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The Junctional Epithelium: From Strength to Defense

¹ Former Professor and Director of the Institute of Oral Structural Biology, Center of Dental and Oral Medicine and Maxillofacial Surgery, University of Zürich, Switzerland; present address, Grossackerstrasse 38, CH-8152 Opfikon, Switzerland;
² former Professor of Periodontics and Director of the Microbiology Testing Laboratory, School of Dental Medicine, University of Pennsylvania, USA; present address, 166 Beach Park Boulevard, Foster City, CA 94404, USA;

*corresponding author FAX +41-1810-4415

KEY WORDS: periodontium • epithelial attachment • junctional epithelium • history

	INTRODUCTION: THE BACKGROUND TO AN INTERNATIONAL COLLABORATION

TOP INTRODUCTION: THE BACKGROUND TO... THE EARLY STUDIES: MAX... THE EARLY STUDIES: HUBERT... COLLABORATIVE STUDIES A NEW LOOK AT... REFERENCES

 
It is rare for two young researchers to engage in scientific cooperation, become friends, and thereafter collaborate over a period of almost 40 years. Max and Hubert met, for the first time, in Boston in March, 1964. Max worked as a research fellow in Periodontology at the Harvard School of Dental Medicine, focusing on the ultrastructure of the oral gingival epithelium (Listgarten, 1964), under the guidance of Dr. John Albright, while Hubert investigated the formation and inhibition of dental calculus under the supervision of Hans R. Mühlemann at the Dental Institute of the University of Zürich. At that time, the junctional epithelium was called the "epithelial attachment", and the nature of the interface between the gingiva and the tooth surface was interpreted differently, depending on whether people believed Bernhard Gottlieb’s or Jens Waerhaug’s theory. Gottlieb (1921) had reported that the "epithelial attachment" is organically united to the tooth surface. Consequently, his disciples believed in the physical strength of this union, a belief that has lasted for decades (see Schroeder and Listgarten, 1971). Later, on the basis of experimental findings in dogs, Waerhaug (1952) concluded that the "epithelial attachment" belongs to the lining of the "physiological pocket", that its cells adhere only weakly to the tooth surface, and that the bottom of that pocket is to be found at the cemento-enamel junction. While one school of thought postulated a strong union, the other implied the existence of a potential pocket between hard and soft tissues. Since these theories had some important clinical relevance, proponents of each often debated their concepts in public forums, each arguing in favor of his individual bias.

With the advent of electron microscopy in the early 1960s, it became possible to provide new factual information pertinent to this region. Actually, there are two stories of discovery to be told, one concerned with the nature of the union between the gingiva and the tooth surface—i.e., with what is now called the epithelial attachment apparatus—the other related to the structure and cellular biology of the junctional epithelium. While the nature and strength of this attachment needed to be clarified (see Sawada and Inoue, 1996), subsequent research emphasized the importance of the junctional epithelium in the peripheral host defenses against infection (Schroeder and Listgarten, 1997).

	THE EARLY STUDIES: MAX LISTGARTEN

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The nature of the epithelial attachment apparatus in man was unveiled primarily by Max during the time period up to 1967. Max’s interest in the dento-gingival junction began as a dental student at the University of Toronto. When he asked his teacher in Oral Pathology, Dr. Harry Hunter, to clarify the nature of that junction, he got an evasive answer: "Why not do some research and find out?" Indeed, beginning at Harvard and after his return to Toronto, Max’s research focused on the ultrastructure of the junction between enamel and soft tissues in erupted and unerupted human teeth. Based on transmission electron microscopic findings, he demonstrated, for the first time, that an attachment apparatus around erupted teeth did exist. It consisted of hemidesmosomes and a basement lamina, resembling that at the epithelium-connective tissue interface (Listgarten, 1966a). Simultaneously, Max looked at unerupted human premolars and realized that reduced ameloblasts were attached to the enamel surface by the same apparatus, hemidesmosomes and a basement lamina (Listgarten, 1966b). He also described two cuticular structures located along the enamel surface of erupted teeth. One was later identified as acellular, afibrillar cementum, and the other is most likely a derivative of serum proteins. In addition, Max studied the regeneration of the attachment apparatus two to four months following gingivectomies in young cynomolgus monkeys. The regenerated marginal gingiva became re-attached to the adjacent tooth surface by a newly formed basement lamina and hemidesmosomes (Listgarten, 1967). Max correctly concluded that a reduced enamel epithelium was not needed for an epithelial attachment apparatus to form de novo. On the contrary, with no other epithelial source nearby, the most likely source for the new junction was the keratinized oral gingival epithelium at the wound edge, an epithelium with a different phenotype.

	THE EARLY STUDIES: HUBERT SCHROEDER

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In the meantime, Hubert obtained his training in electron microscopy, first with Virginia Peters at the Institute of Dental Research of New York University in New York (1965) and subsequently with Jörgen Theilade in the Department of Electron Microscopy at the Royal Dental College in Aarhus, Denmark (1965/66). In Aarhus, Hubert’s task was to provide light- and transmission electron microscopic material for a comprehensive and representative description of the strictly normal, human oral gingival epithelium. The respective biopsies had to satisfy specific standardized requirements as to their state of health, random collection, and precise orientation of the region under investigation (Schroeder and Theilade, 1966). During this period of training, Hubert came under the influence of Dr. Harald Löe, who, at that time, was Professor and Chairman of the Department of Periodontology in Aarhus. In fact, Harald generously provided Hubert with a monthly salary. As mentioned above, according to Dr. Jens Waerhaug, Harald’s teacher and mentor, a firm attachment between the epithelium of the "physiological pocket" and the enamel surface did not exist. Therefore, if one were to take biopsies of the normal human marginal gingiva, one could expect the tissue coronal to the incision simply to fall off. And indeed, this seemed to be the case. All biopsies were taken randomly from the labial gingival margin of the mandibular incisors and cuspids. This was part of a general experimental strategy that Hubert had learned from Dr. Ewald Weibel, who, at that time, worked as an assistant professor in the Institute of Anatomy in Zürich. Ewald introduced Hubert to the rather new methodology of quantitative stereology (Weibel et al., 1966) that required multistep random sampling and laboratory techniques needed to arrive at representative sections of well-preserved tissues, indispensible for morphometric and stereologic evaluation. When Hubert left Aarhus, Jörgen Theilade remarked that he would like to use the ultrastructure of the dento-gingival junction as the subject of his doctoral thesis. Thankful for Jörgen’s help, Hubert agreed to stay away from this topic.

Back in Zürich, Hubert began to develop plans to study the initial stages of gingival inflammation with light- and electron microscopy. In 1967, still somewhat inexperienced in gingival cytology, and relying on what his teachers Harald Löe and Hans Mühlemann had told him, Hubert began to collect about 40 gingival biopsies from dental students, as his colleagues had done in Aarhus. Despite his extreme care in clinical and laboratory procedures, all his gingival cross-sections displayed a torn attachment epithelium, with widened intercellular spaces. To use Jens Waerhaug’s terminology, he ended up with a poorly preserved "pocket epithelium". Hubert first assumed that these artifacts were due to improper fixation and tissue handling. In any case, Ewald Weibel advised him that the tissue sections obtained so far were unsuitable for quantitative assessments. Hubert decided to change his methodology for sample collection and processing. A first step was to dissect the entire marginal gingiva from the adjacent tissue, extract the tooth with the dissected piece of gingiva still in situ, and then fix both tooth and soft tissue as Max had done (Listgarten, 1966a). Max had then trimmed the tooth next to the gingiva and decalcified the remaining hard tissue in EDTA before processing the tissue for electron microscopy. Hubert severed the soft tissue mechanically, without prior demineralization. Since this also did not result in a well-preserved attachment epithelium, Hubert decided to decalcify the tooth briefly in EDTA, prior to splitting away the dento-gingival fibers just apical to the cemento-enamel junction with a pointed scalpel. Thereafter, the soft tissue simply fell off undisturbed. With practice, this procedure made it possible for him to obtain a gingival specimen free of artifacts, with an intact dento-gingival junction extending from the gingival margin to the cemento-enamel junction. In other words, Hubert’s success in obtaining well-preserved gingival biopsies was the result of trial and error rather than of creative insight or rebellion against his teachers. That came later. In so doing, Hubert could not help recognizing the true nature of the dento-gingival junction. He explained this to Jörgen Theilade, who released him from his promise to refrain from investigating this subject. In the fall of 1968, Hubert offered a series of papers for publication in Harald’s new Journal of Periodontal Research. His first paper, entitled "Extension and strength of the epithelial attachment", was submitted in January, 1969. Hubert had critically analyzed most of the literature on the dento-gingival junction, from Gottlieb (1921) to Löe (1967, 1968). He had reviewed everything known about the nature of basement laminae in general, their synthesis by epithelial cells, and their attachment to various substrata. He had then interpreted his microscopic findings in the light of his literature search. His conclusions were that, in humans, the epithelial attachment is mediated by a basement lamina produced by the attachment epithelium, that this attachment extends from the cemento-enamel junction to the gingival sulcus bottom, and that it withstands any mechanical force applied. In March, 1969, Harald came to visit Hubert. On a long walk through the woods, Harald persuaded Hubert not to publish this somewhat angrily worded, rebellious manuscript. He correctly argued that this paper was very unfair to the generation of teachers who preceded him.

Before proceeding to describe his ultrastructural findings, Hubert had a terminology problem to solve. During his visit to Zürich, Harald had seen most of Hubert’s material and was ready to admit that it did challenge his previous concept of the dento-gingival junction. Up to that time, the term "epithelial attachment" was generally used to refer to the tooth-related epithelium. Hubert believed that this term could no longer be applied to both the epithelium and the attachment apparatus. Harald suggested retaining the term "epithelial attachment" when referring to the attachment apparatus, i.e., the basement lamina and hemidesmosomes. A new term would be needed for the epithelium itself. After discussions with Hans Mühlemann, Hubert agreed to use the term "junctional epithelium", which had been suggested by Anderson and Stern (1966).

With methodology and terminology problems solved, Hubert proceeded to adopt stereologic methods to his studies on gingival tissues and their initial inflammatory changes, as had been his intention from the very beginning. With step-by-step logic, this resulted in a description of the ultrastructure of the junctional epithelium and its attachment to enamel (Schroeder, 1969a), of the diffusion pathway through its intercellular spaces, traced by means of ruthenium red, lanthanum nitrate, and other molecules (Schroeder, 1969b), of a stereological analysis of the cytological components of human junctional vs. oral gingival epithelia (Schroeder, 1970: Schroeder and Münzel-Pedrazzoli, 1970a,b), and, in particular, of the leucocyte content of the junctional epithelium (Schroeder, 1970, 1971, 1973). The results indicated that the junctional epithelium is a non-keratinizing, non-differentiating, fast-renewing epithelium with distensible intercellular spaces that serve as a pathway for an inflammatory exudate and neutrophilic granulocytes, as a residence for lymphocytes and monocytes, as well as for the inward diffusion of foreign molecules.

	COLLABORATIVE STUDIES

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In August, 1969, Max and Hubert met again at the first International Conference on Periodontal Research in Rochester, NY. Since Max had completed his studies on the de novo formation of the junctional epithelium and its attachment apparatus following resective surgery (Listgarten, 1969), he and Hubert believed that with all the material they had collected independently, it might be a good idea to combine their data into a monograph. Actually, Drs. Helmut Zander and Sigurd Ramfjord reinforced this idea by remarking, "Why don’t you two guys get together and solve this problem once and for all?" With support of Drs. Walter Cohen in Philadelphia and Hans Mühlemann in Zürich, Max and his family were able to spend a short summer leave in Zürich in 1970. Within 8 weeks (June 8 to August 2), Max and Hubert managed to write and deliver the manuscript to the publisher. There is no doubt that this monograph (Schroeder and Listgarten, 1971) would not have been ready on time had it not been for the dedicated assistance of two laboratory technicians, Katharina Rossinsky and Susanne Münzel-Pedrazzoli. Also, Max and Hubert were fortunate to have this monograph included in Dr. Thomas Karger’s new series "Monographs in Developmental Biology", and to receive support and approval of Alexander Wolsky, the series editor, and Marie Nylen and Alphonse Burdi, the reviewers. The question of who should be the first author was solved by Max’s suggestion to flip a coin. Hubert won senior authorship by 4 flips out of 7. Still unresolved was the origin of the junctional epithelium under physiological conditions. Without any direct evidence favoring either the reduced enamel epithelium or the oral gingival epithelium, Max and Hubert were temporarily at a loss. Around that time, Dr. Vincent Provenza, from the University of Maryland in Baltimore, delivered a guest lecture in Zürich, about the late stages of amelogenesis. This and a newly published paper (Glavind and Zander, 1970) helped with the interpretation of Hubert’s micrographs. It became clear that the reduced enamel epithelium becomes transformed into junctional epithelium while the tooth erupts. This meant that the primary attachment apparatus persists throughout the eruption process, an interpretation that, up to now, had neither been confirmed nor refuted (Schroeder, 1996). Eventually, Dr. Frank Everett from Portland, OR, the last living pupil of Bernhard Gottlieb, gladly accepted the task of writing a foreword to the monograph, which appeared exactly 50 years after Gottlieb’s landmark paper (1921).

	A NEW LOOK AT FUNCTION

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Thereafter, two questions still remained unanswered: Why did the neutrophilic granulocytes, as Hubert had demonstrated (Schroeder, 1973), tend to accumulate in the most coronal part of the junctional epithelium? And why were up to 60% of all leucocytes in this epithelium non-neutrophils? The answer to the first question was provided when Tonetti et al. (1994) demonstrated that the junctional epithelial cells synthesize and express IL-8 with increasing intensity as they approach the sulcus bottom. As a result, neutrophils are retained near the sulcus bottom and, together with junctional epithelial cells (Lange and Schroeder, 1971), stand ready to phagocytose any bacterium that attempts to enter the junctional epithelium. Therefore, neutrophils play a key role in protecting the gingiva against bacterial invasion (Schroeder, 1977: Schroeder et al., 1989a,b). The answer to the second question was supplied early on, namely, that mononuclear leucocytes, mainly lymphocytes and monocytes, might reside only temporarily within the junctional epithelium, possibly to recognize antigens, prior to re-entering the underlying connective tissue (Schroeder, 1973). Schroeder and Listgarten (1997), when reviewing recently published clinical and laboratory data, concluded that the junctional epithelium serves as a compartment not only for the migration of neutrophils but also for the transient influx of mononuclear leucocytes, an initial step in the immune-mediated defense, at least in the juvenile gingiva. Thus, the junctional epithelium is a major participant in host defenses against bacterial infection.

Received July 11, 2002; Accepted October 30, 2002

	REFERENCES

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Glavind L, Zander HA (1970). Dynamics of dental epithelium during tooth eruption. J Dent Res 49:549–555.[Abstract/Free Full Text]

Gottlieb B (1921). Der Epithelansatz am Zahne. Dtsch Monatsschr Zahnheilk 39:142–147.

Lange D, Schroeder HE (1971). Cytochemistry and ultrastructure of gingival sulcus cells. Helv Odontol Acta 15(Suppl 6):65–86.

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Schroeder HE, Listgarten MA (1971). Fine structure of the developing epithelial attachment of human teeth. In: Monographs in developmental biology 2. Wolsky A, editor. Basel: Karger (2nd ed., 1977).

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