Assessment of efficacy of Anti-IgE (Omalizumab) therapy in patients with severe allergic asthma in a tertiary care hospital of Eastern India

Introduction: Immunoglobulin E dependent mechanisms play an important role in the development of airway inflammation in allergic asthma. Atopic patients with severe asthma frequently have poorly controlled disease. Many have poor asthma control despite intensive treatment. Severe allergic asthma patients frequently treated with oral corticosteroids and therefore may develop serious side-effects. Anti-IgE antibody had been used in severe persistent allergic asthma in Western countries. However, its long-term efficacy in patients in India has not been reported. Objective: To assess the efficacy of anti IgE therapy in patients with severe allergic asthma. Method: 30 (16 male and 14 female) patients, with mean age of 49 having severe persistent allergic asthma, with recurrent exacerbations and on oral/IV steroids, received Omalizumab 150mg/300mg/450 mg for 1 year. Total dose of oral Steroids, use of rescue medications, changes in lung function (FEV1) were recorded at the baseline, 16 weeks & at end of the treatment (52 weeks) and then analyzed. Results: Significant reduction observed in total oral steroid use at 16 week & at 52 weeks. -10.5mg (p<0.003) & 22.5mg respectively. Use of rescue medications decreased by -7.90 puffs(p- <0.001) at 16 weeks and by -13.67 puffs (13.67 (p -<0.001) at 52 weeks. Improvements in lung Function (FEV1) observed with a tune of 700 ml. from Baseline after 52 weeks therapy. Conclusion: Use of anti-IgE antibody for 1 year is well tolerated and led to an overall significant improvement in patients with severe persistent allergic asthma.

Screening of Shuanghuanglian Injection allergenic ingredients based on immune fingerprint / 中国中药杂志

In this paper,immune fingerprint was used to screen the allergenic components of Shuanghuanglian Injection(SHLI) by enzyme-linked immuno sorbent assay(ELISA) combined with HPLC/MS method. ELISA-embedded anti-IgE antibody could successfully adsorb allergens in SHLI and its plasma samples containing drugs through different routes of administration,suggesting that SHLI can induce type I hypersensitivity in rats. HPLC fingerprints and MS map of SHLI and drug-containing plasma samples from different routes of administration before and after anti-IgE antibody adsorption were established. According to the similarity evaluation of HPLC fingerprints and analysis results MS map,the sensitization of traditional Chinese medicine injections can be changed by different administration methods. There were 22 kinds of components that can be adsorbed by specific anti-Ig E antibodies in Shuanghuanglian Injection and its drug-containing plasma,most of them were acids and nitrogen compounds. Based on supramolecular theory,it was inferred that these compounds came from SHLI or body,and may form supramolecular hapten,which results in immunotoxicity and allergic reaction when being used as injection instead of oral liquid. Immune fingerprint is not only used to screen out single component allergen,but also more comprehensive,sensitive and easy to operate. It can provide reference for the future research methods of allergic reaction of traditional Chinese medicine injections.

Pruebas dermatológicas con autosuero en pacientes alérgicos y en pacientes autistas y sus madres / Autoserum skin tests in allergic patients, and in autistic patients and their mothers

Introducción: las alergias se encuentran con frecuencia en pacientes autistas y asimismo el autismo muestra una gran presencia entre los pacientes alérgicos. Objetivo: demostrar que las alergias y el autismo comparten algunos patrones inmunológicos similares. Métodos: la prueba dermatológica con autosuero se utilizó para demostrar la presencia de anti-IgE y/o de anticuerpos de receptores de Ig/E (FcεRIα). Resultados: la prueba ASST confirmó la frecuencia similar de positivos/positivos y de negativos/negativos en pacientes alérgicos y en pacientes autistas. Estas similitudes no existieron cuando se realizó la comparación con el grupo control. Se había hallado una correlación positiva con los resultados obtenidos en pacientes autistas y sus madres. Conclusiones: los pacientes autistas y los pacientes alérgicos comparten ciertas similitudes inmunológicas. Ambos se diferencian del grupo de controles sin estas condiciones. Resulta frecuente encontrar pacientes autistas con síntomas alérgicos y pacientes alérgicos con signos de autismo. Es motivo de análisis si los hallazgos inmunológicos representan un puente clínico entre ambos procesos. Asimismo se mostró una posible correlación genética entre los pacientes con autismo y sus madres(AU)

Introduction: allergies are frequently found among patients with autism and autism shows an increased frequency among the allergic patients. Objective: to demonstrate that allergies and autism share some similar immunological patterns. Methods: the autoserum skin test (ASST) was used to demonstrate the presence of anti-IgE and/or anti-IgE receptor antibodies (FcεRIα). Results: the ASST demonstrated similar frequency, positives/positives and negatives/negatives, considering allergic and autistic patients. These similarities didn't exist when comparing with the control group. A positive correlation had been found with the results of autistic patients and their mothers. Conclusions: autistic and allergic patients share some immunological similarities. Both differ from normal controls. It is not uncommon autistics with allergic symptoms and allergic patients with autism. If the immunological findings represent a clinical bridge between both processes, it is under discussion. Also it was demonstrated a possible genetic correlation between the patients with autism and their mothers(AU)

Blocking of Histamine Release and IgE Binding to FcepsilonRI on Human Basophils by Antibodies Produced in Camels

PURPOSE: The production of camel heavy-chain antihuman IgE (huIgE) that has the potential to block IgE-FcepsilonRI interaction and histamine release by basophils. METHODS: Camels were immunized with a synthetic loop peptide (SLP) designed in a multiple antigen peptide system (MAPS) forming SLP-MAPS immunogen. Camel polyclonal antibodies (PCAs) were produced, purified, characterized using Protein A & G, ELISA, and SDS-PAGE, and tested for their potency to block passive sensitization and histamine release of human basophils using flow cytometry (FCM) and ELISA, respectively. RESULTS: FCM data indicated that camel conventional (IgG1) and heavy chain antibodies (HCAbs; IgG2, and IgG3) had blocking activities of 43.9%, 72%, and 96.6%, respectively. Moreover, both IgG2 and IgG3 achieved remarkable inhibition rates of 93.98% and 97.05% in histamine release, respectively, whereas the IgG1inhibiting activity was 60.05%. CONCLUSIONS: Camel PCAs produced against SLP-MAPS were capable of blocking the IgE-receptor interaction and the release of histamine by basophils with superiority to HCAbs. These findings may pave the way toward the possible use of camel anti-huIgE HCAbs as blocking antibodies in the treatment of IgE-mediated allergy and asthma.

Clinical Characteristics of Angioedema With Eosinophilia

Angioedema with eosinophilia (AE) is a very rare allergy disease, case reports of which have been published sporadically since 1984. Here, we retrospectively analyzed the clinical features of 10 AE patients in Korea. Nine of the 10 subjects were young females, ranging from 23 to 38 years old. Twenty percent of the subjects had episodic-type AE with high serum IgM and eosinophil counts, while 80% were non-episodic type with normal serum IgM levels but high eosinophil counts. All patients had used systemic corticosteroids to control AE. One patient with refractory episodic-type AE was treated with anti-IgE antibody. This is the first study to evaluate the clinical characteristics of AE in a Korean population.

Clinical Characteristics of Angioedema With Eosinophilia

Angioedema with eosinophilia (AE) is a very rare allergy disease, case reports of which have been published sporadically since 1984. Here, we retrospectively analyzed the clinical features of 10 AE patients in Korea. Nine of the 10 subjects were young females, ranging from 23 to 38 years old. Twenty percent of the subjects had episodic-type AE with high serum IgM and eosinophil counts, while 80% were non-episodic type with normal serum IgM levels but high eosinophil counts. All patients had used systemic corticosteroids to control AE. One patient with refractory episodic-type AE was treated with anti-IgE antibody. This is the first study to evaluate the clinical characteristics of AE in a Korean population.

Eficácia da terapia Anti-IgE no controle da asma / Effectiveness of anti-IgE therapy for asthma control

Avaliar parâmetros de resposta à terapia anti-IgE com omalizumabe em pacientes com asma de difícil controle. Métodos: Foram avaliados 24 pacientes com asma de difícil controle, em uso de omalizumabe há pelo menos 32 semanas e considerados como respondedores à terapia. Avaliou-se a pontuação do teste de controle de asma (TCA), a presença de sintomas de asma, a frequência de uso de ß2-agonista de curta ação, as doses de corticoide inalatório e oral e o percentual previsto do volume expiratório forçado no 1° minuto (VEF1), antes e com 16 e 32 semanas de tratamento. Resultados: Na avaliação da pontuação do TCA foram obtidas as médias 12,4 para o momento inicial, 15,7 e 17,9 para a 16ª semana e 32ª semana respectivamente (p < 0,0001). A dose média de corticoide inalatório diminuiu ao longo das 32 semanas, de 1.416 mcg para 1.250 mcg na 32ª semana (p = 0,0797). O número de idas à emergência e de sintomas noturnos também diminuíram. Observou-se redução da dose de corticoide oral, sendo inicialmente a dose média de 17,4 mg e após 16 e 32 semanas 6,7 mg e 4,4 mg, respectivamente(p < 0,0001). Houve aumento na média do VEF1 (% do previsto), de 37,5% no início do tratamentopara 44,0% na 16ª semana (p = 0,007). Conclusões: O omalizumabe como terapia adjuvante no tratamento de pacientes com asma de difícil controle foi eficaz na melhora de parâmetros clínicose funcionais, contribuindo para o controle da asma e diminuição dos riscos futuros...

To assess parameters of response to anti-IgE therapy with omalizumab in patients with difficult-to-control asthma. Methods: Twenty four patients with difficult-to-control asthma using omalizumab for at least 32 weeks and considered as treatment responders were assessed. The Asthma Control Test (ACT) was used to assess the presence of asthma symptoms, frequency of use of short-acting beta2-agonists, inhaled and oral corticosteroid doses, and percentage of predicted forced expiratory volume in 1 second (FEV1) before treatment and after 16 and 32 weeks of treatment. Results: Mean ACT scores were 12.4 before treatment and 15.7 and 17.9 at 16 and 32 weeks post-treatment, respectively (p < 0.0001). Mean dose of inhaled corticosteroid decreased over the 32 weeks, from 1,416 mcg to 1,250 mcg (p = 0.0797). The number of visits to emergency services and nocturnal symptoms also decreased. There was a reduction in the mean dose of oral corticosteroids, from 17.4 mg at baseline to 6.7 mg and 4.4 mg after 16 and 32 weeks of treatment, respectively (p < 0.0001). Finally, an increase was found in the mean percentage values of predicted FEV1, from 37.5% at baseline to 44.0% at week 16 (p = 0.007). Conclusions: Omalizumab as adjunctive therapy in the treatment of patients with difficult-to-control asthma was effective in improving clinical and functional parameters, contributing to the control of asthma and to the reduction of future risks...

Oral Immunotherapy for Food Allergy: Towards a New Horizon

Food allergy has increased dramatically in prevalence over the past decade in westernized countries, and is now a major public health problem. Unfortunately for patients with food allergy, there is no effective therapy beyond food allergen avoidance, and rapid medical treatment for accidental exposures. Recently, oral immunotherapy (OIT) has been investigated as a treatment for this problem. In this review, we will discuss the progress in developing OIT for food allergy, including a novel approach utilizing Xolair (anti-IgE monoclonal antibody, omalizumab) in combination with OIT. This combination may enhance both the safety and efficacy of oral immunotherapy, and could lead to a widely available and safe therapy for food allergy.

What Taiwan contributes to the world of allergy and clinical immunology?

In commemorate the 9th Asia Pacific Congress of Allergy, Asthma, and Clinical Immunology (APCAACI) in Taipei, Taiwan in November this year, some of the seminar works and contributions by the researchers from Taiwan to the advance in the field of allergy and clinical immunology, such as DNA vaccine, traditional Chinese medicine, anti-IgE antibody, and personalized medicine for severe drug allergic reaction, are summarized in this special review.

Newer approaches in the treatment of asthma.

Asthma is a worldwide public health problem. The most effective anti-asthmatic drugs - inhaled β2-agonists and glucocorticoids controls asthma in about 90-95% of patients. However, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden. Therefore, reducing glucocorticoids - related adverse effects using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Although glucocorticoids effectively control the inflammatory process in asthma, they have little effect on the lower airway remodeling processes that appear to play a role in the pathophysiology of asthma. Several new drugs developed to target specific components of the inflammatory process in asthma [e.g. anti-IgE antibodies (omalizumab), cytokines and/or chemokines antagonists, immunomodulators, antagonists of adhesion molecules)], have not yet been proven to be particularly effective. Hence, considering the central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising future therapeutic strategies. Some of these new anti-asthmatic treatment approaches may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease. Hence, the development of novel drugs may allow resolution of these changes.

Successful Treatment of Chronic Eosinophilic Pneumonia with Anti-IgE Therapy

Anti-IgE therapy, using recombinant humanized anti-IgE antibodies, is clinically effective in patients with eosinophil-related disorders such as allergic asthma, allergic rhinitis, and chronic urticaria. Chronic eosinophilic pneumonia tends to respond promptly to systemic corticosteroid therapy, however; relapses are common following corticosteroid tapering. We treated two patients (17- and 19-yr-old males) of chronic eosinophilic pneumonia whose symptoms were cough and dyspnea on exertion. The symptoms were recurrent while tapering off corticosteroid. They were treated with anti-IgE antibody without recurrence for 2 yr and 15 months. Here, we first describe clinical experience of the 2 cases of chronic eosinophilic pneumonia.

Clinical Features of Allergic Bronchopulmonary Aspergillosis in Korea

Allergic bronchopulmonary aspergillosis (ABPA) is a complex disease, triggered by a hypersensitivity reaction to the allergen Aspergillus fumigatus. This disease occurs frequently in patients with cystic fibrosis and severe asthma in Western countries, with a prevalence of 2%-15%. However, there have been only a few case reports in Korea. We investigated the clinical and immunological features of patients with ABPA. Ten adult patients diagnosed with ABPA, according to Greenberger's criteria, were analyzed during the period January 2001 to December 2010 in a tertiary hospital. Skin-prick tests, pulmonary function tests, and high-resolution computed tomography (HRCT) were performed, and total serum IgE and A. fumigatus-specific IgE were measured. The patient cohort consisted of men who were middle-aged (median, 62.5; range, 19.0-79.0 years) at the diagnosis of ABPA with a long duration of asthma (median, 15.0; range, 1-48 years). Approximately 40% of the patients had a history of pulmonary tuberculosis more than 10 years prior to the study (median 23.5; range, 10.0-31.0 years) accompanied by severe obstructive lung function and radiological post-tuberculous destructive lung lesions. These patients also tended to have increased levels of immunologic parameters, such as total eosinophil count, total IgE, and A. fumigates-specific IgE, compared to those without tuberculosis sequels. Two patients with steroid-dependent asthma were treated with anti-IgE therapy and showed good responses. We report the clinical features of 10 ABPA patients, including 4 with histories of post-tuberculosis destructive lesions. Furthermore, anti-IgE antibody therapy may be an alternative strategy in cases of steroid-dependent ABPA.

Treatment of Chronic Spontaneous Urticaria

Chronic spontaneous urticaria is defined as persistent symptoms of urticaria for 6 weeks or more. It is associated with autoimmunity in approximately 45 percent of patients. Therapy is often difficult however the initial approach should employ high-dose non-sedating antihistamines; 4-6 tablets/day may be necessary. It has been shown that the response to 4 tablets/day exceeds 3, and exceeds 2, which exceeds 1. However the dose that corresponds to the maximal dose of first generation antihistamines (hydroxyzine, diphenhydramine) used previously, is 6/day. Yet over half the patients are refractory to antihistamines and other agents should be tried next. Whereas current guidelines (published) often add leukotriene antagonists and/or H2 receptor antogonists next, these are of little utility. Likewise drugs effective for urticarial vasculitis (colchicine, dapsone, sulfasalazine, hydroxychloroquine) are effective in a small percentage of patients and no study suggests that the response rate of any of them exceeds the 30% placebo responses seen in most double-blind, placebo controlled studies. The drugs that are effective for antihistamine-resistant chronic spontaneous urticaria are corticosteroids, cyclosporine, and Omalizumab. Use of steroids is limited by toxicity. If used at all, a dose of no more than 10 mg/day should be employed with a weekly reduction of 1 mg. The response rates to cyclosporine and Omalizumab are each close to 75%. Cyclosporine can be used effectively if care is taken to monitor blood pressure, urine protein, blood urea nitrogen, and creatinine, every 6 weeks. Omalizumab has the best profile in terms of efficacy/toxicity and, once approved by federal agencies for use in chronic spontaneous urticaria, a dramatic change in the treatment paradigm, whether associated with autoimmunity or not, is predicted. A phase 3 trial is currently in place. Refractoriness to both Omalizumab and cyclosporine is expected to be less than 5 percent of patients. Other agents, can then be tried.

Omalizumab in allergic diseases, a recent review.

Omalizumab is a biological engineered molecule, targeting the Cε3 domain of the IgE molecule. It binds with free IgE and prevents free IgE from attaching to high-affinity IgE receptor (FcεRI) on effector cells such as mast cells, basophils and also on dendritic cells. The result is a blocking of mediator release from these cells and the inhibition of antigen presentation by dendritic cells. In addition, omalizumab downregulates FcεRI expression on these effector cells. Omalizumab prevents early and late phase allergic reactions of skin and lungs. Omalizumab has been investigated extensively in moderate-to-severe asthma in adults and children. It effectively reduces rates of asthma exacerbation, emergency visits for asthma and hospital admissions among these patients. Currently, omalizumab is primarily indicated for patients, age 6 years and over, with moderate to severe asthma (GINA step 4). Omalizumab was investigated in patients with seasonal allergic rhinitis (to ragweed, birch and grass pollens) and has been found to improve rhinitis symptoms and to reduce medication use among these patients. Administered together with allergen immunotherapy, omalizumab reduced incidence of side effects and rates of anaphylaxis from allergen immunotherapy. Omalizumab has been investigated in the treatment of food allergy, atopic dermatitis and urticaria. Despite benefits observed from these initial trials, it further deserves investigations to clarify optimal conditions for use in these conditions. Side effects from omalizumab were few, however, it requires careful considerations in administration of this agent. An observational period (up to 2 hours after the first three doses) and the availability of auto-injectable epinephrine are recommended. Pharmacoeconomics of omalizumab is briefly reviewed. Omalizumab represents a major breakthrough of translational medicine in allergy.

Anticuerpo monoclonal anti-inmunoglobulina E en el tratamiento de la rinitis alérgica / Anti-immunoblobulin E monoclonal antibody in the treatment of allergic rhinitis

La rinitis alérgica (RA) es una enfermedad con alta incidencia a nivel mundial, sus síntomas están directamente relacionados con la exposición a un alérgeno ambiental que desencadena una cascada inflamatoria mediada por inmunoglobulina E. El tratamiento convencional actual de la RA consta del control ambiental, farmacoterapia e inmunoterapia; la reciente aparición de los anticuerpos monoclonales para el manejo de las enfermedades alérgicas parece ser prometedora. Estudios han demostrado que el Omalizumab, un anticuerpo monoclonal humanizado anti IgE, es capaz de modificar la respuesta inflamatoria dependiente de IgE, constituyéndose en una posible alternativa al manejo de la RA.

Allergic rhinitis (AR) is a disease with global high prevalence, its symptoms are directly related to environmental exposure to an allergen that triggers an inflammatory cascade mediated by Immunoglobulin E. The current standard treatment of AR consists of environmental control, pharmacotherapy and immunotherapy; the recent emergence of Monoclonal Antibodies for the management of allergic diseases appears promising. Studies have shown that Omalizumab, an anti-IgE humanized monoclonal antibody, is capable of modify the inflammatory IgE-dependent response, becoming a possible alternative to the management of AR.

Clinicoepidemiologic features of chronic urticaria in patients having positive versus negative autologous serum skin test: A study of 100 Indian patients.

Background: Chronic urticaria patients who demonstrate autoantibodies against the high-affinity receptor of IgE (FceRI) or IgE itself tend to have a high itch and wheal score, and systemic symptoms may have a significant bearing on their management in terms of super pharmacologic doses of antihistamines needed or use of immunomodulators. Most studies have used histamine release assays rather than autologous serum skin tests (ASSTs) for correlating urticaria severity and histamine releasing activity. Methods: An ASST was performed in 100 (M:F, 31:69) chronic urticaria patients aged between 14 and 63 (mean, 32.69 ± 13) years with an objective to study the clinicoepidemiologic features like age, sex, age of onset and duration, frequency and distribution of wheals, urticaria severity, angioedema and systemic manifestations in ASST-positive and ASST-negative patients. Results: ASST was positive in 46% of the patients and negative in 54% of the patients, respectively. Both groups showed no statistically significant difference for epidemiological details. However, the ASST-positive patients had a higher mean urticaria activity score, frequent involvement of more body sites, particularly palms and soles, presence of throat angioedema and general constitutional, respiratory or gastrointestinal symptoms in comparison with the ASST-negative patients. Conclusions: Apparently, ASST-positive patients have more severe clinical manifestations of chronic urticaria. The knowledge will be useful for the treating dermatologists and patients alike in view of its therapeutic implications.

New Therapeutic Modalities for Asthma: Biologicals from a Practical Point of View / 대한내과학회지

Asthma is a representative allergic disease of chronic airway inflammation. Dyspnea, wheezing, cough, and chest tightness are typical symptoms. Treatment consists of inhaled corticosteroid, beta2 agonist, leukotriene modifiers, and xanthines such as theophylline. Clinical practice guidelines for asthma have been developed since early 1990s. However, there are still many uncontrolled asthma patients with severe refractory symptoms, frequent exacerbations and even mortality. These patients cause high socioeconomic burden but the management of these patients are not well covered by clinical practice guidelines. High-dose steroid, methotrexate, cyclosporine, gold, IVIG, and macrolides have been suggested as therapeutic modalities for refractory asthma but with limited treatment effect and side effects. It is necessary to develop new therapeutic modalities for asthma. Biologicals, or biologics, are a variety of protein-based therapeutics, e.g. antibodies, soluble receptors, recombinant protein-based receptor antagonists and other related structures. New biologicals for the treatment of asthma are being developed. Here I will focus on three biologicals from a practical point of view: a humanized monoclonal anti-IgE antibody (omalizumab), anti-IL5, and TNF-alpha antagonist.

Perfil de ativação de basófilos e evidência de fatores liberadores de histamina na urticária crônica idiopática / Basophils activation profile and evidence of histamine release factor in chronic idiopathic urticaria

INTRODUÇÃO: A Urticária Crônica é caracterizada pelo aparecimento de pápulas eritematosas, pruriginosas recorrentes e transitórias que duram por mais de seis semanas. Na maioria dos pacientes a causa é indeterminada, definida como idiopática (UCI), entretanto, um sub-grupo apresentam autoanticorpos contra a cadeia alfa do receptor de alta afinidade para IgE (FceRI), que são expressos na superfície de mastócitos e basófilos, tornando-os células alvo nesta doença. OBJETIVOS: Avaliar em pacientes com UCI, submetidos ao teste intradérmico de soro autólogo (ASST), o perfil de ativação dos basófilos, pela intensidade de expressão de marcadores de ativação/desgranulação e pela capacidade dos basófilos em responder aos estímulo com a IL-3 e anticorpo anti-IgE. Além disto, a presença de fator liberador de histamina foi avaliado nos soros dos pacientes. METODOLOGIA: Pacientes com UCI (n= 37) foram selecionados no Ambulatório de Urticária do Departamento de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da USP e submetidos ao ASST. O grupo controle foi constituído por indivíduos saudáveis (n=38). A análise da expressão de FceRI, CD63, CD123 e CD203c em basófilos de sangue periférico foi realizada por citometria de fluxo. No ensaio in vitro de estimulação dos basófilos com anti-IgE, as células foram previamente incubadas com IL-3. O ensaio de liberação de histamina mediada por soros de pacientes com UCI foi realizado com três diferentes doadores de leucócitos e a histamina liberada dosada por ELISA de competição. RESULTADOS: Há um baixo número de basófilos no sangue periférico nos pacientes com UCI, coincidente com o baixo nível sérico de histamina. Os escassos basófilos no sangue periférico mostram elevada expressão de FceRI e uma regulação positiva da expressão de CD203c e CD63, independentemente do ASST. A análise funcional dos basófilos, mostra que somente a incubação com IL-3 recombinante já induz aumento significante da expressão de CD203c...

INTRODUCTION: Chronic Urticaria is characterized by recurrent, transitory, pruritic and erythematous wheals present for at least six weeks. In most patients the cause is unknown, defined as idiopathic (CIU), however, a sub-group has autoantibodies against the alfa chain of the high affinity IgE receptor (FceRIa) expressed on mast cells and basophils surface making it the target cells in this disease. OBJECTIVES: To evaluate in CIU patients, undergone autologous serum skin test (ASST), the activation profile of the basophils assessed by the expression of activation/degranulation markers and by the ability to release histamine in response to IL-3 priming and cross-linking with anti-IgE antibodies. Furthermore, the presence of histamine releasing factor in sera of patients was evaluated. METHODS: CIU patients (n = 37) were selected from the Dermatological Outpatient Clinic of the Hospital das Clínicas de São Paulo (HC-FMUSP) and submitted to the ASST. The control group consisted of healthy subjects (n=38). The analysis of the expression of FceRI, CD63, CD123 and CD203c on basophils from peripheral blood was assessed by flow cytometry. For the in vitro stimulation with anti-IgE antibodies, the cells were previously primed with human recombinant IL-3. The histamine release assay mediated by sera from patients with CIU was performed with three different donors of leukocytes and released histamine measured by competition ELISA. RESULTS: There is a low number of basophils in peripheral blood of patients with CIU, reflecting a low serum levels of histamine. The scarce basophils in peripheral blood show high expression of FceRI and an up-regulation of CD203c and CD63 marker expression, independently of the ASST. The functional analysis of basophils, revealed that recombinant IL-3 per se induces a significant increase in CD203c expression and the histamine release from basophils of patients with CIU, which are enhanced followed for 15 and 40 minutes...

Anti-IgE mAb Suppresses Systemic Anaphylaxis through the Inhibitory IgG Receptor FcgammaRIIb in Mice: Interaction between Anti-IgE and FcgammaRIIb

BACKGROUND: Anti-IgE mAb which binds circulating but not receptor-bound IgE has been shown to be effective in treatment for asthma and other allergic diseases. However, the mechanisms by which anti-IgE mAb influences the pathophysiological responses are remained to be illustrated. This study was undertaken to examine the therapeutic efficacy of non-anaphylactogenic anti-mouse IgE mAb using murine models of IgE-induced systemic fatal anaphylaxis. METHODS: Active systemic anaphylaxis was induced by either penicillin V (Pen V) or OVA and passive systemic anaphylaxis was induced by either anaphylactogenic anti-mouse IgE or a mixture of anti-chicken gamma globulin (CGG) IgG1 mAb and CGG. The binding of the Fc portion of anti-IgE to CHO-stable cell line expressing mouse FcgammaRIIb was examined using flow cytometry. Fc fragments of anti-IgE mAb were prepared using papain digestion. The expression of phosphatases in lungs were assessed by Western blotting and immunohistochemistry. RESULTS: Anti-IgE mAb prevented IgE- and IgG-induced active and passive systemic fatal reactions. In both types of anaphylaxis, anti-IgE mAb suppressed antigen-specific IgE responses, but not those of IgG. Anti-IgE mAb neither prevented anaphylaxis nor suppressed the IgE response in FcgammaRIIb-deficient mice. The Fc portion of anti-IgE mAb was bound to murine FcgammaRIIb gene-transfected CHO cells and inhibited systemic anaphylaxis. Anti-IgE mAb blocked the anaphylaxis-induced downregulation of FcgammaRIIb-associated phosphatases such as src homology 2 domain-containing inositol 5-phosphatase (SHIP) and phosphatase and tensin homologue deleted on chromosome ten (PTEN). CONCLUSION: Anti-IgE mAb prevented anaphylaxis by delivering nonspecific inhibitory signals through the inhibitory IgG receptor, FcgammaRIIb, rather than targeting IgE.

Papel de los anticuerpos en la urticaria autoinmune / Antibodies role in autoimmune urticaria

Autoimmune urticaria occurs in patients in whom there are functional autoantibodies directed against FcepsilonR1 and IgE. The antibodies concerned are of subtypes IgG1 and IgG3. It is generally more severe and treatment-resistant. The significance of diagnosing autoimmune urticaria is that patients can be offered an explanation for an otherwise unremitting and puzzling condition. It also opens up the prospect of effective treatment by immunomodulatory treatment in selected patients with autoimmune urticaria. The utologous serum skin test is used as a screening test for autoimmune urticaria. The sensitivity and specificity are about 80% respectively. The diagnosis can be confirmed by demonstrating release of histamine from target basophils or dermal mast cells. Treatment of autoimmune urticaria involves the use of low sedation H1 antihistamines in licensed dosages. Off-label dosages are used if the condition is still poorly controlled. Prednisolone can be used in acute and severe flare-ups. Immunomodulatory treatment with cyclosporin can be considered in recalcitrant cases.

La urticaria autoinmune aparece en pacientes que generan autoanticuerpos funcionales contra el FcepsilonR1 y la IgE. Los anticuerpos involucrados pertenecen al subtipo IgG1 e IgG3. Generalmente es una forma de urticaria más grave y resistente al tratamiento. La importancia de diagnosticar urticaria autoinmune radica en que al hacerlo los enfermos pueden recibir una explicación acerca de una enfermedad desconcertante y que habitualmente no remite. En casos seleccionados de urticaria autoinmune también se abre un espectro de tratamientos eficaces que incluyen terapias inmunomuduladoras. La prueba de suero autólogo se utiliza como estudio de rastreo para esta patología. La sensibilidad y especificidad son cercanas al 80%. El diagnóstico puede confirmarse mediante la demostración de liberación de histamina de basófilos o células cebadas de dermis. El tratamiento de la urticaria autoinmune consiste en la utilización de antihistamínicos H1 con escaso efecto sedante en las dosis recomendadas. Las dosis superiores a las habituales se utilizan en pacientes en quienes la enfermedad se controla escasamente. En casos agudos y durante las exacerbaciones puede administrarse prednisolona. El tratamiento inmunomodulador con ciclosporina puede considerarse en casos refractarios.