Paul Ehrlich's doctoral thesis: a milestone in the study of mast cells.

The history of mast cell research begins with a name and a date. The name is that of Paul Ehrlich; the date is the 17 June 1878. That day, the 24-year-old medical student from Strehlen (Schlesien) presented his doctoral thesis at the Medical Faculty of Leipzig University. The title of his dissertation was ‘Contribution to the theory and practice of histological dyes’ (‘Beiträge zur Theorie und Praxis der histologischen Färbung’) (Ehrlich, 1878). This work is a beautiful and admirable example of analytical experimental method and foresight. Ehrlich’s thesis was organized into two parts. In the first part, he overviews the chemical bases of many important histological reactions and, in the second part, he discusses the chemical, technological and histological properties of aniline dyes. In the chapter dedicated to the histological applications of this class of chemical compounds, he presents his personal point of view about a type of cell, which he named as ‘mast cell’ (‘Mastzelle’). He stated that ‘aniline dyes display an absolutely characteristic behaviour toward the protoplasmic deposits of certain cells’ that were ‘chemically so sharply’ distinguished from the group of Waldeyer’s ‘Plasmazellen’. With this term, he referred to a broad and heterogeneous category of cells previously described by Waldeyer. Among Waldeyer’s ‘Plasmazellen’, there was a group of connective tissue cells exhibiting large dimension and round shape, which could be distinguished ‘from white blood cells on the basis of their significantly large size and lack of contractile activity’. Ehrlich emphasized his assumption that most of those cells that he had described in connective tissues as reactive to aniline staining did not correspond to Waldeyer’s description, which was otherwise based on purely morphological criteria, not chemical. ‘Anilophilic cells should be strongly separated from ‘‘Plasmazellen’’’, he insisted. These aniline-reactive cells ‘represent sui generis elements and must be distinguished from Waldeyer’s ‘Plasmazellen’ by a different denomination’. He then came to the central part of his presentation. ‘From the descriptive point of view’, he said, aniline-positive cells should be ‘most conveniently described as ‘‘granular cells of the connective tissue’’ (‘‘granulierte Bindgewebezellen’’); from the physiological standpoint, these cells may provisionally be indicated as mast cells (‘‘Mastzellen’’) because, like fat cells, they represent a further development (‘‘Weiterentwicklung’’) of the fixed cells of connective tissue’. Ehrlich’s concept is absolutely remarkable in that, although mast cells ‘are localized with extremely high frequency around blood vessels in the loose connective tissues’, ‘it seems not justified to regard them as members of a perivascular system’. He also provided a notable explanation to support his view: aniline-reactive cells indeed ‘have a tendency to collect around developing preformed structures in connective tissues’. In discussing this point, he added that ‘in certain acinar glands (goat parotid), the pattern of mast cell accumulation [inside the organ] is not determined by the branching of the vascular system but by the ramification of the gland excretory ducts’. In the course of his dissertation, Ehrlich underlined the concept that mast cells must be principally distinguished on the ground of their reactivity to aniline dyes, not simply by their shape and morphological appearance. ‘Granular cells are characterized by the presence of a still undetermined chemical substance’, ‘which is bound to the granular storages in the protoplasm’ and which reacts to aniline dyes giving typical metachromasia. The binding of this chemical substance to aniline dyes shows different staining: red–violet with cyanine, orange with fuchsin and red with dahlia and gentian. Finally, he provided an extremely precise description of mast cell microscopical features. ‘The typical aspect of ‘‘granular cells’’ is as follows. The mostly stainless protoplasm appears as being filled by more or less numerous grains of variable size. These granules exhibit subtle nuances specific for each staining procedure. The nucleus is mostly not stainable, even in samples which otherwise display beautiful nuclear staining reactions. In flattened cells, the nucleus appears as a characteristically clear spot, due to the absence of the coloured granules and this picture nearly gives the impression of a lacuna in the cell body’. Many interesting aspects of Ehrlich’s dissertation deserve some comments. He first coined the term ‘Mastzellen’ to describe the aniline-reactive granular cells he found in connective tissues. The German word ‘Mast’ (from the Greek larsór 1⁄4 breast) implies a nourishing and ‘suckling’ function for these cells. Certainly, mast cells do not provide nutrients in a strict sense; however, they are deeply involved in the ‘trophism’ of tissues. Mast cells are increasingly being recognized as key cells for connective tissue homeostasis, remodelling and repair. They also express relevant angiogenic activity. Their granules indeed contain proteases and cytokines that are known to exert ‘trophic’ effects (survival, growth and chemotactic) on different cells, such as fibroblasts, myofibroblasts, smooth muscle cells, neurones and endothelial cells. Therefore, the ‘provisional’ term ‘Mastzellen’ seems more and more appropriate for describing these cells. Ehrlich also observed that mast cells did not strictly belong to a diffuse perivascular system (according to Waldeyer’s concept of ‘Perivaskuläresysteme’), despite their characteristic arrangement close to capillaries. This is indeed an absolutely correct statement. Mast cells often British Journal of Haematology, 2003, 123, 19–21