Aikaterini Detoraki

Angiogenesis and lymphangiogenesis in bronchial asthma

To cite this article: Detoraki A, Granata F, Staibano S, Rossi FW, Marone G, Genovese A. Angiogenesis and lymphangiogenesis in bronchial asthma. Allergy 2010; 65: 946–958.

The human heart as a shock organ in anaphylaxis.

SummaryAnaphylaxis is a potentially fatal, immediate hypersensitivity reaction. Mast cells and basophils, by elaborating vasoactive mediators and cytokines, are the main primary effector cells of anaphylaxis. Mast cells have been identified in human heart between myocardial fibers, perivascularly, in the adventitia, and in the arterial intima. Mast cells isolated from human heart tissue (HHMC) of patients undergoing cardiac transplantation express high affinity immunglobulin E (IgE) receptors (FcεRI), C3a, C5a, and kit receptors (KIT). Anti-IgE, anti-FcεRI, and immunoglobulin superallergens induce in vitro secretion of preformed mediators (histamine, tryptase, chymase, and renin) and the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HHMC. Complement is activated and anaphylatoxin forms during anaphylaxis. C5a and C3a cause the in vitro release of histamine and tryptase from HHMC. Therapeutic (general anesthetics, protamine, etc.) and diagnostic agents (radio contrast media, etc.), which can cause anaphylactoid reactions, activate HHMC in vitro. Low concentrations of histamine and cysteinyl leukotrienes given to subjects undergoing diagnostic catheterisation caused significant systemic and coronary hemodynamic effects. These data indicate that human heart mast cells and their mediators play a role in severe anaphylactic reactions.

Role of Superallergens in Allergic Disorders

A significant percentage of allergic diseases (e.g. certain cases of intrinsic asthma, chronic idiopathic urticaria, and atopic dermatitis) cannot be explained by the classical mechanisms of IgE/allergen-mediated activation of basophils and mast cells. We found that protein Fv, an endogenous protein synthesized in the human liver and increased during viral hepatitis, act as a superallergen by binding to IgE of the VH3 family and activating human basophils and mast cells. Similarly, envelope gp120 of HIV-1 and protein A of Staphylococcus aureus are viral and bacterial superallergens, respectively, because they interact with IgE VH3+. Protein L binds to the V domain of he kappa light chains of IgE. Our results demonstrate that endogenous, viral and bacterial products activate primary effector cells of allergic disorders to release proinflammatory mediators and cytokines thereby acting as immunoglobulin superantigens (superallergens).

Protein Fv Produced during Viral Hepatitis Is an Endogenous Immunoglobulin Superantigen Activating Human Heart Mast Cells

Protein Fv, an endogenous protein produced in the liver, is released in biological fluids during viral hepatitis. Acute and chronic viral hepatitis can be associated with cardiovascular derangements. Protein Fv induced the release of histamine, tryptase and the de novo synthesis of prostaglandin D2 and cysteinyl leukotriene C4 from mast cells isolated from human heart tissue (HHMC). Protein Fv absorbed with protein A-Sepharose coated with polyclonal IgG did not induce histamine secretion. The maximal percent histamine secretion induced by protein Fv correlated (rs = 0.60; p < 0.05) with that induced by anti-IgE, whereas there was no correlation between the release caused by proteins Fv and C5a. Preincubation of HHMC with protein Fv or anti-IgE caused complete cross-desensitization to subsequent challenge with heterologous stimulus. HHMC from which IgE had been dissociated no longer released histamine in response to anti-IgE and protein Fv. A human monoclonal IgE blocked both anti-IgE- and protein Fv-induced release. Three human monoclonal IgM VH3+ inhibited protein-Fv-induced secretion of histamine from HHMC, whereas monoclonal IgM VH6+ did not inhibit the release induced by protein Fv. Protein Fv acts as an endogenous immunoglobulin superantigen by interacting with the VH3 domain of IgE to induce the release of mediators from HHMC.

Omalizumab in patients with eosinophilic granulomatosis with polyangiitis: a 36-month follow-up study

Abstract Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis characterized by asthma and blood eosinophilia, with the lung being the organ most frequently affected. Oral glucocorticoids and/or immunosuppressive drugs are the mainstay therapy of EGPA. Occasional reports suggest that EGPA patients can be treated with omalizumab in addition to conventional therapy to achieve asthma control. To investigate the long-term effects of omalizumab in patients with EGPA and asthma (2 females, 3 males, age 41–64 years), we carried out a 36-month follow-up observational study. At the time of enrollment, the patients were on maintenance therapy and had moderate to severe allergic asthma, eosinophilia and rhinosinusitis. Mononeuropathy/polyneuropathy and/or histological evidence of tissue eosinophilic infiltration were also present. Methods: Patients were treated with omalizumab (300–600 mg s.c. every 2–4 weeks) as add-on therapy to prednisone, inhaled steroids and bronchodilators. During omalizumab treatment, spirometry, the asthma control test (ACT) score and eosinophilia were evaluated, and prednisone dosage was recorded. Results: During the 36 months of omalizumab treatment asthma progressively improved as indicated by spirometry and the ACT score. Eosinophilia progressively decreased. The oral prednisone dose was reduced or withdrawn during treatment. No adverse events were recorded. Conclusions: In patients with EGPA and moderate to severe allergic asthma, omalizumab can be beneficial and safe. It enables corticosteroid tapering while decreasing eosinophilia and improving asthma symptoms over 36 months.

Angiogenesis, Lymphangiogenesis and Atopic Dermatitis

Angiogenesis and morphological and functional alterations of microvessels are hallmark features of chronic inflammatory disorders, including certain skin diseases. Vascular endothelial growth factors (VEGFs) are key regulators of blood vessel growth. The VEGF family includes VEGF-A, -B, -C, -D and placental growth factor. VEGF-A and -B are the most important proangiogenic factors, while VEGF-C and -D primarily regulate lymphangiogenesis. Angiopoietins are promoters of neovascularization by interacting with Tie-1 and Tie-2 receptors present on endothelial cells. High levels of VEGF-A have been detected in skin tissue of atopic dermatitis (AD) patients and correlate with disease activity. The vascular changes in the skin of AD patients appear to be linked to the inflammatory process. Effector cells of skin inflammation (human mast cells, basophils, eosinophils, macrophages, lymphocytes, etc.) are major sources of a vast array of angiogenic and lymphangiogenic factors. The role of lymphangiogenesis in AD is largely unknown.

Superallergens: a new mechanism of immunologic activation of human basophils and mast cells.

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Assessing allergenicity of different tomato ecotypes by using pooled sera of allergic subjects: identification of the main allergens

An evaluation of the potential allergenicity of different tomato ecotypes is reported. Twelve tomato ecotypes were assessed through a proteomic approach, using pools of sera of allergic patients from two different regions (Emilia Romagna in Northern Italy and Campania in Southern Italy), in order to identify the major allergens and evaluate differences in IgE binding properties of the tomato cultivars. Pooled sera of allergic people from Emilia Romagna showed as the main allergen a suberization-associated anionic peroxidase, whereas pooled sera of allergic patients from Campania were mostly reactive to profilin. The two proteins were identified through a proteomic approach based on the use of high-resolution mass spectrometric techniques. Quite interestingly, in some cases, several ecotypes showed a less reactivity toward patients’ sera than other, potentially indicating the possibility to identify ipoallergenic varieties. Anyway, the allergenic pattern response to tomatoes was serum-specific, indicating that the allergenic properties of different tomato ecotypes are defined by the specific proteins to which the patient is sensitized, a strong indication that ipoallergenicity of the different ecotypes is possible, but mostly related to the individual susceptibility.

Omalizumab in elderly patients with chronic spontaneous urticaria: An Italian real-life experience

BACKGROUND Omalizumab therapy is effective and safe in patients with chronic spontaneous urticaria (CSU) resistant to nonsedating histamine1 (H1) antihistamines (nsAHs). OBJECTIVE To evaluate the efficacy and safety of omalizumab in elderly (aged ≥65 years) patients with nonsedating H1-antihistamine-refractory CSU in a real-life setting. METHODS Patients with nonsedating H1-antihistamine-refractory CSU (n = 322) treated with omalizumab administered every 4 weeks in doses of 300 mg for 24 weeks were divided into 2 groups according to age at omalizumab treatment onset: 15 to 64 years and 65 years or older. Treatment response was assessed using a 7-day urticaria activity score (UAS7). Adverse effects of omalizumab therapy were recorded. RESULTS Among patients, 32 (9.9%) were 65 years or older. At baseline, CSU characteristics were generally similar among the groups, although the presence of angioedema was statistically significantly lower in patients younger than 65 years. Any differences in weekly itch severity score, hive score, and UAS7 between the 2 age groups were not significant at weeks 4, 12, and 24, with the exception of the hive score at 24 weeks and the UAS7 at week 24. No significant between-group differences were seen in the proportion of patients with a UAS7 of 6 or lower and with a UAS7 score of 0 at weeks 4, 12, 24, and 40. The proportion of patients with at least one adverse event reported as suspected to be caused by study drug was 10% in the younger group vs 6.3% in the older group (P = .53). CONCLUSION Our study found that omalizumab is a well-tolerated and effective therapy for elderly patients with nonsedating H1-antihistamine-refractory CSU.

The Role of Omalizumab in Patients With Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss): Comment on the Article by Jachiet et al

only patients with radiographic progression at year 1, most were found to have MBDA scores in the high disease activity (HDA) range (abatacept 78.9% [15 of 19]; adalimumab 57.1% [12 of 21]). Importantly, and especially since RA is a chronic disease, at year 2, the correlation between radiographic progression and an HDA MBDA score was much less striking (abatacept versus adalimumab 50% [12 of 24] versus 44.4% [8 of 18]). Of major importance, however, is that the year 1 findings evaluating progressors do not nullify our observation that for nonprogressors, the MBDA test results at years 1 and 2 did not correctly identify most patients’ radiographic status. Most patients with an HDA score were nonprogressors at both year 1 and year 2 (abatacept versus adalimumab 81.7% versus 76% year 1 and 75.5% versus 82.2% year 2), meaning an HDA score in this study did not reliably distinguish between radiographic progressors and nonprogressors for patients with RA treated over 2 years with either abatacept or adalimumab on background methotrexate. We also found that a low disease activity (LDA) score did not correlate well with nonprogression as asserted by Curtis et al (Table 1 herein). Thus, in clinical practice, based on the results of our analysis, the utility of the MBDA score with respect to determining the likelihood of radiographic progression is much less than satisfactory, as there are many patients with an HDA score who do not progress radiographically and many with an LDA score who do progress. We fully agree with Pincus and colleagues and their assessment of the importance of clinical disease activity measures in RA that can be relied upon when making treatment decisions. It is still important to evaluate the whole patient with a careful history and physical examination, as well as assessment of laboratory and imagining parameters. Composite clinical measures remain the gold standard for therapeutic decisions in RA. A patient-reported clinical measure, such as the RAPID3, could be considered when deciding to initiate, change, or discontinue therapy. In addition to the primary objectives of assessing the relative safety and efficacy of the use of abatacept or adalimumab on background methotrexate, the AMPLE trial was designed to serve as a platform to explore biomarker-related analyses that could help further our understanding of the therapeutic interventions and clinical responses seen in a prospective head-to-head trial. In the absence of a clear understanding of which are the most relevant biomarkers to consider, we have looked at multiple types of biomarker analyses that could be useful in this endeavor; this included the MBDA test. We concur with the accompanying editorial published in the same issue of Arthritis & Rheumatology that encourages further efforts in this area (7), as there is a need to develop clinically relevant tools both for patients with RA and for clinicians. We look forward to the results of these efforts. Supported by Bristol-Myers Squibb. Dr. Fleischmann has received consulting fees from AbbVie, Akros, Amgen, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Sanofi-Aventis, and UCB (less than