ReviewA closer look at chemokines and their role in asthmatic responses
Section snippets
Asthma
The word “asthma”, which literally means panting, was already employed by Greek physicians of antiquity such as Hippocrates. Aretaeus of Cappadocia in the second century AD gave the first accurate clinical description of asthma: “the symptoms of its approach are heaviness of the chest; sluggishness to one's accustomed work, and to every other exertion; difficulty of breathing in running on a steep road”, and acknowledged that the disease was potentially fatal. It was not before 1910 that
Chemokines and their receptors
Chemokines represent a large family of proteins secreted by many immune and non-immune cells with an essential role in inflammatory and immune reactions. Chemokines have been divided in four main groups based on their molecular structure and the position of two cysteine residues: CC and CXC (alpha), and the less described C and CX3C families. So far, 28 CC (CCL), 16 CXC (CXCL), 2C (CL) and 1 CX3C (CX3CL) chemokine ligands have been identified (Table 1). All groups of chemokines bind to their
Animal models for allergic asthma
Experimental support for the role of several immunological mechanisms in allergic diseases is largely derived from animal models for asthma. Although rat and guinea pig models are relevant, the mouse model is most used, due to the superior availability of immunological tools, such as congenic, transgenic and knock out mouse strains, antibodies and recombinant protein mediators. Although the mouse model does not replicate human disease perfectly, much of what is known about the immunobiology of
Chemokine targets in asthma
Although the chemokine system initially seemed an excellent target for treatment of diverse inflammatory diseases, recently it is realized that targeting chemokines is not as straight forward. The main problems with targeting the chemokine system for treatment have been the large number of different chemokines (about 50) that are upregulated during inflammation, the overlap in chemokine function and the pleiotrophy of chemokine–receptor interaction. In addition, treatment of asthma by targeting
Conclusions
Without a doubt, chemokines play an important role in the establishment and persistence of allergic asthma. In this multifactorial disease, chemokines and their receptors are involved at multiple levels in different stages of disease (Fig. 2). Classically, chemokines were thought to be involved in the recruitment of leukocytes. Recently however, research suggests that chemokines can also influence the immune response by activation and differentiating different cell populations involved in
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2019, ImmunobiologyCitation Excerpt :Uptake of allergen is enhanced by IgE bound to high-affinity receptors on dendritic cells that facilitate allergen internalization (Kitamura et al., 2007; Holgate, 2014). Once the dendritic cell has engaged allergen, it receives signals to migrate to local lymphoid collections where antigen presentation of a selected antigen peptide to the T-cell receptor (TCR) initiates sensitization and the subsequent immune response to the specific allergen (Smit and Lukacs, 2006). Allergy immunotherapy changes the response to allergen exposure by inducing immunological tolerance (Larché et al., 2006).
Identification of pyrazolopyrimidine arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists
2017, Bioorganic and Medicinal ChemistryAberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice
2015, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Similarly, high ORMDL3 expression in lung mucoepidermoid carcinoma NCI-H292 cells that increases ceramide levels (data not shown) significantly enhanced expression of cytokines and chemokines (see Fig E2 in this article's Online Repository at www.jacionline.org) in response to HDM, a ubiquitous indoor allergen contaminated with LPS from colonizing bacteria and one of the most clinically relevant human aeroallergens contributing to allergic asthma worldwide.33,34 Collectively, these data suggest that when highly overexpressed, ORMDL3 does not decrease ceramide levels but rather increases them, and the excess ceramide enhances production of the same cytokines and chemokines that are increased in human asthmatic patients35,36 and mouse models of asthma.34 Because ORMDL3 has been linked to asthma susceptibility,1-8 we next sought to examine its expression in lungs of mice challenged intranasally with HDM in a mouse model of human allergic asthma that recapitulates the cardinal clinical features of human asthma, including airway hyperreactivity, cellular infiltration into the lung, inflammation, production of HDM-specific IgE, and mucus hypersecretion.33,34
Applications of chemokines as adjuvants for vaccine immunotherapy
2018, ImmunobiologyCitation Excerpt :Chemokines modulate lymphocyte development, priming and effector functions, and play a vital role in immune surveillance. Many chemokines have been shown to be effective immunological adjuvants in a variety of model systems, enhancing protection induced by viral, bacterial, and parasitic vaccines (Smit and Lukacs, 2006). These chemokines have also increased various immunological parameters in tumor immunization models and clinical trials (Esche et al., 2005).