DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells

Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mphis), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis-derived material was detected in CD14(-)HLA-DR(+)DC-SIGN(+) cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN-mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.     

Circulating regulatory anti-T cell receptor antibodies in patients with myasthenia gravis

Serum anti-T cell receptor (TCR) Ab's are involved in immune regulation directed against pathogenic T cells in experimental models of autoimmune diseases. Our identification of a dominant T cell population expressing the Vbeta5.1 TCR gene (TCRBV5-1), which is responsible for the production of pathogenic anti-acetylcholine receptor (AChR) autoantibodies in HLA-DR3 patients with early-onset myasthenia gravis (EOMG), prompted us to explore the occurrence, reactivity, and regulatory role of anti-TCR Ab's in EOMG patients and disease controls with clearly defined other autoantibodies. In the absence of prior vaccination against the TCR, EOMG patients had elevated anti-Vbeta5.1 Ab's of the IgG class. This increase was restricted largely to EOMG cases with HLA-DR3 and with less severe disease, and it predicted clinical improvement in follow-up studies. EOMG patient sera containing anti-TCR Ab's bound specifically the native TCR on intact Vbeta5.1-expressing cells and specifically inhibited the proliferation and IFN-gamma production of purified Vbeta5.1-expressing cells to alloantigens in mixed lymphocyte reaction and the proliferation of a Vbeta5.1-expressing T cell clone to an AChR peptide, indicating a regulatory function for these Ab's. This evidence of spontaneously active anti-Vbeta5.1 Ab's in EOMG patients suggests dynamic protective immune regulation directed against the excess of pathogenic Vbeta5.1-expressing T cells. Though not sufficient to prevent a chronic, exacerbated autoimmune process, it might be boosted using a TCR peptide as vaccine.     

Prevalence of insulin resistance syndrome in southwestern France and its relationship with inflammatory and hemostatic markers

OBJECTIVE: To assess the prevalence and relationships of insulin resistance syndrome (IRS) with inflammatory and hemostatic markers in a representative sample of the population of Southwestern France aged 35-64 years. RESEARCH DESIGN AND METHODS: In this cross-sectional study, data were collected from 597 men and 556 women and were assessed regarding BMI, blood pressure, total and HDL cholesterol levels, triglyceride level, glucose level, plasma insulin level, white blood cell count, fibrinogen level, factor VII level, von Willebrand factor, C-reactive protein level, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule-1, and soluble CD(14). Insulin resistance was defined by homeostasis model assessment > or =3.8. RESULTS: Prevalence of IRS was higher in men than in women (23 vs. 12%, respectively; P < 0.001) and increased with age in both sexes (9, 24, and 34% for age groups 35-44, 45-54, and 55-64 years, respectively, for men and 4, 10, and 21% for women). After adjusting for age, alcohol consumption, tobacco smoking, and also for menopause in women, subjects (men and women) with IRS had significantly higher white blood cell count, factor VII levels, coagulating factor VII levels, and C-reactive protein levels than the other subjects. In men, further increases in soluble intercellular adhesion molecule and soluble vascular cell adhesion molecule-1 were noted, whereas in women, the differences were borderline significant. Conversely, no differences were found in fibrinogen, von Willebrand factor, and soluble CD(14) in both sexes. CONCLUSIONS: IRS is relatively common in residents of Southwestern France and is related to a deleterious increase in hemostatic and inflammatory parameters.     

GSM-900MHz at low dose temperature-dependently downregulates α-synuclein in cultured cerebral cells independently of chaperone-mediated-autophagy

The expanding use of GSM devices has resulted in public concern. Chaperone-mediated autophagy (CMA) is a way for protein degradation in the lysosomes and increases under stress conditions as a cell defense response. α-synuclein, a CMA substrate, is a component of Parkinson disease. Since GSM might constitute a stress signal, we raised the possibility that GSM could alter the CMA process. Here, we analyzed the effects of chronic exposure to a low GSM-900MHz dose on apoptosis and CMA. Cultured cerebral cortical cells were sham-exposed or exposed to GSM-900MHz at specific absorption rate (SAR): 0.25W/kg for 24 h using a wire-patch cell. Apoptosis was analyzed by DAPI stain of the nuclei and western blot of cleaved caspase-3. The expression of proteins involved in CMA (HSC70, HSP40, HSP90 and LAMP-2A) and α-synuclein were analyzed by western blot. CMA was also quantified in situ by analyzing the cell localization of active lysosomes. 24 h exposure to GSM-900MHz resulted in ～0.5°C temperature rise. It did not induce apoptosis but increased HSC70 by 26% and slightly decreased HSP90 (<10%). It also decreased α-synuclein by 24% independently of CMA, since the localization of active lysosomes was not altered. Comparable effects were observed in cells incubated at 37.5°C, a condition that mimics the GSM-generated temperature rise. The GSM-induced changes in HSC70, HSP90 and α-synuclein are most likely linked to temperature rise. We did not observe any immediate effect on cell viability. However, the delayed and long term consequences (protective or deleterious) of these changes on cell fate should be examined.