BackgroundPrimary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques.Methods and FindingsExperiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD−CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response.ConclusionsThese data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs. Characterization of underlying mechanisms would be helpful in designing new therapeutic strategies to dampen B-cell activation and increases HIV/SIV specific antibody response.

IntroductionB cell-activating factor belonging to the TNF family (BAFF) has emerged as an important regulator of B-cell homeostasis and survival: it acts alone or in combination with B-cell receptor (BCR), IL-4, or CD40 ligands. 1-4 BAFF binds 3 different TNF receptors: BCMA (B-cell maturation), 5,6 TACI (transmembrane activator and CAML interactor), 7 and BAFF-R/BR3 (BLys receptor 3). 8 A highly similar homolog (called "a proliferation-inducing ligand" or APRIL) 1 also binds TACI and BCMA but not BAFF-R. 9 BCMA, TACI, and BAFF-R are mostly found on B lymphocytes, [10][11][12] whereas BAFF-R is also present on a subset of T cells. 11,13 Accordingly, BAFF produced by antigen-presenting cells provides T-cell costimulation. 13 The BAFF/BAFF-R pair is essential for survival of immature T2, B2, and marginal zone (MZ) B cells, [14][15][16] but not for that of B1 cells, 17,18 whereas TACI exerts a negative control over 20 BCMA has no obvious effect on mature B-cell survival, but is important for long-term plasma cell biology 10,12 and antigen presentation. 21 BAFF-or BAFF-R-deficient mice form only rudimentary germinal centers (GCs) and produce low levels of IgG in response to T-dependent (TD) antigens. 22,23 In contrast, TACI-deficient mice display an impaired response to type II T cell-independent antigens, suggesting that TACI is required for B1 cell survival. 24 BAFF-R and TACI provide signals for isotype switching toward IgG and IgE, but the switch to IgA is mainly controlled by TACI. 17,25 Many BAFF transgenic mice show signs of autoimmunelike diseases, 2,26 whereas aged APRIL-transgenic mice display a progressive expansion of B1 cells infiltrating the peritoneum and lymphoid organs. 27 These various observations support a major role for the TACI/APRIL and BAFF-R/BAFF pairs in B1 and B2 cell physiology, respectively.Like CD40L, BAFF mainly promotes NF-B and MAPK activation. 28,29 Triggering BAFF-R results in activation of NF-B2 and NF-B1 pathways, whereas triggering BCMA and TACI only activate the NF-B1 pathway. 7,9,28,30,31 Different sets of MAPK and transcription factors are activated downstream from BCMA, TACI, and BAFF-R. 29,32,33 In particular, it has been shown that p38MAPK but not ERK is stimulated early after BAFF-R triggering. 34 Lymphocyte recirculation, which is essential for maintaining an effective immune system, is tightly regulated by the expression of adhesion molecules, chemoattractant receptors, and environmental cytokines. 35,36 Trafficking of human naive and memory B cells is mainly orchestrated by CXCR4/CXCL12, CXCR5/CXCL13, and CCR7/CCL21 (or CCL19) pairs. 37,38 The efficiency of the humoral response depends on the chemotactic response of mature B cells that is modulated by BCR-and IL-4-receptor triggering and CD40/CD40L interactions. 37,[39][40][41][42] In particular, BCR triggering enhances the chemotactic response of naive B cells to CCL21 but decreases that to CXCL13. In contrast, CD40L enhances the migration of memory B cells to CXCL13 without modifying that of CXCL12, CCL21, or CCL19. ...

The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8 þ memory in T-cell responses associated with antitumor properties.

Our results suggest that circulating inflammatory monocytes from advanced CKD or HD patients trans differentiate into OCs in vitro and play a relevant role in mineral bone disorders and that LIGHT and RANKL represent new potential therapeutic targets in these settings.

BackgroundConflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. Except in individuals repeatedly exposed to HIV-1 but yet remaining uninfected, HIV-specific IgAs are frequently absent in mucosal secretions from HIV-infected patients. However, little is known about the organization and functionality of mucosal B-cell follicles in acute HIV/SIV infection during which a T-dependent IgA response should have been initiated. In the present study, we evaluated changes in B-cell and T-cell subsets as well as the extent of apoptosis and class-specific plasma cells in Peyer’s Patches, isolated lymphoid follicles, and lamina propria. Plasma levels of IgA, BAFF and APRIL were also determined.ResultsPlasma IgA level was reduced by 46% by 28 days post infection (dpi), and no IgA plasma cells were found within germinal centers of Peyer’s Patches and isolated lymphoid follicles. This lack of a T-dependent IgA response occurs although germinal centers remained functional with no sign of follicular damage, while a prolonged survival of follicular CD4+ T-cells and normal generation of IgG plasma cells is observed. Whereas the average plasma BAFF level was increased by 4.5-fold and total plasma cells were 1.7 to 1.9-fold more numerous in the lamina propria, the relative proportion of IgA plasma cells in this effector site was reduced by 19% (duodemun) to 35% (ileum) at 28 dpi.ConclusionOur data provide evidence that SIV is unable to initiate a T-dependent IgA response during the acute phase of infection and favors the production of IgG (ileum) or IgM (duodenum) plasma cells at the expense of IgA plasma cells. Therefore, an early and generalized default in IgA production takes place during the acute of phase of HIV/SIV infection, which might impair not only the virus-specific antibody response but also IgA responses to other pathogens and vaccines as well. Understanding the mechanisms that impair IgA production during acute HIV/SIV infection is crucial to improve virus-specific response in mucosa and control microbial translocation.

Different subsets of lymphocytes have the capacity to promote or counteract the progression of solid cancers, including hepatocellular carcinoma (HCC). Therefore, to determine the infiltrative ability and functional status of major immune cell subtypes into tumor may lead to novel insights from the perspective of immunotherapy. After obtaining single cell suspensions from freshly collected specimens of HCC tumor, along with paired peritumor tissues and peripheral blood mononuclear cells (PBMCs) from 14 patients, we flow-cytometrically identified and quantified the relative frequencies of lymphocyte subsets within the tissues of origin. We found that the recruitment in the tumor of cytotoxic cells, namely the terminally differentiated CD4+ and CD8+ T cells (TEFF), is impaired, whereas the effector memory CD4+ T cells (TEM) are more attracted in this site. Concerning the other subsets, the frequency of NK CD56hi and NKT CD56hi cells infiltration in the tumor is increased, whereas that of NKT CD56low is reduced. Although CD4+ and CD8+ T cells settled in the tumor show a higher degree of activation than the circulating counterpart, they occur with a more exhausted phenotype. Overall, these data demonstrate the prevalently immunosuppressive nature of HCC microenvironment, and prompt us to search for strategies to enhance the activity of anti-tumor immune cell subsets.

Background Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. Methods We studied the intestinal–renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. Results IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ β7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. Conclusions Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal–renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.

Our findings reveal that the pattern of BAFF expression by myeloid cells and pDC is altered in PHI patients and constitutes a valuable marker of immune activation whose circulating levels correlate with CXCL10 levels. Due to their homing in different tissue areas, pDC and myeloid cells might target different B-cell subsets through their mBAFF expression or soluble BAFF release.