Patricia M. Sterba

Cultured peripheral blood mast cells from chronic idiopathic urticaria patients spontaneously degranulate upon IgE sensitization: Relationship to expression of Syk and SHIP-2.

Recently, signaling changes in the FcvarepsilonRI pathway involving inositol lipid phosphatases have been identified in the basophils of chronic idiopathic urticaria (CIU) subjects. Based on the profile of basophil FcvarepsilonRI-mediated histamine degranulation, we have segregated CIU subjects into two groups, CIU Responder (CIU R) or CIU Nonresponder (CIU NR). In the present study, we compared expression of SHIP-1, SHIP-2, and Syk protein to histamine release (HR) from mast cells (MC) cultured from the peripheral blood of CIU R, CIU NR, and normal subjects. The MC of CIU R donors contained significantly increased Syk and decreased SHIP-2 as compared to CIU NR (Syk: p=0.038, SHIP-2: p=0.038) and normals (Syk: p=0.042, SHIP-2: p=0.027). Spontaneous HR from CIU donors was increased two-fold compared to normals (p=0.04). In summary, our results suggest a possible predilection for urticarial MC to spontaneously degranulate upon IgE sensitization contributing to the increased pruritus associated with CIU.

Basophil histamine release activity and disease severity in chronic idiopathic urticaria.

BACKGROUND Altered basophil degranulation phenotypes are found in patients with chronic idiopathic urticaria (CIU). OBJECTIVE To evaluate CIU disease severity in relation to basophil histamine release (HR) characteristics. METHODS Patients with CIU were recruited from allergy and dermatology clinics. Patients with recent use of systemic corticosteroids or immunosuppressants were excluded. Patients completed disease severity surveys and had blood basophils isolated and stimulated for HR using polyclonal goat anti-human IgE and N-formyl-met-leu-phe. The HR was measured using automated fluorometry. Multivariate linear regression analyses were used to investigate relationships between HR data and CIU disease measures. RESULTS Fifty patients completed surveys, of which 34 were further categorized into 2 subgroups based on basophil HR response to anti-IgE stimulation: responders (> or = 10% HR) and nonresponders (< 10% HR). Responders and nonresponders reported similar use of oral corticosteroids, work absences, and quality-of-life impairment but differed in their patterns of medications used for CIU. Basophil responders had a trend of higher use of the emergency department for CIU management. Multivariate regression revealed that patients with the basophil responder phenotype experienced significantly higher current itch scores (P = .02) compared with nonresponders. CONCLUSIONS Quality-of-life impairment is similar in CIU basophil subsets. Patients with CIU with a basophil responder phenotype report longer disease duration, a higher frequency of emergency department use, and significantly higher itch severity.

Interval shifts in basophil measures correlate with disease activity in chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) significantly impacts the quality of life of those affected through symptoms of pruritus and recurrent skin lesions. In active CSU disease, reduced IgE‐mediated basophil histamine release (HR) and basopenia are observed. We sought to examine the relationship between interval changes in basophil measures and shifts in patient‐reported disease impairment. Simultaneous symptom and basophil evaluations were completed at two sequential study visits, and interval changes in measures were compared between visits for each subject (n = 38). These measures included Skindex‐29, current itch and hives scores, total leukocyte histamine content (an indirect measure of blood basophil presence), and basophil HR in response to anti‐IgE and formyl‐methionine‐leucine‐phenylalanine. Overall, interval improvements in disease measures in CSU subjects were associated with increased basophil numbers (total leukocyte histamine content) and IgE‐mediated HR. This suggests these measures are potential biomarkers for CSU disease improvement and further implicates a role for basophils in CSU.

Suppression of Basophil FcεRI Activation by Serum from Active Chronic Idiopathic/Spontaneous Urticaria (CIU/CSU) Subjects

Abbreviations: CIU/CSU, chronic idiopathic/spontaneous urticaria; BHR, basophil histamine release; fMLP-N, formylmethionine-leucyl-phenylalanine

Relationship of IgE to basophil phenotypes in peanut-sensitized adults.

reduced percentage of IFN-g positive cells (see Fig E2, A, in this article’s Online Repository at www.jacionline.org). However, IL17 and IFN-g CD4 lymphocytes did not increase in H2Rdeficient animals, suggesting that CD4 cells are not the cellular source for elevated cytokine secretion. No changes in IL-17 or IFN-g lymphocytes was observed in mesenteric lymph node cells (see Fig E2, B). The percentage of Foxp3 cells within PPs was similar in wild-type and H2R-deficient animals and levels remained unaltered after L saerimneri 30a gavage (results not shown). The biological consequences of biogenic amine secretion in vivo by the resident microbiota are largely unknown. Histamine can have both proinflammatory and anti-inflammatory effects on immunoregulatory processes, depending on which histamine receptor is activated. With the exception of scombroid poisoning, it is currently unknownwhether histamine secretion by the microbiota is altered during, or contributes to, mucosal inflammatory disorders. Interestingly, L saerimneri 30a secretes approximately 100-fold higher levels of histamine, compared with the levels previously described for L rhamnosus. This suggests that the amount of histamine secreted by a microbe may be critical in determining its pathological versus protective effects. Maintenance of mucosal homeostasis is heavily dependent on appropriate sampling and processing of microbial ligands by the innate immune system, in particular dendritic cells. In vitro studies have demonstrated that TLR responses to microbial ligands are significantly influenced by histamine signaling through H2R. In this report, we demonstrate that the H2R is required for IL-6 and IL-17 mucosal responses, suggesting that H2R is a critical immunoregulatory receptor that significantly influences the in vivo immune response to histamine-secreting microbes within the intestine. These observations suggest that histamine from the enteric microbes might exert immunoregulatory effects in vivo; however, it remains to be determined, on a case-by-case basis, whether these effects are protective or pathological. This report also highlights the need to carefully select and screen putative probiotic bacterial strains before human consumption. It is unknown whether the pathological effects seen in mice after the administration of L saerimneri 30a are solely due to histamine secretion because this bacterium also secretes cadaverine, which was previously demonstrated to be toxic in rodents. Regardless of the mechanism, this is a cautionary note, which clearly stresses that not all Lactobacilli strains can be considered safe. Ruth Ferstl, PhD Remo Frei, PhD Elisa Schiavi, PhD Patrycja Konieczna, PhD Weronika Barcik, MSc Mario Ziegler, Dipl-Ing Roger P. Lauener, MD Christophe Chassard, PhD Christophe Lacroix, PhD Cezmi A. Akdis, MD Liam O’Mahony, PhD