Basophil Fc epsilon RI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria

Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States
Journal of Allergy and Clinical Immunology (Impact Factor: 11.25). 03/2007; 119(2):441-8. DOI: 10.1016/j.jaci.2006.09.035
Source: PubMed

ABSTRACT Basophils are implicated in the pathogenesis of chronic idiopathic urticaria (CIU). Autoantibodies to the IgE receptor (FcepsilonRI) and serum histamine releasing activity have been detected in some subjects with CIU, although their role in vivo is unclear. Basophils of patients with CIU have altered FcepsilonRI-mediated histamine release (HR); however, the mechanism is unknown. In the basophil FcepsilonRI signaling pathway, protein levels of Src-homology 2-containing-5'-inositol phosphatase (SHIP)-1 are inversely correlated with the release of mediators or releasability. A related phosphatase, SHIP-2, is a negative regulator of monocyte IgG receptor (FcgammaR) signaling . We hypothesized that SHIP levels are altered in CIU basophils.
Blood basophils were isolated from cold urticaria, CIU, or normal donors, and FcepsilonRI-dependent and independent HR were quantified. Protein levels of SHIP-1, SHIP-2, spleen tyrosine kinase, and phosphorylated Akt were determined by Western blotting. Subjects' serum was tested for serum histamine releasing activity and anti-FcepsilonRIalpha antibodies.
CIU basophils displayed a bimodal response to anti-IgE activation. One half of CIU subjects' basophils had reductions in anti-IgE-induced HR and were designated nonresponders (CIU NR). CIU NR basophil HR remained diminished at 10-fold to 30-fold higher doses of anti-IgE. CIU anti-IgE responder basophils had HR similar to normal subjects. SHIP-1 and SHIP-2 proteins were increased in CIU NR basophils and were linked to reduced phosphoAkt after anti-IgE stimulation. CIU basophil anti-IgE response was not related to the presence of serologic factors.
In CIU basophils, the observed changes in FcepsilonRI signaling pathway molecule expression may underlie changes in releasability.
Patients with CIU can be segregated on the basis of basophil functional phenotype.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Potentially pathogenic IgG autoantibodies to IgE or its receptor, Fc epsilonRIalpha, have been detected in approximately 40% of chronic idiopathic urticaria (CIU) patients. CIU patients' basophils display distinct altered Fc epsilonRIalpha-mediated degranulation. CIU patients with basophil histamine release in response to polyclonal goat anti-human IgE > or = 10% are classified as CIU responders (CIU-R) and < 10% are CIU non-responders (CIU-NR). We compared the presence of autoantibodies to basophil degranulation phenotypes and to disease status (active or inactive). Sera were collected from non-CIU subjects and CIU subjects who participated in a longitudinal study of disease severity and had defined basophil degranulation phenotypes. Immunoenzymetric assays (IEMA) quantified IgG anti-Fc epsilonRIalpha and anti-IgE. IgG anti-Fc epsilonRIalpha antibody was detected in 57% of CIU-R (n=35), 55% of CIU-NR (n=29), and 57% of non-CIU subjects (n=23), whereas IgG anti-IgE was present in 43% of CIU-R, 45% of CIU-NR, and 30% of non-CIU subjects. Both the autoantibody levels and the functional basophil phenotype remained stable in subjects with active disease (n=16), whereas there was an enhancement in basophil function as subjects evolved into a state of remission (n=6), which appears independent of the presence of autoantibody. IEMAs detected a similar frequency of autoantibodies in CIU-R, CIU-NR, and non-CIU subjects. Basophil function may be independent of IEMA-detected autoantibodies.
    Journal of Investigative Dermatology 08/2008; 128(8):1956-63. DOI:10.1038/jid.2008.55 · 6.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although commonly encountered in clinical practice, chronic urticaria (CU) remains difficult to treat. In contrast to acute urticaria, neither exogenous triggers nor specific immunoglobulin E are identified in most chronic cases. A body of evidence suggests that CU is represented within the spectrum of immune-mediated inflammatory diseases (IMID). Our understanding of the CU disease pathogenesis now recognizes a role for T cells, B cells, and autoantibodies, and intrinsic abnormalities of histamine-releasing effector cells, thus providing new targets of intervention beyond the current mainstay of often inadequate symptomatic treatment directed against histamine receptors and steroids, with their attendant morbidities. Agents previously used to treat other autoimmune and inflammatory diseases have demonstrated efficacy in CU. Newer biologic and nonbiologic immunomodulatory agents approved for other indications and in clinical development provide potential options for this often severe disease.
    Current Allergy and Asthma Reports 07/2008; 8(4):277-287. DOI:10.1007/s11882-008-0046-2 · 2.45 Impact Factor