Genetic Variation Determines Mast Cell Functions in Experimental Asthma

Abstract

Mast cell-deficient mice are a key for investigating the function of mast cells in health and disease. Allergic airway disease induced as a Th2-type immune response in mice is employed as a model to unravel the mechanisms underlying inception and progression of human allergic asthma. Previous work done in mast cell-deficient mouse strains that otherwise typically mount Th1-dominated immune responses revealed contradictory results as to whether mast cells contribute to the development of airway hyperresponsiveness and airway inflammation. However, a major contribution of mast cells was shown using adjuvant-free protocols to achieve sensitization. The identification of a traceable genetic polymorphism closely linked to the KitW-sh allele allowed us to generate congenic mast cell-deficient mice on a Th2-prone BALB/c background, termed C.B6-KitW-sh. In accordance with the expectations, C.B6-KitW-sh mice do not develop IgE- and mast cell-dependent passive cutaneous anaphylaxis. Yet, unexpectedly, C.B6-KitW-sh mice develop full-blown airway inflammation, airway hyperresponsiveness, and mucus production despite the absence of mast cells. Thus, our findings demonstrate a major influence of genetic background on the contribution of mast cells in an important disease model and introduce a novel strain of mast cell-deficient mice.

Mast Cell–deficient KitW-sh “Sash” Mutant Mice Display Aberrant Myelopoiesis Leading to the Accumulation of Splenocytes That Act as Myeloid-Derived Suppressor Cells

“…Our comparative analyses of C57BL/6-Kit W-sh and C.B6-Kit W-sh confirmed the increase of CD11b/Gr-1 double-positive cells in the spleen of both strains, which was even more pronounced in C.B6-Kit W-sh mice. However, on either genetic background, the numbers of these bona fide neutrophils in bone marrow and blood were unaffected by the Kit W-sh mutation (26). This prompted us to investigate the impact of the Kit W-sh allele on peripheral myelopoiesis in detail.…”

“…Following the identification of a traceable polymorphism linked to the Kit W-sh allele, we generated congenic mast cell-deficient mice on a BALB/c background, referred to as C.B6-Kit W-sh (26). Our comparative analyses of C57BL/6-Kit W-sh and C.B6-Kit W-sh confirmed the increase of CD11b/Gr-1 double-positive cells in the spleen of both strains, which was even more pronounced in C.B6-Kit W-sh mice.…”

“…Mice C.B6-Kit W-sh mice (H-2 d ) were generated as previously described and backcrossed at least 12 generations (26). BALB/c wild-type littermates were obtained from crosses between heterozygous C.B6-Kit W-sh/+ mice.…”

Mast Cell-Deficient KitW-sh Mice Develop House Dust Mite-Induced Lung Inflammation despite Impaired Eosinophil Recruitment

“…A potential ‘Th2 bias' may occur when using BALB/c mice and/or OVA which may result in underestimation of the effect of Th1-dependent inflammatory reactions. The mouse strain used has been shown to be of importance for asthma models in a series of experiments [29], but only in an OVA Th2-dependent model. Importantly, the effects of HDM are not exclusively Th2 dependent: effects of HDM extract includes activating toll-like receptor 2- and 4-dependent pathways [30] and proteolytic activity targeted at airway epithelial tight junctions [26,31,32].…”

G Proteins Gαi1/3Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization

“…Mast cell number, function (56,57), and susceptibility to VAAS vary across different genetic backgrounds (58,59). Although Bphs was mapped by using the SJL/J-derived Hrh1 allele (11,12), up to 75% of the available inbred mouse strains harbor this same allele (11; R. Noubade, unpublished data).…”