Rethinking the central role of mast cells in virally-mediated asthma exacerbations

A generation ago allergic diseases were viewed as “Type I” hypersensitivity disorders characterized by allergic/IgE sensitization with allergen binding to IgE-coated mast cells (and basophils) producing an immediate and late phase response. Indeed, eosinophils were envisioned as having little more of a role than to “clean up” after the mast cell by enzymatically degrading histamine and cysteinyl leukotrienes. Subsequent investigations appropriately established an essential role for the eosinophil in producing many of the inflammatory and physiological features of asthma. This eosinophil-centric model led to a shift in guidelines-based therapies with a dominant role for corticosteroids (CCS) and, more recently, the emergence of interleukin (IL)-5- and IL-5 receptor-targeting biologics. This current paradigm has reached the point where mast cells often earn, at best, passing reference in our thinking regarding asthma pathogenesis. It should be noted, however, that that while not blocking mast cell degranulation, CCS do mitigate the surge in airway mast cells that occurs with allergy seasons and that a role for the expression of IL-5 receptors on mast cells as a plausible mechanism for efficacy of IL-5-targeting biologics has not been adequately explored.

Recent studies, however, argue for mast cells having a more central role in asthma. This includes observations that although eosinophil-targeting therapies can be quite effective, a remarkable number of patients fail to respond to these approaches. A full discussion of the basis for these failures is beyond the scope of this treatise but this failure does include the need for reconsideration of the role of the “lowly” mast cell. One of the first studies to reengage our thinking about mast cells was a randomized trial of imatinib – an inhibitor of the mast cell-associated tyrosine kinase ckit – in severe asthma. This agent produced clinically significant improvements that were associated with reduced numbers of mast cells and reduced serum tryptase concentrations.¹

An even more obvious basis for reconsidering a role for mast cells in asthma arises from considering the cellular mechanisms producing the therapeutic efficacy derived from the targeting of IgE with omalizumab. This biologic was FDA approved almost entirely based on its ability to prevent asthma exacerbations. What is fascinating about that clinical outcome is that – especially in children and adolescents – virtually all (>80%) asthma exacerbations are triggered by respiratory viruses, and these were almost exclusively caused by rhinovirus (RV) infections.^2,3 The basis by which anti-IgE could prevent an RV-mediated asthma exacerbation is not inherently obvious, after all, these are not “allergic” reactions to the virus. One hint to the mechanism came from early studies – including those from our research group⁴ – demonstrating that RV-induced exacerbations were most likely to occur in a highly atopic patient and that while RV infections occur year-round, RV-induced exacerbations only occurred with the concomitant exposure to allergens to which the patient was sensitive. Thus, in North America seasonal surges in asthma hospitalization occur in May in those allergic to grass and in autumn in those allergic to dust mites, alternaria, and weeds.⁴ This concept was further supported by the ability of omalizumab to prevent these seasonal surges⁵ and, even more impressively, our studies confirming the ability of pre-treatment with this biologic to prevent a decline in lung function from developing after an experimental RV inoculation.⁶

The interpretation of these results has been that RV is acting to potentiate an ongoing IgE-mediated allergic reaction to these bystander allergens (figure 1A). This could argue that omalizumab is acting to “strip” the IgE off mast cells (and basophils) and it thereby prevents an enhanced allergic reaction from producing the exacerbation. An alternative proposed explanation is that the RV is somehow augmenting the capacity of IgE to facilitate allergen uptake by IgE receptor-expressing antigen-presenting cells (such as dendritic cells) and thereby causes a “surge” in Th2-mediated inflammation (figure 1B). However, this alternative explanation must be discarded because of the rapidity of the development of the RV-induced exacerbation. In patients presenting for urgent care secondary to asthma exacerbations it was impossible to know exactly how long they had been infected. But in experimental inoculations, it is now established that these exacerbations start to develop within a day and peak at 3–4 days, well before even the most accelerated adaptive immune response could develop.

Figure 1:

Models of RV induced asthma exacerbations and their attenuation by IgE-targeting therapies. 1A. RV-induced exacerbations reflect potentiation of an ongoing mast cell-mediated allergic reaction to bystander allergens with attenuation mediated by “stripping” the IgE off the mast cell. 1B. RV potentiates IgE-facilitated antigen uptake by dendritic cells with expansion of allergen-specific Th2 lymphocytes. 1C. RV-induces release of the alarmins IL-25/IL-33/TSLP from airway epithelium with induction of eosinophilic inflammation and the asthma exacerbation. 1D. An established IgE/mast cell-mediated allergic reaction induces expression of a transformed airway programmed to produce IL-25/IL-33/TSLP when infected with RV. Attenuation of the mast cell reaction to bystander allergens promotes expression of an airway that no longer produces eosinophilic inflammation when infected. Abbreviations: DC – dendritic cell; IL – interleukin; ILC – innate lymphoid cell; RV – rhinovirus; Th2 – T helper type 2; TSLP – thymic stromal lymphopoietin.

However, another observation from RV challenge studies forces consideration of an even more important role of the mast cell in asthma. Besides attenuating the decline in lung function, our studies demonstrated that omalizumab prevented the surge in eosinophilia from developing after RV inoculation.⁶ This eosinophilic surge develops rapidly and parallels the decline in lung function. That an eosinophil-mediated inflammatory response could underlie the RV-induced asthma exacerbation is compellingly supported by the ability of eosinophil-targeting biologics (anti-IL-5 and anti-IL-5 receptor antibodies) to prevent these exacerbations. This assignment of a central role of eosinophil-mediated inflammation in driving the virally-mediated exacerbation, makes it necessary to reconsider the mechanism by which omalizumab prevents exacerbations. It is plausible that it is mast cell-derived IL-5 that is solely or at least largely responsible for producing the eosinophilic inflammatory response to RV infection and that this is blocked in the presence of omalizumab (as depicted in figure 1A). Such a mechanism would support this treatise regarding a heightened role for mast cells in asthma. However, this seems unlikely and other mechanisms (and sources of IL-5) have to be considered.

As noted, this surge in eosinophils cannot be ascribed to activation of adaptive T lymphocytes – either IL-5-producing T cells targeting RV cells or those targeting the bystander allergen – as, although we have recently shown, these cells do expand after an RV infection,⁷ this expansion does not occur until ~5–7 days post infection. However, as an alternative mechanism, recent studies have pointed to the capacity of the innate immune system to rapidly engage an eosinophilic response to “danger” signals, including those produced by RV infection (figure 1C). This early eosinophilia is an epithelial cell-driven reaction with the rapid production of 3 cytokines – IL-25, IL-33, and TSLP – generating a type 2/eosinophilic inflammatory state.⁸ These cytokines are envisioned as acting on innate lymphoid 2 cells (ILC2s) to drive their release of IL-5 and the subsequent eosinophilia.⁹ But if this were the mechanism of the eosinophilia and the associated decline in lung function, how is this being prevented with anti-IgE? This requires adding another layer to the pathway displayed in figure 1C. It then becomes important to appreciate that RV is acting on an epigenetically-modified airway, that is, an airway programmed to produce IL-25/IL-33/TSLP in response to RV. Clearly this T2/eosinophilic state does not develop when non-asthmatics have an RV infection. In the omalizumab studies, to prevent the asthma exacerbation, this agent was delivered for several weeks. It is then reasonable to speculate that perhaps this pretreatment provided sufficient time to attenuate the T2-promoting nature of the epithelium. The primary agent driving this T2-promoting epithelium is thought to be IL-13, a finding that potentially explains the efficacy of IL-4 receptor-targeting therapies in also preventing exacerbations. Currently, ILC2 and perhaps Th2 cells are viewed as the primary source of the IL-13 producing the asthma-promoting transformed airway.¹⁰ But, again, there is no role for IgE in driving ILC2 activation and anti-IgE therapeutics will not reduce the production of IL-13 by these cells (figure 1C). This raises consideration that perhaps ILC2s are not the primary source of the IL-13 or of other mediators responsible for generating the asthma-promoting airway. There is, however, another obvious source for IL-13 and that is the “lowly” mast cell. It is then reasonable to propose that by blocking ongoing allergen-IgE-mast cell activation with the associated release of mast cell-derived IL-13, omalizumab restores a healthier epithelium, one that can no longer secrete the trifecta of T2-promoting cytokines when infected with RV. This model (figure 1D) reverses the concept that RV produces an exacerbation by enhancing an ongoing allergic reaction and argues instead that it is actually the previously engaged allergic reaction that produces a state in which RV-infected epithelium can drive the exacerbation. This is certainly a concept that warrants further investigation, including, most importantly, reimagining the role of mast cell-targeting therapies in asthma.

Abbreviations:

CCS

corticosteroids

DC

dendritic cell

IL

interleukin

ILC

innate lymphoid cell

R

receptor

RV

rhinovirus

Th2

T helper type 2

TSLP

thymic stromal lymphopoietin