Immunological Responses to Envenomation.

Venoms are complex mixtures of toxic compounds delivered by bite or sting. In humans, the consequences of envenomation range from self-limiting to lethal. Critical host defence against envenomation comprises innate and adaptive immune strategies targeted towards venom detection, neutralisation, detoxification, and symptom resolution. In some instances, venoms mediate immune dysregulation that contributes to symptom severity. This review details the involvement of immune cell subtypes and mediators, particularly of the dermis, in host resistance and venom-induced immunopathology. We further discuss established venom-associated immunopathology, including allergy and systemic inflammation, and investigate Irukandji syndrome as a potential systemic inflammatory response. Finally, this review characterises venom-derived compounds as a source of immune modulating drugs for treatment of disease.

Collocation of avian and mammal antibodies to develop a rapid and sensitive diagnostic tool for Russell's Vipers Snakebite.

Russell's vipers (RVs) envenoming is an important public health issue in South-East Asia. Disseminated intravascular coagulopathy, systemic bleeding, hemolysis, and acute renal injury are obvious problems that develop in most cases, and neuromuscular junction blocks are an additional problem caused by western RV snakebite. The complex presentations usually are an obstacle to early diagnosis and antivenom administration. Here, we tried to produce highly specific antibodies in goose yolks for use in a paper-based microfluidic diagnostic kit, immunochromatographic test of viper (ICT-Viper), to distinguish RVs from other vipers and even cobra snakebite in Asia. We used indirect ELISA to monitor specific goose IgY production and western blotting to illustrate the interaction of avian or mammal antibody with venom proteins. The ICT-Viper was tested not only in prepared samples but also in stored patient serum to demonstrate its preliminary efficacy. The results revealed that specific anti-Daboia russelii IgY could be raised in goose eggs effectively without inducing adverse effects. When it was collocated with horse anti-Daboia siamensis antibody, which broadly reacted with most of the venom proteins of both types of Russell's viper, the false cross-reactivity was reduced, and the test showed good performance. The limit of detection was reduced to 10 ng/ml in vitro, and the test showed good detection ability in clinical snake envenoming case samples. The ICT-Viper performed well and could be combined with a cobra venom detection kit (ICT-Cobra) to create a multiple detection strip (ICT-VC), which broadens its applications while maintaining its detection ability for snake envenomation identification. Nonetheless, the use of the ICT-Viper in the South-East Asia region is pending additional laboratory and field investigations and regional collaboration. We believe that the development of this practical diagnostic tool marks the beginning of positive efforts to face the global snakebite issue.

Sublingual Immunotherapy for Other Indications: Venom Large Local, Latex, Atopic Dermatitis, and Food.

There is some evidence to support the use of sublingual immunotherapy (SLIT) in food allergy, although its role is unclear. One randomized, double-blind, placebo-controlled trial supports the safe and efficacious use of dust mite SLIT in children with mild to moderate atopic dermatitis, but these data have not been confirmed. Although there are several randomized, double-blind, placebo-controlled trials to support the use of SLIT-LATEX, this product is not available in the United States and extrapolation of these effects to latex extracts is unsubstantiated. There is also insufficient evidence to support the use of SLIT for venom hypersensitivity at this time.

Venom Immunotherapy: Questions and Controversies.

Questions and controversies regarding venom immunotherapy (VIT) remain. It is important to recognize risk factors for severe sting anaphylaxis that guide the recommendation for testing, epinephrine injectors, and VIT. Premedication, rush VIT, and omalizumab are successful in overcoming recurrent systemic reactions to VIT. A maintenance dose is adequate in children, but higher doses are needed in high-risk patients. The consensus on risk of ß-blockers and angiotensin-converting enzyme inhibitors in patients on VIT has shifted to the belief that risk is small. The decision to stop VIT after 5 years rests on known risk factors rather than any diagnostic tests.

History of Envenoming Therapy and Current Perspectives.

Each year, millions of humans fall victim to animal envenomings, which may either be deadly or cause permanent disability to the effected individuals. The Nobel Prize-winning discovery of serum therapy for the treatment of bacterial infections (tetanus and diphtheria) paved the way for the introduction of antivenom therapies for envenomings caused by venomous animals. These antivenoms are based on polyclonal antibodies derived from the plasma of hyperimmunized animals and remain the only specific treatment against animal envenomings. Following the initial development of serum therapy for snakebite envenoming by French scientists in 1894, other countries with high incidences of animal envenomings, including Brazil, Australia, South Africa, Costa Rica, and Mexico, started taking up antivenom production against local venomous animals over the course of the twentieth century. These undertakings revolutionized envenoming therapy and have saved innumerous patients worldwide during the last 100 years. This review describes in detail the above-mentioned historical events surrounding the discovery and the application of serum therapy for envenomings, as well as it provides an overview of important developments and scientific breakthroughs that were of importance for antibody-based therapies in general. This begins with discoveries concerning the characterization of antibodies, including the events leading up to the elucidation of the antibody structure. These discoveries further paved the way for other milestones in antibody-based therapies, such as the introduction of hybridoma technology in 1975. Hybridoma technology enabled the expression and isolation of monoclonal antibodies, which in turn formed the basis for the development of phage display technology and transgenic mice, which can be harnessed to directly obtain fully human monoclonal antibodies. These developments were driven by the ultimate goal of producing potent neutralizing monoclonal antibodies with optimal pharmacokinetic properties and low immunogenicity. This review then provides an outline of the most recent achievements in antivenom research, which include the application of new biotechnologies, the development of the first human monoclonal antibodies that can neutralize animal toxins, and efforts toward creating fully recombinant antivenoms. Lastly, future perspectives in the field of envenoming therapies are discussed, including rational engineering of antibody cross-reactivity and the use of oligoclonal antibody mixtures.

False-Positive Results of Serological Tests for Allergy in Alcoholic Patients.

BACKGROUND AND OBJECTIVE: Alcohol consumption is associated with enhanced TH2 immune responses. Objective: To investigate the frequency of false-positive results in serological tests for allergy in alcoholic patients. METHODS: A total of 138 alcoholic patients consecutively admitted to hospital underwent a panel of allergy tests that included serum total IgE, a multiallergen IgE test (UniCAP Phadiatop), and skin prick tests to relevant aeroallergens in the area, which were considered the standard reference for atopy. In selected cases with positive specific IgE (sIgE) to cross-reactive carbohydrate determinants (CCDs) on ImmunoCAP, we determined sIgE to hymenoptera venom components (ADVIA Centaur) and a microarray of 103 allergen components (ISAC). RESULTS: Increased serum total IgE (>170 IU/mL) was observed in 59/110 (54%) of nonatopic (skin prick test-negative) patients. The result of the multiallergen IgE test was positive in 46 nonatopic patients (42%). This finding was closely associated with high serum concentrations of total IgE and sIgE to CCDs. The vast majority of patients with positive CCD-sIgE showed positivity to glycosylated plant and hymenoptera allergen components on ISAC and ADVIA Centaur. Only 1 out of 26 patients with positive sIgE to CCD and hymenoptera venom developed honeybee venom allergy after a median follow-up of 166 months. Correlations between measurements of sIgE to CCD markers on ImmunoCAP, ADVIA Centaur, and ISAC were imperfect. CONCLUSIONS: Serological tests for allergy should be interpreted with caution in alcoholic patients, who frequently have increased levels of total IgE and CCD-sIgE and subsequent positivity of sIgE to glycosylated allergen components, irrespective of the method used.

Adverse reactions to drugs and biologics in patients with clonal mast cell disorders: A Work Group Report of the Mast Cells Disorder Committee, American Academy of Allergy, Asthma & Immunology.

Providers caring for patients with mastocytosis are tasked with the decision to consider therapeutic options. This can come with some trepidation because information available in the public domain lists numerous mast cell (MC) activators based on data that do not discriminate between primates, rodents, and MC lines; do not consider dosage; and do not take into account previous exposure and resultant clinical findings. This being said, there is support in the literature for an enhanced MC response in some patients with mastocytosis and in cases in which there is a greater incidence of adverse reactions associated with certain antigens, such as venoms and drugs. Thus this report provides a comprehensive guide for those providers who must decide on therapeutic options in the management of patients with clonal MC disease.

Recombinant glycoproteins resembling carbohydrate-specific IgE epitopes from plants, venoms and mites.

BACKGROUND: N-linked glycans present in venoms, pollen and mites are recognized by IgE antibodies from >20% of allergic patients but have low or no allergenic activity. OBJECTIVES: To engineer recombinant glycoproteins resembling carbohydrate-specific IgE epitopes from venoms, pollen and mites which can discriminate carbohydrate-specific IgE from allergenic, peptide-specific IgE. METHODS: One or two N-glycosylation sites were engineered into the N-terminus of the non-allergenic protein horse heart myoglobin (HHM) using synthetic gene technology. HHM 1 and HHM 2 containing one or two N-glycosylation sites were expressed in baculovirus-infected High-Five™ insect cells and a non-glycosylated version (HHM 0) was obtained by mutating the glycosylation motif. Recombinant HHM proteins were analyzed regarding fold and aggregation by circular dichroism and gel filtration, respectively. IgE reactivity was assessed by ELISA, immunoblotting and quantitative ImmunoCAP measurements. IgE inhibition assays were performed to study cross-reactivity with venom, plant and mite-derived carbohydrate IgE epitopes. RESULTS: HHM-glycovariants were expressed and purified from insect cells as monomeric and folded proteins. The HHM-glycovariants exhibited strictly carbohydrate-specific IgE reactivity, designed to quantify carbohydrate-specific IgE and resembled IgE epitopes of pollen, venom and mite-derived carbohydrates. IgE-reactivity and inhibition experiments established a hierarchy of plant glcyoallergens (nPhl p 4 > nCyn d 1 > nPla a 2 > nJug r 2 > nCup a 1 > nCry j 1) indicating a hitherto unknown heterogeneity of carbohydrate IgE epitopes in plants which were completely represented by HHM 2. CONCLUSION: Defined recombinant HHM-glycoproteins resembling carbohydrate-specific IgE epitopes from plants, venoms and mites were engineered which made it possible to discriminate carbohydrate- from peptide-specific IgE reactivity.

Mammalian Meat Allergy Accompanied by Venom Allergy: A Review of 12 Cases.

There has recently been an increase in mammalian meat allergy (MMA) in the Black Sea Region of Turkey. It has been associated with the expansion of tick populations.Tick bites appear to result in sensitization to the carbohydrate allergen galactose-alpha-1, 3-galactose, which is present in many types of mammalian meats. In this study, we have emphasized that  Ixodes ricinus named tick type which is implicated in meat allergy, is found in domestic animals of Black Sea Region of Turkey. A new concept has been recently raized; suggesting that having an alpha-gal allergy is associated with an increased risk of sensitization to multiple venom spesific immunoglobulin (Ig) E. Our aim is to evaluate the clinical characteristics of adult patients with MMA and its relationship with insect sting reactions in Turkey. Patients referring to the allergy outpatient clinic with possible MMA were interviewed regarding reactions to a stinging insect. Demographic features and detailed histories of the patients were recorded. Skin prick test (SPT) with commercial beef extract and venom allergens, as well as prick to prick tests with raw beef and cooked beef were performed. Serum total IgE and beef meat specific IgE were measured. Of 50 interviewed patients, 12 patients (4 male [33,3%] and 8 female [66,6%]) had a history of venom hypersensitivity reaction. The mean age was 36.50±13.35 years (range:18-61). History of other allergic diseases was present in 8 (66.6%) patients. Both venom and meat allergy were confirmed with SPT or prick to prick tests in these 12 patients. Among these patients sensitization to honey bee venom was more frequent (83%). MMA and venom allergy are influenced by the same environmental exposures. We believe that there may be shared immunologic factors and similar antigens; making venom allergic patients more susceptible to MMA.

Usefulness of omalizumab and sting challenge test in hymenoptera venom allergy and mastocytosis

No disponible

Secreted venom allergen-like proteins of helminths: Conserved modulators of host responses in animals and plants.

Despite causing considerable damage to host tissue at the onset of parasitism, invasive helminths establish remarkably persistent infections in both animals and plants. Secretions released by these obligate parasites during host invasion are thought to be crucial for their persistence in infection. Helminth secretions are complex mixtures of molecules, most of which have unknown molecular targets and functions in host cells or tissues. Although the habitats of animal- and plant-parasitic helminths are very distinct, their secretions share the presence of a structurally conserved group of proteins called venom allergen-like proteins (VALs). Helminths abundantly secrete VALs during several stages of parasitism while inflicting extensive damage to host tissue. The tight association between the secretion of VALs and the onset of parasitism has triggered a particular interest in this group of proteins, as improved knowledge on their biological functions may assist in designing novel protection strategies against parasites in humans, livestock, and important food crops.

Genome-wide analysis of gene expression after one year of venom immunotherapy.

Background Insect venom immunotherapy (VIT) is used to protect patients against Hymenoptera insects' venom allergy (HVA), which can result in severe systemic or even life-threatening conditions. Molecular mechanisms triggered by VIT remain largely unknown. Objective To compare genome-wide gene expression of patients with severe HVA prior to VIT and 12 months after. Methods Whole blood RNA samples were analyzed on an expression array. Results from differential expression obtained on a microarray platform were confirmed by quantitative real -time PCR (qRT-PCR). Subsequently we applied unsupervised clustering. Relative blood cell proportions and gene expression profiles were used as an input to csSAM to compute cell specific differential gene expression. Finally, transcription factor enrichment analysis was performed in MotifLab. Results & conclusions Comparison of genome-wide expression patterns for whole blood and qRT-PCR experiments revealed no significantly up and/or down regulated genes. This has been corroborated by unsupervised clustering. We found a significant upregulation of 26 genes in macrophages, of 15 genes in monocytes and 2 genes in T regulatory cells (Tregs). Analysis of the promoter sequences of these upregulated genes revealed a significant over-representation of binding motifs specific for kruppel-like factor 4, retinoic acid receptor gamma, and vitamin D receptor. Our results indicate that changes of gene expression invoked by VIT in peripheral blood may have a too small effect to be detected by conventional biostatistical approaches. When blood cell composition was taken into account we uncovered numerous changes of cell-specific gene expression. Given the regulatory implications we hypothesize that above-mentioned alterations may contribute to activation of anti-inflammatory signals in the innate branch of the immune system.

CAP-Inhibition, Molecular Diagnostics, and Total IgE in the Evaluation of Polistes and Vespula Double Sensitization.

Cross-reactions between Polistes dominula and Vespula species are common in southern Europe. Currently, only CAP-inhibition demonstrates high accuracy in identifying genuine sensitizations, but this method is time-consuming and expensive, so a new approach is required. This study investigates skin tests, molecular diagnostics, total IgE (tIgE), and the Ves v 5/Pol d 5 (or vice versa) ratio. The ratio generated low-accuracy results and poor agreement with CAP-inhibition, and we did not find any agreement between CAP-inhibition test and double values of Ves v 5/Pol d 5. Nevertheless, a slight diagnostic improvement was obtained when Ves v 5/tIgE and Pol d 5/tIgE were measured.

Scratching the Surface of an Itch: Molecular Evolution of Aculeata Venom Allergens.

Hymenopteran insects are infamous for their sting, and their ability to cause severe anaphylaxis and in some cases death. This allergic reaction is a result of allergens present in the venom. Hymenopterans have many common venom allergens, the most widespread of which include phospholipase A1, phospholipase A2, acid phosphatase, hyaluronidase, serine protease and antigen 5. While there have been studies that look at the phylogenetic histories of allergens within closely related species, to our knowledge, this is the first study using evolutionary analyses to compare across Hymenoptera the types of selection that are occurring on allergens. This research examined the publicly available sequences of six different groups of allergens and found that allergens had diverged and formed closely related clades which share greater sequence similarities. We also analysed the patterns of selection and found that they are predominately under the influence of negative selection.

Short- and long-term management of cases of venom-induced anaphylaxis is suboptimal.

BACKGROUND: Venom-induced anaphylaxis (VIA) accounts for severe reactions. However, little is known about the short- and long-term management of VIA patients. OBJECTIVE: To assess the short- and long-term management of VIA. METHODS: Using a national anaphylaxis registry (C-CARE), we identified VIA cases presenting to emergency departments in Montreal and to emergency medical services (EMSs) in western Quebec over a 4-year period. Data were collected on clinical characteristics, triggers, and management. Consenting patients were contacted annually regarding long-term management. Univariate and multivariate logistic regressions were used to identify factors associated with epinephrine use, allergist assessment, and administration of immunotherapy. RESULTS: Between June 2013 and May 2017, 115 VIA cases were identified. Epinephrine was administered to 63.5% (95% confidence interval [CI], 53.9%-72.1%) of all VIA cases by a health care professional. Treatment of reactions without epinephrine was more likely in reactions occurring at home and in nonsevere cases (no hypotension, hypoxia, or loss of consciousness). Among 48 patients who responded to a follow-up questionnaire, 95.8% (95% CI, 84.6%-99.3%) were prescribed epinephrine auto-injector, 68.8% (95% CI, 53.6%-80.9%) saw an allergist who confirmed the allergy in 63.6% of cases, and 81.0% of those with positive testing were administered immunotherapy. Among cases with follow-up, seeing an allergist was less likely in patients with known ischemic heart disease. CONCLUSION: Almost 30% of patients with suspected VIA did not see an allergist, only two thirds of those seeing an allergist had allergy confirmation, and almost one fifth of those with confirmed allergy did not receive immunotherapy. Educational programs are needed to bridge this knowledge-to-action gap.