The increase in airway smooth muscle (ASM) mass is a major structural change in asthma. This increase has been attributed to ASM cell (ASMC) hyperplasia and hypertrophy. The distance between ASMC and the epithelium is reduced, suggesting migration of smooth muscle cells toward the epithelium. Recent studies have suggested a role of chemokines in ASMC migration toward the epithelium; however, chemokines have other biological effects. The objective of the current study is to test the hypothesis that chemokines (eotaxin, RANTES, IL-8, and MIP-1α) can directly influence ASMC mass by increasing the rate of proliferation or enhancing the survival of these cells. Human ASMCs were exposed to different concentrations of eotaxin, RANTES, IL-8, or MIP-1α. To test for proliferation, matched control and stimulated ASMC were pulsed with [3H]thymidine, or ASMCs were stained with BrdU and then analyzed with flow cytometry. Apoptosis was measured using Annexin V staining and flow cytometry. Expression of phosphorylated p42/p44 and MAPKs was assessed by Western blot. In a concentration-dependent manner, chemokines including eotaxin, RANTES, IL-8, and MIP-1α increased ASMC’s [3H]thymidine incorporation and DNA synthesis. IL-8, eotaxin, and MIP-1α decreased the rate of apoptosis of ASMCs compared with the matched controls. A significant increase in phosphorylated p42/p44 MAPKs was seen after treating ASMCs with RANTES and eotaxin. Moreover, inhibition of p42/p44 MAPK phosphorylation reduced the level of chemokine-induced ASM proliferation. We conclude that chemokines might contribute to airway remodeling seen in asthma by enhancing the number and survival of ASMCs.

IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3 regulatory T cells (Treg). Using mice carrying a transgene under the control of the promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags.

The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19CD138 cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c CD19CD138 cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19CD138IL-10 cells dramatically decreased allergic airway inflammation in wild-type and Sema4c mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138 B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138 B cells.

The IL-4 and IL-21 in vitro assays distinguish two groups of CVID subjects and can be used with baseline B cell subpopulation phenotyping to better identify patients experiencing more vs. fewer clinical non-infectious complications and potentially to modulate therapy.

BackgroundSemaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development.MethodsHuman tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C−/− mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation were analyzed by confocal microscopy.ResultsGene array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24 h, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C−/− mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ human B-cells. Within 72 h of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F-actin, B-cell receptor, and Plexin-B2. Cell polarization was impaired in Sema4C−/− mice.ConclusionWe have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles.

ABSTRACT. Hematologic data gathered over a period of 4.8 years from 196 owl monkeys, Aotus trivirgatus, were analyzed to find if karyotypic differences existed. It was found that none of 30 animals of karyotypes K-I and K-VI developed hemolytic anemia, whereas 46 of 99 animals of K-II, K-III and K-IV did (p<0.005). Analysis of hemograms of normal owl monkeys showed that mean percent eosinophils varied markedly, K-I monkeys having lowest counts, 3.2 ~, and K-VI animals having the highest, 33 ~. These results establish that idiopathic eosinophilia and hemolytic anemia in this species are probably unrelated but susceptibility to both has a strong genetic component.

Background: Multiple animal antigens, spores and pollens were collected and identified from the Kuwaiti atmosphere. The role for these antigens in mediating allergic rhinitis for Kuwaiti residents needs to be evaluated. Objective: To investigate the causes (both indoors and outdoors) of allergic rhinitis for Kuwaiti residents. Method: This is a retrospective study of all positive skin tests that we obtained in our Allergy clinic in Mubarak Alkabeer Hospital in Kuwait, during the period between May 2013 and December 2015, from patients who presented with allergic rhinitis symptoms and/or signs. They underwent skin prick tests to a battery of common allergens (german cockroach, cat dander, dog dander, house dustmites mix, cladosporium, aspergillus mix, penicillium mix, alternaria, grass pollens mix, Russian thistle pollens, mugwort pollens, rough pigweed pollens, sorrel pollens, compositae pollens, olive pollens, and date palm pollens). A wheal of ≥3 mm was considered a positive skin test. Results: A total of 177 patients with rhinitis (90 females and 87 males) had positive test results to at least one allergen and were considered allergic. 77.9% of the patients had positive results to Russian thistle pollens, 39.9% to cat dander, 29.9% to grass pollens mix, 22.6% to compositae pollens, 22.6% to mugwort pollens, 22% to house dust mites mix, 21.4% to olive pollens, 20.9% to German cockroach, 20.3% to dog dander, 18.1% to rough pigweed pollens, 15.8% to date palm pollens, and 12.4% to sorrel pollens, 14.7% to penicillium, 10.7% to cladosporium, 10.7% to aspergillus mix, and 4% to alternaria. Conclusion: Russian Thistle pollen is the commonest sensitization for Kuwaiti residents with allergic rhinitis. Background: Environmental allergies affect many individuals of all ages. There are several aeroallergens that can trigger allergic reactions, namely allergic rhinitis and allergic asthma. In this study, we aimed to determine the prevalence of various environmental allergies in the Kingston, Ontario region. Methods: A chart review of skin prick test (SPT) results was completed on all patients in the practice of an academic Allergist affiliated with Queen's University. Patients who demonstrated positive SPT (defined as ≥3 mm than the negative control) to one or more allergens were included, and their age, gender and specific positive tests were recorded. Allergens evaluated included dust mites (D. pteronyssinus and D. farinae), dog dander, cat epithelium, tree mixes, birch pollen, other trees, grass mixes, ragweed mixes, short ragweed, other weeds, cockroach and numerous moulds. Of all patients reviewed, 1161 had positive SPT results to one or more allergens. Data analysis was completed with SPSS. Results: Dust mite was the most prevalent allergen (62.6%). The second and third most common were ragweed (52.6%) and cats (51.6%), respectively. The prevalence of other allergens, in order of decreasing frequency, were grass (49.7%), trees (43.1%), birch (34.8%), short ragweed (30.8%), molds (29.7%), other trees (25.6%), dog (...

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