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Rheumatology 2001; 40: 826-827
© 2001 British Society for Rheumatology
Heberden Historical Series |
The LE cell
Rheumatology Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
The name lupus, derived from the Latin for wolf, was used first as a medical term by Rogerius (c. 1230) and later by Paracelsus (1493–1541) and Sennert (1611). A more recognizable description of the disease was reported by Cazenave in 1838, who went on to name the disease ‘lupus érythèmateux’ with his colleague Clausit in 1852. In a series of publications, Hebra and his son-in-law Kaposi differentiated the systemic, or disseminated, and discoid forms. Between 1895 and 1903, Osler described many of the recognizable features of the disease as we now know it.
Autoantibodies are a characteristic feature of systemic lupus erythematosus (SLE), and their presence has suggested an autoimmune pathogenesis. The Venereal Disease Research Laboratory (VDRL) test, a serological test for syphilis, was developed before World War I. It was a German, Hauck, who noted in 1910 that this test was often positive in patients with lupus. Further significant clinical and laboratory observations followed between the wars, including Libman and Sacks’ description of endocarditis and Klemperer and Baehr's report of glomerular disease.
The year 1948 was to be a landmark year in the history of SLE. American clinical haematologists Malcolm Hargraves and Robert Morton, working with laboratory technician Helen Richmond, were the first to describe the LE cell [1]. They had observed two unusual phenomena in several bone marrow preparations, which they termed the ‘tart cell’ and the ‘LE cell’. These observations had been made during a period of intense evaluation of diagnostic bone marrow examinations at the Mayo Clinic, Rochester, Minnesota, USA. They first reported their findings to the Midwest Haematology Club in Chicago in 1946 and 1947, then later in a staff meeting at the Mayo Clinic in January 1948. The huge significance of their observations was unclear to them at the time, and indeed baffled many colleagues as well.
In their short report, Hargraves and colleagues first described the so-called tart cell—they were keen to avoid confusion with the morphologically similar LE cell. The former had been observed in most of the bone marrow preparations they had examined, but in increased numbers in certain patients, such as those with lymphoblastoma and metastatic carcinoma. An apparent secondary nucleus (and a third in some cases) was seen in histiocytes, and occasionally in eosinophils and polymorphs. The appearance of part of this structure outside the cell suggested that it may have been an abortive nucleus in the process of being extruded, and they later termed the phenomenon ‘nucleophagocytosis’. The ‘tart cell’ was named after a patient in whose marrow many such cells were found, and not after a small round pastry as many were led to believe at the time!
In the LE cell, nuclei are phagocytosed by mature polymorphonuclear leucocytes and digested (Fig. 1
). Hargraves and colleagues had two hypotheses for the appearances they observed: first, that there was phagocytosis of free nuclear material, leading to the development of homogeneous round vacuoles containing lysed nuclear material, and secondly that there was autolysis of one or more lobes of the polymorph nucleus. The vacuolated area containing partially digested nuclear material resembled that of the tart cell, but because of the variability in the appearance of chromatin in the LE cell, the authors were able to distinguish them clearly. The material observed in the LE cell was confirmed by Morton to be nuclear by positive staining with Feulgen. Interestingly, they also observed that once the nuclear material had been phagocytosed, surrounding polymorphs rapidly moved away, suggesting that the chemotactic attractiveness of the material had been lost.
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The LE cell was so termed because of its exclusive presence in the bone marrow of 25 patients with confirmed or suspected SLE at the Mayo Clinic. The first three cases were children, the first a 9-yr-old with, very unusually, hypergammaglobulinaemia, plasmacytosis and Bence-Jones proteinuria, the second, also 9-yr-old, with unexplained anaemia and purpura, and the third a boy with cryoglobulinaemia and purpura [2]. A more conclusive link with SLE came after the LE cell phenomenon was observed in the marrow of a patient with classical SLE.
LE cells are not usually found in peripheral blood, although Sundberg and Lick, also at the Mayo Clinic, observed in 1949 that the LE cell phenomenon could form in the buffy coat of peripheral blood after a period of incubation [3]. LE cells have since been found in synovial fluid, cerebrospinal fluid and pericardial and pleural effusions from patients with SLE.
In 1949, Haserick and Bortz addressed the important question of whether the LE cell phenomenon was a primary cytological alteration or secondary to a constituent of the plasma of these patients [4]. They added plasma from patients with SLE to bone marrow preparations from normal subjects and compared the results with control preparations from the same subjects. Plasma from patients with SLE induced the LE cell phenomenon in these marrows, with the formation of clumps of polymorphs around amorphous masses of nuclear material. The highest number of LE cells developed when plasma from the sickest patient was used. Furthermore, plasma from a patient with discoid lupus failed to induce the phenomenon. Hargraves made similar, independent observations [5].
Thus, the formation of LE cells appeared to be secondary to a factor in the plasma of patients with SLE. Haserick and Sundberg emphasized the value of bone marrow examination in the diagnosis of SLE [6]. For a while, the LE cell phenomenon was the most specific test available for the diagnosis of SLE, and it supported the autoimmune theory for its pathogenesis. It was some time before the nature of this factor in the plasma became apparent. A number of workers eventually discovered the ability of the LE factor to bind to nuclei and ribonucleoprotein. We now know that the autoantibodies that lead to the LE cell phenomenon bind histones. The work surrounding the discovery of antinuclear factors will be covered in a later topic in this series.
The discovery of the LE cell phenomenon remains a fundamental observation in the pathogenesis of SLE. Along with the VDRL test, the LE cell preparation remains in the American College of Rheumatology's criteria for the classification of SLE [7]. We may not come across it that often in the clinic any more, but the LE cell continues to illustrate many of the mysteries of this fascinating disease.
References
- Hargraves MM, Richmond H, Morton R. Presentation of two bone marrow elements; the ‘tart’ cell and ‘LE’ cell. Proc Staff Meet Mayo Clin1948;23:25–8.
- Hargraves MM. Discovery of the LE cell and its morphology. Proc Staff Meet Mayo Clin1969;44:579–9.
- Sundberg RD, Lick NB. LE cells in the blood in acute disseminated lupus erythematosus. J Invest Dermatol1949; 12:83–4.[ISI]
- Haserick JR, Bortz DW. Normal bone marrow inclusion phenomena induced by lupus erythematosus plasma. J Invest Dermatol1949;13:47–9.[ISI]
- Hargraves MM. Production in vitro of the LE cell phenomenon: use of normal bone marrow elements and blood plasma from patients with acute disseminated lupus erythematosus. Proc Staff Meet Mayo Clin1949;24:234–7.
- Haserick JR, Sundberg RD. The bone marrow as a diagnostic aid in acute disseminated lupus erythematosus. J Invest Dermatol1948;11:209–13.[ISI]
- Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982;25:1271–7.[ISI][Medline]
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