Epstein-Barr Virus-Induced Gene 3 (EBI3): A Novel Diagnosis Marker in Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma

The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations

HIV-1 Efficient Entry in Inner Foreskin Is Mediated by Elevated CCL5/RANTES that Recruits T Cells and Fuels Conjugate Formation with Langerhans Cells

Male circumcision reduces acquisition of HIV-1 by 60%. Hence, the foreskin is an HIV-1 entry portal during sexual transmission. We recently reported that efficient HIV-1 transmission occurs following 1 h of polarized exposure of the inner, but not outer, foreskin to HIV-1-infected cells, but not to cell-free virus. At this early time point, Langerhans cells (LCs) and T-cells within the inner foreskin epidermis are the first cells targeted by the virus. To gain in-depth insight into the molecular mechanisms governing inner foreskin HIV-1 entry, foreskin explants were inoculated with HIV-1-infeceted cells for 4 h. The chemokine/cytokine milieu secreted by the foreskin tissue, and resulting modifications in density and spatial distribution of T-cells and LCs, were then investigated. Our studies show that in the inner foreskin, inoculation with HIV-1-infected cells induces increased CCL5/RANTES (1.63-fold) and decreased CCL20/MIP-3-alpha (0.62-fold) secretion. Elevated CCL5/RANTES mediates recruitment of T-cells from the dermis into the epidermis, which is blocked by a neutralizing CCL5/RANTES Ab. In parallel, HIV-1-infected cells mediate a bi-phasic modification in the spatial distribution of epidermal LCs: attraction to the apical surface at 1 h, followed by migration back towards the basement membrane later on at 4 h, in correlation with reduced CCL20/MIP-3-alpha at this time point. T-cell recruitment fuels the continuous formation of LC-T-cell conjugates, permitting the transfer of HIV-1 captured by LCs. Together, these results reveal that HIV-1 induces a dynamic process of immune cells relocation in the inner foreskin that is associated with specific chemokines secretion, which favors efficient HIV-1 entry at this site

Expression of IL-27 by tumor cells in invasive cutaneous and metastatic melanomas [corrected]..

Interleukin (IL)-27 is a cytokine of the IL-12 family that displays either immunostimulatory or immunosuppressive functions depending on the context. In various murine tumor models including melanoma models, ectopic expression of IL-27 has been shown to play an anti-tumoral role and to favor tumor regression. In this study, we investigated whether IL-27 might play a role in the development of melanoma in humans. We analyzed the in situ expression of IL-27 in melanocytic lesions (n = 82) representative of different stages of tumor progression. IL-27 expression was not observed in nevus (n = 8) nor in in situ melanoma (n = 9), but was detected in 28/46 (61%) cases of invasive cutaneous melanoma, notably in advanced stages (19/23 cases of stages 3 and 4). In most cases, the main source of IL-27 was tumor cells. Of note, when IL-27 was detected in primary cutaneous melanomas, its expression was maintained in metastatic lesions. These in situ data suggested that the immunosuppressive functions of IL-27 may dominate in human melanoma. Consistent with this hypothesis, we found that IL-27 could induce suppressive molecules such as PD-L1, and to a lesser extent IL-10, in melanoma cells, and that the in situ expression of IL-27 in melanoma correlated with those of PD-L1 and IL-10

Chronic Meningococcemia Cutaneous Lesions Involve Meningococcal Perivascular Invasion Through the Remodeling of Endothelial Barriers.

International audienceChronic meningococcemia is a form of sepsis with frequent polymorphous skin lesions. Both in vivo and in vitro data suggest that, in these lesions, meningococci gain access from the capillary lumen to the peripheral extravascular compartment, in the absence of vascular dislocation, through a paraendothelial route

HIV-1-infected cells affect secretion of chemokines by the inner foreskin.

<p>Inner foreskin explants were inoculated in a polarized manner for 4 h with either non-infected or HIV-1-infected PBMCs, washed, and further incubated in medium in a non-polarized manner. The levels of twelve chemokines and cytokines were measured the next day in the culture supernatants, using a custom multiplex bead immunoassay and quantified by flow cytometry or specific ELISA. Shown are mean folds±SEM secretion of each analyte (derived from two independent explants), calculated as [secretion after exposure to HIV-1-infected PBMCs/secretion after exposure to non-infected PBMCs], for either chemokines/cytokines not altered (A) or altered (B) following exposure to HIV-1-infected cells. In (B), p = 0.0105, 0.0308, 0.0166, 0.0045 for INF gamma, CCL3/MIP-1 alpha, CCL20/MIP-3 alpha and CCL5/RANTES, respectively, Student's t-test, n = 2.</p

CCL5/RANTES mediates T-cell recruitment into the epidermis.

<p>(A) Representative FACS profiles out of two independent experiments, showing epidermal single-cell suspensions derived from inner foreskin explants exposed for 4 h to either medium alone (left), non-infected PBMCs (middle), or HIV-1-infected PBMCs (right). Cells were stained with PE-conjugated anti-human CD3 mAb and numbers represent the percentages of CD3+ cells in the framed windows (determined based on the non-specific staining of a matched isotype control Ab). (B) Inner foreskin explants were exposed for 4 h to either non-infected PBMCs (white bar) or HIV-1-infected PBMCs: alone (black bar); in the presence of 40 µg/ml control goat IgG Ab (dark grey bar); in the presence of 20 or 80 µg/ml neutralizing goat Ab to CCL5/RANTES (light grey bars). Following infection, epidermal single-cell suspensions were prepared and stained for CD3 expression as described above. Shown are mean folds increase±SEM of the percentages of CD3+ cells, normalized against that following exposure to non-infected PBMCs and derived from two independent explants. p = 0.0129 infected vs. non-infected and p = 0.0128 infected+CCL5 Ab 80 µg/ml vs. infected; Student's t-test.</p

HIV-1-infected cells modify the spatial distribution of LCs in inner foreskin.

<p>(A) Representative images of normal inner foreskin (top), and inner foreskin explants exposed to either non-infected (left) or HIV-1-infected (right) PBMCs for 1 h (middle) or 4 h (bottom). Explants were then stained with anti-langerin Ab and visualized with AEC (normal foreskin) or DAB (foreskin explants) peroxidase substrates. The black double-headed arrows denote individual distances of LCs from the apical surface for each condition and are marked as [a_i]-[e_i] respectively. Images are representative of three independent experiments. Scale bars = 20 µm. (B) Calculated mean±SEM distances covered by LCs, following exposure of inner foreskin explants to either non-infected (white bars) or HIV-1-infected (grey bars) PBMCs. For exposure to non-infected PBMCs, the distances after 1 h and 4 h were calculated as [b]-[a] and [c]-[b], respectively, where a, b, c are means of the individual [a_i], [b_i], [c_i] distances (measured for 106, 193 and 148 different cells in three independent explants). For exposure to HIV-1-infected PBMCs, the distances after 1 h and 4 h were calculated as [a]-[d] and [e]-[d], respectively, where d and e are mean of the individual [d_i] and [e_i] distances (measured for 186 and 108 different cells in three independent explants). *p<0.0001 infected vs. non-infected at 4 h; Student's t-test. (C) shows the actual distances from the apical surface measured for each experimental condition. *p<0.0001 vs. normal foreskin; Student's t-test.</p