Efficacy and safety of hymenoptera venom immunotherapy.

Background: Being stung by Hymenoptera species can cause life-threatening anaphylaxis. Although venom immunotherapy (VIT) seems to be the most effective treatment, its long-term efficacy, and risk factors for adverse events remain unclear. Objective: The objective was to investigate the long-term efficacy of VIT and evaluate adverse events and risk factors related to this. Method: Patients who received VIT in a tertiary-care adult allergy clinic between January 2005 and July 2022 were included. Patients' data were compared with those of individuals who had been diagnosed with bee and/or wasp venom allergy during the same period but had not received VIT and experienced field re-stings. Results: The study included 105 patients with venom allergy, of whom 68 received VIT and 37 did not receive VIT. Twenty-three patients (34%) completed 5 years of VIT, and the overall mean ± standard deviation VIT duration was 46.9 ± 20.9 months. Re-stings occurred in 5 of 23 patients who completed 5 years of VIT, and none of them developed a systemic reaction. Eighteen patients (40%) experienced re-stings after prematurely discontinuing VIT, of whom eight (44%) developed a systemic reaction. In the control group of patients who did not receive VIT, 26 patients (70.3%) experienced re-stings, and all had systemic reactions (100%), with no change in their median Mueller scores. There was a significant difference in the median Mueller score change between the patients who received VIT and the controls who did not (p = 0.016). A total of 13 patients (19%) experienced adverse events while receiving VIT, which were systemic reactions in nine honeybee VIT. The use of ß-blockers was determined as the most important risk factor (odds ratio 15.9 [95% confidence interval, 1.2-208.8]; p = 0.035). Conclusion: It was confirmed that VIT was effective in both reducing the incidence and the severity of re-sting reactions. These effects were more pronounced in the patients who completed 5 years of VIT.

Complement activation in wasp venom-induced acute kidney injury.

Previous studies have highlighted the significant role of complement activation in kidney injuries induced by rhabdomyolysis, intravascular hemolysis, sepsis, and ischemia-reperfusion. Nevertheless, the specific role and mechanism of complement activation in acute kidney injury (AKI) caused by wasp venom remain unclear. The aim of this study was to elucidate the specific complement pathway activated and investigate complement activation in AKI induced by wasp venom. In this study, a complement-depleted mouse model was used to investigate the role of complement in wasp venom-induced AKI. Mice were randomly categorized into control, cobra venom factor (CVF), AKI, and CVF + AKI groups. Compared to the AKI group, the CVF + AKI group showed improved pathological changes in kidneys and reduced blood urea nitrogen (BUN) levels. The expression levels of renal complement 3 (C3), complement 5 (C5), complement 1q (C1q), factor B (FB), mannose-binding lectin (MBL), and C5b-9 in AKI group were upregulated compared with the control group. Conversely, the renal tissue expression levels of C3, C5, C1q, FB, MBL, and C5b-9 were decreased in the CVF + AKI group compared to those in the AKI group. Complement activation occurs through all three pathways in AKI induced by wasp venom. Furthermore, complement depletion by CVF attenuates wasp venom-induced nephrotoxicity, suggesting that complement activation plays a primary role in the pathogenesis of wasp venom-induced AKI.

Evaluation of the Cytokine Response Induced by Specific Allergen Immunotherapy in Patients with Vespa velutina Anaphylaxis.

INTRODUCTION: Changes in the cytokine profile from type 2 to type 1 together with the induction of regulatory cells are expected during hymenoptera venom immunotherapy (VIT). The present study was aimed to investigate the changes in type 1, type 2, and regulatory cytokines induced by a Vespula spp. VIT in patients with anaphylaxis to Vespa velutina. METHODS: Twenty consecutive patients with anaphylaxis due to Vespa velutina were treated with Vespula spp. VIT. Serum cytokines (IL-4, IL-5, IL-10, IL-13, and IFN-É£) were measured at baseline, 6, and 12 months after starting VIT. RESULTS: A significant increase in serum IFN-y was detected after 6 and 12 months of VIT. An increase in serum IL-10 and a decrease in IL-5 were observed after 12 months. IL-4 was undetectable all along the study, and an unexpected increase of IL-13 was present at 12 months of treatment. CONCLUSION: Vespula spp. VIT seems to be able to induce a shift to type 1 cytokine production measured through IFN-y levels and IL-10 production after, at least, 6 and 12 months of VIT, respectively.

Management of Double Sensitization to Vespids in Europe.

Wasp allergy with a diagnostic profile of double sensitizations to vespid venom is a frequent clinical problem in areas where different genera of wasps are present. Identification of the insect responsible for serious reactions poses a diagnostic challenge as the only effective treatment to date is immunotherapy based on the specific venom. In southern Europe, the double sensitization to Vespula and Polistes venoms is highly frequent. It has been shown that the major allergenic proteins (Phospholipase A1 and Antigen 5) share sequences across the different genera and species, which would be the cause of cross-reactivity. Additionally, the minor allergens (Dipeptidyl-peptidases, Vitellogenins) have been found to share partial sequence identity. Furthermore, venom contains other homologous proteins whose allergenic nature still remains to be clarified. The traditional diagnostic tools available are insufficient to discriminate between allergy to Vespula and Polistes in a high number of cases. IgE inhibition is the technique that best identifies the cross-reactivity. When a double sensitization has indeed been shown to exist or great uncertainty surrounds the primary sensitization, therapy with two venoms is advisable to guarantee the safety of the patient. In this case, a strategy involving alternate administration that combines effectiveness with efficiency is possible.

Venom Immunotherapy: From Proteins to Product to Patient Protection.

In this review, we outline and reflect on the important differences between allergen-specific immunotherapy for inhalant allergies (i.e., aeroallergens) and venom-specific immunotherapy (VIT), with a special focus on Venomil® Bee and Wasp. Venomil® is provided as a freeze-dried extract and a diluent to prepare a solution for injection for the treatment of patients with IgE-mediated allergies to bee and/or wasp venom and for evaluating the degree of sensitivity in a skin test. While the materials that make up the product have not changed, the suppliers of raw materials have changed over the years. Here, we consolidate relevant historical safety and efficacy studies that used products from shared manufacture supply profiles, i.e., products from Bayer or Hollister-Stier. We also consider the characterization and standardization of venom marker allergens, providing insights into manufacturing controls that have produced stable and consistent quality profiles over many years. Quality differences between products and their impacts on treatment outcomes have been a current topic of discussion and further research. Finally, we review the considerations surrounding the choice of depot adjuvant most suitable to augmenting VIT.

Bee- and Wasp-Venom Sensitization in Schoolchildren of High- and Low-Socioeconomic Status Living in an Urban Area of Indonesia.

BACKGROUND: There is not much known about venom allergy in tropical regions. Here, we studied the prevalence of specific IgE (sIgE) and skin prick test (SPT) reactivity and reported sting-related symptoms, in high- and low-socioeconomic status (SES) schoolchildren living in urban city of Makassar in Indonesia. METHODS: Children from high- (n = 160) and low- (n = 165) SES schools were recruited. Standardized questionnaires were used to record information on allergic disorders as well as sting-related symptoms. Parasitic infection, SPT reactivity, and sIgE to Apis mellifera (bee-venom) as well as Vespula spp. (wasp-venom) were assessed. RESULTS: SPT reactivity to bee- and wasp-venom was 14.3 and 12.7%, while the prevalence of sIgE was 26.5 and 28.5%, respectively. When SES was considered, prevalence of SPT to bee- and wasp-venom was higher in high-SES than in low-SES schoolchildren (bee: 22.8 vs. 5.7%, p < 0.001; and wasp: 19.6 vs. 5.7%, p < 0.001). Conversely, sIgE to both venoms was lower in high-SES than in low-SES (bee: 19 vs. 34%, p = 0.016; and wasp: 19 vs. 38%, p = 0.003). Furthermore, among SPT positive subjects, considerable proportion had no detectable sIgE to bee- (65.85%) or wasp-venom (66.67%). Altogether the sensitizations were rarely translated into clinical reaction, as only 1 child reported significant local reaction after being stung. No association with parasitic infections was found. CONCLUSIONS AND CLINICAL RELEVANCE: Sensitization against bee- or wasp-venom is quite prevalent among schoolchildren in Indonesia. The discordance between SPT and sIgE might suggest the direct (non-IgE) effect of venoms in skin reactivity. Recorded sensitizations had poor clinical relevance as they rarely translated into clinical symptoms.

A parasitoid wasp of Drosophila employs preemptive and reactive strategies to deplete its host's blood cells.

The wasps Leptopilina heterotoma parasitize and ingest their Drosophila hosts. They produce extracellular vesicles (EVs) in the venom that are packed with proteins, some of which perform immune suppressive functions. EV interactions with blood cells of host larvae are linked to hematopoietic depletion, immune suppression, and parasite success. But how EVs disperse within the host, enter and kill hematopoietic cells is not well understood. Using an antibody marker for L. heterotoma EVs, we show that these parasite-derived structures are readily distributed within the hosts' hemolymphatic system. EVs converge around the tightly clustered cells of the posterior signaling center (PSC) of the larval lymph gland, a small hematopoietic organ in Drosophila. The PSC serves as a source of developmental signals in naïve animals. In wasp-infected animals, the PSC directs the differentiation of lymph gland progenitors into lamellocytes. These lamellocytes are needed to encapsulate the wasp egg and block parasite development. We found that L. heterotoma infection disassembles the PSC and PSC cells disperse into the disintegrating lymph gland lobes. Genetically manipulated PSC-less lymph glands remain non-responsive and largely intact in the face of L. heterotoma infection. We also show that the larval lymph gland progenitors use the endocytic machinery to internalize EVs. Once inside, L. heterotoma EVs damage the Rab7- and LAMP-positive late endocytic and phagolysosomal compartments. Rab5 maintains hematopoietic and immune quiescence as Rab5 knockdown results in hematopoietic over-proliferation and ectopic lamellocyte differentiation. Thus, both aspects of anti-parasite immunity, i.e., (a) phagocytosis of the wasp's immune-suppressive EVs, and (b) progenitor differentiation for wasp egg encapsulation reside in the lymph gland. These results help explain why the lymph gland is specifically and precisely targeted for destruction. The parasite's simultaneous and multipronged approach to block cellular immunity not only eliminates blood cells, but also tactically blocks the genetic programming needed for supplementary hematopoietic differentiation necessary for host success. In addition to its known functions in hematopoiesis, our results highlight a previously unrecognized phagocytic role of the lymph gland in cellular immunity. EV-mediated virulence strategies described for L. heterotoma are likely to be shared by other parasitoid wasps; their understanding can improve the design and development of novel therapeutics and biopesticides as well as help protect biodiversity.

Clinical manifestation of multiple wasp stings with details of whole transcriptome analysis: Two case reports.

INTRODUCTION: Multiple wasp stings is an emergency result from systemic reactions to the toxin with a wide range of manifestations, and we presented 2 patients with distinct clinical and transcriptomic findings. PATIENT CONCERNS: Two patients without systemic disease presented with nearly 90 painful papules after attacked by a swarm of wasps (Vespa basalis). DIAGNOSIS: Patient 1 was a 44-year-old healthy male whose clinical manifestations mainly comprised hemolysis, hepatic injury, rhabdomyolysis, and acute kidney injury. Patient 2 was a 49-year-old healthy female who presented with severe acute respiratory distress syndrome (ARDS) in addition to certain clinical manifestations that were also found in patient 1. We used ribo- nucleic acid sequencing (RNA-Seq) to characterize the inflammatory responses of 2 patients with distinct clinical manifestations after multiple wasp stings. INTERVENTIONS: Both 2 patients received 5 sessions of plasmapheresis, and patient-1 further received mechanical ventilation for 8 days as well as 8 sessions of hemodialysis until day 17. OUTCOMES: Both patients recovered uneventfully after the aforementioned management. We used RNA-Seq to demonstrate a largely regulated neutrophil-predominated immune response in patient 1. In patient 2, we found a profound neutrophilc response on week 1 and a robust neutrophilic as well as pro-inflammatory responses on week 2. Furthermore, we found increased expression of signals that were associated with renal system process on week 2. CONCLUSION: In conclusion, we report 2 patients who manifested with shared and distinct presentations after an attack by the same swarm of wasps. Both patients had hemolysis, rhabdomyolysis, hepatic injury and acute kidney injury, and 1 patient had ARDS. The whole transcriptomic analyses were consistent with the distinct clinical manifestation, and these results suggest the potential of RNA-Sequencing to disentangle complex inflammatory responses in patients with multiple wasp stings. Plasmapheresis and corticosteroid were administered to both patients and case 2 also underwent 8 sessions of hemodialysis.

Anaphylaxis to Vespa velutina nigrithorax: Pattern of Sensitization for an Emerging Problem in Western Countries.

OBJECTIVE: To define the sensitization pattern of patients with anaphylaxis to Vespa velutina nigrithorax (VVN). METHODS: We studied 100 consecutive Spanish patients with anaphylaxis to Hymenoptera venom and systematically determined specific IgE (sIgE) to whole venoms (Vespula species, Polistes dominula, Apis mellifera, Vespa crabro, and Dolichovespula maculata) and their molecular components (rApi m 1, rApi m 5, rApi m 10, rVes v 1, rVes v 5, rPol d 5, and cross-reactive carbohydrates). Specific IgE to VVN venom and its antigen 5 (nVesp v 5) were measured in a subsample. RESULTS: Seventy-seven patients had anaphylaxis to VVN. Of these, only 16 (20.8%) reported previous VVN stings, but were stung by other Hymenoptera. Positive sIgE (>0.35 kUA/L) to each of the whole venoms was detected in >70% of patients (Vespula species in 100%). The components showing >50% positivity were rApi m 5 (51.4%), rPol d 5 (80.0%), and rVes v 5 (98.7%). This pattern was similar to that of Vespula species anaphylaxis (n=11) but different from that of A mellifera anaphylaxis (n=10). Specific IgE to nVesp v 5 was positive in all patients (n=15) with VVN anaphylaxis and was correlated with sIgE to both rVes v 5 (R=0.931) and rPol d 5 (R=0.887). CONCLUSIONS: VVN has become the commonest cause of Hymenoptera anaphylaxis in our area. Most cases report no previous VVN stings. Their sensitization pattern is similar to that of patients with anaphylaxis to other Vespidae. Specific IgE to antigen-5 from VVN, Vespula species, and P dominula are strongly correlated in patients with VVN anaphylaxis.

Cross-Reactive Carbohydrate Determinant in Apis mellifera, Solenopsis invicta and Polybia paulista Venoms: Identification of Allergic Sensitization and Cross-Reactivity.

Allergic reactions to Hymenoptera venom, which could lead to systemic and even fatal symptoms, is characterized by hypersensitivity reactions mediated by specific IgE (sIgE) driven to venom allergens. Patients multisensitized to sIgE usually recognize more than one allergen in different Hymenoptera species. However, the presence of sIgE directed against Cross-Reactive Carbohydrate Determinant (CCD), which occurs in some allergens from Hymenoptera venom, hampers the identification of the culprit insects. CCD is also present in plants, pollen, fruits, but not in mammals. Bromelain (Brl) extracted from pineapples is a glycoprotein commonly used for reference to sIgE-CCD detection and analysis. In sera of fifty-one Hymenoptera allergic patients with specific IgE ≥ 1.0 KU/L, we assessed by immunoblotting the reactivity of sIgE to the major allergens of Apis mellifera, Polybia paulista and Solenopsis invicta venoms. We also distinguished, using sera adsorption procedures, the cases of CCD cross-reaction using Brl as a marker and inhibitor of CCD epitopes. The presence of reactivity for bromelain (24-28 kDa) was obtained in 43% of the patients, in which 64% presented reactivity for more than one Hymenoptera venom in radioallergosorbent (RAST) tests, and 90% showed reactivity in immunoblot analysis to the major allergens of Apis mellifera, Polybia paulista and Solenopsis invicta venoms. Sera adsorption procedures with Brl lead to a significant reduction in patients' sera reactivity to the Hymenoptera allergens. Immunoblotting assay using pre- and post-Brl adsorption sera from wasp-allergic patients blotted with non-glycosylated recombinant antigens (rPoly p1, rPoly p5) from Polybia paulista wasp venom showed no change in reactivity pattern of sIgE that recognize allergen peptide epitopes. Our results, using Brl as a marker and CCD inhibitor to test sIgE reactivity, suggest that it could complement diagnostic methods and help to differentiate specific reactivity to allergens' peptide epitopes from cross-reactivity caused by CCD, which is extremely useful in clinical practice.

Sensitization to Hymenoptera venom in pollen allergic patients: Frequency and involvement of cross-reacting carbohydrate determinants (CCD).

Sensitization to Hymenoptera venom in patients without a history of systemic allergic reactions to Hymenoptera stings is frequently found and can be due to the presence of specific IgE to cross-reactive carbohydrate determinants (CCD). This study investigates 105 pollen allergic subjects for the presence of specific IgE to honeybee or wasp venom, pollen, the MUXF3 carbohydrate epitope from bromelain and recombinant Hymenoptera venom components. In addition, in a subgroup of patients (n = 10) a basophil activation test (BAT) using bee and wasp venom was performed. Specific IgE to Hymenoptera venom was detected in 45.7% of the pollen allergic subjects and in 26.7% of the non-atopic controls, both without a history of systemic allergic reactions to Hymenoptera stings. The high sensitization rate in atopic patients could partially be explained by cross-sensitization between pollen and Hymenoptera venom due to specific IgE to CCDs. In our study population, only 20% showed a sensitization to CCDs. Primary sensitization due to sting exposure, high total IgE values or unspecific binding and detection of low affinity antibodies in the test procedure could be reasons. Thus, determination of specific IgE to Hymenoptera venom in patients without a history of systemic allergic reactions as screening test is not recommended.

Comparison of Clinical Manifestations, Treatments, and Outcomes between Vespidae Sting and Formicidae Sting Patients in the Emergency Department in Taiwan.

BACKGROUND: Hymenopteran stings are the most common animal insult injury encountered in the emergency department. With increasing global spread of imported fire ants in recent decades, the rate of Formicidae assault has become a serious problem in many countries. Formicidae-associated injuries gradually increased in Taiwan in recent decades and became the second most common arthropod assault injury in our ED. The present study aimed at comparing the clinical characteristics of Formicidae sting patients with those of the most serious and common group, Vespidae sting patients, in an emergency department (ED) in Taiwan. METHODS: This retrospective study included patients who were admitted between 2015 to 2018 to the ED in a local teaching hospital in Taiwan after a Vespidae or Formicidae sting. Cases with anaphylactic reaction were further compared. RESULTS: We reviewed the records of 881 subjects (503 males, 378 females; mean age, 49.09 ± 17.62 years) who visited our emergency department due to Vespidae or Formicidae stings. A total of 538 (61.1%) were categorized into the Vespidae group, and 343 (38.9%) were sorted into the Formicidae group. The Formicidae group had a longer ED length of stay (79.15 ± 92.30 vs. 108.00 ± 96.50 min, p < 0.01), but the Vespidae group had more cases that required hospitalization (1.9% vs. 0.3%, p = 0.04). Antihistamines (76.8% vs. 80.2%, p < 0.01) were more frequently used in the Formicidae group, while analgesics were more frequently used in the Vespidae group (38.1% vs. 12.5%, p < 0.01). The Vespidae group had more local reactions, and the Formicidae group had more extreme, systemic, or anaphylactic allergic reactions. Creatine kinase was significantly higher in the Vespidae group with an anaphylactic reaction. Sting frequency in both groups exhibited the same positive associations with average temperature of the month and weekend days. CONCLUSION: Formicidae sting patients presented to the ED with higher rate allergic reactions and spent more time in the ED than Vespidae sting patients. However, Vespidae sting patients had more complications and higher rates of admission, especially with anaphylactic reaction. Laboratory data, especially creatine kinase data, were more valuable to check in Vespidae sting patients with an anaphylactic reaction in the ED. Both groups exhibited positive correlations with temperature and a higher rate on weekend days.

Comparison of the Safety Profiles of 3 Different Hymenoptera Venom Immunotherapy Protocols: A Retrospective 2-Center Study of 143 Patients.

INTRODUCTION: Venom immunotherapy (VIT) is highly effective and the treatment of choice for patients with a history of systemic anaphylactic reactions to a Hymenoptera sting. It has been assumed that VIT protocols with a rapid dose increase during the induction phase are associated with a higher frequency of systemic reactions (SR); however, study data addressing this issue are conflicting. OBJECTIVE: The aim of this study was to compare the safety of 3 different Hymenoptera VIT protocols (half-day ultra-rush, 3-day rush, 3-week cluster). METHODS: This retrospective 2-center study included 143 Hymenoptera venom-allergic patients, who underwent 147 VIT procedures during the years 2015-2018. Twenty cluster, 75 rush, and 52 ultra-rush VIT protocols were performed with honeybee (54 protocols) and wasp (93 protocols) venom. All documented side effects were classified into large local and SR (Ring and Messmer classification). RESULTS: SR were observed during 11 (7.5%) VIT procedures and did not exceed severity grade II. SR occurred more frequently in cluster compared to accelerated protocols. This result was observed for both honeybee (cluster: 25%, rush: 8.7%, and ultra-rush: 15.8%) and wasp VIT (cluster: 12.5%, rush: 0%, and ultra-rush: 6.1%), though the differences were statistically significant only in the wasp VIT subgroup. Honeybee venom elicited more SR than wasp venom (14.8 and 3.2%, respectively, p = 0.01). The risk for SR did not depend on age, sex, concomitant antihypertensive medication, hypertryptasemia, or severity of the index sting reaction. CONCLUSION: Accelerated VIT protocols, namely, rush and ultra-rush protocols are safe therapeutic options for Hymenoptera venom-allergic patients and displayed fewer SR than cluster VIT protocols in our study.

Functional Profile of Antigen Specific CD4+ T Cells in the Immune Response to Phospholipase A1 Allergen from Polybia paulista Venom.

Insect venom can cause systemic allergic reactions, including anaphylaxis. Improvements in diagnosis and venom immunotherapy (VIT) are based on a better understanding of an immunological response triggered by venom allergens. Previously, we demonstrated that the recombinant phospholipase A1 (rPoly p 1) from Polybia paulista wasp venom induces specific IgE and IgG antibodies in sensitized mice, which recognized the native allergen. Here, we addressed the T cell immune response of rPoly p 1-sensitized BALB/c mice. Cultures of splenocytes were stimulated with Polybia paulista venom extract and the proliferation of CD8+ and CD4+ T cells and the frequency of T regulatory cells (Tregs) populations were assessed by flow cytometry. Cytokines were quantified in cell culture supernatants in ELISA assays. The in vitro stimulation of T cells from sensitized mice induces a significant proliferation of CD4+ T cells, but not of CD8+ T cells. The cytokine pattern showed a high concentration of IFN-γ and IL-6, and no significant differences to IL-4, IL-1ß and TGF-ß1 production. In addition, the rPoly p 1 group showed a pronounced expansion of CD4+CD25+FoxP3+ and CD4+CD25-FoxP3+ Tregs. rPoly p 1 sensitization induces a Th1/Treg profile in CD4+ T cell subset, suggesting its potential use in wasp venom immunotherapy.

Large local reactions and systemic reactions to insect stings: Similarities and differences.

BACKGROUND: Large local reactions (LLR) to Hymenoptera stings were considered as IgE-mediated late-phase inflammatory reactions. However, in older studies, most patients with LLR were skin test positive, but only around 50% had detectable sIgE determined by the RAST system. METHODS: Data of 620 patients were evaluated retrospectively: 310 patients who suffered from LLR and 310 patients with previous systemic sting reactions (SSR). We aimed to clarify if sIgE can generally be detected by the CAP system in patients with LLR; sIgE levels and clinical parameters were compared between patients with LLR and SSR. RESULTS: Positive sIgE levels were detected in 80.7% of patients with LLR, and in 95.2% of patients with SSR (p<0.001). Of the 310 patients with LLR, 80.6% had a LLR with a size of 10-20cm, whereas 19.4% had swellings >20cm, with a mean duration of seven days. In only 2.9% of patients, LLRs occurred after stings on the trunk, while 14.8% of SSR resulted from stings on this site (p<0.001). Similarly, LLR were also less frequent on the capillitium compared to SSR (8.1% versus 26.2%; p = 0.035). CONCLUSIONS: LLR usually persisted over seven days and about one fifth of patients had swellings greater than 20cm. Contrary to SSR, LLR were less frequently observed on the capillitium and on the trunk. In most patients with LLR, sIgE could be detected. However, total IgE and sIgE levels to bee or vespid venom did not differ between patients with LLR and SSR.

A RhoGAP venom protein from Microplitis mediator suppresses the cellular response of its host Helicoverpa armigera.

Female parasitoid wasps normally inject virulence factors together with eggs into their host to counter host immunity defenses. A newly identified RhoGAP protein in the venom of Microplitis mediator compromises the cellular immunity of its host, Helicoverpa armigera. RhoGAP1 proteins entered H. armigera hemocytes, and the host cellular cytoskeleton was disrupted. Depletion of MmGAP1 by injection of dsRNA or antibody increased the wasp egg encapsulation rate. An immunoprecipitation assay of overexpressed MmGAP1 protein in a Helicoverpa cell line showed that MmGAP1 interacts with many cellular cytoskeleton associated proteins as well as Rho GTPases. A yeast two-hybrid and a pull-down assay demonstrated that MmGAP1 interacts with H. armigera RhoA and Cdc42. These results show that the RhoGAP protein in M. mediator can destroy the H. armigera hemocyte cellular cytoskeleton, restrain host cellular immune defense, and increase the probability of successful parasitism.

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.

BACKGROUND: Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD. METHODS: A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48 months), respectively. RESULTS: During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re-stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient-based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom-specific IgG4 concentrations increased during VIT (P < .001) although tryptase and IgE were unaltered. CONCLUSION: Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re-stings.