The Osler slide, a demonstration of phagocytosis from 1876: Reports of phagocytosis before Metchnikoffs 1880 paper

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and several related ones had been reported in 1875 by William Osler, who also had demonstrated the cellular uptake of carbon particles inkittens injected with India ink. In 1869 a Philadelphia physician described the uptake of bacteria by leukocytes in saliva and urine. Bothinvestigators postulated a protective role for this cellular phenomenon. Neither of these reports has been generally cited in histories ofimmunology. These two papers are summarized here along with a short review of other reports describing phagocytosis which predatingMetchnikoVs entrance into the Weld. 2006 Elsevier Inc. All rights reserved.Keywords: Phagocytosis; E. MetchnikoV; W. Osler; J.G. Richardson; Miners lung; Pneumoniosis1. IntroductionThe recognition of phagocytosis is generally credited toElie MetchnikoV (18451916). His extensive studies in the1880s of this phenomenon in various animal systems ledhim later to propose the concept of cellular immunity. Hisenduring fame rests on having convinced the world of thebiological and clinical importance of this concept and in sodoing having greatly stimulated the emerging Weld ofimmunology.However, MetchnikoV was not the Wrst to describephagocytosis. Before his earliest paper about it appeared in1880, over 30 reports of the phenomenon had Wlled the sci-entiWc literature; most were in German but two were inEnglish [1,2]. With a single exception, these two have notbeen cited in historical surveys of immunology. One, aCanadian report in 1875 by William Osler entitled On thePathology of Miners Lung, has assumed renewed histori-from autopsy material he studied [3,4] (Fig. 1). A modernphotomicrograph of this slide shows the uptake of coaldust particles by human alveolar cells and represents theearliest extant example of phagocytosis (Fig. 2). Oslersdescription of this cellular phenomenon and a relatedreport in 1869 by a Philadelphia physician is the main focusof this brief communication.1.1. Oslers On the pathology of miners lungIn his 1875 report, Osler used the term anthracosis,which today is known commonly as black lung disease andmedically as pneumoconiosis [4] (Fig. 3). The Wrst half ofhis paper concerned pathological Wndings in the lungs oftwo cases of miners lung. He noted that the gross lungspecimens had a uniform, deep blue-black colour. In tis-sue sections of the lung he saw [c]orpuscles in which thebulk of the carbon is contained the carbon particles Cellular Immunology 2Rapid commThe Osler slide, a demonstratiReports of phagocytosis befoCharles T. Department of Microbiology, Immunology, and Molecular Genetics, CReceived 16 May 2006;Available onlinAbstractRecently at the Medical Historical Museum of McGill Universitfrom the lung of a patient with pneumoconiosis. Photomicrographs0008-8749/$ - see front matter 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.cellimm.2006.05.008cal interest with the recent discovery of a slide made in 1876* Fax: +1 859 257 8994.E-mail address: cambros@uky.edu.40 (2006) 14www.elsevier.com/locate/ycimmunicationon of phagocytosis from 1876re MetchnikoVs 1880 paperAmbrose ollege of Medicine, University of Kentucky, Lexington, 40536, USA accepted 23 May 2006e 31 July 2006y, Dr. Rick Fraser discovered a microscope slide prepared in 1876 show the presence of coal dust particles in alveolar cells. This caseWlling the cells in diVerent degrees. He drew pictures ofseveral of these carbon-Wlled cells, showing them as usu-ally round, sometimes oval, occasionally irregular, [and]very rarely approaching the spindle form.The second part of Oslers paper described experimentsin which he injected India ink into the axillae and lungs ofone-day-old kittens. Connective tissue teased from the axil-lae 24 h later and Wxed on slides showed microscopicallyCourtesy of Prof. Rick Fraser, Department of Pathology, McGill University.Fig. 2. Photomicrograph of slide prepared from Oslers 1875 case of minerslung, showing ingestion of coal dust particles by alveolar cells. Courtesy ofProf. Rick Fraser, Department of Pathology, McGill University.Fig. 3. Left: Oslers article, Canada Med. & Surg. J., 1875. Right: Wmand not coined by MetchnikoV until 1884 [5].1.2. Other reports of phagocytosis prior to MetchnikoVs 1880 paperMany of the 30-plus pre-MetchnikoV reports of phago-cytosis concerned the uptake of red cells or various inertparticles by cells in diVerent animal systems [2]. Three arti-cles in the German literature were similar to Oslers 1875Canadian paper on miners lung. The phagocytosis of coaldust (Kohlenstaubin) was described by Slavjansky in 1869and by Ruppert in 1878 and of silica dust (Kiesselstaubin)by von Jns in 1876 [68].Nine other reports described the ingestion of microor-ganisms by white blood cells. Those for which an interpre-tation was given can be divided into two groups. In one theauthors maintained that the process facilitated spread oforganisms throughout the body. For example, Hayem in1870 and Klebs in 1872 observed bacteria in white bloodcells; Waldeyer in 1872 noted bacteria in peritoneal puscells; and Koch in 1876 found anthrax bacilli in spleen andlymph node cells [9,10].In contrast, a protective role from the cellular ingestionof microorganisms was inferred by four investigators:Richardson, Panum, Grawitz, and MullendorV. The latterthree are the German reports frequently cited in histories ofphagocytosis. Panum [11] restated the observations of2 C.T. Ambrose / Cellular Immunology 240 (2006) 14that all the leucocytes were loaded with the dark gran-ules. Slide preparations of the lungs revealed tissueseverywhere inWltrated with small and large cellular ele-ments in which the bulk of the pigment was held. Thelarger cells rounded or oval in outline contained thegreatest number of granules amoeboid movements wereseen in most of these corpuscles.Osler concluded that the Wxation of the carbon gran-ules in cellular bodies [in the lungs] must be regarded asan eVort [by the body] to render harmless what mightotherwise be very irritating substances. This sentence andothers above describe phagocytosis and state a protectivefunction for it without using the speciWc term, not yet in useFig. 1. The Osler slide. Prepared from Oslers 1875 case of miners lung.. Osler, age 28, 1877. Courtesy of Osler Library, McGill University.C.T. Ambrose / Cellular ImBirch-Hirschfeld, who found that micrococci introducedinto the circulation often disappear by penetrating intoblood cells, which then accumulate in lymph nodes andspleen. Grawitz (1877) visualized microscopically theuptake of a fungal parasite by white corpuscles, while Mul-lendorf (1879) described the consumption of spirilla bywhite blood cells (Verzehrugsprozess) [12,13].Preceding the earliest of these three German reports wasone by an American, Joseph G. Richardson (18361886),entitled On the Identity of the White Corpuscles of theBlood with the Salivary, Pus, and Mucous Corpuscles.[14]. His 1869 paper remained unnoticed for 111 years untilbeing brieXy mentioned in a book with the general title ofBlood, Pure, and Eloquent [15]. Indeed, this article has alsoremained overlooked since then. A short summary of thisincunabular American work follows.In his 6-page article Richardson extended Cohnheimsidentity of the pus and white blood corpuscles to includesalivary corpuscles and pus globules found in purulentcystitis. The refracting particles in incessant motionobserved in these latter cells look very like the germs ofbacteria. Richardson speculated that it seems notimprobably that the white corpuscles, either in the capillar-ies or lymphatic glands, collect during their amoebaform[sic] movements, those germs of bacteria, which my ownexperiments indicate always exist in the blood to a greateror less amount. He judged that nucleated corpuscleswhen thus loaded may be eliminated through saliva,under the mercurial inXuence and, similarly, that a dis-charge of pus from a seton really constitutes that thera-peutic value of these [two] remedial measures. [14].This neglected American paper is noteworthy because itantedates the three commonly cited German studies ofmicrobial phagocytosis and the four ignored reports onuptake of coal dust or silica particles. Richardson proposeda protective role by expulsion from the body of bacteria-laden leukocytes in saliva or pus. Although he did not con-sider the intracellular destruction of bacteria within thebody, his explicit recognition of phagocytosis included itsprotective role, just as did Oslers conclusions about theuptake of coal dust particles by alveolar cells. Neitherauthor is mentioned in chronicles of immunology, asjudged by a long search of that literature [16].2. ConclusionIt is paradoxical that these two very early reportsdescribing phagocytosis, while written in English, havebeen essentially ignored in the histories of immunology,notably the English language ones. Two explanations cometo mind.First, the dominance of German research in 19th-cen-tury zoology was likely a factor. European investigatorsthen probably had little access to (or interest in) the medi-cal or biological literature from North American and thuswere unaware of Richardsons 1869 paper from Philadel-phia and Oslers 1875 report from Montreal. In contrast,munology 240 (2006) 14 3the three pre-MetchnikoV reports in German noted abovewere cited in successive reviews. The studies of Panumand Grawitz were described in MetchnikoV s 1901 over-view of this Weld, Limmunit dans les maladies infectie-uses, and its 1905 or 1907 English editions [17].MullendorVs 1879 researches resurfaced in Herrlingers1956 review of the historical development of the conceptof phagocytosis (Die historische Entwicklung desBegriVes Phagocytose) [18]. Earlier such surveys ofimmunology (e.g., by Zinsser, etc.) reported primarilyEuropean publications which were initially so dominantbut which overlooked the infrequent research reportsfrom 19th-century North American [19]. Later reviewslargely perpetuated the coverage of early ones. Thus theprimary papers by Richardson and Osler escaped noticeboth early and later.Second, in the 1890s, before the debate over humoraland cellular immunity arose, there had emerged two oppos-ing schools of thought about the function of phagocytes:(1) that such cells were simple scavengers removing agedred cells, the debris of disintegrating tissues, foreign parti-cles, and dead microorganisms, as was argued by Baumgar-ten, Hess, Nuttall and others or (2) that these cellsrepresented an active host defense against invading patho-genic agents, as proposed by MetchnikoV [20]. The uptakeof inert particles, like coal dust in Oslers report, may haveseemed more akin to the natural disposal of eVete tissuebreak-down products and thus less interesting to reviewersof this new phenomenon. But this does not explain theneglect of Richardsons report of the cellular uptake ofactive bacteria.Finally, this survey of pre-MetchnikoV reports of phago-cytosis indicates that these two natal studies from NorthAmerica have been neglected in the written histories ofearly immunology. Thus it seems appropriate to alert futurechroniclers of this history that the earliest extant laboratoryartifact associated with cellular immunology may be the1876 Osler slide showing phagocytosis in a miners autop-sied lung. There can be no ignoring this.References[1] E. MetchnikoV, ber die intracellure Verdauung bei Coelenteraten,Zoologischer Anzeiger 3 (1880) 261263.[2] An unpublished historical survey of this literature in table form isavailable upon request at cambros@uky.edu.[3] Some of Oslers gross specimens are still preserved in the MedicalHistorical Museum at McGill University. The slide described inthis text was found there recently by Dr. Rick Fraser, Departmentof Pathology, McGill University, who determined that it hadbeen prepared in 1876 by a medical student as part of a coursein history then taught by Osler. The slide is included in theMuseums Greenwood Collection. Personal communication tothe author on 17 September 2005, 28 February 2006, and 2 March2006.[4] W. Osler, On the pathology of miners lung, Canad. Med. Surg. J. 4(1875) 145169.[5] E. MetschnikoV, ber eine Sprosspilzkrankheit der Daphnien. Bei-trag zur Lehre ber den Kamp der Phagocyten gegen Krankheitserre-ger, Arch. Pathol. Anat. 96 (1884) 177195.4 C.T. Ambrose / Cellular Immunology 240 (2006) 14[6] K. Slavjansky, Experimentelle Beitrge zur Pneumonokoniosis-Lehre,Arch. Pathol. Anat. 48 (1869) 326332.[7] H. Ruppert, Experimentelle Untersuchungen ber Kohlenstaubinha-lation, Arch. Pathol. Anat. 72 (1878) 1436.[8] A. von Jns, Experimentelle Untersuchungen ber Kieselstaubinha-lation, Archiv fr Experimentelle Pathologie und Pharmakologie 5(1876) 169194.[9] Hayem and Waldeyer, cited in (a) H. Zinsser, Infection and Resis-tance, third ed., Macmillan Co., New York, 1923, p. 333 and in (b) E.MetchnikoV, Immunity in Infective Diseases, F.G. Binnie (Tr.), John-son Reprint Corp., New York, 1968, p. 514.[10] R. Koch, cited in R. Herrlinger, Die historische entwicklung desbegriVes phagocytose, Ergebnisse der Anatomie und Ent-wicklungsgeschichte 35 (1956) 334357.[11] P.L. Panum, Das putride Gift, die Bakterien, die putride Infectionoder Intoxication und die Septicmie, Arch. Pathol. Anat. 60(1874) 301352.[12] Grawitz, cited in E. MetchnikoV, Immunity in Infective Diseases,F.G. Binnie (Tr.), Johnson Reprint Corp., New York, 1968,p. 515.[13] J. MuellendorV, ber Rckfallstyphus nach Beobachtaungen imstdtischen Kranken-haus zu Dresden 1879, Deut. Med. Wochensch-rift 5 (1879) 620622, 630632, & 642644.[14] J.G. Richardson, On the identity of the white corpuscles of the bloodwith the salivary, pus, and mucous corpuscles, Penn. Hosp. Reports 2(1869) 249254.[15] Charles G. Craddock, Defenses of the body: the initiators of defense,the ready reserves, and the scavengers, in: Maxwell M. Wintrobe(Ed.), Blood, Pure, and Eloquent, A Story of Discovery, of People,and of Ideas, McGraw-Hill Book Co., New York, 1980, p. 428.[16] Starting with the English translations of MetchnikoVs two books,Wrst published in 1893 and 1905/7, this search included publicationsby Zinsser (1923), Mudd et al. (1934), Herrlinger (1956), Bullock(1960), Lechevalier & Solotorovsky (1965), Brieger (1968), Mazumdar(1972), Craddock (1980), Karnovsky (1981), Hirsch & Hirsch (1982),Bibel (1988), Silverstein (1989), Chernyak & Tauber (1988), Tauber &Chernyak (1991). More precise citations are available on request fromcambros@uky.edu.[17] Elie MetchnikoV, Immunity in Infective Diseases (Francis G. Binnie,Tr.), University Press, Cambridge, UK, 1907, p. 515.[18] Robert Herrlinger, Die historische Eentwicklung des BegriVes Phago-cytose, Ergebnisse der Anatomie und Entwicklungsgeschichte 35(1956) 334335.[19] H. Zinnser, Infection and Immunity, third edition, The MacmillanCo., New York, 1923, 333334.[20] Anonymous, Phagocytes, JAMA, 12 (1889) 630631.The Osler slide, a demonstration of phagocytosis from 1876IntroductionOslers On the pathology of miners lungOther reports of phagocytosis prior to Metchnikoffs 1880 paperConclusionReferences