Studies on plasma immunoreactive human brain natriuretic peptide (hBNP) levels in patients with congestive heart failure and present forms of hBNP in human cardiac ventricle

By using a specific radioimmunoassay (RIA) for human brain natriuretic peptide (hBNP), we measured immunoreactive hBNP (ir-hBNP) in plasma from patients with congestive heart failure (CHF). There appeared to be relationship between the enhanced ir-hBNP secretory activity and the severity of the failing heart as well as that of immunoreactive human atrial natriuretic peptide (ir-hANP). However, the secretion of ir-hBNP was augmented much more than that of ir-hANP in sever CHF patients. Gel permeation chromatography coupled with the RIA revealed that ir-hBNP in human ventricle is composed with gamma-hBNP and hBNP (1-32) as well as that of human atrium. However, we found differences of the gamma-hBNP/hBNP (1-32) ratio in atrial and ventricular tissues. These findings suggest that the hBNP secretion mechanism differ in the two areas of human heart.     

Lower expression of Th1-related cytokines and inducible nitric oxide synthase in mice with streptozotocin-induced diabetes mellitus infected with Mycobacterium tuberculosis

Diabetes mellitus is an important predisposing factor for tuberculosis. The aim of this study was to investigate the mechanism underlying this association using a murine model. Mice with streptozotocin-induced diabetes mellitus were prone to Mycobacterium tuberculosis infection, as indicated by increased numbers of live bacteria in lung, liver and spleen. In diabetic mice, the levels of IL-12 and IFN-gamma in the lung, liver and spleen were lower than those in control animals on day 14 postinfection, while the opposite was true for IL-4 levels in the lung and liver. The expression pattern of inducible nitric oxide synthase (iNOS), in the two mice types was as for IL-12 and IFN-gamma. In addition, peritoneal exudate cells obtained from diabetic mice produced lower amounts of IL-12 and NO than those from control mice, when stimulated in vitro with M. bovis BCG. Spleen cells from diabetic mice infected with M. tuberculosis produced a significantly lower amount of IFN-gamma upon restimulation with purified protein derivatives (PPD) than those from infected nondiabetic mice. Interestingly, addition of high glucose levels (33 mM) to the cultures of PPD-restimulated spleen cells reduced the synthesis of IFN-gamma only in diabetic mice, and not in nondiabetic mice. Finally, control of blood glucose levels by insulin therapy resulted in improvement of the impaired host protection and Th1-related cytokine synthesis. Our results suggest that the reduced production of Th1-related cytokines and NO account for the hampered host defense against M. tuberculosis infection under diabetic conditions.     

The role of IL-17 in systemic lupus erythematosus and its potential as a therapeutic target

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies production and immune complex deposition with systemic clinical manifestations. Interleukin (IL)-17-producing cells play a crucial role in disease pathogenesis and represent an attractive therapeutic target.

Areas covered: This review provides an update on the possibility of targeting IL-17 in SLE. The rational for this approach as well as currently available and future targets are discussed.

Expert opinion: Although human expression studies and animal models indicate that IL-17 blocking may be a promising therapeutic strategy for SLE, direct evidence for IL-17 inhibition in SLE patients is unavailable. Biologic therapies and small-molecule drugs that target IL-17 production are required for the achievement of a favorable clinical effect in SLE patients.     

Novel immunosuppressive effect of FK506 by augmentation of T cell apoptosis

We have recently reported the accumulation of oligoclonal activated T cells in the spontaneously developed autoimmune pancreatitis in aly/aly mouse. In this study, we examined the effects of FK506 in this mouse model in preventing autoimmune pancreatitis and investigated its action on calcium signalling apoptosis of alymphoplasia (aly) lymphocytes in vitro. Mice were treated with FK506 from 8 to 25 weeks of age. At the age of 15 weeks, minimal mononuclear cell infiltration was observed in the pancreas in both the FK506 treated group and the control group. Furthermore, a marked cell infiltration associated with destruction of acini and partial fatty changes were observed in 25-week-old control mice. In contrast, FK506 treated mice showed almost no tissue destruction or mononuclear cell infiltration at the age of 25 weeks. Furthermore, at 15 weeks of age, most mononuclear cells in FK506-treated mice were TUNEL positive, whereas only a few were positive in control mice. This augmentation of T cell apoptosis by FK506 was confirmed using naive splenocytes activated by PMA and ionomycin in vitro. Finally, a suppressive effect of FK506 on Bcl-2 production but not on Bax production was confirmed by Western blotting. This unique effect of FK506 on the augmentation of T cell apoptosis is probably one of the mechanisms explaining its beneficial effect on aly autoimmune pancreatitis.     

Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts

Leflunomide, an isoxazol derivative structurally unrelated to other immunomodulatory drugs, has proven to be efficacious in the treatment of rheumatoid arthritis (RA). This study was conducted to elucidate the mechanism by which leflunomide mediated antirheumatic effects. We investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinase (MAPK) activation in IL-1beta-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially suppressed IL-1beta-induced ERK1/2 and p38 kinase activation. In contrast, A77 1726 efficiently suppressed IL-1beta-stimulated JNK1/2 kinase activation. Although no suppressive effect was demonstrated on MMP-2, A77 1726 markedly inhibited MMP-1, 3, and 13 secretions from IL-1beta-stimulated rheumatoid synovial fibroblasts. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was constitutively produced from rheumatoid synovial fibroblasts and the suppressive effects of A77 1726 on TIMP-1 production were minimal. Our results suggest that the suppression of the MAPK signalling pathway and MMP synthesis in rheumatoid synovial fibroblasts is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.     

Epithelial Cell Rests of Malassez and OX6‐Immunopositive Cells in the Periodontal Ligament of Rat Molars: A Light and Transmission Electron Microscope Study

It has been shown that human and cat epithelial cell rests of Malassez (ERM) consist of heterogeneous cell populations. Immunohistochemical and immunoelectron microscopic analyses have verified the presence of neuroendocrine and Merkel‐like cells in both of these epithelia. During experimental orthodontic tooth movement, immunocompetent cells have also been found in the vicinity of ERM in rat periodontal ligament (PDL), but have not been characterized in normal rat PDL. The aim of this study was to investigate the presence and distribution of MHC class II antigen presenting cells by using OX6 antibody in ERM of rat molars by light and transmission electron microscopy. Immunohistochemical and immunoelectron microscopic observations of rat maxillary molars confirmed the presence of OX6‐positive cells in contact with ERM. Some immunopositive cytoplasmic processes containing vesicles interdigitated with cells of the Malassez epithelial clusters. Based on these findings it can be concluded that immunocompetent cells are localized close to Malassez epithelial clusters in normal rat PDL. Furthermore, the ultrastructural evidences indicate a possible interaction between the epithelial and immunocompent cells and suggest morphological and functional properties for ERM. Anat Rec, 291:242–253, 2008. © 2008 Wiley‐Liss, Inc.     

Stimulatory effect of CD5 antibody on B cells from patients with rheumatoid arthritis

In order to clarify the role of CD5 antigen on B cell in autoimmunity, we examined B cells from patients with rheumatoid arthritis (RA). The percentages of CD5 positive B cells were increased in peripheral blood from RA compared with normal. Normal and RA B cells were stimulated with two kinds of monoclonal antibodies to CD5 (Leu-1, SL-1) which recognize different epitopes. RA B cells proliferated and secreted IgM by CD5 antibody stimulation in combination with IL-1. Our observations imply that CD5 positive B cells in RA are in their differentiation stage and that CD5 antigen might be one of the triggers to activate CD5 positive B cells in vivo to produce autoantibody.