DJ-1 regulates mast cell activation and IgE-mediated allergic responses.

BACKGROUND: DJ-1 is an antioxidant protein known to reduce levels of reactive oxygen species (ROS), but its presence or function in mast cells and allergic diseases is unknown. OBJECTIVES: We sought to determine the role and mechanism of DJ-1 in allergic responses in vitro and in vivo. METHODS: ROS and DJ-1 levels in serum or culture medium were measured with ELISA kits. The role of DJ-1 was evaluated in mast cell cultures and passive cutaneous anaphylaxis in normal or DJ-1 knockout (KO) mice. The mechanism of DJ-1 action was examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biological approaches. RESULTS: Patients with atopic dermatitis had increased levels of ROS and diminished levels of DJ-1. DJ-1 KO mice exhibited enhanced passive cutaneous anaphylaxis and augmented ROS levels in sera and bone marrow-derived mast cells (BMMCs). Furthermore, antigen-induced degranulation and production of TNF-α and IL-4 were significantly amplified in DJ-1 KO and anti-DJ-1 small interfering RNA-transfected BMMCs compared with that seen in wild-type (WT) BMMCs. Studies with these cells and BMMCs transfected with small interfering RNAs against the phosphatases Src homology domain 2-containing protein tyrosine phosphatase (SHP) 1 and SHP-2 revealed that the DJ-1 KO phenotype could be attributed to suppression of SHP-1 activity and enhancement of SHP-2 activity, leading to strengthened signaling through linker for activation of T cells, phospholipase Cγ, and mitogen-activated protein kinases. CONCLUSIONS: A deficiency or constitutive activation of DJ-1 can have implications in mast cell-driven allergic diseases, such as asthma and anaphylaxis.

Polydesensitisation with reducing elevated serum total IgE by IFN-gamma therapy in atopic dermatitis: IFN-gamma and polydesensitisation (PDS).

BACKGROUND: AD patients exhibit sensitisation to multiple allergens due to a Th1/Th2 imbalance. Until now, it was impossible to improve the polysensitised status and elevated serum total IgE levels. In this study, the effects of IFN-gamma on systemic polysensitisation to multiple allergens and on serum total IgE levels are investigated. METHODS: A total of 44 AD patients whose food allergies were completely controlled and who were polysensitised to multiple allergens according to the SPT were selected. Twenty-two of these patients received IFN-gamma therapy twice a week for 2 months, and 22 patients did not receive this therapy. The blood eosinophil % and serum total IgE levels were assessed, and a skin prick test for 51 allergens was performed before and after the IFN-gamma therapy. RESULTS: With IFN-gamma therapy, the polysensitisation status was improved, as demonstrated by a decrease in the positive allergen count and skin reactivity (systemic polydesensitisation). The improvement in the polysensitised status was accompanied by a decrease in serum total IgE levels. The change in serum total IgE levels was significantly correlated with the change in polysensitisation status. CONCLUSIONS: IFN-gamma therapy resulted in systemic polydesensitisation with reduced levels of serum total IgE. IFN-gamma is indicated in AD patients with high serum total IgE levels whose food allergies are well controlled and who are polysensitised to multiple allergens.

Treatment of primary eosinophilic colitis using immunoglobulin/histamine complex.

Primary eosinophilic colitis (PEC) is a primary eosinophilic gastrointestinal disorder, and immunoglobulin/histamine complex (IHC) may be an effective therapeutic for PEC. IHC has a nonallergen-specific antinociceptive effect in the treatment of histamine-mediated pain.

Effects of the immunoglobulin/histamine complex on panic disorder concurrent with chronic spontaneous urticaria: a case report.

BACKGROUND: Panic disorder and panic attacks are two of the most common problems in psychiatry. A psychoimmunological correlation between allergic diseases and panic disorder has been strongly suggested. Histamine H1 receptor antagonists have been suggested as alternative drugs for the treatment of panic disorder. Chronic spontaneous urticaria (CSU) and panic disorder improved simultaneously with selective serotonin reuptake inhibitor antidepressants. Panic disorder has also been treated with the antihistamine chlorpheniramine. The immunoglobulin/histamine complex is a histamine-fixed immunoglobulin preparation that was reported to be effective in treating CSU. This case report describes the successful treatment of a patient with concomitant panic disorder and CSU for 23 years using immunoglobulin/histamine complex therapy. CASE PRESENTATION: This report describes a 52-year-old female Korean patient who suffered from CSU with panic disorder for 23 years. Basic allergy tests (blood tests and skin prick tests) were conducted before and after treatment for the evaluation of allergic conditions. A multiple allergosorbent test (MAST) for the detection of allergen-specific IgE levels was also performed. The clinical severity of CSU was evaluated using the urticaria severity score system. Diagnostic interviews systematically assessed the diagnostic criteria outlined by the DSM-V, and the patient was evaluated before, during and after treatment using the Beck Depression Inventory (BDI-2) for depression, the State-Trait Anxiety Inventory (STAI) for anxiety and the Beck Hopelessness Score (BHS) for hopelessness. The patient received 2 ml of Histobulin™ (12 mg human immunoglobulin/0.15 µg histamine complex) once a week by subcutaneous injection for the treatment of CSU. Initial improvement of CSU was achieved after the third injection. After the twenty-seventh injection of Histobulin™, she showed no symptoms or signs and ceased allergic medication use. With the remission of CSU, allergic rhinitis was also completely resolved. The frequency of the common cold was significantly decreased during and after treatment. The medication frequency and development of clinical manifestations of panic disorder changed in parallel with the clinical severity of CSU. Moreover, the patient exhibited no clinical manifestations and ceased medication for panic disorder and sleeping pills for insomnia simultaneously with the remission of CSU. In the psychological evaluation, the BDI, STAI and BHS scores improved accordingly. CONCLUSIONS: The immunoglobulin/histamine complex was effective in treating CSU and concomitant panic disorder in this patient and could be effective in treating some types of panic disorder. Considering the mechanisms of action of histamine and the immunoglobulin/histamine complex together with the patient's clinical progress, histamine seemed to be related to panic disorder in this case. The concept of histamine-mediated syndromes, including allergies and psychiatric disorders, shows that a wider disease identity may be needed. Further studies on the immunopathogenesis of panic disorder and the mechanisms of action of the immunoglobulin/histamine complex are necessary.

Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental contact urticaria by regulating the functions of mast cells and T cells.

Contact urticaria (CU) is an inflammatory skin disorder triggered by specific substances upon skin contact, leading to immediate acute or chronic manifestations characterized by swelling and redness. While mesenchymal stem cells (MSCs) are increasingly recognized for their therapeutic potential in immune diseases, research on the efficacy and mechanisms of stem cell therapy for urticaria remains scarce. This study investigates the regulatory role of embryonic-stem-cell-derived multipotent MSCs (M-MSCs) administered in a CU mouse model. Therapeutic effects of M-MSC administration were assessed in a Trimellitic anhydride-induced contact urticaria model, revealing significant inhibition of urticarial reactions, including ear swelling, itchiness, and skin lesion. Moreover, M-MSC administration exerted control over effector T cell activities in major lymphoid and peripheral tissues, while also suppressing mast cell degranulation in peripheral tissues. Notably, the inhibitory effects mediated by M-MSCs were found to be TGF-ß-dependent. Our study demonstrates the capacity of M-MSCs to regulate contact urticaria in a murine model, harmonizing the activation of inflammatory T cells and mast cells. Additionally, we suggest that TGF-ß derived from M-MSCs could play a pivotal role as an inhibitory mechanism in contact urticaria.

Allergen-specific responses of CD19(+)CD5(+)Foxp3(+) regulatory B cells (Bregs) and CD4(+)Foxp3(+) regulatory T cell (Tregs) in immune tolerance of cow milk allergy of late eczematous reactions.

Foxp3-expressing cells among CD19(+)CD5(+) B cells were identified as regulatory B cells. Food allergy manifesting as late eczematous reactions is regarded as a non-IgE-mediated food allergy. The diagnosis for milk allergy manifesting as late eczematous reactions was made on the basis of the findings obtained from a double-blind placebo-controlled food challenge in patients with atopic dermatitis. Twelve patients with milk allergy and 12 patients who could tolerate milk were selected. On casein stimulation, the CD19(+)CD5(+)Foxp3(+) B cell (Breg) fraction in CD5(+) B cells decreased from 4.4±1.1% to 3.1±0.7% (P=0.047, n=12) in the milk allergy group and increased from 4.4±1.3% to 5.2±1.4% (P=0.001, n=10) in the milk-tolerant group. On the other hand, on allergen stimulation, the number of CD4(+)Foxp3(+) regulatory T cells (Tregs) in the milk allergy group and milk-tolerant group increased from 2.6±0.7% to 3.4±0.6% (P=0.014, n=9) and from 2.7±1.0% to 3.5±1.0% (P=0.038, n=10), respectively. In conclusion, allergen-specific responses of Bregs, rather than those of Tregs, seem to influence the immune responses (i.e., allergy or tolerance) to a food allergen.

Tolerogenic effects of interferon-gamma with induction of allergen-specific interleukin-10-producing regulatory B cell (Br1) changes in non-IgE-mediated food allergy.

In this study, specific oral tolerance induction using interferon-gamma (IFN-γ) could successfully treat food allergies. Allergen-specific IL-10-producing regulatory B cell (Br1) responses are characteristic in immune tolerance of food allergies. The in-vivo effects of IFN-γ on allergen-induced changes in Br1 proportion and numbers in food allergies were investigated. Oral food challenges were conducted and 20 allergic patients to cow's milk were selected. Of these 20 patients, five were treated with IFN-γ and milk (SOTI group), five were treated with only milk, five were treated with only IFN-γ, and five did not receive any treatment. In addition, 10 milk-tolerant subjects were involved in this study. Peripheral blood mononuclear cells (PBMCs) were stimulated using casein and stained for CD5, CD19, annexin V, and IL-10 before and after treatment. Allergy tolerance was induced only in the SOTI group along with induction of allergen-induced Br1 changes. Thus, IFN-γ can show tolerogenic effects in vivo when introduced with an allergen, which may be at least partly due to its effect on allergen-induced Br1 responses.

Immunotherapy using Histobulin™ in psoriasis: A case report.

There is no cure for psoriasis. A psoriasis patient was treated with Histobulin™. The patient's clinical symptoms and signs disappeared after the eighth injection and did not recur for more than 18 months. Histobulin™ was effective in the treatment of psoriasis and is suggested as a curative therapeutic for psoriasis.

Immunotherapy using Histobulin in atopic dermatitis.

Histobulin was effective in atopic dermatitis. Allergic diseases may be classified as allergen-specific and non-allergen-specific. Histobulin appears to exert immediate preventive effects against upper respiratory infection.

Histobulin as a complementary but essential therapeutic for Intravenous Immune Globulin Therapy of Pfeiffer-Weber-Christian disease with multiple allergic diseases and its effects on allergic disease: A case report.

Histobulin is complementary to IVIG therapy but is an essential therapeutic for PWCD. Histoublin is recommended not only in atopic dermatitis and multiple food allergies but also in patients with multiple allergic diseases.

Induction of remission in chronic urticaria by immunotherapy using immunoglobulin/histamine complex (Histobulin™): a case report.

BACKGROUND: Symptom control is a major concern in chronic urticaria. Histobulin™ is a histamine/immunoglobulin complex that has been approved for allergic rhinitis, bronchial asthma and chronic urticaria in some countries. Not only has the immunoglobulin/histamine complex been reported to be effective in allergic diseases, including chronic urticaria, but recently, the possibility of remission induction in chronic urticaria by the immunoglobulin/histamine complex has been reported. CASE PRESENTATION: Histobulin™ was administered until remission was induced instead of fixing the number of administrations in four cases of chronic urticaria. Two patients showed an early response and finished treatment with 12 injections of Histobulin™, and the other two patients showed a late response and were injected 43 and 46 times. Remission was induced successfully in all four cases. CONCLUSIONS: Histobulin™ is not only effective but also induces remission in CSU. The Histobulin™ therapy protocol in CSU may be better if the treatment is continued until remission is achieved. Based on the responses of the patients, early responders and late responders were present. The progression of the disease during treatment consisted of a slow improvement phase and a rapid improvement phase. Uniquely, the appropriate allergy laboratory results, including blood eosinophil fraction, total IgE and eosinophil cationic protein level, were normal in all 4 cases. Further studies concerning the mechanisms of Histobulin™ may be needed.

Intravenous Immune Globulin (IVIG) Therapy After Unsuccessful Treatment with Corticosteroid and Cyclosporine A in Pfeifer-Weber-Christian Disease: A Case Report.

BACKGROUND Pfeifer-Weber-Christian disease (PWCD), also referred to as idiopathic nodular panniculitis, is a rare idiopathic disease characterized by lobular panniculitis of adipose tissue with systemic symptoms and multiple organ involvement and is usually treated with corticosteroids and cyclosporine A. We report a case of PWCD that was unresponsive to standard treatment but responded to intravenous immune globulin (IVIG) therapy. CASE REPORT A 35-year-old Korean woman presented with fever, malaise, myalgia, and painful nodules in the left breast. Histology of the breast nodules showed lobular panniculitis consistent with PWCD. She did not respond to corticosteroid and cyclosporine A. She was effectively treated with intravenous immune globulin (IVIG). IVIG therapy began with 60 g (1 g/kg) 4 times per week, 2 times every other week. Subsequently, the IVIG dose was reduced for maintenance therapy to 25 g (400 mg/kg) twice every other week and monthly. The patient showed immediate and dramatic improvement. General signs and symptoms, such as fever, malaise, and myalgia, were absent, and the masses had nearly subsided, with several very small hard nodules remaining for 3 months until the time of this report. CONCLUSIONS IVIG was an effective immunomodulatory therapeutic for PWCD in this case. This report shows that PWCD is a rare condition that is difficult to diagnose, but the histopathology of nodular panniculitis supports the diagnosis. In cases that do not respond to standard immunosuppressive therapy, including corticosteroids and cyclosporine A, IVIG therapy may lead to a favorable response with rapid symptomatic relief.

Mesenchymal stem/stromal cell therapy in atopic dermatitis and chronic urticaria: immunological and clinical viewpoints.

Allergic diseases are immune-mediated diseases. Allergies share a common immunopathogenesis, with specific differences according to the specific disease. Mesenchymal stem/stromal cells (MSCs) have been applied to people suffering from allergic and many other diseases. In this review, the immunologic roles of MSCs are systemically reviewed according to disease immunopathogenesis from a clinical viewpoint. MSCs seem to be a promising therapeutic modality not only as symptomatic treatments but also as causative and even preventive treatments for allergic diseases, including atopic dermatitis and chronic urticaria.

CD1dhiPD-L1hiCD27+ Regulatory Natural Killer Subset Suppresses Atopic Dermatitis.

Effector and regulatory functions of various leukocytes in allergic diseases have been well reported. Although the role of conventional natural killer (NK) cells has been established, information on its regulatory phenotype and function are very limited. Therefore, the objective of this study was to investigate the phenotype and inhibitory functions of transforming growth factor (TGF)-ß-producing regulatory NK (NKreg) subset in mice with MC903-induced atopic dermatitis (AD). Interestingly, the population of TGF-ß-producing NK cells in peripheral blood monocytes (PBMCs) was decreased in AD patients than in healthy subjects. The number of TGF-ß+ NK subsets was decreased in the spleen or cervical lymph node (cLN), but increased in ear tissues of mice with AD induced by MC903 than those of normal mice. We further observed that TGF-ß+ NK subsets were largely included in CD1dhiPD-L1hiCD27+ NK cell subset. We also found that numbers of ILC2s and TH2 cells were significantly decreased by adoptive transfer of CD1dhiPD-L1hiCD27+ NK subsets. Notably, the ratio of splenic Treg per TH2 was increased by the adoptive transfer of CD1dhiPD-L1hiCD27+ NK cells in mice. Taken together, our findings demonstrate that the TGF-ß-producing CD1dhiPD-L1hiCD27+ NK subset has a previously unrecognized role in suppressing TH2 immunity and ILC2 activation in AD mice, suggesting that the function of TGF-ß-producing NK subset is closely associated with the severity of AD in humans.

Allergen-specific B cell subset responses in cow's milk allergy of late eczematous reactions in atopic dermatitis.

B cells have regulatory functions in immune responses. Antigen-specific responses of B cell subsets by allergen stimulation ex vivo were examined in milk allergy of late eczematous reactions. Eight milk allergy subjects and 13 milk tolerant subjects were selected by DBPCFC. PBMCs were stimulated by casein ex vivo and stained for B cell subsets using monoclonal antibodies. CD19+ B cells unchanged from 8.7+/-3.8% to 8.0+/-5.1% (p=0.504, n=8) in the milk allergy group and decreased in the milk tolerant group from 8.5+/-3.2% to 5.0+/-1.6% (p=0.001, n=13). The fraction of apoptotic B cells in B cells significantly decreased 4.4+/-3.1% to 1.3+/-0.4% (p=0.027, n=4) in the allergy group and insignificantly increased from 2.8+/-0.6% to 5.4+/-2.6% (p=0.059, n=6) in the milk tolerant group. CD5+ regulatory B1 cell% in B cells decreased in milk allergy subjects from 36.2+/-5.0% to 31.0+/-5.7% (p=0.010) and unchanged in milk tolerant subjects from 41.6+/-10.2% to 43.8+/-10.0% (p=0.413). IL-10 producing CD19+CD5+ regulatory B cell% in CD19+CD5+ regulatory B cells significantly decreased from 24.9+/-6.5% to 13.8+/-5.6% (p=0.002, n=5) by casein stimulation in milk allergy group and unchanged from 44.8+/-11.3% to 43.9+/-10.0% (p=0.297, n=5) in the milk tolerant group. B cell subset responses to IL-4 and IL-5 were also similar in both groups. B cell subset changes seemed to have diagnostic value. Exact immunologic roles of regulatory CD5+ B1 cells need further investigation.

Characterisation of allergen-specific responses of IL-10-producing regulatory B cells (Br1) in Cow Milk Allergy.

CD19+CD5+ regulatory B cells regulate immune responses by producing IL-10. IL-10-producing regulatory B cell (Br1) responses by allergen stimulation were investigated in human food allergy. Six milk allergy patients and eight milk-tolerant subjects were selected according to DBPCFC. PBMCs were stimulated by casein in vitro and stained for intracellular IL-10 and apoptosis. In response to allergen stimulation, Br1 decreased from 26.2+/-18.3 to 15.5+/-8.9% (p=0.031, n=6) in the milk allergy group and increased from 15.4+/-9.0 to 23.7+/-11.2% (p=0.023, n=8) in the milk-tolerant group. Apoptotic non-IL-10-producing regulatory B cells increased from 21.8+/-9.3 to 38.0+/-16.1% (p=0.031, n=6) in the milk allergy group and unchanged from 28.8+/-13.8 to 28.0+/-15.0% (p=0.844, n=8) in the milk-tolerant group. Br1 may be involved in the immune tolerance of food allergies by producing IL-10 and simultaneously undergoing apoptosis in humans. The exact roles for Br1 in immune tolerance needs to be further investigated.

Eosinophilia as a predictor of food allergy in atopic dermatitis.

Food allergy plays an important role in atopic dermatitis (AD). Adequate predictors and guidelines for when dietary manipulation is indicated for AD are needed. The clinical significance of eosinophilia as a predictor for food allergy of late eczematous reactions in AD was investigated. Three hundred three patients with AD were studied, using elimination diets and food challenge tests. Food allergy prevalence was compared in groups of eczematoid AD patients with high or normal eosinophil levels. The effects on the blood eosinophil fraction of an elimination diet and milk allergy provocation of late eczematous reactions were evaluated. The prevalence of food allergy was 51.1% (135/264) in patients with eczematoid AD. The major type of food allergy in AD was late eczematous, rather than IgE mediated. Among eczematoid AD patients, 44.9% had high eosinophil levels. In patients with eczematoid AD, the food allergy prevalence was 70.8% (85/120) in the high eosinophil group and 34.7% (50/144) in the normal blood eosinophil group. An elimination diet improved clinical severity and decreased blood eosinophil levels. In milk allergy patients, a milk challenge significantly increased the blood eosinophil level. Skin-prick tests and food-specific IgE tests were useful for diagnosing IgE-mediated food allergy. Eosinophilia appeared to be a significant predictor of food allergy in AD and an indicating factor for diet manipulation, including an elimination diet. Food allergy may be responsible for eosinophilia in AD. Food allergy patterns for AD in Korea were different from those in western countries.

Clinical characteristics of oral tolerance induction of IgE-mediated and non-IgE-mediated food allergy using interferon gamma.

Food allergies are classified as IgE-mediated food allergies (IFAs) and non-IgE-mediated food allergies (NFAs). Recently, oral immunotherapy (OIT) has been found to be successful for treating both IFA and NFA, especially using interferon (IFN) gamma. This study was designed to clarify the clinical characteristics of IFA and NFA and compare the therapeutic characteristics of OIT using subcutaneously administered IFN-gamma for both types of food allergy. In this study, 148 patients were categorized into the IFA and NFA group following food challenge, skin-prick test and food-specific IgE tests. The patients were then treated using protocols specific for IFA and NFA using subcutaneous IFN-gamma injection as a randomized controlled trial. The principle of complete allergy resolution at prior dose in the case of IFA was also evaluated. Only the patients with IFA and NFA treated with OIT using IFN-gamma achieved tolerance successfully. Tolerance was achieved from low-dose range in IFA and in high-dose range for NFA. Complete tolerance was not obtained without achieving complete allergy resolution at each dose of the allergen before increasing the dosage in IFA. Both IFA and NFA can be successfully treated with OIT using IFN-gamma but show different clinical and therapeutic characteristics. IFN-gamma is necessary for the tolerance induction but not for tolerance maintenance. Additional study for the mechanisms of tolerance induction by IFN-gamma is needed.

Tango therapy for Parkinson's disease: Effects of rush elemental tango therapy.

Tango therapy is very effective by applying tango elements according to the clinical severity and status of a patient. Maximization of the clinical effects of tango therapy in patients with Parkinson's disease may be achieved by the proper prescription of tango elements according to the clinical status of a patient.