Sweat allergy is defined as a type I hypersensitivity against the contents of sweat, and is specifically observed in patients with atopic dermatitis (AD) and cholinergic urticaria (CholU). The allergic reaction is clinically revealed by positive reactions in the intradermal skin test and the basophil histamine release assay by sweat. A major histamine-releasing antigen in sweat, MGL_1304, has been identified. MGL_1304 is produced at a size of 29 kDa by Malassezia (M.) globosa and secreted into sweat after being processed and converted into the mature form of 17 kDa. It induces significant histamine release from basophils of patients with AD and/or CholU with MGL_1304-specific IgE, which is detected in their sera. Patients with AD also show cross-reactivity to MGL_1304-homologs in Malassezia restricta and Malassezia sympodialis, but MGL_1304 does not share cross antigenicity with human intrinsic proteins. Malassezia or its components may penetrate the damaged epidermis of AD lesions and interact with the skin immune system, resulting in the sensitization and reaction to the fungal antigen. As well as the improvement of impaired barrier functions by topical interventions, approaches such as anti-microbial treatment, the induction of tolerance and antibody/substance neutralizing the sweat antigen may be beneficial for the patients with intractable AD or CholU due to sweat allergy. The identification of antigens other than MGL_1304 in sweat should be the scope for future studies, which may lead to better understanding of sweat allergy and therapeutic innovations.

Although there is a growing acceptance that sweat could play a detrimental role in various allergic skin diseases, the possibility that sweat is also involved in maintenance of skin hydration and skin-specific immune responses has not been acknowledged. We initially describe physiological role of sweat in both maintaining skin hydration and thermoregulation. The purpose of this article is to provide the reader with objective evidence that sweating is intimately linked to vital stratum corneum barrier function and usefulness of application of moisturizers in clinical care of allergic skin diseases. This review also covers how sweating disturbance would leave the skin vulnerable to the development of various allergic skin diseases, such as atopic dermatitis. New therapeutic approaches would specifically target such sweating disturbance in these allergic skin diseases.

We have reported characteristic cutaneous manifestations of Sjögren syndrome (SS) with special references to autoimmune anhidrosis or hypoidrosis and related mucocutaenous manifestations in addition to annular erythema or cutaneous vasculitis. Although significance of cutaneous manifestations of SS has been gradually recognized in rheumatologists, sudomotor function has not been fully evaluated and recognized in the diagnosis of SS except for dermatologists. SS is a relatively underestimated collagen disease in contrast to SLE, systemic sclerosis, or dermatomyositis, special care should be needed not to make misdiagnosis of SS when we see the patients with common skin disease such as, drug eruption, infections skin disease or xerosis in the daily practice. In contrast to pathomechanisms of dry skin observed in SS, we recently reported that reduced sweating function and dry skin seen in atopic dermatitis (AD) are mediated by histamine or substance P, those are usually restored to normal levels after improvement of the dermatitis by topical corticosteroid ointment with or without oral anti-histamine. Therefore, xerotic skin lesions seen in SS and AD might be attributable to different pathomechanisms with similar dry skin manifestations. We recently reported that SS promotes dry skin when complicated with AD possibly due to acceleration of hypoidrosis. In this review, we would like to summarize our recent understanding of regulatory mechanism of impaired sweating function in allergic inflammatory skin diseases by introducing clinical presentations of AD/SS overlap cases as the model of hypoidrotic inflammatory skin diseases.

Sweat is a transparent hypotonic body fluid made from eccrine sweat glands. Various ingredients contained in sweat are involved in a broad sense in skin homeostasis including temperature regulation, skin moisture, and immune functions. Thus, sweat plays a major role in maintaining skin homeostasis. Therefore, abnormal sweating easily compromises human health. For example, in atopic dermatitis (AD), perspiration stagnation accompanying sweat tube or sweat pore blockage, leakage of perspiration from the sweat gland to the outside tissue, and impaired secretion of sweat from the sweat gland are confirmed. In recent years, the hypothesis that atopic dermatitis is a sweat stasis syndrome has been clarified by the establishment of a sweat and sweat gland dynamic analysis technique. Secretion of sweat and leakage into tissues is caused by dermatitis and is thought to promote itching. Furthermore, from the metabolomic analysis of sweat of patients with atopic dermatitis, it was confirmed that the glucose concentration in AD sweat increased according to severity and skin phenotype, suggesting that elevated glucose affected the homeostasis of the skin. Multifaceted analyses of sweat from subjects with AD have revealed new aspects of the pathology, and appropriate measures to treat sweat can be expected to contribute to long-term control of AD.

Inhaled bronchodilator treatment with a long acting muscarinic antagonist (LAMA) reduces symptoms and the risk of exacerbations in COPD and asthma. However, increasing evidence from cell culture and animal studies suggests that anti-muscarinic drugs could also possess anti-inflammatory effects. Recent studies have revealed that acetylcholine (ACh) can be synthesized and released from both neuronal and non-neuronal cells, and the released ACh can potentiate airway inflammation and remodeling in airway diseases. However, these anti-inflammatory effects of anti-muscarinic drugs have not yet been confirmed in COPD and asthma patients. This review will focus on recent findings about the possible involvement of ACh in airway inflammation and remodeling, and the anti-inflammatory effect of anti-muscarinic drugs in airway diseases. Clarifying the acetylcholine-mediated inflammation could provide insights into the mechanisms of airway diseases, which could lead to future therapeutic strategies for inhibiting the disease progression and exacerbations.

Background: About one-third of the Japanese population suffers from Japanese cedar pollinosis, which is frequently accompanied by Japanese cypress pollinosis. Recently, a novel major Japanese cypress pollen allergen, Cha o 3, was discovered. However, whether a Cha o 3 homolog is present in Japanese cedar pollen remains to be determined.

Methods: Western blot analysis was performed using Cha o 3–specific antiserum. In addition, cloning of the gene encoding Cry j 4 was conducted using total cDNA from the male flower of Japanese cedar trees. Allergen potency and cross-reactivity were investigated using a T-cell proliferation assay, basophil activation test, and ImmunoCAP inhibition assay.

Results: A low amount of Cha o 3 homolog protein was detected in Japanese cedar pollen extract. The deduced amino acid sequence of Cry j 4 showed 84% identity to that of Cha o 3. Cross-reactivity between Cry j 4 and Cha o 3 was observed at the T cell and IgE levels.

Conclusions: Cry j 4 was discovered as a counterpart allergen of Cha o 3 in Japanese cedar pollen, with a relationship similar to that between Cry j 1–Cha o 1 and Cry j 2–Cha o 2. Our findings also suggest that allergen-specific immunotherapy (ASIT) using Japanese cedar pollen extract does not induce adequate immune tolerance to Cha o 3 due to the low amount of Cry j 4 in Japanese cedar pollen. Therefore, ASIT using Cha o 3 or cypress pollen extract coupled with Japanese cedar pollen extract is required in order to optimally control allergy symptoms during Japanese cypress pollen season.

Background: The unintentional usage of adrenaline auto-injectors may cause injury to caregivers or patients. To prevent such incidents, we assessed the causative factors of these incidents.

Methods: The Anaphylaxis Working Group of the Japanese Society of Pediatric Allergy and Clinical Immunology requested that society members register cases in which adrenaline auto-injectors were unintentionally used. One hundred cases were reported from June 2015 to March 2016. We identified the root causes of 70 child and 25 adult cases, separately.

Results: The incidents occurred with repeated prescriptions as well as the first prescription. Three cases resulted in a failure to administer an adrenaline auto-injector to children with anaphylaxis. Four caregivers used it with improper application (epilepsy or enteritis). Among the child cases, the median age at the time of the incident was 5.5 years (range, 2–14 years). Five children injected the adrenaline auto-injector on their own body trunk. Twenty children were not the allergic patients themselves. Improper management protocol of the device and the child's development were concomitantly involved in most of the cases. A variety of human behaviors were identified as the root causes in the adult cases. At least 34 cases were associated with mix-ups between the actual and training device.

Conclusions: Health workers should provide sufficient education regarding safety use of adrenaline auto-injector for caregivers tailored to their experience levels at both first and repeated prescriptions. Such education must cover anticipatory behavior based on normal child development. Devices should also be further improved to prevent such incidents.

Background: The association between eczema and mental health problems in schoolchildren has been underexplored. We aimed to investigate this association with the validated questionnaires.

Methods: Of 46,648 invited children, we analyzed 9954 (21.3%) in the 2nd to the 8th grades from the ToMMo Child Health Study conducted in 2014 and 2015, a cross-sectional survey in Miyagi Prefecture, Japan. We defined eczema status as “normal,” “mild/moderate,” or “severe,” based on the presence of persistent flexural eczema and sleep disturbance, according to the International Study of Asthma and Allergies in Childhood (ISAAC) Eczema Symptom Questionnaire. Clinical ranges of Strengths and Difficulties Questionnaire (SDQ) total difficulties scores and four SDQ subcategories of emotional symptoms, conduct problems, hyperactivity/inattention, and peer problems were defined as scores ≥16, ≥5, ≥5, ≥7, and ≥5, respectively.

Results: The mean SDQ total difficulties score significantly increased as eczema status worsened (all P ≤ 0.004 for trend). The OR of scores in the clinical range for SDQ total difficulties were 1.51 (95% CI, 1.31–1.74) for mild/moderate eczema and 2.63 (95% CI, 1.91–3.63) for severe eczema (P < 0.001 for trend), adjusted for sex, school grade, current wheeze, and disaster-related factors, using normal eczema as a reference. The association between severity of eczema and four SDQ subcategories showed a similar trend (all P ≤ 0.017 for trend).

Conclusions: We found a significant association between severity of eczema and mental health problems. The presence of eczema was associated with four SDQ subcategories.

Background: Sarcoidosis is a systemic disorder characterized by the accumulation of lymphocytes and monocyte/macrophage lineage cells that results in the formation of non-caseating granulomas. Thymus- and activation-regulated chemokine (TARC)/CCL17 is an important chemokine in the amplification of Th2 responses, which are achieved by recruiting CCR4-expressing CD4⁺ T lymphocytes. TARC concentrations are known to increase in the serum of sarcoidosis patients; however, its role in the assessment of severity and prognosis of sarcoidosis remains unknown. The objective of this study is to elucidate the role of TARC in sarcoidosis by investigating its expression in peripheral blood and at inflammatory sites. We also examined its relationship with clinical features.

Methods: Serum levels of TARC, soluble interleukin 2 receptor, angiotensin-converting enzyme, and lysozyme were measured in 82 sarcoidosis patients. The Th1 and Th2 balance in circulating CD4⁺ T cells was evaluated by flow cytometry. The immunohistochemical staining of TARC and CCR4 was performed in order to identify the source of TARC in affected skin tissues.

Results: TARC serum levels were elevated in 78% of patients and correlated with disease severity. The percentage of CCR4⁺ cells and the CCR4⁺/CXCR3⁺ cell ratios were significantly higher in sarcoidosis patients than in normal subjects (P = 0.002 and P = 0.015, respectively). Moreover, TARC was expressed by monocyte/macrophage lineage cells within granulomas. The abundancy as well as distribution of TARC staining correlated with its serum levels.

Conclusions: The present results suggest that elevations in TARC drive an imbalanced Th2- weighted immune reaction and might facilitate prolonged inflammatory reactions in sarcoidosis.

Background: Cochineal dye is used worldwide as a red coloring in foods, drinks, cosmetics, quasi-drugs, and drugs. The main component of the red color is carminic acid (CA). Carmine is an aluminum- or calcium-chelated product of CA. CA and carmine usually contain contaminating proteins, including a 38-kDa protein thought to be the primary allergen. Severe allergic reactions manifest as anaphylaxis. The aim of this study was to review all Japanese reported cases and propose useful diagnostic chart.

Methods: All reported Japanese cases of cochineal dye-induced immediate allergy were reviewed, and newly registered cases were examined by skin prick test (SPT) with cochineal extract (CE) and measurement of CE and carmine-specific serum IgE test. Two-dimensional (2D) western blotting using patient serum was conducted to identify the antigen.

Results: Twenty-two Japanese cases have been reported. SPT and the level of specific IgE test indicated that six cases should be newly registered as cochineal dye allergy. All cases were adult females, and all cases except three involved anaphylaxis; 13 cases involved past history of local symptoms associated with cosmetics use. Japanese strawberry juice and fish-meat sausage, and European processed foods (especially macarons made in France) and drinks were recent major sources of allergen. 2D western blotting showed that patient IgE reacted to the 38-kDa protein and other proteins. Serum from healthy controls also weakly reacted with these proteins.

Conclusions: SPT with CE and determination of the level of CE and carmine-specific IgE test are useful methods for the diagnosis of cochineal dye allergy.

Background: Most of the patients develop food allergy early in life. The factors related to parental immune condition might be one of the conceivable causes.

Methods: We reported murine models of food allergy and oral OVA tolerance. To investigate the influence of parental immune condition on infant food allergy, female and male mice with food allergy or oral tolerance were mated with each other.

Results: Food allergy was suppressed by decreased IgE production in the offspring of mice with food allergy. On the contrary, anaphylaxis for OVA was induced in the offspring of mice with oral tolerance. The suppression of food allergy being dependent on a maternal factor was revealed in the offspring after cross-mating mice with food allergy and oral tolerance. Because OVA-specific IgG, presumed to be from the allergic mother, was detected in the serum of naïve infants from mothers allergic to food, we assumed that the suppression was dependent on a specific IgG. The serum IgG purified by a G-protein column was administered before OVA sensitization in the food allergy model, and OVA-specific IgE production was found to be diminished in the administered mice. However, OVA-specific monoclonal IgG₁ and IgG_2a administration could not suppress food allergy. Because we detected OVA-IgG immune complex in the serum of mothers allergic to food, it might be a cause of maternal immune suppression.

Conclusions: We demonstrated that maternal specific IgG conjugated food antigen is an important factor related to the development of food allergy and acquiring tolerance.