Borish, Larry C.
Professor, Medicine: Asthma, Allergy and Immunology
PO Box 801355
Innate immune mechanisms of rhinovirus (RV)-induced asthma exacerbations. Immune and cellular mechanisms of asthma. Immune mechanisms in chronic hyperplastic eosinophilic sinusitis (CHES).
(1) The current research being performed in my laboratory focuses on the innate immune mechanisms involved in the ability of rhinovirus (RV) to induce asthma exacerbations. These studies are based upon the observations that most asthma exacerbations in children and young adults result from RV infections; however, the etiology of these RV-induced exacerbations remain poorly understood. We hypothesize that the immune responses generated in the nose of asthmatics underlie subsequent systemic modulation of the immune system, and that in susceptible individuals (i.e., those with pre-existing asthma) this modified nasal milieu is responsible for the asthma exacerbation. Specifically, we proposed that this modification produces a distinct pattern of immune responsiveness to RV in the upper airway of asthmatics, which triggers the development of a Th2 cytokine signature state that drives the adverse outcome of RV infection in the lower airway of asthmatics. In addition, we proposed that the intensity of this Th2-inducing nasal airway milieu is further exaggerated in these allergic asthmatics, by a concomitant defect in the development and expression of effective anti-RV immune responses, leading to greater susceptibility to RV and more severe viral infections. To support this mechanism, we will confirm in these studies our prediction that similar reactions will occur in the nose and circulation of patients with just allergic rhinitis (AR), but that in the absence of asthma no lower airway manifestations develop. Ultimately determining the etiology of rhinovirus-induced asthma exacerbations will identify specific targets to prevent and treat these episodes.
(2) Immune and molecular mechanisms in aspirin-exacerbated respiratory disease (AERD):
We are investigating the role of cysteinyl leukotrienes and cytokines in the development of aspirin-exacerbated respiratory disease (AERD). We hypothesize that cysteinyl leukotrienes and other arachidonate metabolites promote eosinophil, fibroblast and fibrocyte proliferation, secretion of proinflammatory cytokines, and the aggressive remodeling characteristic of asthma, sinusitis and nasal polyposis. Concentrations of cysteinyl leukotrienes (CysLTs) and their receptors are significantly higher in tissue obtained from subjects with AERD as compared to aspirin tolerant asthma or the healthy airway. AERD is characterized by upregulation of CysLT synthesis pathways and CysLT receptors, including novel receptors that are targeted by CysLTE4, occurring concomitantly with downregulation of PgE2 synthesis (cox2 and mPGES1) and responsiveness (EP2) pathways. These aberrations are controlled by cytokines including IL-4 and IL-13 acting through the transcription factor pStat6 but AERD is also characterized by prominent expression of IFN-gamma. Therapeutic aspirin desensitization functions, at least in part, through blocking gene transcription mediated through diminished expression of pStat6 in the nucleus. Our current studies emphasize the role of CysLTs acting through this putative CysLTE4 receptor pathway, in particular on eosinophils, as well as aberrant signaling mechanisms involving PgE2. These studies involve transcriptome screening, proteomics, and genome-wide searches to identify unique molecular pathways responsible for the development of aspirin-exacerbated respiratory disease.