Intrinsic asthma: not so different from allergic asthma but driven by superantigens?

Abstract

The mechanisms of intrinsic or non-allergic asthma remain uncertain as allergens have no obvious role in driving the inflammatory process in the airways. However, IgE synthesis occurs in the airways, despite negative skin prick tests and serum-specific IgE. Furthermore, the inflammatory process in the airways is very similar between allergic and non-allergic asthma, with increased T-helper type 2 (Th2) cells, mast cell activation and infiltration of eosinophils. This pattern of inflammation is associated with a similar expression of inflammatory mediators, including Th2 cytokines and eosinophilotactic chemokines. There is increasing evidence that microbial superantigens, particularly Staphylococcal enterotoxins are important in amplifying inflammation in atopic dermatitis and chronic rhinosinusitis, in atopic and non-atopic patients. Superantigens may also be important in intrinsic asthma as airway epithelial cells may be colonized by Staphylococci and other superantigen-producing microbes. Superantigens produced locally in the airways may lead to class switching of local B cells, resulting in polyclonal IgE production in the airways and also specific IgE against the superantigen (which functions as a 'superallergen'). This leads to sensitization of mast cells, which can be activated by the usual asthma triggers, such as exercise. Superantigens also cause clonal expansion of T cells, resulting in increased Th2 cells and CD8(+) cells, while suppressing regulatory T cells. Superantigens may also reduce responsiveness to corticosteroids, resulting in more severe asthma. Finally, cytotoxic autoantibodies may also be implicated as IgG antibodies directed against epithelial proteins, such as cytokeratin-18, have been detected in intrinsic asthma, possibly as a result of epithelial damage and this may make epithelial cells more susceptible to microbial colonization. The therapeutic implications are that antibodies against local IgE and microbial superantigens or antibiotic therapy to eradicate the relevant superantigen-producing microorganisms may improve the efficacy of conventional therapy with corticosteroids.

Untangling asthma phenotypes and endotypes

“…Superantigens may contribute to its pathogenesis via class switching of local B cells, resulting in endobronchial polyclonal IgE production and also by generating specific IgE against superantigens that also cause clonal expansion of T cells, resulting in increased Th2 cells and CD8 + cells, while suppressing regulatory T cells. Superantigens could also reduce the responsiveness to corticosteroids, resulting in more severe asthma (31). Free light chains eliciting immediate hypersensitivity responses via mast cell degranulation have also been suggested as a pathogenic mechanism in intrinsic asthma (32).…”

Vacinação com BCG e redução do risco de asma

“…The authors conducted a 10-year retrospective cohort study in which they evaluated those individuals in terms of the incidence of asthma (according to the number of BCG vaccine doses received). No statistically significant differences were found between the groups of individuals who received one, two or three or more doses of the BCG vaccine with regard to the prevalence of asthma, which was 16.4% (216/1,317), 16 (12,13) The exposure of the immune system to infectious agents or microbial products, especially during childhood, seems to promote a balanced immune response, with modulation or regulation of the Th1 and Th2 systems. (19,20) However, the lack of exposure, in a less septic environment, would facilitate the incidence of allergic and autoimmune diseases in subgroups of predisposed individuals.…”

“…(12) In non-atopic asthma, the chronic inflammatory process is quite similar to that of atopic asthma; however, it is not possible to identify the production of specific IgE against a relevant aeroallergen. (13) It is unlikely that the risk factors and potential protective factors for these two different asthma phenotypes are the same. Other T lymphocyte subgroups have been characterized, including regulatory T cells and follicular T helper cells (Th17, Th22 and Th9 cells), revealing the complexity of this microsystem, which has been described as playing an important role in modulating the interrelation between the innate immune response and the acquired immune response and, consequently, in maintaining health by mounting an effective immune response without autoimmunity or hypersensitivity.…”

Airway exposure to staphylococcal enterotoxin A potentiates allergen-induced bone marrow eosinophilia and trafficking to peripheral blood and airways

“…Staphylococcal superantigens bind to major histocompatibility complex class-II molecules without prior antigen processing by antigen-presenting cells, promoting immunostimulation (11). Clinical studies show that Staphylococcus aureus and its enterotoxins have been associated with aggravation of allergic diseases (1,2,4,23,42), including dermatitis, chronic rhinosinusitis, and asthma (26,36,42). Airway exposure to staphylococcal enterotoxin types A (SEA) and B (SEB) aggravates the pulmonary allergic inflammation, increases sensitization to inhaled allergens, and decreases T cell sensibility to steroids (10,15).…”