Impact of mast cell deficiency on immunological parameters and autoimmunity

Mast cells originate from hematopoietic stem cells and leave the bone marrow as early lineage progenitors. After entering peripheral tissues they differentiate into mature cells expressing the stem cell factor receptor Kit and the high-affinity receptor for immunoglobulin IgE FcεRI. Mast cells have long been recognized as the principle effector cells in IgE-mediated type I hypersensitivity. In recent years several lines of evidence have suggested that mast cells might be involved in other disease models as well, including autoimmune models for multiple sclerosis and rheumatoid arthritis. So far, these studies have relied on mice lacking mast cells due to naturally occurring mutations of the tyrosine kinase Kit. However, impaired Kit signalling as in KitW/Wv mice does not only result in mast cell deficiency, but causes many defects in multiple other cell types inside and outside of the immune system. Thorsten Feyerabend in our laboratory generated a new Cre knock-in strain by insertion of Cre recombinase into the mast cell carboxypeptidase A (Cpa3) locus. Surprisingly, Cpa3Cre/+ mice selectively lack mast cells in connective and mucosal tissues due to genotoxic effects of sustained Cre expression and hence represent a novel mast cell deficiency model with intact Kit function. The present study demonstrated the entire absence of mast cells in skin and peritoneal cavity by flow cytometry, histology and mRNA expression profiling. Cpa3Cre/+ mice were fully refractory to IgE-mediated anaphylaxis, and this defective response was rescued by reconstitution with cultured mast cells. With exception of the complete ablation of mast cells and a partial reduction in basophils, other hematopoietic lineages in Cpa3Cre/+ mice developed normally. Contrasting previous studies in KitW/Wv mice, Kit-proficient Cpa3Cre/+ mice were fully susceptible to antibody-mediated K/BxN arthritis and experimental autoimmune encephalomyelitis (EAE). The different results obtained from Kit mutant mice compared to selectively mast cell-deficient Cpa3Cre/+ mice call for a careful re-evaluation of the immunological function of mast cells beyond allergy