Table 3.

A hierarchy of mast cell and/or mast cell-derived protease role(s) and some examples of concordant and discordant findings

Rolea,b	Definition	Examples
Unique or nonredundant	Only MCs can perform that function	Findings in multiple model systems (including kit mutant MC-deficient mice and MC knockin mice, and in the more recent MC-deficient mice with normal Kit) support the conclusion that MCs have important or even in some cases nonredundant/unique roles in many acute, IgE-dependent responses (Heger, Seidler, et al., 2014; Lilla et al., 2011; Miyajima et al., 1997; Sawaguchi et al., 2012; Takeishi et al., 1991; Wershil et al., 1987; Zhou et al., 2007) Studies in both various MC-deficient mice and in MC-associated protease-deficient mice are consistent in supporting an important role for MCs (Akahoshi et al., 2011; Marichal et al., 2013; Metz et al., 2006) and their proteases [namely, CPA3 (Schneider et al., 2007) and mMCP-4 (Akahoshi et al., 2011)] in reducing the pathology and mortality induced by the venoms (Akahoshi et al., 2011; Marichal et al., 2013; Metz et al., 2006) or toxic components of venoms (Metz et al., 2006; Schneider et al., 2007) of certain reptiles (Akahoshi et al., 2011; Metz et al., 2006; Schneider et al., 2007) or arthropods (Akahoshi et al., 2011; Marichal et al., 2013; Metz et al., 2006)
Important	That aspect of the response would be substantially different (e.g., by 50% or more) in the absence of MCs
Redundant or overlapping	MCs can contribute to the assessed feature of the response along with other effector or regulatory elements, but their potential contribution may only be revealed if one or more of the other partially redundant or overlapping elements is impaired	Different models of MC deficiency have yielded different results when the possible contributions of MCs have been examined in certain complex biological responses. In each of those responses, it is likely that multiples types of immune cells may have redundant or overlapping roles. Such responses include antibody-dependent arthritis (Elliott et al., 2011; Lee et al., 2002; Mancardi et al., 2011; Nigrovic & Lee, 2007; Zhou et al., 2007), EAE (Bennett et al., 2009; Brown & Hatfield, 2012; Feyerabend et al., 2011; Li et al., 2011; Piconese et al., 2011; Secor et al., 2000), and cutaneous contact hypersensitivity (Askenase et al., 1983; Biedermann et al., 2000; Bryce et al., 2004; Dudeck et al., 2011; Galli & Hammel, 1984; Grimbaldeston et al., 2007; Mekori, Chang, Wershil, & Galli, 1987; Mekori & Galli, 1985; Norman et al., 2008; Otsuka et al., 2011). In models of airway inflammation and airway hypersensitivity, it has been reported that both the details of the model system (Kobayashi et al., 2000; Kung et al., 1995; Nakae et al., 2007; Sawaguchi et al., 2012; Takeda et al., 1997; Williams & Galli, 2000; Yu et al., 2006, 2011), and mouse strain background (Becker et al., 2011), can influence the extent to which MCs are important for the development of various features of the responses; this is also likely to be true regarding the ability to discern the importance of the MC’s contribution to many other biological responses
Non-contributory	MCs play no role in that feature of the response	As an example, MCs are not required (or are “non-contributory”) for development of a chronic IgE-dependent cutaneous response that is dependent on basophils (Lilla et al., 2011; Mukai et al., 2005)

^aIn particular biological responses, such as models of host defense or disease, MCs may influence some features of the response more importantly than others. Indeed, in some biological responses, MCs might have any combination of the four roles listed, depending on which features of the response one measures. The number of biological responses in which essentially all features of the response are fully and uniquely dependent on MCs may be small.

^bIn certain biological responses, the roles of individual MC-associated proteases may be to limit some of the “global” effects of MCs in that setting. For example, evidence from studies in MC knockin mice and other models indicates that MCs can contribute to airway allergic inflammation, airway hyper-reactivity, and tissue remodeling in certain models of allergic inflammation of the airways (Kobayashi et al., 2000; Kung et al., 1995; Nakae et al., 2007; Reuter et al., 2008; Taube et al., 2004; Williams & Galli, 2000; Yu et al., 2006, 2011). However, in a model of ovalbumin-induced allergic airway inflammation (Waern et al., 2009) similar to one that was shown to be enhanced by MCs (Williams & Galli, 2000), and in another model of allergic airway inflammation elicited by HDM (Waern et al., 2013), MC-associated mMCP-4 was reported to have effects that limit airway inflammation (Waern et al., 2009, 2013), airway hyper-reactivity to methacholine (Waern et al., 2009, 2013), and airway smooth muscle thickening (Waern et al., 2009, 2013).

This is a modified and updated version of the information in Boxes 2 and 4 from Reber et al. (2012).