Systemic Mastocytosis (SM)

Systemic mastocytosis is a rare hematological disease characterized by excessive proliferation of mast cells throughout the body’s tissues, often affecting multiple organ systems including the bones, joints, lymph, liver, spleen, lungs, nerves, and skin.¹

Mast cells, a type of white blood cell produced in the bone marrow, are granulocytes containing various inflammatory chemical mediators including histamine, heparin, growth factors, and cytokines, which are released during allergic reactions or following exposure of an individual with systemic mastocytosis to environmental triggers.² 

Urticaria Pigmentosa

In 1869, Charles Blakely, an English physician, performed the first skin test by applying pollen to a surface wound in his skin to ascertain if pollen caused his hay fever allergy. The resulting skin response confirmed an allergic reaction to the substance.³ 

Around the same time in 1869, Nettleship and Tay described pigmented skin lesions that later became known as urticaria pigmentosa.⁴

Mast Cells

In 1863, Friedrich von Recklinghausen first described granulated cells in unstained connective tissues of various animal species, especially tadpole tails.⁵

In 1879, Paul Ehrlich, a renowned chemist and physician who eventually immersed himself in histological laboratory research, gave these granulated cells their name when he presented his doctoral thesis at the Medical Faculty of Leipzig University.³ He called them “Mastzellen,” or mast cells, translating roughly as “well-fed cells.”⁵

Using aniline dye staining techniques, he confirmed the presence of these granulated cells within the connective tissues, particularly around blood vessels. He hypothesized that a substance contained within the granules of these mast cells reacted metachromatically to the aniline dye. Although he correctly noted that mast cells proliferated during chronic inflammatory states and within tumors, Ehrlich ultimately was unable to determine what substance was contained within mast cells or describe the exact function of mast cells.³ 

Ehrlich’s unique background in chemistry and medicine allowed him to conceptualize biological principles and translate their practical applications to the field of precision medicine. His research significantly advanced the fields of immunology, microbiology, and hematology, resulting in him receiving the Nobel Prize in Physiology and Medicine in 1908 for his foundational work (in collaboration with Elie Metchnikoff) on immunological defense mechanisms.⁶  

In 1887, following Ehrlich’s discovery of mast cells, Unna established the connection between urticaria pigmentosa lesions and mast cell infiltration of the skin tissues.^4,7 

Anaphylaxis

In 1902, Paul Portier and Charles Richet described anaphylaxis after injecting toxins from the sea anemone, Physalia, into dogs who became hypersensitive to the toxin. After the first exposure to the toxin, the second injection resulted in the rapid death of the dogs, highlighting a novel concept at the time that not all immune responses were protective. Anaphylaxis is derived from the Greek words “ana,” meaning “against,” and “phylaxis,” meaning “protection.”⁵

Other physicians and scientists described similar hypersensitivity reactions, including Maurice Arthus in 1903, Pirquet and Schick in 1905, and Maximillian Ramirez in 1919.

In 1921, two German physicians, Otto Carl Willy Prausnitz and Heinz Küstner, working together at the Hygiene Institute at the University of Breslau performed self-experimentation that demonstrated that an allergy (Küstner’s severe fish allergy) could be transferred from an allergic person (Küstner) to a healthy person (Prausnitz). Prausnitz exhibited an immediate skin reaction (cutaneous anaphylaxis) following the application of fish extract.⁵

Histamine 

In 1907, Adolf Windhaus and W. Vogt chemically synthesized histamine by removing the carboxyl group from the amino acid, histidine, before the biological significance of histamine was discovered.^8,9 

In 1910, Sir Henry Hallett Dale and colleagues at the Wellcome Physiological Research Laboratories isolated histamine from the fungal parasite, Claviceps purpurea, contaminating an ergot extract. Ergotism is a disease caused by fungal infections of rye and cereal products.^3,5,9,10 

In 1929, after nearly 20 years of purifying and isolating histamine from several organ tissues and researching the physiological effects of histamine on the tissues, Dale presented his research in a lecture series titled “Croonian Lectures: On Some Chemical Factors in the Control of the Circulation.”¹¹ He described how histamine produced a physiological response associated with allergic reactions and anaphylaxis.^8,11 He also suggested that histamine was not the only substance released during tissue inflammation or injury, a theory which was later confirmed with the discovery of cytokines and eicosanoids.³

It was not until much later in 1953 that James F. Riley and Geoffrey B. West discovered that mast cell granulocytes contained histamine and suggested that the release of histamine was responsible for anaphylaxis.^3,5

Discover of Systemic Mastocytosis

Initially, for the first 80 years following Nettleship and Tay’s publication, mastocytosis was considered strictly a skin disease due to its association with urticaria pigmentosa⁷; however, in 1933, Touraine hypothesized that mastocytosis could potentially affect the internal organs.¹²

It was not until 1949 when the first true case of systemic mastocytosis was reported by J.M. Ellis. He described his findings from an autopsy performed on a 1-year-old female infant of African ancestry who presented with urticaria pigmentosa from birth along with gastrointestinal complaints. Ellis documented the proliferation of mast cells within the internal organs, including the liver, spleen, pancreas, kidneys, bone marrow, and lymph nodes.^7,12,13 

Over the next decades, clinicians and researchers described diagnostically distinct classifications of 5 subtypes of systemic mastocytosis. It was also discovered that patients could have urticaria pigmentosa without systemic involvement, forming the nonsystemic classification of cutaneous mastocytosis.⁴

Researchers have also focused on detailing the molecular mechanisms of systemic mastocytosis as well as the origins of mast cells.

Immunoglobulin E

In 1966 and 1967, Kimishige and Teruko Ishizaka, a husband-and-wife team working at the Children’s Asthma Research Institute in Denver, Colorado, identified the last class of immunoglobulins, immunoglobulin E (IgE); the “E” stands for “erythema.” Simultaneously, S.G.O. Johansson and Hans Bennich at Uppsala University in Sweden independently identified the same immunoglobulin.⁵  

The Ishizakas continued their research, discovering that basophils and mast cells had IgE binding sites that were activated when an allergen bound to their receptors along with serum IgE.⁵ It is this binding of IgE and the allergen to the mast cell that triggers the release of histamine, cytokines, and eicosanoids.¹⁴ 

In 1974, Henry Metzger analyzed a mast cell line, confirming the high affinity of mast cells for IgE.⁵   

Origins of Mast Cells

In the 1970s, Japanese researcher, Yukihiko Kitamura, discovered that mast cells were derived from hematopoietic stem cells within the bone marrow.

At the end of the 1980s, researchers confirmed that mast cells and basophils released cytokines and growth factors, indicating that mast cells and basophils not only respond to allergens, but also regulate diverse physiological functions.⁵ 

Research over the last 2 decades has demonstrated that mast cells release over 30 different kinds of cytokines, growth factors, interferons, and chemokines in addition to histamine.⁵

References

1. Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Accessed April 20, 2022.
2. Genetic testing – mastocytosis skin; urticaria pigmentosa (cutaneous mastocytosis) – Gen KIT. Valencian Institute of Microbiology (IVAMI). Accessed April 20, 2022.
3. Beaven MA. Our perception of the mast cell from Paul Ehrlich to now. Eur J Immunol. 2009;39(1):11-25. doi:10.1002/eji.200838899
4. Valent P, Akin C, Hartmann K, et al. Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res. 2017;77(6):1261-1270. doi:10.1158/0008-5472.CAN-16-2234
5. Blank U, Falcone FH, Nilsson G. The history of mast cell and basophil research – some lessons learnt from the last century. Allergy. 2013;68(9):1093-1101. doi:10.1111/all.12197
6. Valent P, Groner B, Schumacher U, et al. Paul Ehrlich (1854-1915) and his contributions to the foundation and birth of translational medicine. J Innate Immun. 2016;8(2):111-120. doi:10.1159/000443526 
7. Birt AR, Nickerson M. Generalized flushing of the skin with urticaria pigmentosa. Arch Dermatol. 1959;80(3):311-317. doi:10.1001/archderm.1959.01560210053010
8. A timeline of histamine and its receptors. Nat Med. 2010;16(10):1064. doi:10.1038/nm1010-1064
9. Figueroa K, Shankley N. One hundred years of histamine research. In: Thurmond RL, ed. Histamine in Inflammation. Boston, MA: Springer; 2010:1-9.
10. Hatch MC. Histamine – more than just a runny nose! Accessed April 20, 2022.
11. Dale HH. Croonian lectures on some chemical factors in the control of the circulation. Lancet. 1929;213(5520):1233-1237. doi:10.1016/S0140-6736(00)49141-5
12. Jaishankar D. Systemic mastocytosis: background. Medscape. Updated June 21, 2021. Accessed April 20, 2022.
13. Ellis JM. Urticaria pigmentosa; a report of a case with autopsy. Arch Pathol (Chic). 1949;48(5):426-435. 
14. Amin K. The role of mast cells in allergic inflammation. Respir Med. 2012;106(1):9-14. doi:10.1016/j.rmed.2011.09.007

Reviewed by Kyle Habet, MD, on 4/24/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.