Abstract
Characteristic of allergic asthma, CD4+Th2 lymphocytes secrete Th2 cytokines, interleukin (IL)-4, IL-13, and IL-5 that mediate the inflammatory immune response. Surface expression of CD2 and its ligand, CD58, is increased on the monocytes and eosinophils of asthma patients, which correlate with elevated serum IgE levels, suggesting that CD2 may contribute to allergic airway inflammation. Using a murine model of asthma, we observed that house dust mice extract (HDME)-exposed Balb/c mice have increased airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia, and elevated levels of Th2 cytokines in the lungs, as well as increased serum IgE levels as compared to the control mice. In contrast, with the exception of serum IgE levels, all the other parameters were significantly reduced in HDME-treated Cd2−/− mice. Interestingly, Il13 but not Il4 or Il5 gene expression in the lungs was dramatically decreased in HDME-exposed Cd2−/− mice. Of note, the gene expression of IL-13 downstream targets (Muc5b and Muc5ac) and high affinity IL-13Rα2 were upregulated in the lungs of HDME-exposed Balb/c mice but were significantly reduced in HDME-exposed Cd2−/− mice. Consistently, gene expression of microRNAs regulating mucin production, inflammation, airway smooth muscle cell proliferation and IL-13 transcripts were increased in the lungs of HDME-exposed Cd2−/− mice. Given the established role of IL-13 in promoting goblet cell hyperplasia, lung inflammation and AHR in allergic asthma, our studies reveal a unique role for CD2 in the regulation of Th2-associated allergic asthma.
Highlights
Asthma, a chronic inflammatory disorder, can manifest with high serum IgE levels, airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia and airway remodeling [1, 2]
CD58 is highly expressed on the eosinophils of asthmatic patients [8] and increased expression of FcεRI on CD2high monocytes from asthma patients correlates with higher serum IgE levels [9]
Lung samples from control subjects who died from other causes and individuals who died from complications of asthma were obtained from either the International Institute for the Advancement of Medicine (IIAM) or National Disease Resource Interchange (NDRI) and their use was approved by Institutional Review Board at Rutgers University
Summary
A chronic inflammatory disorder, can manifest with high serum IgE levels, AHR, lung inflammation, goblet cell hyperplasia and airway remodeling [1, 2]. CD58 is highly expressed on the eosinophils of asthmatic patients [8] and increased expression of FcεRI on CD2high monocytes from asthma patients correlates with higher serum IgE levels [9]. While these studies provide a causal link between CD2 and asthma, the specific role of CD2 in allergic asthma remains to be defined. Exposure of WT Balb/c mice to an airborne allergen such as HDME induced a quintessential allergen-induced AHR, inflammation and goblet cell hyperplasia in association with high levels of serum IgE, Th2 cytokines and mucus production. We demonstrate that CD2 critically modulates gene expression of alarmins such as IL-25, IL-13 receptors (IL-13Rα1 and IL13Rα2) and several microRNAs that have known roles in the pathogenesis of allergic asthma
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