Małolepszy J

Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors

Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells (TH1 and TH2) at the site of inflammation. The diversity of TH1 and TH2 function is not predetermined but depends on signals that drive the cells towards either subset. Histamine, released from effector cells (mast cells and basophils) during inflammatory reactions can influence immune response. Here we report that histamine enhances TH1-type responses by triggering the histamine receptor type 1 (H1R), whereas both TH1- and TH2-type responses are negatively regulated by H2R through the activation of different biochemical intracellular signals. In mice, deletion of H1R results in suppression of interferon (IFN)-γ and dominant secretion of TH2 cytokines (interleukin (IL)-4 and IL-13). Mutant mice lacking H2R showed upregulation of both TH1 and TH2 cytokines. Relevant to T-cell cytokine profiles, mice lacking H1R displayed increased specific antibody response with increased immunoglobulin-ε (IgE) and IgG1, IgG2b and IgG3 compared with mice lacking H2R. These findings account for an important regulatory mechanism in the control of inflammatory functions through effector-cell-derived histamine.

Are Single Nucleotide Polymorphisms of the Immunoglobulin A Fc Receptor Gene Associated with Allergic Asthma

Background: Eosinophils are important components of allergic inflammation. The immunoglobulin A (IgA) Fc receptor (FcαRI), encoded by the FCAR gene, is a possible candidate for eosinophil activation at mucosal surfaces, where IgA is abundant. Both elevated cell surface expression of FcαRI and increased avidity for IgA were described on eosinophils from allergic subjects. The aim of our study was to examine the possible association of FCAR gene polymorphisms with allergic asthma. Methods: We screened three regions of the FCAR gene: (1) the promoter region, (2) exon 3, encoding the first extracellular domain (EC1), and (3) exon 5, coding for the transmembrane and cytoplasmic domain, for new and published polymorphisms using a sensitive temperature gradient gel electrophoresis technique and compared their frequencies in 112 patients diagnosed with allergic asthma and 100 healthy controls. Results: Six polymorphisms, including two novel ones, were detected. No differences between patients and controls were found in the distribution of any of these polymorphisms. Conclusion: FcαRI polymorphism does not seem to be a risk factor in allergic asthma. Nevertheless, this is the first report on the distribution of 6 single nucleotide polymorphisms of the FCAR gene in a human population and the first study on FCAR polymorphism in allergic asthma.

Treatment with Ebastine Changes Expression of Histamine H1 and H2 Receptor mRNA on Peripheral Blood Mononuclear Cells

AbstractBackground: Histamine H1 and H2 receptors both belong to a family of G protein-coupled receptors that often show opposite actions on cell activity. Ebastine, a piperidine derivative, and its active metabolite, carebastine, are very potent second-generation histamine H1 receptor antagonists. Objective: To investigate the influence of treatment with ebastine on the expression of histamine H1 receptor and H2 receptor mRNA on peripheral blood mononuclear cells (PBMC). Patients: The study was performed in five grass pollen-allergic individuals with seasonal allergic rhinitis. All subjects showed positive skin-prick tests with mixed grass pollen. The study was performed out of the grass pollen season. Methods: Blood samples were obtained before and after treatment with ebastine (Kestine®, Rhône-Poulenc-Rorer, France) 10 mg/day for 7 days. PBMC were isolated using density-gradient centrifugation. Histamine H1 and H2 receptor mRNA expression were determined using semiquantitative reverse transcription polymerase chain reaction. Results: Prior to ebastine treatment, mRNA expression measured by the peak area for histamine H1 and H2 receptors was 33, 323 (± 33, 269) relative fluorescence units (RFU)and 59, 511 (± 31, 621) RFU, respectively. After treatment, histamine H1 and H2 receptor mRNA expression increased to 42, 061 (± 28, 263 ) and 89, 913 (+ 13, 053) RFU, respectively, and this difference was statistically significant (p < 0.01) in contrast to the difference prior to the treatment. Ebastine-induced histamine H1 and H2 receptor upregulation, however, moved the balance towards histamine H2 receptor dominance. Conclusions: In conclusion, ebastine induced H1 and H2 receptor upregulation, but moved the balance towards H2 receptor dominance. This potent H1 receptor antagonist, in addition to reducing allergic symptoms, is able to influence inflammatory responses. Since H2 receptor stimulation shows suppressive effects on cell activation, this can contribute to long-term anti-inflammatory actions of anti-histamines.