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The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan. Interestingly, the global reduction in the host capability to respond effectively to these challenges is coupled with a progressive increase in the general proinflammatory status, termed 'inflammaging'. Consistent with the definition of immunosenescence, it has been suggested that the cumulative effect of prolonged exposure of the periodontium to microbial challenge is, at least in part, a contributor to the effects of aging on these tissues. Thus, it has also been hypothesized that alterations in the function of resident immune and nonimmune cells of the periodontium contribute to the expression of inflammaging in periodontal disease. Although the majority of aging research has focused on the adaptive immune response, it is becoming increasingly clear that the innate immune compartment is also highly affected by aging. Thus, the phenomenon of immunosenescence and inflammaging, expressed as age-associated changes within the periodontium, needs to be more fully understood in this era of precision and personalized medicine and dentistry.

During the last two to three decades our understanding of the immunobiology of periodontal disease has increased exponentially, both with respect to the microbial agents triggering the disease process and the molecular mechanisms of the host engagement maintaining homeostasis or leading to collateral tissue damage. These foundational scientific findings have laid the groundwork for translating cell phenotype, receptor engagement, intracellular signaling pathways and effector functions into a ‘picture’ of the periodontium as the host responds to the ‘danger signals’ of the microbial ecology to maintain homeostasis or succumb to a disease process. These findings implicate the chronicity of the local response in attempting to manage the microbial challenge, creating a ‘Double Indemnity’ in some patients that does not ‘insure’ health for the periodontium. As importantly, in reflecting the title of this volume of Periodontology 2000, this review attempts to inform the community of how the science of periodontal immunology gestated, how continual probing of the biology of the disease has led to an evolution in our knowledge base and how more recent studies in the postgenomic era are revolutionizing our understanding of disease initiation, progression and resolution. Thus, there has been substantial progress in our understanding of the molecular mechanisms of host–bacteria interactions that result in the clinical presentation and outcomes of destructive periodontitis. The science has embarked from observations of variations in responses related to disease expression with a focus for utilization of the responses in diagnosis and therapeutic outcomes, to current investigations using cutting‐edge fundamental biological processes to attempt to model the initiation and progression of soft‐ and hard‐tissue destruction of the periodontium. As importantly, the next era in the immunobiology of periodontal disease will need to engage more sophisticated experimental designs for clinical studies to enable robust translation of basic biologic processes that are in action early in the transition from health to disease, those which stimulate microenvironmental changes that select for a more pathogenic microbial ecology and those that represent a rebalancing of the complex host responses and a resolution of inflammatory tissue destruction.

Methods -Utilizing a research data bank containing information from 1450 orthodontically treated patients, pre-and post-treatment radiographs from 460 individuals were evaluated for EARR of the four permanent maxillary incisors. Sixty-seven unrelated Caucasians with moderate to severe EARR were identified and were age-/sex-matched with orthodontically treated Caucasian controls yielding 38 females and 29 males per group. Factors tested for an association with EARR included the following: 1) treatment duration, 2) extraction of maxillary premolars, 3) numerous cephalometric measurements, and 4) DNA polymorphisms within/near candidate genes in a pathway previously implicated in EARR such as the purinergic-receptor-P2X, ligand-gated ion channel 7 (P2RX7; rs208294, rs1718119, and rs2230912), caspase-1 (CASP1; rs530537, rs580253, and rs554344), interleukin-1 beta (IL1B; rs1143634), Results -A long length of treatment and the presence of specific genotypes for P2RX7 SNP rs208294 were significantly associated with EARR.Conclusion -EARR occurrence was associated with both genetic and treatment-related variables, which together explained 25% of the total variation associated with EARR in the sample tested.

The Glypican 3 (Gpc3) gene is expressed abundantly in the fetal liver, is inactive in the normal adult liver, and is frequently reactivated in hepatocellular carcinoma (HCC). This reactivation in HCC has led to considerable interest in Gpc3 as a diagnostic tumor marker and its possible role in tumorigenesis. Despite this interest, the basis for Gpc3 regulation is poorly understood. On the basis of the similarities between Gpc3 and alpha-fetoprotein expression in the liver, we reasoned that common factors might regulate these 2 genes. Here we identify zinc fingers and homeoboxes 2 (Zhx2) as a regulator of Gpc3. Mouse strainspecific differences in adult liver Gpc3 messenger RNA levels and transgenic mouse studies indicate that Zhx2 represses Gpc3 expression in the adult liver. We also demonstrate that Gpc3 is activated in the regenerating liver following a carbon tetrachloride treatment and that the level of Gpc3 induction is controlled by alpha-fetoprotein regulator 2 (Afr2). Conclusion: We show that Zhx2 acts as a repressor of Gpc3 in the adult liver, and this raises the interesting possibility that Zhx2 might also be involved in Gpc3 reactivation in HCC. We also show that Gpc3 is activated in the regenerating liver in an Afr2-dependent manner. Zhx2 and Afr2 represent the first known regulators of Gpc3. (HEPATOLOGY 2007;46:1541-1547

Periodontitis is an infectious, inflammatory disease that is associated with a complex interplay between specific bacteria, host response, and environmental factors. Because of its high degree of familial aggregation, specifically for the more aggressive forms of the disease, genetics factors have been implicated in disease pathogenesis for several decades. This review provides an overview of what we currently know regarding the genetic and epigenetic contributions to periodontal disease and discusses future opportunities in the field.

These data indicate that one mechanism by which gliomas cause immunosuppressive effects is the induction of monocytes to release soluble factors that promote activated T-cell apoptosis. The loss of activated T cells leads to T lymphopenia and contributes to the deficiencies in cell-mediated immunity that have been observed during testing of glioma patients' immune function.

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