Vascular Endothelial Growth Pattern During Demineralized Bone Matrix Induced Osteogenesis

The purpose of the current study was to determine the timely ingrowth of blood vessels associated with demineralized bone matrix (DMB) induced osteogenesis. Critical-size (10 × 5mm), full thickness bony defects in rabbit parietal bone were implanted with DBM. Histological and ultrastructural changes were examined 1, 2, 3, 4, 5, 6, 7 and 14 days later. Neovascularization was assessed by immunohistochemical staining for factor VIII antigen (marker for vascular endothelium) and also confirmed by staining using pan-endothelial antibody (CD31) (a marker for endothelium). Immunohistochemical evaluation revealed a positive staining for CD31 and Factor VIII expressed by endothelial cells by day 3 post grafting. By day 4, small blood vessels were first seen budding from host bed towards the grafted DBM. Ultrastructural identification of cells in the early stages of healing revealed the presence of macrophages. The monocyte-derived macrophage appears to play a central role in the repair process using DBM. Results of this study demonstrated a rapid vascularization during the DBM induced osteogenesis. This rapid vascularization is vital to the healing and bone induction ability of the DBM.     

PDC expressing CD36, CD61 and IL-10 may contribute to propagation of immune tolerance

Human plasmacytoid dendritic cells (PDC) are blood dendritic cell antigen 2 (BDCA2) and blood dendritic cell antigen 4 (BDCA4) positive leukocytes that do not express common lineage markers. They have been described as proinflammatory innate immune cells and are the major source of αIFN in the human body. PDC-derived secretion of type I IFNs upon triggering of nucleic acid-sensing toll-like receptors (TLR) primes immune cells to rapidly respond to microbial stimuli and promotes a Th1 response. Here, we report that human PDC express CD36 and CD61 (β3 integrin), both involved in uptake of apoptotic cells and in induction of tolerance. Freshly isolated PDC and PDC within human blood leukocytes constitutively express IL-10. Thus, PDC may possess a so far neglected role in propagation of immune tolerance.     

An update on the cutaneous manifestations of coeliac disease and non-coeliac gluten sensitivity

Introduction: Coeliac disease is a gluten-induced immune-mediated enteropathy, characterised by the expression of specific genotypes and the production of autoantibodies. The inflammatory process specifically targets the intestinal mucosa, but gastrointestinal and extraintestinal signs and symptoms can also be present. Non-coeliac gluten sensitivity (NCGS) can be diagnosed in individuals who have intestinal and/or extraintestinal symptoms related to the ingestion of gluten, but do not have autoantibodies and do not suffer from lesions in the duodenal mucosa. Among the extraintestinal manifestations, cutaneous manifestations are the most common for both diseases. Purpose: We conducted this review to illustrate the common and uncommon features underlying the association of coeliac disease and NCGS with cutaneous manifestations related to gluten ingestion. Areas covered: The roles of innate and adaptive immunity in the cutaneous appearance of gluten sensitivity will be discussed.     

Interleukin-17

The particular interest of IL-17, a homodimeric cytokine of about 32kDa, is the strict requirement for an activation signal to induce its expression from a rather restricted set of cells, human memory T cells or mouse αβTCR⁺CD4^?CD8^? thymocytes. In contrast with the tightly controlled expression pattern of this gene, the IL-17 receptor, a novel cytokine receptor, is ubiquitously distributed but apparently more abundant in spleen and kidney. In addition to its capture by the T lymphotropic Herpesvirus Saimiri (HVS), this cytokine is inducing the secretion of IL-6, IL-8, PGE₂, MCP-1 and G-CSF by adherent cells like fibroblasts, keratinocytes, epithelial and endothelial cells. IL-17 is also able to induce ICAM-1 surface expression, proliferation of T cells, and growth and differentiation of CD34⁺ human progenitors into neutrophils when cocultured in presence of irradiated fibroblasts. In vitro, IL-17 synergjzes with other proinflammatory signals like TNFα for GM-CSF induction, and with CD40-ligand for IL-6, IL-8, RANTES and MCP-1 secretion from kidney epithelial cells. In vivo, injection of IL-17 induces a neutrophilia, except in IL-6-KO mice. The involvement of IL-17 in rejection of kidney graft has also been demonstrated. The role of this T cell secreted factor in various inflammatory processes is presently investigated.     

T regulatory cells lacking CD25 are increased in MS during relapse

Dysregulation of inflammatory responses is considered to be a key element in autoreactive immune responses. T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4⁺CD25⁺FoxP3⁺ Tregs in autoimmunity has been extensively investigated. Recently, it was shown that Tregs in systemic lupus erythematosus lacked CD25 but were biologically functional. These data warrants for further investigation of CD25^? Tregs in human autoimmunity. We analyzed relapsing–remitting multiple sclerosis (MS) patients by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3, and the IL7R (CD127). Further, the level of Tregs was compared in remitting and relapsing patients and correlated with disease duration. Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls (p < 0.05), indicating that Tregs attempt to restrain immune activity during relapse. The proportion of Tregs tended to be decreased with disease duration, while CD25⁺CD4⁺ and CD25⁺CD8⁺ effector T-cell proportions were elevated and positively correlated with overall disease duration (p < 0.05). In conclusion, while MS patients in remission have normal levels of Tregs of different phenotype, relapsing patients show an increased proportion of systemic CD25^? FoxP3⁺ Tregs. With time, the proportion of Tregs decrease while effector T cells expand.     

Inhibition of Fas-mediated Apoptosis by Antigen: Implications for Lymphomagenesis

Apoptotic deletion of expanded B cell populations is essential in avoidance of autoimmune disease and immune regulation of some B cell malignancies. The role of CD4+ T cells in B cell apoptosis is evident from the high incidence of B cell tumors and autoimmunity in patients with T cell diseases such as the acquired immune deficiency syndrome (AIDS). We have previously demonstrated that in Epstein-Barr Virus (EBV) negative Burkitt's lymphoma (BL), a tumor derived from proliferating centroblasts of the germinal center, the malignant lymphocytes can be induced to express Fas (CD95) by ligation of CD40 at the B cell surface. Upon CD40 engagement, BL cells are sensitized to T-cell derived death signals provided by Fas ligand (FasL, CD95L). HBL-3 is a cell line derived from an AIDS-related BL in which the tumor IgM binds the human erythrocyte "i" antigen. To determine whether Fas-mediated apoptosis of BL cells is reduced in the context of antigen to which the tumor IgM binds, we stimulated HBL-3 cells with CD40 ligand (CD40L, CD154) in the presence and absence of human erythrocytes expressing the "i" antigen, and measured Fas-mediated apoptosis upon exposure to an agonistic anti-Fas antibody. We observed that HBL-3 cells were sensitized to Fas-mediated death by exposure to CD40L. When i+ RBCs were present, Fas-mediated apoptosis in HBL-3 cells was reduced by greater than 30%. In contrast, there was no reduction in Fas-mediated apoptosis in the presence of i &#109 (I+) RBCs. These findings demonstrate that Fas-mediated deletion of BL cells is inhibited upon surface IgM engagement by antigen for which the malignant clone has affinity.     

Separation Methods of T Cells,Natural Killer,and Dendritic Cells from Peripheral Blood of Cancer Patients using Interleukin-2 and Functional Analysis of Natural Killer Cells after Separation

We aimed to induce three different immune cell subsets from a single blood sample from cancer patients to target different biological characters of cancer cells. In the presence of 6000 IU/ml IL-2, natural killer (NK) cells adhere to plastic. By using this ability, we could separate dendritic cells, T cells, and NK cells from peripheral blood mononuclear cells. The cultured NK cells demonstrated higher nonspecific cytotoxicity against tumor cell lines than did the T cells. Furthermore, adherent NK cells demonstrated higher cytotoxicity than nonadherent NK cells, although there was no difference between adherent and nonadherent NK cells in natural cytotoxicity receptors (NKp30, NKp44, NKp46) and NKG2D expression. With these results, we confirmed that we could induce dendritic cell, T cell, and higher cytotoxic NK cells from a single blood draw, and this methodology facilitates to the use of these cells for clinical grade conditions.     

Emergence of chronic Lyme arthritis: Putting the breaks on CD28 costimulation

Lyme disease is a debilitating infection that is caused upon a bite of Borrelia burgdorferi (Bb)-infected ticks. One of the most prominent clinical manifestations is the development of chronic Lyme arthritis. Months after Bb infection, ~60% of untreated Lyme patients experience intermittent arthritic attacks that may last for years. The use of the CD28^?/? mouse in Bb infection has helped to shed light into the mechanisms that govern this inflammatory process, which seems to be tightly regulated. In this current review, the effect of immunoregulation, as well as CD28 deficiency in the development of chronic Lyme arthritis is discussed.     

Promotion and prevention of autoimmune disease by CD8+ T cells

Until recently, little was known about the importance of CD8+ T effectors in promoting and preventing autoimmune disease development. CD8+ T cells can oppose or promote autoimmune disease through activities as suppressor cells and as cytotoxic effectors. Studies in several distinct autoimmune models and data from patient samples are beginning to establish the importance of CD8+ T cells in these diseases and to define the mechanisms by which these cells influence autoimmunity. CD8+ effectors can promote disease via dysregulated secretion of inflammatory cytokines, skewed differentiation profiles and inappropriate apoptosis induction of target cells, and work to block disease by eliminating self-reactive cells and self-antigen sources, or as regulatory T cells. Defining the often major contribution of CD8+ T cells to autoimmune disease and identifying the mechanisms by which they alter the pathogenesis of disease is a rapidly expanding area of study and will add valuable information to our understanding of the kinetics, pathology and biology of autoimmune disease.