| Abstract|| |
Root resorption seems to be related to a complex combination of mechanical factors and biological activity, which comprehends the role of immunologic structures including specialized cells. The aim of this research was to explain the development of the process - from mineralization to the destruction of hard tissues - and the possible relationship between root resorption and immunology, along with discussing current concepts described in the literature.
Keywords: Allergy and immunology, odontogenesis, root resorption, tooth resorption
|How to cite this article:|
Silva LB, Guimaraes CS, Santos RA. Immunology of root resorption: A literature review. Indian J Dent Res 2008;19:340-3
Dental resorptions constitute a challenge to dentistry due to the organic complexity that such processes unchain. The concern and curiosity on this subject are not recent. The oldest report about resorptions of the dental structures was described by Michael Blum in 1530, probably the first book about the science and art of the dental surgery. However, the scientific study of root resorptions are considered recent, embracing nearly a period of two decades in which more questions than responses have appeared. In order to comprehend this process, it is necessary to study the formation and degradation of hard tissues, as well as the cells involved in it. 
|How to cite this URL:|
Silva LB, Guimaraes CS, Santos RA. Immunology of root resorption: A literature review. Indian J Dent Res [serial online] 2008 [cited 2013 May 26];19:340-3. Available from: http://www.ijdr.in/text.asp?2008/19/4/340/44539
| Literature Review|| |
It is easy to understand why three of the four hard tissues in the body (bone, cementum, and dentin) have many similarities in their formation. They all are specialized connective tissues, and collagen (mainly type I) plays a large role in determining their structure. Although enamel is not a connective tissue and has no collagen involved in its makeup, its formation still follows many of the principles involved in the formation of hard connective tissue. ,,,,
Hard tissue formation involves cells situated close to a good blood supply, producing an organic matrix capable of accepting mineral (hydroxyapatite). These cells thus have the cytological features of cells that both synthesize and secrete protein. For all the hard tissues, except enamel, this matrix consists of collagen and ground substance, and the mineral is located around and within the collagen fibers. In enamel, most of the organic matrix is lost once mineralization has been initiated to accommodate more minerals. ,,,,,
Mineralization in the connective hard tissues entails an initial nucleation mechanism involving a cell-derived matrix vesicle. After initial nucleation, further mineralization is achieved by nucleation related to the collagen fibers. In enamel, the mechanism of initial mineralization is thought to be an extension from the apatite crystals of dentin, with further crystal growth dictated by the enamel matrix. 
The degradation and removal of hard tissues are a cellular event brought about by giant multinucleated cells formed through asynchronous fusion of mononuclear cells belonging to the macrophage lineage and originating from the hematopoietic system. They are called 'clasts' and are easy to identify under the light microscope because of their size (50-100 µm), their multinucleation (2-10 nuclei/cell), and their association with their surface of the bone (occupying shallow depressions known as Howship´s lacunae). Under the electron microscope, multinucleated osteoclasts exhibit a unique set of morphologic characteristics. Adjacent to the mineralized surface their cell membrane is thrown into a myriad of deep folds that form a brush border, sometimes visible by light microscopy in good preparations. At the periphery of the brush border, the plasma membrane is closely apposed to the mineralized surface (within 0.2-0.5 nm), and the adjacent cytoplasm, devoid of cell organelles, is filled with fibrillar contractile proteins. This clear or sealing zone not only attaches the cells to the mineralized surface but also (by sealing the periphery of the brush border) isolates a microenvironment between them and the mineralized surface. The cells organelles consist of many nuclei, each surrounded by multiple Golgi complexes, an array of mitochondria and free polysomes, a rough endoplasmic reticulum, many coated transport vesicles, and numerous vacuolar structures. It has been known for years that osteoclasts are rich in acid phosphatases as well as other lysosomal enzymes. This concentration of enzymes, however, is not associated with lysosomal structures as in most other cells. Instead, it is known that the enzymes are synthesized in the rough endoplasmic reticulum, transported to the Golgi complexes, and from there, in coated transport vesicles, moved to the brush border (where by a process of exocytosis, their release occurs into the sealed compartment adjacent to the mineralized surface). Another recently recognized feature of osteoclasts is the presence of a proton pump associated with the ruffled border, pumping hydrogen ions into the sealed compartment. ,,
Thus, the sequence of resorptive events is considered to be: attachment of clasts to the mineralized surface; creation of a sealed acidic environment through action of the proton pump, which demineralizes and exposes the organic matrix; degradation of this exposed organic matrix to its constituent amino acids by the action of released enzymes such as acid phosphatase and cathepsin B; and uptake of mineral ions and amino acids by the cell. 
The resorptive cells of dental hard tissue are called odontoclasts and are similar in most respects to osteoclasts, although maybe somewhat smaller. Odontoclasts possess endocytotic vesicles containing liberated apatite crystals, which suggests that demineralization in the resorptive environment is not as complete compared to osteoclasts. 
Some structures and some cellular types of the organism, since the very beginning of the intrauterine life, must be concealed from the immunologic system so that they are not interpreted as 'nonself' structures. One of these structures is the dentin.
During the dentinogenesis, the coronary dentin is protected by the recently formed enamel as well as the dental external epithelium, stellate reticulum, stratum intermedium, and by the ameloblasts. The root dentin is protected by Hertwig's epithelial root sheath, by the intermediate cementum, and, after the fragmentation of the sheath, by the cementoblasts and cementum. Such structures keep the dentin protected against the immunologic system during the development of the natural tolerance, and in case the dentinary proteins are exposed, they may cause an immunologic response against the 'self' components of the organism - known as an autoimmune reaction. ,
Once exposed to the immunologic system, a cascade of events takes place for the lymphocytes to recognize and activate other cellular types to differentiate in order to eliminate the 'nonself' components. In the case of the dentin, osteoclasts are the primary cellular type involved in root resorption, and they come from the lineage of the macrophages - phagocitic cells located in the tissues derived from the monocytes playing an important role in the immune response. One of the ways for macrophages to be activated is by microbial products, such as endotoxins and cytokines from T cells, such as IFN-g. When activated they kill microorganisms, secrete pro-inflammatory cytokines, and present the antigens to T auxiliary cells. Macrophages can also acquire different morphologies in the varied tissues of the body, such as Kupffer cells in the liver and osteoclasts in the bone, or even odontoclasts to destroy dental structures. 
The action mechanism against antigens demands different responses depending on the characteristics of the pathogen and the site of attack. It is observed that the host organism develops innate and adaptive immune defense mechanisms, the former, on one hand, being nonspecific, attacking any nonself components or antigens; and the latter, on the other hand, extremely specific. Both types of immune responses act together in order to eliminate pathogenic antigens through the discrimination of what are self and what is not. The review describes the key mechanism used by the immunologic system to respond to such antigens. 
The process of root resorption in humans is a complex and interesting biological phenomenon; not only because it is a natural process occurring during the exchange of primary and secondary dentitions but also because it is an essential step to attain immunological maturation. Although most root resorption studies attempt to investigate the etiologic factors and predictability of this phenomenon, its origins remain obscure. Nevertheless, in some occasions, the immunologic system attacks the dentition in an unknown immune response that tries to destroy their roots - a process named idiopathic root resorption.  Tooth replanted after avulsion injuries normally present with pulpal and periodontal sequelae due to severance of the apical neurovasculature and damage to the attachment apparatus.  In replanted teeth, severe damage in the periodontal ligament and absence of infection will lead to replacement resorption, which can be resumed by the approximation and consequent replacement of the dental structures by osseous tissue.  Consequently, if infection of the necrotic pulp occurs, inflammatory root resorption of pulpal origin would ensue.  However, if the attachment damage during the traumatic avulsion is severe and sustained with infective inflammatory stimulation, ankilosis with replacement root resorption or osseous healing would be the final outcome after the periodontal inflammation subsides.
Root resorption can be classified into two general types: physiologic and pathologic resorptions. The former occurs in deciduous teeth as a result of the natural dental exfoliation, and the latter occurs either externally (involving the outer part of the tooth - cementum and dentin) or internally (involving the walls corresponding to pulpal space). They can also be trigged by pressing of impacted teeth on the surrounding teeth, replanted teeth, chronic oclusal trauma, malignant or benign tumors, periapical lesions, metabolic or systemic alterations, hereditariness, orthodontic treatment, dental whiteness, or idiopatic factors.  This complex process would involve the main cells of the more developed organisms' organic defense. The primary defense mechanism is the innate or cellular immunity that is basically unspecific in its phagocitary functions, though capable of activating the second lineage of more sophisticated T cells through chemotactic substances representative of the adaptive or humoral immune response, mainly characterized by the B and T lymphocytes; the former is responsible for the protection of the organism against extracellular antigens through the production of antibodies; and the latter for the organic protection against intracellular antigens. The way by which these cells communicate is established by the intermission of cytokines and chemokines, and by the interaction of the antigen presenting cells with the T lymphocytes. 
Macnab et al.,  proposed that systemic factors, such as the inflammatory chemical mediators produced during asthma are able to reach the periodontal ligament (PDL) and act synergistically to increase root resorption. The aim of their study was to determine if asthmatic patients exhibited a higher incidence of apical root resorption compared with healthy patients after fixed orthodontic treatment. They claim that the displacement of a tooth for an orthodontic load results in the death of many cells in the PDL area; the removal of the consequent necrotized tissue is therefore necessary before the dental movement. They concluded that the combinatory analysis of the teeth showed that asthmatic patients showed more statistically significant dental resorptions than nonasthmatic patients; however, in spite of the higher incidence of the first group, both groups exhibited similar amounts of resorption degree-2 (moderate) and degree-3 (severe).
Cytokines and chemokines are substances used by the immunological cells to communicate. With special interest for this review is the fact that only interleukin-1α has a potent capacity, as far as it is known, to increase root resorption. As the studies concerning root resorption continues, some researchers have tried to associate its origins with a specific antigen, present in the dentin that would trigger the immunologic system.
King and Courts  affirmed that the depression in autoantibody titers to tooth root antigens has been shown to coincide with active root resorption in dogs. The objectives of their study were to develop a quantitative mouse model for root resorption and to determine if a similar drop in tooth root autoantibodies coincided with active root resorption. Uniform areas of necrosis were created in the periodontal ligaments of lower incisors of 36 male Swiss albino mice by inserting a cryoprobe through a skin incision. Contralateral incisors served as controls. At 0, 3, 5, 7, 10, 14, and 21 days, six mice were killed, and blood and incisors were collected. Serum autoantibody titers were determined with an enzyme-linked immunosorbent assay (ELISA) antigen prepared with incisor root extracts harvested from the mice. No root resorptions were evident on the control teeth. Localized lesions on treated teeth were found to be of significant size between 7 and 14 days (P < 0.05), but most of these erupted into the mouth by 21 days. Autoantibody titers were reduced by 3 days, remained depressed until 14 days, and returned to pretreatment levels by 21 days. Furthermore, the mouse, like the dog, harbors a serum autoantibody to tooth root antigens and this is suppressed during active root resorption.
A study was accomplished with the purpose of examining the response to traumatic root resorption in mice after their hyperimmunization with a crude tooth extract (dentin). The hypothesis of their study was that elevated dentin antibody titers would positively correlate with root resorption. The mice were immunized with mouse dentin and controls were sham immunized. All mice were given booster dosages four weeks later with or without mouse dentin, as appropriate. All mice were again given booster dosages twice at weekly intervals with mouse dentin and then twice at weekly intervals with rat dentin, in order to increase mouse serum antibody titers to dentin. Mice were killed ten days later, and serum tested for antibody to dentin antigen. Root resorption was observed on the incisors in the sham-immunized mice but not in the dentin-immunized mice. Only the serum antibody titers to dentin from preimmune mice and bleed five were statistically significant. The authors' data indicate that antibodies do not mediate the traumatic root resorption process as originally hypothesized. They suggest that hyperimmunization with dentin may protect against traumatic root resorption. 
Some works have opined that replacement dental resorption may be a consequence of trauma and may cause transplant and reimplants to fail. Hidalgo, Itano, and Consolaro  demonstrated the participation of the immunopathological response in inflammatory dental resorption. They claim that the mechanisms of the two types of dental resorption are different. The aim of their study was to observe the immune responses of patients who suffered dental trauma with subsequent replacement dental resorption. The ELISA results demonstrated that serum from patients with replacement root resorption contained larger amounts of IgG and smaller amounts of IgM anti-total human-dentin extract and anti-fractions of extract than did serum from control individuals. Their results signal a hypothesis that dentin is immunogenic and the serological profile of patients with replacement dental resorption may be identified through biochemical analysis of their blood. The authors conclude that this method may allow early diagnosis of the dental resorption before it becomes radiographically visible.
| Conclusions|| |
Root resorption seems to be related to a complex combination of mechanical factors and biological activity, which comprehends the role of immunologic structures including specialized cells. Root resorption is a common occurance in odontological clinics. However, although most root resorption studies attempt to investigate the etiologic factors and predictability of this phenomenon, its origins remains obscure.
| Acknowledgment|| |
Our sincere thanks to the University of Pernambuco, and our special thanks to Dr. Ana Paula Veras Sobral for her unconditional support on the construction of this study.
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Luciano B Silva
Department of Endodontics, University of Pernambuco