The Effects of NF-kB Inhibition with p65-TMD-Linked PTD on Inflammatory Responses at Peri-implantitis Sites.

The objective of this study was to find out if suppression of NF-kB complex function by p65-TMD-linked PTD could reduce host inflammation and bone resorption at peri-implantitis sites in rats. Twenty-one male 5-week-old SD rats were divided into three groups: untreated control group (A), silk-induced peri-implantitis group (B), and nt (nucleus transducible)-p65-TMD-treated, silk-induced peri-implantitis group (C). Implant sulcus of a rat in group C were divided into two groups, namely group Cp and Cb. Palatal implant sulcus where nt-p65-TMD solution was applied with an insulin syringe were assigned to group Cp. Buccal implant sulcus without topical nt-p65-TMD application were assigned to group Cb. H&E staining, TRAP staining, and immunohistological staining were done. The crestal bone levels of group A were significantly higher than those of group B at p<0.01. The crestal bone levels of group Cp were significantly higher than those of group Cb at p<0.05. H-E staining showed increased apical migration of junctional epithelium and inflammatory cells in group Cb. TRAP staining revealed more multinucleated osteoclasts in group Cb. As for immunohistological staining, group Cb showed many IL-6-positive cells while group Cp had none. In this study, p65-TMD-linked PTD inhibited NF-kB functions and reduced inflammation and bone resorption at peri-implantitis sites in rats.

Monitoring indices of bone inflammatory activity of the jaw using SPECT bone scintigraphy: a study of ARONJ patients.

Development of quantitative analysis software has enabled application of several standardised uptake values (SUV) for bone analysis in single photon emission computed tomography (SPECT). The present retrospective study aimed to develop a reliable method of monitoring bone inflammatory activity in antiresorptive agent-related osteonecrosis of the jaw (ARONJ) using SPECT quantitative analysis software. Fifteen ARONJ patients underwent SPECT before and after anti-inflammatory therapy. We calculated the mean maximum SUV (SUVmax) of the bilateral cranial bones using quantitative analysis software and used this as the control [C]. We attempted to adjust the SUVmax of the lesion [L] as follows: adjusted SUVmax (aSUVmax) = [L] - [C]. The optimum threshold to calculate the metabolic bone volume (MBV) (cm3) was [C] + 3. The threshold values obtained for each case were input to calculate MBV at each osteomyelitis site. Retrospectively, we compared aSUVmax and MBV of each patient's ARONJ before and after anti-inflammatory therapy. The patients' high aSUVmax or large MBV of the ARONJ reduced rapidly, reflecting individual clinical findings after treatment. Application of SPECT quantitative analysis software to monitor bone inflammatory activity in ARONJ could improve the prognosis-deciding abilities of clinicians and enable them to treat ARONJ effectively.

Biocompatibility of pure and mixed hydroxyapatite and α-tricalcium phosphate implanted in rabbit bone.

Calcium phosphates and hydroxyapatite, in particular, are used as substitute materials in experimental implantology. These materials are primarily used in hard tissue replacement because their chemical and crystallographic characteristics are considered to be similar to the mineral content, osteoconductivity and bioactivity of normal bone. Cytokines, such as interleukin (IL)-1, IL-6, IL-8, IL-10 and antimicrobial protein ß-defensin-2 (ßDef-2), are used as biomarkers of non-specific reactogenicity. Other biomarkers, including bone morphogenetic protein-2/4 (BMP-2/4), bone regeneration protein osteoprotegerin (OPG), bone matrix protein osteopontin (OP) and osteocalcin (OC), are regarded as specific factors of reactogenicity in bone substitution. The aim of our study was to assess the changes in the distribution and expression of the aforementioned proteins in the lower jaws of rabbits following implantation with pure hydroxyapatite (HAP), α-tricalcium phosphate (α-TCP) or a mix of the two (HAP/α-TCP) manufactured under different temperatures. Our results reveal osteoblast proliferation and regions of granulation tissue formation between biomaterial granules close to the original implantation site, but in the control tissue these changes were less noticeable. Our study showed low variability in the distribution of ßDef-2, OPG and all of the tested interleukins and these proteins were less expressed than BMP2/4, OP and OC. But across all experiments, no statistically significant difference in mean ßDef-2, IL-1, IL-6, IL-8, IL-10, OP, OC, BMP-2/4 and OPG expression in osteocytes was detected between experimental and control groups. We concluded that pure and mixed HAP and α-TCP sintered at different temperatures do not affect the production of cytokines and bone-specific proteins; regions with osteoblast proliferation and low levels of anti-inflammatory cytokines IL-6 and IL-10 indicates better biocompatibility for HAP/α-TCP and α-TCP-2 biomaterials and the moderate number of BMP-2/4- and a prevalence of OC- and OP-positive osteocytes in experimental tissues implanted with HAP at 3 months after implantation indicates potential bone regeneration stimulated by pure HAP.

Bacteria take control of tolls and T cells to destruct jaw bone.

Bone undergoes a continuous cycle of remodeling for maintenance and healing. For almost a decade it has been appreciated that the immune system is intricately linked to bone homeostasis. Both acute and chronic inflammatory responses have been shown to impact bone health. A common form of inflammatory disease that causes bone destruction is the chronic infectious disease known as periodontitis (PD). PD is a bacteria-driven inflammation of the tooth-supporting apparatus that leads to resorption of the alveolar (jaw) bone, often leading to tooth loss. At the host-bacteria interface, Toll-like receptors (TLRs) play an instructive role in the development of innate and T cell adaptive responses to oral bacteria. Specifically, it is becoming apparent that TLR2-mediated inflammatory responses represent the major arm of the host immune response during periodontitis, and form an important link between periodontal infection and ensuing periodontal bone loss. This review summarizes the role of TLR2-mediated interplay between immune cells and bone cells in a periodontal disease setting.

Comparative immunology: allorecognition and variable surface receptors outside the jawed vertebrates.

Allograft rejection is one of several undesirable consequences of the adaptive nature of the mammalian immune response. This review examines adaptive immune responses and allorecognition in animals with very different immune responses - jawless vertebrates, arthropods, and two distinct colonial marine invertebrates - with the goal of understanding how immune adaptation and allograft rejection are linked, and conversely how a system works where allograft rejection is a desired outcome rather than an unforeseen consequence.

Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri).

BACKGROUND: Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. OBJECTIVE: To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. DESIGN: Retrospective case series with prospective clinical follow-up. SETTING: Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. PATIENTS: Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. MAIN OUTCOME METHODS: Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. RESULTS: Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. CONCLUSIONS: Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.

Evolution of adaptive immune recognition in jawless vertebrates.

All extant vertebrates possess an adaptive immune system wherein diverse immune receptors are created and deployed in specialized blood cell lineages. Recent advances in DNA sequencing and developmental resources for basal vertebrates have facilitated numerous comparative analyses that have shed new light on the molecular and cellular bases of immune defense and the mechanisms of immune receptor diversification in the "jawless" vertebrates. With data from these key species in hand, it is becoming possible to infer some general aspects of the early evolution of vertebrate adaptive immunity. All jawed vertebrates assemble their antigen-receptor genes through combinatorial recombination of different "diversity" segments into immunoglobulin or T-cell receptor genes. However, the jawless vertebrates employ an analogous, but independently derived set of immune receptors in order to recognize and bind antigens: the variable lymphocyte receptors (VLRs). The means by which this locus generates receptor diversity and achieves antigen specificity is of considerable interest because these mechanisms represent a completely independent strategy for building a large immune repertoire. Therefore, studies of the VLR system are providing insight into the fundamental principles and evolutionary potential of adaptive immune recognition systems. Here we review and synthesize the wealth of data that have been generated towards understanding the evolution of the adaptive immune system in the jawless vertebrates.

The immunohistochemical localization of Fas and Fas ligand in jaw bone and tooth germ of human fetuses.

The cellular localization and roles of bone morphogenetic protein (BMP)-2 and apoptosis-associating factors in human orofacial development remain unclear. In this study, BMP-2, osteocalcin, and TGF-beta, which are bone-differentiating markers, apoptosis-associating factors (i.e., Bcl-2, Bax, Fas, and Fas ligand), apoptotic cells detected by the in situ 3'-end labeling method (TUNEL), and proliferating cell nuclear antigen (PCNA) were immunohistochemically examined in the heads (in particular, the jaw bone and tooth germs) of human fetuses of 11-week pregnancy. BMP-2 was positive in osteoblasts and newly formed osteoid of the incisive and palatal bone of the maxilla and the mandible, which indicated that BMP-2 was exclusively involved in intramembranous ossification in the human fetal head. Fas was positive in the cytoplasm of osteocytes and a few osteoblasts. In contrast, Fas ligand was positive in the cytoplasm of osteoblasts and abundant in the stroma of the osteoblastic layer, periosteum, and perichondrium. The Fas ligand in the stroma was recognized as the soluble form, which was possibly produced by osteoblasts. TUNEL-positive apoptotic cells were found in a few osteocytes and a few osteoblastic cells in new bone, and in monocytes of degenerate Meckel's cartilage. The induction of apoptosis observed in monocytes seems to be caused via a Fas-Fas ligand cell death system, because some of these monocytes were Fas-positive, and most of them were Fas ligand-positive. Interestingly, the abundant soluble Fas ligand observed in the periosteum probably protects the bone-formative zone from the invasion of the activated lymphocytes by binding to Fas expressing in these lymphocytes and killing these cells. Fas and Fas ligand were focally positive in the dental lamina and inner enamel epithelium and cusps of the enamel organ, nevertheless, the presence of TUNEL-positive cells was very rare. Bcl-2 was clearly and Bax was weakly positive in the cells throughout the dental lamina and enamel organ. These findings indicated that Fas-mediated apoptosis was inhibited by the Bcl-2 family in the development of teeth.