RESUMEN
The links between chronic urticaria, IgE sensitization and allergy have been much discussed but little studied. We investigated IgE sensitization and allergy in 128 adult chronic urticaria patients during 2006-2008. During a one-day hospitalisation, the patients answered a standardized questionnaire and underwent blood serum analysis, physical tests and skin prick-tests. IgE sensitization to environmental allergens was defined by the positivity of at least one skin prick test and/or elevated levels of serum IgEâ≥â300 Kui/L. The chronic urticaria was considered allergic if: i) a high correlation between positive skin prick tests to a clinically relevant allergen and the case history was found; ii) complete remission of urticaria occurred within two months of allergen withdrawal. Of 105 patients with interpretable skin prick tests, 46.7% were IgE sensitized. Two patients had clinically relevant positive skin prick tests but their chronic urticaria had many other triggering factors and neither was in complete remission after withdrawal of these allergens. IgE sensitization is higher in chronic urticaria patients than in the global adult population, suggesting that it is one important etiopathogenic factor in chronic urticaria. However, it cannot be considered as the expression of an IgE-mediated allergy but as a chronic inflammatory disease, more frequent in IgE sensitized people and favoured by multiple factors, among which IgE-mediated allergy is exceptional.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Autoinmunidad , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Urticaria/inmunología , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Humanos , Hipersensibilidad/complicaciones , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Pruebas Cutáneas , Urticaria/etiología , Adulto JovenRESUMEN
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is an immune deficiency linked in many cases to heterozygous mutations causing truncations in the cytoplasmic tail of CXC chemokine receptor 4 (CXCR4). Leukocytes expressing truncated CXCR4 display enhanced responses to the receptor ligand CXCL12, including chemotaxis, which likely impair their trafficking and contribute to the immunohematologic clinical manifestations of the syndrome. CXCR4 desensitization and endocytosis are dependent on beta-arrestin (betaarr) recruitment to the cytoplasmic tail, so that the truncated CXCR4 are refractory to these processes and so have enhanced G protein-dependent signaling. Here, we show that the augmented responsiveness of WHIM leukocytes is also accounted for by enhanced betaarr2-dependent signaling downstream of the truncated CXCR4 receptor. Indeed, the WHIM-associated receptor CXCR4(1013) maintains association with betaarr2 and triggers augmented and prolonged betaarr2-dependent signaling, as revealed by ERK1/2 phosphorylation kinetics. Evidence is also provided that CXCR4(1013)-mediated chemotaxis critically requires betaarr2, and disrupting the SHSK motif in the third intracellular loop of CXCR4(1013) abrogates betaarr2-mediated signaling, but not coupling to G proteins, and normalizes chemotaxis. We also demonstrate that CXCR4(1013) spontaneously forms heterodimers with wild-type CXCR4. Accordingly, we propose a model where enhanced functional interactions between betaarr2 and receptor dimers account for the altered responsiveness of WHIM leukocytes to CXCL12.
Asunto(s)
Arrestinas/metabolismo , Quimiocina CXCL12/farmacología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/metabolismo , Receptores CXCR4/química , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Agammaglobulinemia/metabolismo , Secuencias de Aminoácidos , Línea Celular , Quimiotaxis de Leucocito , Dimerización , Humanos , Síndromes de Inmunodeficiencia/genética , Infecciones/genética , Infecciones/inmunología , Infecciones/metabolismo , Mutación , Neutropenia/genética , Neutropenia/inmunología , Neutropenia/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal , Verrugas/genética , Verrugas/inmunología , Verrugas/metabolismo , beta-ArrestinasRESUMEN
BACKGROUND: Iodinated and gadolinium-based contrast media (ICM; GBCM) induce immediate hypersensitivity (IH) reactions. Differentiating allergic from non-allergic IH is crucial; allergy contraindicates the culprit agent for life. We studied frequency of allergic IH among ICM or GBCM reactors. METHODS: Patients were recruited in 31 hospitals between 2005 and 2009. Clinical symptoms, plasma histamine and tryptase concentrations and skin tests were recorded. Allergic IH was diagnosed by intradermal tests (IDT) with the culprit CM diluted 1:10, "potentially allergic" IH by positive IDT with pure CM, and non-allergic IH by negative IDT. FINDINGS: Among 245 skin-tested patients (ICMâ¯=â¯209; GBCMâ¯=â¯36), allergic IH to ICM was identified in 41 (19.6%) and to GBCM in 10 (27.8%). Skin cross-reactivity was observed in 11 patients with ICM (26.8%) and 5 with GBCM (50%). Allergy frequency increased with clinical severity and histamine and tryptase concentrations (pâ¯<â¯0.0001). Cardiovascular signs were strongly associated with allergy. Non-allergic IH was observed in 152 patients (62%) (ICM:134; GBCM:18). Severity grade was lower (pâ¯<â¯0.0001) and reaction delay longer (11.6 vs 5.6â¯min; pâ¯<â¯0.001). Potentially allergic IH was diagnosed in 42 patients (17.1%) (ICM:34; GBCM:8). The delay, severity grade, and mediator release were intermediate between the two other groups. INTERPRETATION: Allergic IH accounted for < 10% of cutaneous reactions, and > 50% of life-threatening ones. GBCM and ICM triggered comparable IH reactions in frequency and severity. Cross-reactivity was frequent, especially for GBCM. We propose considering skin testing with pure contrast agent, as it is more sensitive than the usual 1:10 dilution criteria.