Is asthma really due to a polarized T cell response toward a helper T cell type 2 phenotype?

Abstract

Our understanding of pathogenesis has changed dramatically with time. Records, which date back to 1500 BC, indicate that was considered to be a disease caused by spirits. This viewpoint remained until 1678, when Thomas Willis described to be due to of bronchi by thick humors, swelling of their walls and obstruction from without. That was due to spasm of bronchial smooth muscles was first suggested by Sir John Floyer in 1698. With the advent of fiberoptic bronchoscopy in the 1970s and the use of modern molecular biology tools, it became clear that was a chronic inflammatory disorder of the airways mediated by a multitude of cell types and inflammatory mediators. Mast cells and eosinophils were initially believed to play a central role in driving the airway inflammation associated with asthma; however, the emphasis has now shifted to T lymphocytes. In particular, helper T type 2 (Th2) cells (a subset of T cells) are believed to play a central role in initiating and orchestrating the asthmatic airway inflammatory response (1). The hypothesis for asthma was first suggested by Mosmann in 1989 (2), who had earlier discovered the presence of two distinct subtypes of helper T cells in mice, namely, Th1 and Th2 (3). These two subclasses of helper T cells differ in their production of cytokines and are reciprocally inhibitory. The Th2 lymphocytes produce interleukin 4 (IL-4), IL-5, IL-9, and IL-13, which activate mechanisms important in defense against parasites and in allergic inflammation. Such mechanisms include IgE production, mast cell differentiation, and eosinophil growth, migration, and activation. Th1 lymphocytes produce interferon gamma (IFN-gamma ) and IL-2, which activate mechanisms important in defense against viruses and bacteria (2). A mechanism accounting for the predominance of Th2 cells in asthmatic airway was suggested by the discovery that the context in which antigen-presenting cells process and present allergens critically influences the pattern of helper T cell differentiation. The Th2 hypothesis for describes that is caused by a relative increase in Th2 cellular response in combination with a decrease in Th1 (helper T type 1) response. The consequent alteration in cytokine milieu (most likely in the lung), with excess Th2 products (e.g., IL-4, IL-5, and IL-13) in concert with decreased Th1 products (e.g., IFN-gamma and IL-12), is predicted to drive the phenotype (4). Evidence of such a shift in the Th1/Th2 balance derives from studies of in cellular and murine models, where Th cell polarization and allergen dependence of Th2 responses are most easily defined and from human studies that profile cytokine production. Although this viewpoint has remained popular over the last decade, more recent studies suggest that the Th2 hypothesis for is too simplistic (5). We now provide evidence to argue against the Th2 hypothesis for asthma.