Immunology and Immunotherapy Program
Mineralized Tissue and Salivary Gland Physiology Program
Center for Integrative Biology and Infectious Diseases
OBJECTIVE
The goal of this initiative is to solicit novel research projects designed to provide a fundamental understanding of the intersystem crosstalk between alveolar bone and the immune system, and how osteoimmunology operates in normal and pathologic conditions. It will contribute to our understanding of how both systems are regulated in a physiologic context, at the molecular and cellular levels and at the level of organ systems. Specifically the initiative will solicit research that will identify the influence of the immune system on oral bone biology; the extent to which normal immune responses affect oral bone homeostasis; the consequences of oral bone on adaptive immune responses; the interplay between the immune system and age-related oral bone changes; and the changes in the host immune system that impact oral bone loss. The emerging field of osteoimmunology is important for formulating intervention strategies for periodontitis as well as for basic and clinical studies in related fields.
BACKGROUND
The emerging field of oral osteoimmunology represents a conceptual rethinking of multiple phenomena, interrelating biological events in the oral bone and the immune system. The root of exploration of this interplay begins with the basic understanding that bone provides a microenvironment that is critical for the development of hematopoetic stem cells (HSC), from which all the cells of the mammalian immune system derive, and that various immunoregulatory cytokines influence the fate of bone cells.
The reason bone is an ideal anatomic site for HSC maintenance and differentiation has become clearer with recent findings indicating that osteoblasts (OB) provide key factors for the development of HSC niches. However, there is growing evidence that bone continues to play a role in adaptive immunity at later stages beyond lymphocyte development. For example, it is now known that long-lived memory T and B cells return to specialized niches in the bone marrow. The significance of this observation is currently unknown but could be important in the crosstalk between the bone and immune system.
Bone homeostasis is in turn regulated by immune responses, particularly when the immune system has been activated by infection or becomes disregulated. In conditions such as periodontitis, infiltrating lymphocytes and other mononuclear cells produce key factors, which influence bone turnover by altering the balance between bone formation, mediated by OB, and bone resorption, mediated by osteoclasts (OCs). Beyond such pathological conditions, the question of whether the immune system influences normal oral bone metabolism, either by direct or indirect mechanisms, remains unanswered. However, the discovery of a tumor necrosis factor (TNF) family member, RANKL (receptor activator of NF-κB ligand), as a key differentiation factor for OC, and the findings that RANKL is expressed on activated T and B cells, has provided critical evidence for a potential link between normal immune responses and bone turnover. It is therefore becoming clear that crosstalk between the immune system and oral bone through activated lymphocytes and bone cells occurs throughout life, as all mammals are constantly challenged by a diverse oral microflora, which induces some level of constant low grade immune system activation. Furthermore, as the aging process unfolds, there is an accumulation in the bone marrow of memory T cells and B cells, which express RANKL on their surface. These cells have now been shown to modulate bone turnover, in particular in periodontitis.
Many of the pathologic processes of immune system-stimulated oral bone could represent targets for therapeutic intervention. However, the search for novel interventions and therapies for these conditions has often been pursued in the absence of a solid scientific understanding of the molecular and cellular pathways that underlie these processes. The presence of periodontal disease is measured clinically in several ways, most commonly by determining the loss of periodontal attachment. According to the U.S. Surgeon General Report on Oral Health, most periodontitis affected adults 25 years and older have at least 2mm or more loss of attachment. Oral bone is also lost following infection of the dental pulp. These health concerns grow as people live longer and expect to remain active and fully functional as they age. Future interventions to prevent and treat oral bone diseases will likely require a high degree of specificity, especially because these therapies are often tailored for a segment of the population that is already suffering from or vulnerable to other age-related ailments. These issues place oral osteoimmunology in a position of unique clinical relevance.
The oral cavity has evolved features that make it a physiologically active as well as anatomic barrier. Most of the 700 species of bacteria that constitute the oral microbial consortium are commensals, coexisting without negative impact on the oral bone. The lack of inflammation despite the dense bacterial microflora populating the oral cavity reflects a combination of finely tuned, opposing processes: permanent surveillance for invasive microorganisms, which leads to minimum responses to eradicate these invaders; and tolerance or at least lack of reactivity. Studies over the years have focused on many aspects of the oral bone such that there is now good understanding of many of the key cellular and molecular mechanisms governing the homeostasis of bone. However, a detailed understanding of the extensive cross-talk between the oral bone and the immune system and the biological implications of such interactions remain poorly understood. Examples of gaps in our knowledge are:
- The immunopathological mechanism(s) that link periodontal and pulpal infection and pathological bone resorption
- The role of innate and adaptive immune cells in the normal as well as pathological bone turnover in the oral cavity
- The role of cytokines and other cellular factors in oral bone development and pathology
- The role of cells/factors that regulate B cells and how B cells regulate OB and OC in the oral cavity
- The roles of circulating lymphocytes and other immune cells in normal and pathological oral bone metabolism
- Identification of new therapeutic strategies to prevent inflammation-induced bone loss
- Definition of regulatory signals and pathways that influence both oral bone and immune cells, such as signals between immune cells and neural cells
- Immunomodulatory strategies to reduce or prevent oral bone loss
- Whether osteo-immune cross-talk is different in oral vs axial/appendicular bone
- Ontogeny of osteoimmune interactions in the host
RECOMMENDATIONS FROM WORKSHOPS
There is a broad enthusiasm from several scientists at the 1st International Conference on Osteoimmunology in Greece, May 28- June 2, 2006.