is to do just this, including gathering contemporaneous notes, charts, and correspondence where necessary. The likelihood of true allergy, the mechanisms of immune hypersensitivity, the approach to testing, and the risk of reexposure to the same or related antibiotics can then be considered. Skin testing remains the mainstay of investigation, with challenge testing generally used to confirm tolerance. A basic knowledge of the frequency with which different drugs cause different hypersensitivity responses and that of the patterns of cross-reactivity between related drugs is very useful to a wide range of clinicians.

Immediate cephalosporin allergy

Patients who suffer from acute IgE-mediated allergy to a cephalosporin antibiotic are frequently assumed to be at high risk of allergy to other cephalosporins and penicillins. To define cross-reactivity patterns in patients with confirmed allergy to a cephalosporin. Subjects presenting with a history of immediate allergy to a cephalosporin-family antibiotic between March 2009 and July 2017 were investigated with specific IgE testing to penicillin, amoxycillin and cefaclor, followed by skin prick testing, intradermal testing and drug provocation testing with a panel of penicillins and cephalosporins. Out of 564 subjects with a reported beta-lactam allergy, 90 identified a cephalosporin as their index drug. Fifty-five (61.1%) of the 90 subjects tested had a history consistent with an IgE-mediated reaction, of whom 24 (43.6%) were proven to be allergic to their index cephalosporin. Twenty (83.3%) of the 24 were allergic only to their index cephalosporin. Of the four remaining subjects, two were co-sensitised to another beta-lactam with a similar side chain, while the other two had no specific cross-reactivity pattern. Major and minor penicillin determinants were negative for all cephalosporin-allergic individuals. In our cohort, cephalosporin allergy does not appear to be a class effect, with most cases found allergic only to their index cephalosporin. Co-sensitisation to other cephalosporins or penicillins was uncommon, and when it occurred, was usually consistent with side chain cross-reactivity.

Cross-lineage protection by human antibodies binding the influenza B hemagglutinin

Influenza B viruses (IBV) drive a significant proportion of influenza-related hospitalisations yet are understudied compared to influenza A. Current vaccines target the head of the viral hemagglutinin (HA) which undergoes rapid mutation, significantly reducing vaccine effectiveness. Improved vaccines to control IBV are needed. Here we developed novel IBV HA probes to interrogate humoral responses to IBV in humans. A significant proportion of IBV HA-specific B cells recognise both B/Victoria/2/87-like and B/Yamagata/16/88-like lineages in a distinct pattern of cross-reactivity. Monoclonal antibodies (mAbs) were reconstituted from IBV HA-specific B cells, including mAbs providing broad protection in murine models of lethal IBV infection. Protection was mediated by neutralising antibodies targeting the receptor binding domain, or via Fc-mediated functions of non-neutralising antibodies binding alternative epitopes including the IBV HA stem. This work defines antigenic cross-recognition between IBV lineages and provides guidance for the rational design of improved IBV vaccines for broad and durable protection.

Design of Peptide-Based Nanovaccines Targeting Leading Antigens From Gynecological Cancers to Induce HLA-A2.1 Restricted CD8+ T Cell Responses.

Gynecological cancers are a leading cause of mortality in women. CD8+ T cell immunity largely correlates with enhanced survival, whereas inflammation is associated with poor prognosis. Previous studies have shown polystyrene nanoparticles (PSNPs) are biocompatible, do not induce inflammation and when used as vaccine carriers for model peptides induce CD8+ T cell responses. Herein we test the immunogenicity of 24 different peptides, from three leading vaccine target proteins in gynecological cancers: the E7 protein of human papilloma virus (HPV); Wilms Tumor antigen 1 (WT1) and survivin (SV), in PSNP conjugate vaccines. Of relevance to vaccine development was the finding that a minimal CD8+ T cell peptide epitope from HPV was not able to induce HLA-A2.1 specific CD8+ T cell responses in transgenic humanized mice using conventional adjuvants such as CpG, but was nevertheless able to generate strong immunity when delivered as part of a specific longer peptide conjugated to PSNPs vaccines. Conversely, in most cases, when the minimal CD8+ T cell epitopes were able to induce immune responses (with WT1 or SV super agonists) in CpG, they also induced responses when conjugated to PSNPs. In this case, extending the sequence around the CD8+ T cell epitope, using the natural protein context, or engineering linker sequences proposed to enhance antigen processing, had minimal effects in enhancing or changing the cross-reactivity pattern induced by the super agonists. Nanoparticle approaches, such as PSNPs, therefore may offer an alternative vaccination strategy when conventional adjuvants are unable to elicit the desired CD8+ T cell specificity. The findings herein also offer sequence specific insights into peptide vaccine design for nanoparticle-based vaccine carriers.

Immediate-Type Hypersensitivity Cross-Reactions to Proton Pump Inhibitors: A Descriptive Study of Data from the French National Pharmacovigilance Database

Background: Proton pump inhibitors (PPIs) can trigger immediate-type hypersensitivity reactions (HSRs). Three main patterns of cross-reactivity have been identified: reactions to a single PPI, selective cross-reactions, and cross-reactions with all PPIs. Several hypotheses have been advanced, but no consensus has been reached. Objective: We sought to identify immediate-type hypersensitivity cross-reactions to PPIs using real-world data about hypersensitivity testing from French pharmacovigilance cases. Methods: Potentially relevant immediate-type HSRs reported from January 1985 to February 2015 were extracted from the French pharmacovigilance database using a standardized MedDRA query (SMQ). Cases describing skin tests or oral provocation tests (OPTs) performed with several PPIs that yielded at least one positive result were included. Results: The SMQ extracted 2,119 cases, 38 of which were included in our study. Data collected from skin tests and OPTs indicated cross-reactions with all PPIs (n = 1), reactions to a single PPI (n = 14), or selective cross-reactions (n = 23). Esomeprazole, omeprazole, and pantoprazole concerned 78% of all selective cross-reactions. In more than half of the cases (55.3%), only 2 PPIs were tested. Conclusion: To the best of our knowledge, this PPI cross-reactivity study is the largest to date in terms of population size, describing 38 immediate-type HSRs to PPIs explored by skin tests or OPTs. This paucity of data belies the lack of standardized procedures for PPI hypersensitivity testing. It is likely that PPI HSR workups in everyday clinical practice are often incomplete. Further research to gain insight into selective cross-reactions between PPIs is needed. In the meantime, thorough workups should be completed when a PPI is suspected to have triggered an HSR, instead of routine contraindication to all PPIs.

Managing Cross-Reactivity in Those with Peanut Allergy

Peanut is an allergenic legume that can cross-react with other plant-based foods, notably other legumes and tree nuts. Peanut-allergic individuals can be both cosensitized and coallergic to such items, requiring foresight when eliciting a clinical history of a reaction, in the diagnostic evaluation of such allergies, and in the counseling of patients as to food avoidances after a diagnosis is made. Legume allergens belong to the Fabaceae family and encompass the cupin, prolamin, PR-10, and lipid transfer protein families, which mediate cross-sensitization including that between peanut and tree nut. Among legumes, the most common patterns of clinical cross-reactivity are between peanut and lupine, peanut and soy, as well as chickpea and lentil, though this is highly dependent on geography and prevalence of these foods in the diet. Issues of cross-sensitization may exist between peanut and certain tree nuts, as well as among tree nuts though such patterns do not always result in clinically relevant allergy. Molecular diagnostic testing may be a future tool to help parse out the aforementioned patterns, but oral food challenges are still the gold standard for accurate diagnosis. Although potential desensitization treatments have emerged for peanut allergy, these have not been developed for other legumes and most tree nuts, and desensitization to peanut has not proven to have an effect on legume cross-sensitization.

Food Allergies

Food allergy represents a rapidly growing public health problem in the United States and other westernized nations. Adverse reactions to foods are categorized as either immunologic or nonimmunologic reactions. This distinction is highly important but often confusing to patients and physicians unfamiliar with allergy, who may simply describe any adverse reaction to a food as an “allergy.” A food allergy is an immune-mediated, adverse reaction to one or more protein allergens in a particular food item involving recognition of that protein by specifically targeted IgE or allergen-specific T cells. This chapter discusses the definition, pathophysiology, epidemiology, testing, management, prognosis, and natural history of food allergy. Clinical manifestations are systematically covered, including cutaneous, respiratory, cardiovascular, and gastrointestinal reactions, as well as eosinophilic esophagitis, food protein–induced enterocolitis syndrome, and oral allergy syndrome. Emerging treatments such as food oral immunotherapy are also reviewed. Tables outline signs and symptoms of immediate hypersensitivity reactions to food, the prevalence of major food allergens in the United States, common patterns of cross-reactivity among foods, clinical criteria for the diagnosis of anaphylaxis, and clinical studies involving treatment for food allergies. Figures illustrate the classification of adverse reactions to food, esophageal histology, visual and radiographic features of eosinophilic esophagitis, and a food allergy action plan. This review contains 4 figures, 8 tables, and 64 references. KeyWords: Food allergy, Hypersensitivity, IgE-mediated allergy, Eosinophilic esophagitis, Anaphylaxis