Are mast cells MASTers in HIV-1 infection?

HIV-1 gp120 interacts with IgE V(H)3(+) on the surface of human basophils and mast cells (Fc epsilon RI(+) cells), acting as a viral immunoglobulin superantigen. gp120 from different clades induces mediator release from Fc epsilon RI(+) cells. gp120 also induces IL-4 and IL-13 synthesis in human basophils. The chemokine receptors CCR3 and CXCR4, which are coreceptors of HIV-1 infection, are expressed by human Fc epsilon RI(+) cells. HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells, interacting with CCR3. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor. There is evidence that human Fc epsilon RI(+) cells could be infected in vitro by M-tropic HIV-1 strains.     

Are there systemic changes in the arterial biomechanics of intracranial aneurysm patients?

Current theories on the development of intracranial aneurysm suggest that there is a general weakness of vascular connective tissue. Potential systemic alterations in arterial wall biomechanics were tested in the present study. A three-dimensional in vitro stress-strain analysis was made in the 0-200-0 mmHg pressure range on cylindrical segments excised from the anterior cerebral artery, the radial artery and from the arteria dorsalis pedis of aneurysm patients and of control cadavers. In the anterior cerebral artery from aneurysm patients (intracranial artery segments directly not affected by the aneurysm or by the subarachnoid bleeding), we found the wall thickness to be larger (0.1480+/-.019 versus 0.091+/-0.004 mm), the radius/wall thickness ratio smaller (9.7+/-1.4 versus 14.1+/-1.2), and the tangential wall stress lower [(0.122+/-0.019)x10(6) versus (0.181+/-0.016)x10(6) N/m2 at 100 mmHg] than in control subjects. Reduced radius was found in the extremity arteries studied. Elastic parameters, as incremental distensibility and elastic modulus, were remarkable similar. Our study demonstrates changes in the geometry of walls of arteries not directly affected by aneurysm formation, and it thus confirms systemic vascular pathology in this disease. At the same time, these data show that the molecular and morphological defects of arterial connective tissue formation generally thought to induce intracranial aneurysms will probably not affect the components responsible for the passive elastic properties of the vascular wall.     

Basophils and mast cells: Underdog in immune regulation?

Mast cells and basophilic granulocytes have recently been recognized as potent immunomodulatory cells. Whereas these cells originally were described as potent cells that release their pro-inflammatory contents (i.e. histamine) unconstrained after activation, nowadays this process is considered to be much more subtle. Especially, via the release of pro- and anti-inflammatory cytokines basophils and mast cells now can steer an immune response. Recently, it has become evident that at least in murine models basophils are crucial for the initial induction of a Th2 response in immunologically naive mouse.     

Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk?

Progressive multifocal leukoencephalopathy (PML) is a rare, frequently fatal, infectious complication occurring in immunocompromised patients. PML has been well-reported in patients with chronic inflammatory rheumatic diseases taking immunosuppressive drugs. Awareness of the occurrence of PML in patients with rheumatic diseases has recently been highlighted by the occurrence of several cases of PML following administration of natalizumab and rituximab, biologic agents which have been used for the treatment of rheumatic diseases. Nearly two thirds of cases of PML in patients with rheumatic diseases reported in the medical literature occurred in patients with systemic lupus erythematosus (SLE). Over 40% of PML cases in SLE occurred in patients who had had minimal iatrogenic immunosuppression, suggesting that SLE itself may predispose to PML. The mechanism of this putative predisposition of SLE patients to the development of PML remains unexplained.     

High α-defensin levels in patients with systemic lupus erythematosus

Innate immunity plays a role in systemic lupus erythematosus (SLE). Our objective was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sera from SLE patients and healthy controls were tested for pro-inflammatory human β-defensin 2 (hBD-2) and for α-defensin human neutrophil peptide 1 (HNP-1). hBD-2 could not be detected by enzyme-linked immunosorbent assay (ELISA) and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean α-defensin level in the sera of all SLE patients (11·07 ± 13·92 ng/μl) was significantly higher than that of controls (0·12 ± 0·07 ng/μl). Moreover, 60% of patients demonstrated very high serum levels (18·5 ± 13·36 ng/μl) and 50% showed elevated gene expression in polymorphonuclear cells. High α-defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to α-defensin secretion in SLE patients. Given the immunomodulatory role of α-defensins, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.     

Enteric glial cells: new players in gastrointestinal motility?

The enteric glial cells, in addition to being support structures for the enteric nervous system, have many other additional roles, such as modulators for the homeostasis of enteric neurons, cells involved in enteric neurotransmission and antigen-presenting cells. Moreover, in the last years, data have been accumulating that demonstrate a possible active role of these cells in the pathophysiology of gastrointestinal motor activity. Thus, as also shown by recent evidence in both experimental animal models, and in some human diseases, alterations of enteric glial cells might have some role in the development of intestinal motor abnormalities.     

Are free radical reactions increased in the diabetic eye?

Reactive oxygen species (ROS) are thought to play a significant role in the development of diabetic retinopathy; however, no direct evidence supports ROS generation in vivo. This study used in vivo electron spin resonance (ESR) spectroscopy with a surface resonator to detect local free radical reactions. The ESR signal decay of carbamoyl-PROXYL was enhanced in the eyes of streptozotocin (STZ)-induced diabetic mice. This enhanced signal decay was suppressed by the administration of SOD or the pretreatment with aminoguanidine. We demonstrate, for the first time, specific free radical reactions in the eyes of mice with STZ-induced diabetes.     

Role of Treg cells and TGF-β1 in patients with systemic lupus erythematosus: a possible relation with lupus nephritis

Regulatory T (Treg) cells play an important role in the maintenance of immune tolerance to self and in the pathogenesis of autoimmune disease. Transforming growth factor-beta 1(TGF-β1) is a regulatory cytokine with pleiotropic properties in immune responses. This study was to investigate the role of Treg cells and TGF-β1 in the pathogenesis of patients with lupus nephritis (LN). A total of 42 new-onset systemic lupus erythematosus patients and 22 healthy controls were enrolled. The proportion of Treg cells in peripheral blood mononuclear cells (PBMCs) was evaluated by flow cytometric analysis. The serum and urinary TGF-β1 levels were measured by enzyme-linked immunosorbent assay (ELISA). The results demonstrated a significant decrease in the frequency of CD4(+)CD25(high) and CD4(+)CD25(+)FoxP3(+) T cells in LN patients. The concentration of serum TGF-β1 was found decreased in SLE patients, while urinary TGF-β1 levels were significantly higher in LN patients. Based on our results, decreased Treg cells were accompanied with lower serum TGF-β1 levels and higher urinary TGF-β1 levels in LN patients. TGF-?1 levels in serum may play a key role in the pathogenesis of renal impairment while the significantly increased urinary TGF-β1 levels may be used as a biological marker in prediction of lupus nephritis.     

FcγR-dependent apoptosis regulates tissue persistence of mucosal and connective tissue mast cells

Rodent mast cells can be divided into two major subtypes: the mucosal mast cell (MMC) and the connective tissue mast cell (CTMC). A decade-old observation revealed a longer lifespan for CTMC compared with MMC. The precise mechanisms underlying such differential tissue persistence of mast cell subsets have not been described. In this study, we have discovered that mast cells expressing only one receptor, either FcγRIIB or FcγRIIIA, underwent caspase-independent apoptosis in response to IgG immune complex treatment. Lower frequencies of CTMC in mice that lacked either FcγRIIB or FcγRIIIA compared with WT mice were recorded, especially in aged mice. We proposed that this paradigm of FcγR-mediated mast cell apoptosis could account for the more robust persistence of CTMC, which express both FcγRIIB and FcγRIIIA, than MMC, which express only FcγRIIB. Importantly, we reproduced these results using a mast cell engraftment model, which ruled out possible confounding effects of mast cell recruitment or FcγR expression by other cells on mast cell number regulation. In conclusion, our work has uncovered an FcγR-dependent mast cell number regulation paradigm that might provide a mechanistic explanation for the long-observed differential mast cell subset persistence in tissues.     

Do mast cells link obesity and asthma?

Asthma is a chronic inflammatory disease of the lungs. Both the number of cases and severity of asthma have been increasing without a clear explanation. Recent evidence suggests that obesity, which has also been increasing alarmingly, may worsen or precipitate asthma, but there is little evidence of how obesity may contribute to lung inflammation. We propose that mast cells are involved in both asthma and obesity by being the target and source of adipocytokines, ‘alarmins’ such as interleukin‐9 (IL‐9) and interleukin‐33 (IL‐33), and stress molecules including corticotropin‐releasing hormone (CRH) and neurotensin (NT), secreted in response to the metabolic burden. In particular, CRH and NT have synergistic effects on mast cell secretion of vascular endothelial growth factor (VEGF). IL‐33 augments VEGF release induced by substance P (SP) and tumor necrosis factor (TNF) release induced by NT. Both IL‐9 and IL‐33 also promote lung mast cell infiltration and augment allergic inflammation. These molecules are also expressed in human mast cells leading to autocrine effects. Obese patients are also less sensitive to glucocorticoids and bronchodilators. Development of effective mast cell inhibitors may be a novel approach for the management of both asthma and obesity. Certain flavonoid combinations may be a promising new treatment approach.     

Pathological significance and regulatory mechanism of lymphotoxin β receptor overexpression in T cells of patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Lymphotoxin β receptor (LTβR) signaling plays an important role in autoimmune inflammations. LTβR-Ig fusion protein, LTβR blocking agent, has been used to treat SLE, while its mechanism remains to be fully elucidated. In this study, to investigate the expression of LTβR in the T cells of SLE patients and its roles in the pathogenesis of SLE, we isolated the peripheral blood T cells of SLE patients and normal controls to detect expression of LTβR by flow cytometry and RNA assay. T cells were also stimulated with LIGHT, a ligand of LTβR, and then detected for their LTβR expressions and apoptosis by flow cytometry. Also, their expressions of inflammatory factors and receptors were determined by RNA assay. The results showed that LTβR positive cells were 22.75%
6.98% in CD3+ cells of SLE patients, while there were almost no LTβR positive cells in CD3+ cells of normal persons. Moreover, LTβR expression was remarkably higher in CD3, CD4 and CD8 positive T cells of active SLE patients than non/low active patients (all P < 0.05), and positively correlated with increased Ig level, decreased complement level and renal damage. Moreover, the stimulation of SLE T cells with LIGHT promoted higher expression of LTβR, IL-23R and IL-17A, and apoptosis of T cells. In conclusion, we demonstrated a high expression of LTβR in the T cells of SLE patients which may be associated with pathogenesis of SLE.     

Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?

Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and leptin must be elucidated, as well as the mechanisms that account for the ultradian leptin release.