Ehrlichs Mastzellen

Paul Ehrlich (Fig. 1) is credited with the initial discovery of mast cells (Fig. 2) as we know them today. He was born near Breslau, now known as Wroclaw, Poland, in 1854. He studied to become a medical doctor at the university in Breslau, followed by training in Strasbourg, Freiburg, and Leipzig (1). Ehrlich was greatly influenced by his cousin, Karl Weigert, an eminent histopatholo-gist who pioneered the use of aniline dyes for staining bacteria and tissue sections (1). Weigert had a strong and positive influence throughout Ehrlich's life (1a). As a result, even as a medical student, Ehrlich had a precocious knowledge of structural organic chemistry and a fascination with dyes as probes of

From: Methods in Molecular Biology, vol. 315: Mast Cells: Methods and Protocols Edited by: G. Krishnaswamy and D. S. Chi © Humana Press Inc., Totowa, NJ

Paul Ehrlich


Nobel Laureate PHYSIOLOGY OR MEDICINE 1908 © Nobelstiftelsen

Fig. 1. Picture of Paul Ehrlich (courtesy of © The Nobel Foundation).


Nobel Laureate PHYSIOLOGY OR MEDICINE 1908 © Nobelstiftelsen

Fig. 1. Picture of Paul Ehrlich (courtesy of © The Nobel Foundation).

cellular activity (1a). He already was exposed to the idea that organic chemicals can have differential and specific reactions with various tissues and bacteria.

On June 17, 1878, Ehrlich's date with history was set. On that day, the 24-yr-old medical student presented his doctoral thesis, "Contributions to the theory and practice of histological staining," to the Medical Faculty of Leipzig. The medical student divided his thesis into two halves. In the first part, he talked about the chemical basis of many important histological reactions. In the second part, he gave a detailed discussion about aniline dyes (1). The first description of the mast cell comes in the portion of the thesis dedicated to the

Mast Cell Thionin
Fig. 2. Mast cell in atheromatous plaque (courtesy of George Youngberg, md, East Tennessee State University).

histological applications of the aniline dyes. He presented his point of view that "aniline dyes displayed an absolutely characteristic behavior towards protoplasmic deposits of certain cells," which he called "mastzellen." He sought to distinguish these cells from the Waldeyer's "plasmazellen"—a heterogeneous category of cells described previously by Waldeyer (1).

Ehrlich said that these anilophilic cells, from the descriptive point of view, should be most conveniently described as "granular cells of the connective tissue." He said that from a physiological standpoint, these cells might represent a "further development of the fixed cells of the connective tissue." He also provided a clarification to support his theory: aniline-reactive cells indeed "have a tendency to collect around developing preformed structures in the connective tissue." He said that granular cells are characterized by an "undetermined chemical substance" in the protoplasm with which the aniline dye reacts to give a typical metachromasia (1). To this day, although by no means absolute, mast cells are recognized by the presence of metachromatic granules, when fixed and stained with toluidine blue. Further in his dissertation, Ehrlich provided an extremely accurate description of the microscopic features of the mast cell. He described that the typical aspect of these "granular cells" is mostly unstained protoplasm filled with numerous granules of varying size and a nucleus not mostly stainable, even in samples that otherwise display beautiful nuclear staining. Ehrlich strove to classify these cells using specific histochemi-cal reactions rather than histology, a very progressive concept for his time.

A historically interesting aspect is how Ehrlich decided to call these cells the "mastzellen," or mast cell, as these were plump-appearing cells (well-fed cells). "Mast" may be derived from Greek, which meant breast or from the German "mastung" (from "masticate"). In today's research, mast cells are being increasingly recognized for their role in connective tissue remodeling and repair (1). We now know that their granules contain many proteases and cytokines that are known to exert far reaching effects on other cells types, such as the smooth muscle, fibroblasts, and endothelial cells (much of this is reviewed in later chapters of this book).

Ehrlich also noted that mast cells sometimes localize far from the blood vessels and express a series of biological function not related to vascular functions. He also said that mast cells could be found around developing tissues. The close relationship between mast cell and tumor growth stems from this very same idea. Sadly, the original text of this remarkable work was destroyed in an air raid on Leipzig in 1943. Ehrlich subsequently moved to the Charité Hospital in Berlin, where he continued his work and wrote an influential thesis on the oxygen requirement of cells. In January 1879, the Physiological Society of Berlin reviewed the remarkable paper by Paul Ehrlich about the mast cells that he had discovered as a medical student 2 yr earlier. Ehrlich, in these papers, pointed out that mast cells exhibit a great avidity to basic dyes and characteristically altered the shade of the dye (1).

In 1891 along with Westphal, one of his pupils, he showed another characteristic feature of the mast cell granules in many species, namely the water solubility. Almost 50 yr later, Micheals wrote that "uncounted pages of useless and misleading research have been a result of failure on the part of many investigators to heed the admonition originally given by Ehrlich and Westphal, that mast cell granules are soluble in water and that to preserve them, tissues must be fixed in 50% alcohol and stained in alcoholic thionine" (1).

Ehrlich then studied the special affinity of leucocytes for various dyes. In 1891, he had discovered basophilic granular cells in human blood with my-eloid leukemia. Ehrlich was quick to infer with his characteristic insight that, in higher species, especially humans, the human mast cells are actually leucocytes arising from precursor cells in the bone marrow. He believed that there were two types of mast cells: the first located in connective tissue and the second with their origin in the bone marrow and localized in the peripheral blood. In 1900, Jolly had established the bone marrow origin for the mast cells. Hence, by the time his textbook (Ehrlich and Lazarus, 1898) was revised in 1909, human mast cell origins were better understood. It is now accepted that mast cells arise from a pluripotent cell in the bone marrow that expresses CD43, c-kit, and CD13.

Ehrlich also led the way in observing mast cells in two pathological situations of utmost importance—chronic inflammation and neoplasia. He felt that in both these situations the tissue was "overnourished" because of lymph stasis and that there was an accumulation of tissue fluid rich in nutriments. This state led the mast cells to convert some of this abundant extracellular fluid to specific intracellular granules (1). Thus, according to Ehrlich, mast cells served as an "indices for the nutritional status of the connective tissue," increased and decreased during periods of hypernutrition and starvation. Ehrlich and his pupil Westphal found that mast cells accumulated in many tumors, more so in the periphery of carcinomatous tumors than the substance of the tumor. Besides the discovery of the mast cell, Ehrlich made pioneering contributions to the method of staining the bacillus that causes tuberculosis, the development of a therapeutic antiserum against diphtheria, and to the concepts of antibodies and chemotherapy. Smoking 25 cigars a day, carrying around a pocketful of colored, precisely sharpened pencils, writing daily instructions to his research team, and possessing exceptional clinical knowledge characterized this great personality. On the 150th anniversary of his birth, we cannot help but admire the invaluable contribution he made to the science of immunology.

A chronology of developments in mast cell and immediate hypersensitivity research is provided below. This includes Paul Ehrlich's initial description, culminating in immunological, molecular, and genomic technologies that have accelerated our understanding of immediate hypersensitivity and relevant mast cell biology.

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