Genome-wide association study reveals an association between the HLA-DPB1∗02:01:02 allele and wheat-dependent exercise-induced anaphylaxis.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

Local nasal immunotherapy with birch pollen-galactomannan conjugate-containing ointment in mice and humans.

BACKGROUND: Allergen immunotherapy (AIT) is the only disease-modifying treatment for immunoglobulin (Ig) E-mediated allergy. Owing to the high prevalence and early onset of hay fever and pollen-food allergy syndrome (PFAS), a safer and simpler treatment method than conventional AIT is needed. To develop a local nasal immunotherapy using an ointment containing hypoallergenic pollen and assess its efficacy in mice and healthy humans. METHODS: Hypoallergenicity was achieved by combining pollen and galactomannan through the Maillard reaction to create birch pollen-galactomannan conjugate (BP-GMC). The binding of galactomannan to Bet v 1 was confirmed using electrophoresis and Western blotting (WB). Binding of specific IgE antibodies to BP-GMC was verified using enzyme-linked immunosorbent assay (ELISA) and basophil activation test (BAT). The localization of BP-GMC absorption was confirmed using a BALB/c mouse model. BP-GMC mixed with white petrolatum was intranasally administered to 10 healthy individuals (active drugs, 8; placebo, 2) for 14 days. RESULTS: In electrophoresis and WB, no 17-kDa band was observed. In ELISA and BAT, BP-GMC did not react to specific IgE but was bound to IgA and IgG. In the mouse model, BP-GMC was detected in nasopharyngeal-associated lymphoid tissues. In the active drug group, the salivary-specific IgA level significantly increased on day 15 (p = 0.0299), while the serum-specific IgG level significantly increased on day 85 (p = 0.0006). CONCLUSIONS: The BP-GMC ointment rapidly produced antagonistic antibodies against IgE; it is safe and easy to use and might serve as a therapeutic antigen for hay fever and PFAS.

Efficacy and safety of omalizumab in adult patients with wheat-dependent exercise-induced anaphylaxis: Reduction of in vitro basophil activation and allergic reaction to wheat.

BACKGROUND: In patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA. METHODS: In this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150-600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0-48 weeks) and observation period (48-68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion. RESULTS: During the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study. CONCLUSIONS: Long-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.

Epicutaneously sensitized food-induced anaphylaxis is ameliorated with "oral tolerance" to antigen.

Food allergy is an antigen-specific immunological adverse reaction after exposure to a given food. Multiple clinical studies showed that oral immunotherapy (OIT) is effective for the prevention and treatment for food allergy that is developed in infants and children. However, the effectiveness of OIT for epicutaneously sensitized food allergy remains unclear. Previously, we established a mouse model of epicutaneous-sensitized food allergy. In this model, systemic allergic reaction including intestinal and skin symptoms, such as anaphylaxis, was observed. We treated this model with OIT in two ways (OIT before sensitization or OIT during the sensitization phase) and evaluated the preventive effect of both methods. OIT before sensitization significantly ameliorated mast cell degranulation in sensitized skin, but there was no decrease in rectal temperatures or in mast cell degranulation in the jejunum. However, OIT administered during the sensitization phase significantly ameliorated the decrease in rectal temperature and mast cell degranulation in the skin and jejunum. OIT before sensitization increased the regulatory T cells in mesenteric lymph node (MLN), but not in the spleen, and it reduced antigen-specific IgG, but not IgE, production compared with the non-OIT control. However, OIT during sensitization caused a greater increase in regulatory T cells in both the MLN and spleen and reduced antigen-specific IgE and IgG generation compared with the non-OIT control group. Thus, OIT during the sensitization phase was effective for the prevention of epicutaneous-sensitized food allergy.

Cutaneous basophil infiltration in atopic dermatitis is associated with abundant epidermal infiltration of helper T cells: A preliminary retrospective study.

Atopic dermatitis (AD) is a heterogenous inflammatory skin disorder. Our previous study revealed that basophil infiltration in skin is observed in approximately 60% of AD cases. However, the clinical and histological characteristics of AD associated with basophil infiltration remain unclear. We examined basophil infiltration by immunohistochemical staining of 38 specimens from 34 patients who underwent skin biopsies to diagnose AD from April 2016 to September 2021 at Tokyo Medical and Dental University Hospital. The patients/specimens were divided into two groups, 17 patients/21 specimens associated with little or no basophil infiltration (basophil-low group) and 17 patients/17 specimens associated with marked basophil infiltration (basophil-high group). The clinical characteristics of the patients (age, sex, complications, blood biomarkers, skin symptoms, and treatment) and histological features of the specimens were compared between the groups. Basophil-high patients were significantly younger than basophil-low patients. Blood basophil counts were higher in basophil-high patients than in basophil-low patients. CD4+ T-cell infiltration was more marked in basophil-high specimens than in basophil-low specimens. CD4+ T cells infiltrated into the dermis as well as into the epidermis only in the basophil-high specimens. Thus, basophil-high AD can be characterized by skin lesions associated with abundant helper T-cell infiltration in younger patients.

The potential value of thallium-201 scintigraphy in the diagnosis of squamous cell carcinoma arising from extensive pyoderma.

Squamous cell carcinoma (SCC) arises from a variety of premalignant conditions, including pyoderma. However, an accurate diagnosis of SCC is sometimes challenging due to indistinguishable inflammatory lesions. Here, we present a case of SCC arising from extensive pyoderma, which was successfully diagnosed by taking advantage of thallium-201 scintigraphy. A 49-year-old man presented with an elevated tumor on his right buttock. Computed tomography (CT) and enhanced magnetic resonance imaging (MRI) identified the tumor, but many indistinguishable lesions were also found around the tumor. Histopathology revealed an atypical proliferation of keratinocytes with cancer pearls inside the tumor nests, while histopathology of nodules around the tumor revealed inflammatory tissues. Positron emission tomography CT (PET/CT) revealed an accumulation of 2-deoxy-2-[18 F]-D-glucose at the axillae and inguinal nodes, and at subcutaneous tissues in addition to the tumor. From the CT, enhanced MRI, and PET/CT analyses it was impossible to differentiate many scattered subcutaneous nodules on the trunk from SCCs. However, thallium-201 scintigraphy identified only the tumor and found no accumulation in other nodules. This finding suggests that thallium-201 scintigraphy is useful for the diagnosis of SCC by excluding false-positive signals detected by other imaging technologies.

FcεRI, but not FcγR, signals induce prostaglandin D2 and E2 production from basophils.

Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitro-cultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE + antigen (Ag), but not to IgG + Ag. Release of PGs was almost completely abrogated in cultured basophils from FcRγ-chain(-/-) mice, indicating the involvement of FcεRI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE-mediated stimulation. Thus, basophils could be an important source of PGD2/PGE2 and may contribute to allergic inflammation and immune responses.

Cohort study of subclinical sensitization against galactose-α-1,3-galactose in Japan: Prevalence and regional variations.

Sensitization to galactose-α-1,3-galactose (α-Gal) leads to the development of α-Gal syndrome, which includes red meat allergy and cetuximab-induced anaphylaxis. Since tick bites represent the main cause of α-Gal sensitization, it was speculated that sensitization to α-Gal occurs throughout Japan. However, few cohort studies have investigated α-Gal sensitization in Japan. Therefore, we aimed to elucidate the subclinical sensitization rate to α-Gal in Japan. Sera were obtained from 300 participants without food or cetuximab allergy at Shimane University Hospital (Shimane prefecture), Tokyo Medical and Dental University Hospital (Tokyo metropolis), and Tohoku University Hospital (Miyagi prefecture). ImmunoCAP-bovine thyroglobulin (BTG), ImmunoCAP-beef, and IgE immunoblotting with cetuximab were performed to detect α-Gal-specific IgE. Clinical information was collected from participants using a questionnaire. The overall positivity rate of ImmunoCAP-BTG was 4.0% without significant inter-institute differences, whereas that for ImmunoCAP-beef was 9.7% with a significant inter-institute difference. Tokyo Medical and Dental University Hospital (19.0%) had the highest positivity rate. The positivity rate based on cetuximab IgE immunoblotting was 2.7%, without any significant inter-institute differences. The overall positivity rate for both ImmunoCAP-BTG and cetuximab immunoblotting was 2.0%, with a significant inter-institute difference; 5.0% of Shimane University Hospital was the highest. Two cases showed sensitization against the non-α-Gal epitope of cetuximab. The overall positivity rate for both ImmunoCAP-beef and cetuximab immunoblotting was 1.3%, without significant inter-institute differences. Male sex was associated with positive beef-specific IgE. The prevalence of subclinical sensitization to α-Gal is estimated at 2.0%-4.0% in Japan and may be higher in rural areas, supporting an association between tick bites and α-Gal sensitization. In contrast, the prevalence of subclinical sensitization to beef is 9.7% in Japan and is highest in Tokyo Metropolis, suggesting the presence of another IgE-binding epitope apart from α-Gal and another sensitization route in the sensitization to beef IgE.

An epidemiological survey of anhidrotic/hypohidrotic ectodermal dysplasia in Japan: High prevalence of allergic diseases.

Anhidrotic/hypohidrotic ectodermal dysplasia (A/HED) is a congenital disorder characterized by anhidrosis/hypohidrosis and inadequate hair and dental dysplasia. Large-scale case studies of patients with A/HED have already been conducted overseas, while there has been no large-scale study, but only a few case reports in Japan. Furthermore, an epidemiological study of this disease has not been conducted in Japan to date. The purpose of this study was to investigate the clinical characteristics of A/HED patients, the status of genetic aberrations and complications of A/HED in Japan. Initially, we conducted a physician-initiated questionnaire survey of A/HED patients who visited medical institutions across Japan to investigate their backgrounds, clinical symptoms, genotypes, diagnostic methods and complications of A/HED. We also investigated the presence or absence of various allergic diseases (atopic dermatitis-like skin manifestations, bronchial asthma and food allergies). Questionnaires were also obtained from 26 patients with ectodermal dysplasia (ED) who visited four medical institutions. We compared the incidence of allergic diseases in healthy controls in a similar study to that of patients. Twenty-four of those patients were considered to have A/HED, of which 18 had a confirmed genetic diagnosis and were genotyped. All patients had anhidrosis or hypohidrosis, hair and dental dysplasia, and unique facial appearance; 23 patients had several cutaneous manifestations and seven patients had periorbital pigmentation. In addition, there was a significantly higher incidence of atopic dermatitis-like cutaneous manifestations, bronchial asthma and food allergies in the A/HED patients than in healthy controls. We report the results from a questionnaire survey of 24 patients with A/HED. This is the first report of a large number of A/HED patients in Japan. This study clarifies the status of clinical diagnosis and genetic testing of A/HED patients in Japan, as well as the characteristics of their skin symptoms and allergic complications.

Basophil-derived mouse mast cell protease 11 induces microvascular leakage and tissue edema in a mast cell-independent manner.

Mouse mast cell protease 11 (mMCP-11) is the most recently identified member of the mouse mast cell tryptase family. This tryptase is preferentially produced by basophils in contrast to other members that are expressed by mast cells but not basophils. Although blood-circulating basophils have long been considered as minor and redundant relatives of tissue-resident mast cells, recent studies illustrated that basophils and mast cells play distinct roles in vivo. To explore the in vivo role of basophil-derived mMCP-11, here we prepared recombinant mMCP-11 and its protease-dead mutant. Subcutaneous injection of the wild-type mMCP-11 but not the mutant induced edematous skin swelling with increased microvascular permeability in a dose-dependent manner. No apparent infiltration of proinflammatory cells including neutrophils and eosinophils was detected in the skin lesions. The cutaneous swelling was abolished by the pretreatment of mice with indomethacin, a cyclooxygenase inhibitor, suggesting the major contribution of prostaglandins to the microvascular leakage. Of note, the cutaneous swelling was elicited even in mast cell-deficient mice, indicating that mast cells are dispensable for the mMCP-11-induced cutaneous swelling. Thus, basophil-derived mMCP-11 can induce microvascular leakage via prostaglandins in a mast cell-independent manner, and may contribute to the development of basophil-mediated inflammatory responses.

Recurrent Auricular Pseudocyst: Successful Treatment Using a Dental Silicon Cast.

Auricular pseudocysts (APs) are benign intercartilaginous cysts at the auricle. Various therapeutic options have been used to treat APs, but they frequently recur in usual clinical practice. Here, we report a case of AP successfully treated using a silicon cast. A 65-year-old male presented with a cyst on his right auricle. Although a local injection of steroid was administered, the cyst had recurred. A dental silicon cast was applied after removal of the contents of the cyst by suction. There was no recurrence of the cyst 6 years after that treatment. Dental silicon casts are a novel technique for an appropriate fixation over auricles in the treatment of APs and had an effective therapeutic result in our case.

Supraclavicular Scrofuloderma: A Diagnostic Challenge without Apparent Clinical Manifestations of Tuberculosis.

Scrofuloderma is one of the cutaneous manifestations of tuberculosis and usually occurs when underlying tuberculosis such as lymphadenitis directly involves the skin. However, the diagnosis of scrofuloderma without other apparent clinical manifestations of tuberculosis is sometimes challenging. A 27-year-old male from Bangladesh presented with a dome-shaped tumor on his right clavicle. MRI showed a high-density area that expanded from the lymph nodes between the internal jugular vein and the common carotid artery into the tumor on his right clavicle. Bacterial examinations of cultures from the tumor detected Mycobacterium tuberculosis. Further examinations for pulmonary tuberculosis including chest X-ray and computed tomography did not detect any lesions suggestive of pulmonary tuberculosis. From those examinations, the diagnosis of scrofuloderma was made. We emphasize the importance of recognizing a variety of clinical manifestations of tuberculosis including scrofuloderma due to the recent increase of immigrants from developing countries.

Chronic prurigo: A retrospective study of 168 cases.

Chronic prurigo is classified into two clinical subtypes: prurigo nodularis (PN) and prurigo chronica multiformis (PCM) in Japan. In this study, we retrospectively investigated the clinical features of 168 patients with chronic prurigo (103 with PN and 65 with PCM) diagnosed at the Tokyo Medical and Dental University, and compared age, sex, prevalence of comorbidities, blood test results, histology and treatment efficacy in both groups. We found that patients with PCM were significantly older than those with PN. Males were more frequently diagnosed with PCM than females; however, both sexes were similarly affected by PN. Chronic infection was more prevalent in PN, whereas diabetes was more common in PCM. For both subtypes, serum immunoglobulin E levels were elevated above the normal range. However, serum thymus and activation-regulated chemokine/CCL17 levels and the number of blood eosinophils were significantly higher in patients with PCM than in those with PN. Histologically, much higher numbers of CD4+ cells than CD8+ cells were distributed in the lesions of both subtypes. Eosinophils were distributed predominantly in intracollagenous lesions in PCM but were observed mainly in perivascular lesions in PN. There were no differences in basophil and mast cell distributions in the lesions of the two groups. Treatment efficacy was also similar in both subtypes. Together, both subtypes exhibit inflammation patterns predominantly driven by T-helper 2 cells. With respect to PCM, elevated numbers of blood eosinophils and the recruitment of these cells into intracollagenous areas may be important for pathogenesis.

Isolation of food-derived bacteria inducing interleukin-22 in B cells.

Recently, we found a novel function of the lactic acid bacterium Tetragenococcus halophilus derived from miso, a fermented soy paste, that induces interleukin (IL)-22 production in B cells preferentially. IL-22 plays a critical role in barrier functions in the gut and skin. We further screened other bacteria species, namely, Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Weissella, Pediococcus, and Bacillus, in addition to Tetragenococcus and found that some of them possessed robust IL-22-inducible function in B cells in vitro. This process resulted in the augmented expression of activation markers CD86 and CD69 on B and T cells, respectively. However, these observations were not correlated with IL-22 production. We isolated Bacillus coagulans sc-09 from miso and determined it to be the best strain to induce robust IL-22 production in B cells. Furthermore, feeding B. coagulans sc-09 to mice augmented the barrier function of the skin regardless of gut microbiota.

Ultrasonography as an auxiliary diagnostic tool for morphea profunda: A case report.

Morphea profunda is a rare subtype of localized scleroderma and it is difficult to evaluate the conditions of sclerotic changes at an early stage. Studies using ultrasonography to evaluate localized scleroderma are limited and, to date, the characteristic findings of morphea profunda assessed by ultrasonography have never been reported. Here, we present a case of morphea profunda diagnosed with the assistance of ultrasonography. A 69-year-old Japanese woman with a past history of morphea en plaque on her lower abdomen presented with skin indurations of her bilateral lower back and thighs. To evaluate the stiffness of the subcutis, fascia and muscle, we utilized ultrasonography and found an unexpected hyperechogenicity not only of the dermis but also in the deeper tissue. The diagnosis was revised to morphea profunda after we performed a deep skin biopsy, including the muscle tissue. From this case, we assert that ultrasonography is a useful alternative tool to assist in the differential diagnosis of morphea profunda.