CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose.

There are two major mechanisms reported to prevent the autoreactivity of islet-specific CD8(+) T cells: ignorance and tolerance. When ignorance is operative, na?ve autoreactive CD8(+) T cells ignore islet antigens and recirculate without causing damage, unless activated by an external stimulus. In the case of tolerance, CD8(+) T cells are deleted. Which factor(s) contributes to each particular outcome was previously unknown. Here, we demonstrate that the concentration of self antigen determines which mechanism operates. When ovalbumin (OVA) was expressed at a relatively low concentration in the pancreatic islets of transgenic mice, there was no detectable cross-presentation, and the CD8(+) T cell compartment remained ignorant of OVA. In mice expressing higher doses of OVA, cross-presentation was detectable and led to peripheral deletion of OVA-specific CD8(+) T cells. When cross-presentation was prevented by reconstituting the bone marrow compartment with cells incapable of presenting OVA, deletional tolerance was converted to ignorance. Thus, the immune system uses two strategies to avoid CD8(+) T cell-mediated autoimmunity: for high dose antigens, it deletes autoreactive T cells, whereas for lower dose antigens, it relies on ignorance.     

Systematic review of the treatment and prognosis of the odontogenic keratocyst

OBJECTIVES: To clarify the natural history of the odontogenic keratocyst (OKC) and to evaluate treatments with respect to the likelihood of recurrence. STUDY DESIGN: A systematic review of the literature was completed pertaining to the treatment and prognosis of the OKC. Each investigation was evaluated based on 4 inclusion criteria. Each study that met the 4 inclusion criteria was then evaluated based on 8 standards. RESULTS: Of 2290 citations reviewed pertaining to the OKC, 14 investigations were found to meet the 4 inclusion criteria. Resection was found to have the lowest recurrence rate (0%) but the highest morbidity rate. Simple enucleation was reported to have a recurrence rate of 17% to 56%. Simple enucleation combined with adjunctive therapy, such as the application of Carnoy's solution or decompression before enucleation, was reported to have recurrence rates of 1% to 8.7%. CONCLUSIONS: Although the existing literature consists of retrospective consecutive case series, it appears that resection or enucleation with adjunctive therapy is associated with recurrence rates that are lower than those associated with enucleation alone.     

Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw

OBJECTIVE: Following publication of the first reports of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates in 2003, a call for national multidisciplinary guidelines based upon a systematic review of the current evidence was made by the Canadian Association of Oral and Maxillofacial Surgeons (CAOMS) in association with national and international societies concerned with ONJ. The purpose of the guidelines is to provide recommendations regarding diagnosis, identification of at-risk patients, and prevention and management strategies, based on current evidence and consensus. These guidelines were developed for medical and dental practitioners as well as for oral pathologists and related specialists. METHODS: The multidisciplinary task force established by the CAOMS reviewed all relevant areas of research relating to ONJ associated with bisphosphonate use and completed a systematic review of current literature. These evidence-based guidelines were developed utilizing a structured development methodology. A modified Delphi consensus process enabled consensus among the multidisciplinary task force members. These guidelines have since been reviewed by external experts and endorsed by national and international medical, dental, oral surgery, and oral pathology societies. RESULTS: Recommendations regarding diagnosis, prevention, and management of ONJ were made following analysis of all current data pertaining to this condition. ONJ has many etiologic factors including head and neck irradiation, trauma, periodontal disease, local malignancy, chemotherapy, and glucocorticoid therapy. High-dose intravenous bisphosphonates have been identified as a risk factor for ONJ in the oncology patient population. Low-dose bisphosphonate use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of ONJ. Prevention, staging, and treatment recommendations are based upon collective expert opinion and current data, which has been limited to case reports, case series, surveys, retrospective studies, and 2 prospective observational studies. Recommendations: In all oncology patients, a thorough dental examination including radiographs should be completed prior to the initiation of intravenous bisphosphonate therapy. In this population, any invasive dental procedure is ideally completed prior to the initiation of high-dose bisphosphonate therapy. Non-urgent procedures are preferably delayed for 3 to 6 months following interruption of bisphosphonate therapy. Osteoporosis patients receiving oral or intravenous bisphosphonates do not require a dental examination prior to initiating therapy in the presence of appropriate dental care and good oral hygiene. Stopping smoking, limiting alcohol intake, and maintaining good oral hygiene should be emphasized for all patients receiving bisphosphonate therapy. Individuals with established ONJ are most appropriately managed with supportive care including pain control, treatment of secondary infection, removal of necrotic debris, and mobile sequestrate. Aggressive debridement is contraindicated. CONCLUSION: Our multidisciplinary guidelines, which provide a rational evidence-based approach to the diagnosis, prevention, and management of bisphosphonate-associated ONJ in Canada, are based on the best available published data and the opinion of national and international experts involved in the prevention and management of ONJ.     

CD4+ T Cell Help Impairs CD8+ T Cell Deletion Induced by Cross-presentation of Self-Antigens and Favors Autoimmunity

Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I–restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8⁺ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4⁺ T cell help on this process. Small numbers of autoreactive OVA-specific CD8⁺ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic β cells. Coinjection of OVA-specific CD4⁺ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8⁺ T cells indicated that CD4⁺ T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8⁺ T cell tolerance induced by cross-presentation.There is now considerable evidence that CD8⁺ T cell responses can be induced in vivo by professional APCs capable of MHC class I–restricted presentation of exogenous antigens (1–3). This mechanism is known as cross-presentation and was suggested to be instrumental in the immune response to pathogens that avoid professional APCs (2–4). However, if this pathway was only directed towards induction of immunity, cross-presentation of self-antigens to autoreactive CD8⁺ T cells would result in autoimmunity. Recently, in studies using transgenic mice that express a membrane-bound form of OVA under the control of the rat insulin promoter (RIP-mOVA), we have shown that this is not the case. RIP-mOVA mice express membrane-bound OVA in pancreatic islets, kidney proximal tubular cells, thymus and testis. In these mice, OVA was found to enter the class I presentation pathway of a bone marrow– derived cell population and then activate transgenic OVA-specific CD8⁺ T cells (OT-I cells) (3) in LNs draining the sites of antigen expression. Although this form of activation initially led to proliferation of OT-I cells, it ultimately caused their deletion (5). Thus, cross-presentation can remove autoreactive CD8⁺ T cells, and may tolerize the CD8⁺ T cell compartment to self-antigens. These studies, however, did not explain why cross-presentation of a self-antigen induced CD8⁺ T cell tolerance, whereas foreign antigens induced immunity (1–4, 6).In numerous models, CD4⁺ T cell help has been shown to be important for the induction or maintenance of immune responses by CD8⁺ T cells (7–11), but such help is not always essential (12–14). CD4⁺ T cell help has also been shown to be important for avoiding CTL tolerance induction (15–17). In these reports, however, it was not known whether CD8⁺ T cells were activated by cross-presentation or by direct recognition of antigen. Thus, whether CD4⁺ T cell help can affect tolerance induced by cross-presentation has not been addressed. Recently, we demonstrated that cross-priming by foreign antigens requires CD4⁺ T cell help for induction of CTL immunity (6). In this study, we have investigated the influence of such help on the deletion of CD8⁺ T cells induced by cross-presentation of self-antigens.     

Pigmented lesions of the oral cavity: review, differential diagnosis, and case presentations

Pigmented lesions are commonly found in the mouth. Such lesions represent a variety of clinical entities, ranging from physiologic changes to manifestations of systemic illnesses and malignant neoplasms. Evaluation of a patient presenting with a pigmented lesion should include a full medical and dental history, extraoral and intraoral examinations and, in some cases, biopsy and laboratory investigations. In this paper, an algorithm is proposed for the assessment of pigmented lesions of the oral cavity, and 3 patients with such lesions are described.