Final Report Summary - MAST-CELL-FUNCTIONS (Genetically defined and selectively mast cell-deficient mouse model to unravel the immunological roles of mast cells)
Mast cells were discovered by Paul Ehrlich in 1878 who, as a medical student, experimented with aniline dyes and discovered large, strongly granulated cells that reside in many tissues and display a unique staining reaction; he termed them mast cells which in German means ‘well fed cells’. Today, it is known that, although mast cells are strictly confined to tissues and cannot be found in the peripheral blood of healthy humans or animals, they belong to the immune system and arise from hematopoietic stem cells. The essential contribution of mast cells to wide spread allergic diseases, including the often fatal anaphylactic reaction, for example to bee stings, is firmly documented. However, immunologists have a hard to time to accept that the ‘real’ function of mast cells is to promote undesired symptoms, or even cause serious diseases to harmless substances. In fact, the very immunological meaning of allergy also remains enigmatic. For these reasons, immunologists have long wondered about positive, or protective functions of mast cells in immunology, and in inflammation. To this end, experimental tools are required to study immune response in model organisms that either do (normal) or do not have mast cells (mast cell deficient). The model of choice for the past nearly 40 years were mouse mutants lacking expression of the receptor tyrosine kinase Kit (Kit mutants). While these mutants lack mast cells, they are also affected by a plethora of additional defects inside and outside of the immune system. This fact has prevented the unequivocal identification of mast cell functions in vivo. Moreover, humans lacking mast cells have not been described to date, and hence correlations between mast deficiency and immune defects are unknown in humans.
Between 2000 and 2009, we had generated a series of mouse mutants to study mast cell development and functions in vivo. One of these mice (Cpa3-Cre mice) was completely devoid of mast cells in all tissues that we studies. Functionally, these mutants were fully protected from allergic diseases. But surprisingly, other immune functions were completely normal in the absence of mast cells. This was perplexing and we began a systematic search for diseases which were either ameliorated or worsened by mast cells. In this 6-year research project, we studied with the help of expert collaborators functions of mast cells in host defense against venom toxins, bacteria (sepsis), protozoa (Leishmania major) and helminthes (Strongyloides ratti), mast cells in autoimmunity (EAE, arthritis, type1 diabetes), mast cells in immune metabolism, mast cells in the skin, and mast cells in tumor biology. For almost all of these conditions there were earlier reports that had suggested important roles for mast cells. Despite these claims, with the exception of protection from some venoms, and impaired immunity to some helminthes, we could not identify an impact of mast cells on these highly diverse pathological conditions. As a result, it remains enigmatic what mast cells are good for, at least as far as it is measurable in the laboratory. Nevertheless, the development of new and conclusive mouse mutants provided us the technology to re-address long standing questions in immunology in a rigorous manner. This shall help the field to identify new leads to follow in the quest to discover the physiological function of mast cells in vivo.
Between 2000 and 2009, we had generated a series of mouse mutants to study mast cell development and functions in vivo. One of these mice (Cpa3-Cre mice) was completely devoid of mast cells in all tissues that we studies. Functionally, these mutants were fully protected from allergic diseases. But surprisingly, other immune functions were completely normal in the absence of mast cells. This was perplexing and we began a systematic search for diseases which were either ameliorated or worsened by mast cells. In this 6-year research project, we studied with the help of expert collaborators functions of mast cells in host defense against venom toxins, bacteria (sepsis), protozoa (Leishmania major) and helminthes (Strongyloides ratti), mast cells in autoimmunity (EAE, arthritis, type1 diabetes), mast cells in immune metabolism, mast cells in the skin, and mast cells in tumor biology. For almost all of these conditions there were earlier reports that had suggested important roles for mast cells. Despite these claims, with the exception of protection from some venoms, and impaired immunity to some helminthes, we could not identify an impact of mast cells on these highly diverse pathological conditions. As a result, it remains enigmatic what mast cells are good for, at least as far as it is measurable in the laboratory. Nevertheless, the development of new and conclusive mouse mutants provided us the technology to re-address long standing questions in immunology in a rigorous manner. This shall help the field to identify new leads to follow in the quest to discover the physiological function of mast cells in vivo.