HCV presumably causes these lymphoproliferations by chronic antigenic stimulation and/or direct mutagenic effects on B cells. It has been speculated that the interaction of HCV with B cells and the expansion of antigen-triggered

B cells happens in germinal center-like structures in the livers of HCV carriers. We studied rearranged immunoglobulin VH genes from seven B-cell follicles microdissected from the livers of three unselected chronic HCV patients. The follicles consisted of polyclonal naive and memory B-cell populations with only rare indication of minor clonal expansions and no evidence for active somatic hypermutation. Frequent detection of VH check details rearrangements using the VH1-69 gene segment nevertheless indicated that at X-396 manufacturer least a fraction of

the B cells is HCV-specific and/or autoreactive. Thus, the typical intrahepatic B-cell follicles in chronic HCV carriers do not function as ectopic germinal centers for clonal expansion and affinity maturation of B cells. Hence, autoreactive and HCV-specific B-cell clones might either develop in secondary lymphoid organs or in intrahepatic follicles only under particular, yet undefined, circumstances. “
“Pulmonary tuberculosis (TB) is an infectious disease disturbing status of public health, and accurate diagnosis of TB would effectively help control the disturbance. Our study tried to establish a classification tree model that distinguished active TB from non-TB individuals. We used matrix-assisted laser desorption/ionization Tau-protein kinase time of flight mass spectrometry (MALDI-TOF MS) combined with weak cationic exchange (WCX) magnetic beads to analyse 178 serum samples containing 75 patients with active TB and 103 non-TB individuals (43 patients with common pulmonary diseases and 60 healthy controls). Samples were randomly divided into a training set and a test set. Statistical softwares were applied to construct this model. An amount of 48 differential expressed peaks (P < 0.05) were identified by the training set, and our model was set up by three of them, m/z 7626, 8561 and 8608. This model can discriminate patients with active TB from patients

with non-TB with a sensitivity of 98.3% and a specificity of 84.4%. The test set was used to verify the performance, which demonstrated good sensitivity and specificity: 85.7% and 83.3%, respectively. Differential expressed peaks between smear-positive and smear-negative active TB also have been analysed. It came out that m/z 8561 and 8608 not only acted as vital factors in the pathogenesis of active TB but also played an important role in regulating different active TB status. In conclusion, MALDI-TOF MS combined with WCX magnetic beads was a powerful technology for constructing classification tree model, and the model we built could serve as a potential diagnostic tool for active TB. Tuberculosis (TB) is a contagious and airborne disease caused by the infection of Mycobacterium tuberculosis (M.tb).

As a general observation, the iIEL compartment showed substantially higher basal [Ca2+]i levels than systemic T cells (Fig. 1B). The systemic populations had equal basal [Ca2+]i levels, though 50% less in relation to iIEL populations (Fig. 1B). In spite of these differences, all five T-cell populations showed robust ionomycin-induced Ca2+-fluxes (Fig. 1C). However, Ca2+ response amplitudes were higher in CD8+ p-αβ and CD8− p-γδ representing systemic T cells. Next, we studied the Ca2+-flux of isolated iIEL or systemic T cells from γδ reporter mice after TCR-clustering with antibodies. For this, we applied an anti-γδ TCR mAb clone (GL3) and an anti-CD3ε clone (145-2C11, here 2C11) and subsequently clustered

them on the cell surface with secondary goat anti-hamster antibody. This procedure induced robust anti-CD3-induced Ca2+-fluxes in the systemic populations CD8+ p-αβ and CD8− p-γδ (Fig. 1D). Similarly, clustering selleck chemicals with anti-γδ TCR mAb specifically induced

Ca2+-flux of systemic CD8− p-γδ cells (Fig. 1D). However, in the iIEL compartment, we observed discrete Ca2+-fluxes in response to anti-CD3 or anti-γδ TCR mAb only in CD8− i-γδ but not in CD8+ i-γδ (Fig. 1E). This suggested that high basal [Ca2+]i levels in γδCD8αα+iIEL correlated with TCR-unresponsiveness. Taken together, we found that systemic αβ and γδ T cells showed comparable Ca2+-flux responses to TCR ligation, whereas Rapamycin CD8αα+ αβ and γδ iIEL were presumably pre-activated and thus refractory to further stimulation of the TCR complex and displayed high intrinsic [Ca2+]i levels. These results suggest a chronic stimulation of CD8α+ iIEL in vivo. Next, we sought to investigate the outcome of αβ- and γδ-specific TCR stimulation on isolated iIEL in ex vivo stimulation assays. Since systemic γδ T cells in lymph nodes, spleen and circulation 19, 21, 34 as well as intraepithelial γδ T cells in the skin 35 have been described to be biased to produce IL-17A, we tested whether this pro-inflammatory cytokine was produced by intestinal γδ Myosin iIEL. We found that, irrespective of CD8α expression,

γδ iIEL did not produce IL-17A upon stimulation with anti-TCR mAb or PMA/ionomycin (Fig. 2). This is in accordance with a recent report showing that intestinal γδ IEL are not ‘pre-wired’ toward a specific lineage 36. Therefore, we focused in this study on the well-established γδ IEL effector molecules CC chemokine ligand 4 (CCL4) and IFN-γ. Chemokine and cytokine production of αβ, γδ and total iIEL from WT mice was monitored by stimulation with plate-bound anti-γδ TCR (GL3 and GL4), anti-αβ TCR (H57-597, called H57) and anti-CD3 (2C11), respectively, followed by cytokine measurement in the supernatants. Here, αβ or γδ TCR triggering induced similar concentrations of CCL4 (Fig. 3A, upper panel), whereas higher amounts of IFN-γ were produced through anti-αβ TCR stimulation (Fig. 3A, lower panel).

4 of the main paper. Fig. S5. CD146 versus CD70 expression, analysed as in Fig. 4 of the main paper. Fig. S6. CD146 versus CD45RA expression in T cells from healthy donors (HDs) and systemic lupus erythematosus (SLE) patients, analysed as in Fig. 4 of the main paper. #Indicates a single donor in whom carryover of CD3− antigen-presenting cells (APC) from an adjacent well caused 100% of T cells to be aberrantly positive for CD146.

Fig. S7. CXCR3 expression in total versus CD146+ CD4 and CD8 T cells from healthy donors FGFR inhibitor (HDs) and systemic lupus erythematosus (SLE) patients; paired analysis as in Fig. 4b,c of the main paper (P > 0·05, not significant). Fig. S8. CD146 versus CD31 expression, analysed as in Fig. 4 of the main paper. Fig. S9. CD146 versus CD54/intercellular adhesion molecule 1 (ICAM-1) expression, analysed in healthy donors (HDs) and systemic lupus erythematosus (SLE) patients, as in Fig. 4 of the main paper. Fig. S10. CD146+ lymphocytes greatly outnumber CD146+ circulating endothelial cells. Peripheral blood mononuclear cells (PBMCs) from a healthy donor were co-stained for CD45 (leucocyte common antigen), CD146 and CD34 (the latter is expressed both on haematopoietic Selleckchem Small molecule library progenitors and on endothelial cells). Numbers represent percentages or frequencies. In the CD45+ leucocyte gate a proportion of cells stained for either CD146

or CD34, but not both.

In the CD45− gate, a small number of CD34+CD146+ double-positive events were detected, which may be circulating endothelial cells (versus one event detected in isotype control). Table S1. Clinical characteristics of patients. “
“Several studies have demonstrated that some strains of lactic acid bacteria (LAB) can elicit natural killer (NK) cell activities via interleukin-12 (IL-12) induction and protect against influenza virus (IFV) infection. LAB strains that strongly induce IL-12 are expected to be effective in protecting against IFV infection. In this study, we screened 85 strains for their ability to induce the in vitro production of IL-12, and Lactobacillus paracasei MoLac-1 most strongly induced IL-12. To examine the immunomodulating effects of MoLac-1, we have performed Methocarbamol in vitro studies using murine splenocytes. Heat-killed MoLac-1 cells induced IL-12 and interferon-γ (IFN-γ) production by murine splenocytes. Experiments using splenocytes depleted of various cell populations indicated that macrophages might be a major source of MoLac-1-induced IL-12 secretion. Intracellular staining of IFN-γ suggested that MoLac-1 activated NK cells and induced IFN-γ production by NK cells in vitro. Oral administration of heat-killed MoLac-1 increased the proportion of NK cells in spleen, and ameliorated the symptoms of IFV infection in mice.

CFSE labeling (1 μM) and flow cytometry analysis were performed as previously described [30]. We thank Stephen Cobbold for the kind gift of YTS 177.4 antibody, Corinne Cordier and Jérôme

Mégret for cell sorting. This work was supported by the Association Française contre les Myopathies and the Agence Nationale de la Recherche (ANR-11-JSV3). Vismodegib clinical trial M. Carpentier, P. Chappert, and M. Lalfer were supported by the French Ministry of Research. C. Kuhn was supported by the Fondation pour la Recherche Médicale (FRM). The authors declare no financial or commercial conflict of interest. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. “
“Interleukin-21 (IL-21) exerts critical functions in T helper type 17 (Th17) cell development. However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear. Here we showed that IL-21 induced the differentiation of human naive CD8+ T cells into Tc22 cells without the expression of IL-17. The addition of transforming growth factor-β inhibited the production of IL-22 but induced the production of IL-17. Both IL-15 and IL-2 induced interferon-γ production

but did not induce differentiation of Tc22, which suggests that common γ-chain signals are not specific to promote IL-22 synthesis. The IL-21 induced naive CD8+ MAPK Inhibitor Library molecular weight T cells to produce IL-22 in greater amounts than memory CD8+ T cells. In addition, we demonstrated that IL-21 promoted the proliferation and increased the expression of IL-21 receptors on activated naive CD8+ T cells. Furthermore, IL-21 increased the expression of granzyme B molecules. Analysis of molecular mechanisms indicated that IL-21 induced phosphorylation of signal transducers and activators of transcription 1, 3 and 5 in CD8+ T cells. Overall, our data indicated that IL-21, Progesterone an effector cytokine produced by CD4+ T cells,

might mediate the cross-talk between CD4+ and CD8+ T cells through the production of IL-22. Interleukin 21 (IL-21) is a recently identified member of the common γ-chain (γc) -signalling family of cytokines that includes IL-2, IL-7 and IL-15.1 Interleukin-21 is an effector cytokine that is produced by various T helper cell subsets, including T follicular helper cells, T helper type 17 (Th17), Th2 and Th1 cells, and natural killer T cells.2,3 The functional IL-21 receptor consists of IL-21R and γc IL-21R is expressed on T cells, B cells, natural killer cells, dendritic cells, macrophages and epithelial cells, indicating roles of IL-21 in both innate and adaptive immune responses.4 Interleukin-21 signals via the janus kinase–signal transducers and activators of transcription (JAK-STAT) pathway.

[6] In particular, Omipalisib the vascular inflammation in the cerebral deep white matter

might contribute to the insufficiency of the blood flow to the cerebral subcortical white matter and cortex. The pathomechanism of the lesions in the basal ganglia and thalamus might be IRIS because MRI abnormalities in these lesions were evident along with those in the cerebral deep white matter and the pathology involved inflammation. The pathomechanism of the cerebellar lesions was difficult to identify; there were no apparent findings of inflammation or PML. Cryptococcal IRIS mainly manifests as lymphadenitis.[7] While cerebellitis has been reported as a manifestation of cryptococcal IRIS in the CNS,[8] pathological confirmation was absent. Thus, our case would be the first case of possible cryptococcal IRIS occurring in the brain which could be pathologically verified. The presence of the brain lesions and the absence of lymphadenitis in our case might be SP600125 cost due to some immunological

host factor of the patient, including HLA. Perivascular cuffing was also observed in an autopsy case of NSD.[9] Brain MRI before the treatment with methylprednisolone was normal in our case, and systemic corticosteroids are highly effective for most of the neurological manifestations in NSD patients.[3] Therefore, the brain pathologies in our case were unlikely as manifestation of NSD. In conclusion, our autopsy case suggests that cryptococcal meningitis can accompany lymphocytic inflammation predominantly in cerebral deep white matter as a manifestation of IRIS. “
“Y. H. Huang, W. W. Zhang, L. Lin, J. Feng, X. X. Zhao, W. H. Guo and W. Wei (2010) Neuropathology and Applied Neurobiology36, 237–247 Could changes in arterioles impede the perivascular drainage of interstitial fluid from the cerebral white matter in leukoaraiosis? Y-27632 2HCl Aims: Leukoaraiosis (LA) is the increase in fluid in cerebral white matter with hyperintensity on T2-weighted MR imaging that occurs in 25% of individuals over 65 years of age and in Alzheimer’s disease. Age, hypertension,

diabetes mellitus and cardiac disease are the major risk factors for LA. Ischaemia is considered to be the cause of LA, but the aim of the present study is to assess whether changes in arterioles in LA could impede perivascular lymphatic drainage of interstitial fluid from the cerebral white matter. Methods: We quantified arteriolosclerosis and immunohistochemical changes in the extracellular matrix in arterioles of cerebral white matter in 20 hypertension autopsy cases with LA and in 10 controls. Results: The ratio of the area immunoreactive for collagen types I, III, V and VI to the cross-sectional area of arterioles was significantly higher in LA patients compared with controls (P < 0.001). Changes were observed in collagen IV and laminin. The walls of white matter arterioles in LA were significantly thicker (P < 0.

Mucormycosis is commonly present in recipients of hematopoietic stem cell/solid organ transplants as well as patients with haematological malignancies, diabetes mellitus, burns, trauma and low birth weight.[1-3] Rhizopus spp. is most commonly the root of invasive mucormycosis.[2, 4] The lung is easily infected because the respiratory tract is the most frequent entry route of sporangiospores. When entering the body, the spores first challenge the innate immune cells (phagocytes, neutrophils). One of the early host responses after a fungal attack is the production of high levels of reactive oxygen species (ROS; including hydrogen

peroxide [H2O2] and hydroxyl radicals).[5] Lumacaftor This so-called oxidative burst might induce apoptosis of the pathogen. This apoptotic-like phenotype has been observed in yeast and Aspergillus fumigatus.[6, 7] Experimental data indicate that an apoptotic pathway is induced by a host–pathogen interaction. Moreover,

amphotericin B (AmB), the most selleck kinase inhibitor active anti-Mucorales agent, has also been seen as a strong trigger for inducing cell death in the opportunistic pathogen A. fumigatus.[7] In this paper, we tried to study whether the apoptotic-like phenotype can be observed in Rhizopus arrhizus induced by H2O2 and AmB. Rhizopus arrhizus was provided by the Fungal Genetic Stock Center (Kansas, MO, USA). H2O2 (30%, m/v; Beijing Chemical works, Beijing, China) diluted in water and AmB (Sigma-Aldrich Co., St. Louis, MO, USA) dissolved in dimethyl sulfoxide were stored at 4 and selleck chemicals llc −80 °C, respectively. Media used in this study included potato dextrose agar (PDA) and Yeast peptone glucose medium (YPG, a rich medium containing 0.3% yeast extract, 1% peptone and 2% glucose, PH4.5). Rhizopus arrhizus isolates were grown on PDA for 5 days at 28 °C. Freshly harvested

sporangiospores (2.5 × 104 spores ml−1) were inoculated into 100 ml flasks containing 30 ml of YPG liquid medium at 30 °C with constant shaking (200 rpm). Various concentrations of H2O2 (0–25 mmol l−1) and AmB (0–8 μg ml−1) from stock solution were added to YPG at the time of spore inoculation (0 h). The growth assay was performed in 96-well plates at 30 °C using microplate reader at OD450 (Model 550, Bio-RAD, Hercules, California, USA). Viability was assessed using the XTT method (XTT, 100 μg ml−1, menadione, 25 μmol l−1) after inoculation.[8, 9] Genomic DNA was extracted from mycelia of the exponential phase after exposure to different concentrations of H2O2 (0, 1.2, 3.6 and 6.0 μmol l−1) and AmB (0, 0.25, 0.5 and 1 μg ml−1) in phosphate-buffered saline (PBS; pH 7.4) for up to 3 h. DNA was examined on a 1.5% (w/v) agarose gel in TAE buffer and visualised after ethidium bromide staining. Rhizopus arrhizus cells (2.

, 2003; Glansdorp et al., 2004; Rasmussen et al., 2005). Recently, several crystal structures of the quorum-sensing regulatory proteins with their cognate AIs have been reported

(Vannini et al., 2002; Bottomley et al., 2007; De Silva et al., 2007; Kim et al., 2010), and in line BAY 73-4506 manufacturer with that computational modelling approaches have been employed to design potential QSIs. Yang et al. (2009a b) applied molecular docking and virtual screening and identified three recognized drugs, salicylic acid, nifuroxazide, and chlorzoxazone, as QSIs of P. aeruginosa (Yang et al., 2009a b). AI structurally unrelated QSIs were discovered by Soulere et al. (2010) through docking-based screening on a 2344 chemical compounds library (Soulere et al., 2010). Besides docking, structure-activity relationship methods

are also applied to design and identify novel QSIs (Steenackers et al., 2010; Brackman et al., 2011). Over the past few years, researchers have identified quorum-quenching enzymes from many prokaryotic and eukaryotic organisms, which degrade quorum-sensing signal molecules (Dong et al., 2007). Bacillus spp. produces a N-acyl-homoserine lactone lactonase that hydrolyses this major group quorum sensing AI in Gram-negative www.selleckchem.com/products/VX-809.html bacteria (Augustine et al., 2010). Mammalian cells was shown to produce paraoxonases (PON1, PON2, and PON3) that hydrolytically inactivate quorum sensing signal N-(3-oxododecanoyl)-l-homoserine lactone from P. aeruginosa (Teiber et al., 2008). Recently, metagenomic approaches are widely applied to identify novel enzymes from nature. Bijtenhoorn et al. (2011) isolated and biochemically characterized Calpain a novel N-acyl-homoserine lactone hydrolase, BpiB05, from the soil metagenome (Bijtenhoorn et al., 2011). BpiB05 is not distantly related to any of the currently

known N-acyl-homoserine lactone hydrolases and strongly reduces motility, pyocyanin synthesis and biofilm formation by P. aeruginosa (Bijtenhoorn et al., 2011). Quorum-quenching enzymes have been immobilized on surfaces and applied as anti-biofilm agents (Kim et al., 2011; Ng et al., 2011). Secondary metabolites may serve as intercellular pathogenic signals, which regulate numerous phenomena including biofilm formation (Dufour & Rao, 2011). Thus, metabolic intervention can be used to affect development and differentiation of biofilms. The green tea epigallocatechin gallate was shown to reduce both quorum sensing and biofilm development of P. aeruginosa through inhibiting the enoyl-acyl carrier protein reductase from the type II fatty acid synthesis pathway (Yang et al., 2010). A cyclopropane-containing fatty acid, lyngbyoic acid, from the marine cyanobacterium was shown to directly inhibit LasB enzymatic activity and reduce the production of pyocyanin and elastase in P. aeruginosa (Kwan et al., 2011).

Results. The average length of the “minimal” incisions was 3.9 ± 0.6 cm (range, 3.1–6.1 Acalabrutinib manufacturer cm), with an average reduction in length of 51% as compared with the “classical” incisions (range, 30–75%; P < 0.001). There were no perioperative morbidities. Conclusions. Minimally invasive peripheral nerve surgery applied to the above procedures yields successful surgical outcomes while shortening incision lengths and maximizing patient satisfaction without sacrificing patient safety. © 2010 Wiley-Liss, Inc. Microsurgery, 2010. "
“The

gold standard for the treatment of segmental nerve defect is an autogenous nerve graft. However, donor site morbidity is an inevitable complication. We substituted an autogenous

nerve graft with an inside-out vein graft for the treatment of segmental sensory nerve defect and the clinical results were evaluated retrospectively. Eleven patients of sensory nerve defects have undertaken inside-out vein grafts for the recovery of sensation. The involved nerves were digital nerves in three cases, peroneal nerves in two cases, saphenous nerve intwo cases, and superficial radial nerves in four cases. The average length of defects was 2.71 cm (1–6 cm). Donor veins were harvested4 mm longer than nerve defects and everted to promote nerve regeneration. Patients’ objective satisfactions and two-point discriminations were determined, the Semmes-Weinstein monofilament test was performed, and British Medical Council sensory functional scores were evaluated. BMN 673 supplier Sensory functional selleck chemicals scores recovered to over S3 in all cases. No donor site morbidity was caused by vein harvesting, and all patients achieved satisfactory results with protective sensation at involved sites. The inside-out vein graft offers a good surgical alternative to an autogenous nerve graft for the reconstruction of sensory nerve defects without donor site morbidity. © 2011 Wiley-Liss, Inc. Microsurgery, 2011. “
“The sensory reconstruction of the lower extremity is one of the main goals in lower extremity

reconstruction. Reconstructive options endowing sensory recovery are limited. The aim of this report is to evaluate the neurotized sural flap in reconstruction of foot and ankle defects. Seven cases that were operated for foot and ankle skin defects with the neurotized sural flap were reported. The largest flap was 10 cm × 14 cm in size. Median age was 38 years. Four defects were on the heel, two were on the ankle, and one was on the dorsum of the foot. The sural nerve was coaptated to a recipient nerve in seven patients. All flaps survived totally. Follow-up time ranged between 9 and 29 months. All cases had hot–cold perception and two-point discrimination at average 14 ± 1.63 mm at 6th month. Sensory conduction test revealed very low action potentials related to stimulation of the flap.

, 1987; Jaffar-Bandjee et al., 1995). The 18AWT isolates were not significantly different

from the 18A parent for elastase or total protease activity (Fig. 3a and b). However, eight of the 18ASTY isolates (STYs 2–4 and 6–10) showed a significant increase in elastase activity (Fig. 3a), while all of the 18ASTY isolates, except for 18ASTY-7, produced significantly higher levels of protease than the parental strain (Fig. 3b). Because the relative changes in both protease and elastase activity measurements were similar, it is Enzalutamide molecular weight possible that the increase in total protease activity can be attributed to the elastase activity. None of the PAO1 biofilm isolates (neither WT nor SCV) differed significantly from the PAO1 parent for the elastase or protease activity (Fig. 3c and d). The production of elastase and NVP-LDE225 price other acute virulence factors in P. aeruginosa is known to be regulated by QS, and the loss of QS and acute virulence factor expression has been associated with chronic infection (Heurlier et al., 2006; Smith et al., 2006a). Therefore, N-acyl homoserine

lactone (AHL) signal production was assessed for the biofilm isolates. Using the A. tumefaciens A136 monitor strain, which responds to AHLs with acyl chains > 4 carbons in length (Fuqua & Winans, 1996), it was observed that the 18AWT isolates were not significantly different from the parental strain, while almost all of the 18ASTY isolates showed a significant increase in AHL signal production (Fig. 4a). The PAO1 isolates, in contrast, generally showed a reduction in long-chain AHL production (e.g. 3-oxo-C12-homoserine lactone, C12-HSL) (Fig. 4b). This was particularly true for isometheptene the PAO1WT isolates, while the PAO1SCV isolates showed a less consistent overall pattern, where some isolates such as PAO1SCV-1 and PAO1SCV-8 showed a general reduction in QS signal production. The isolates were also tested for short-chain AHL production (e.g. C4-HSL), by performing drop plate assays using the C. violaceum CVO26 monitor

strain (McClean et al., 1997) (Fig. 4c). The results mirrored those of the A. tumefaciens A136 assay, where the 18AWT, PAO1WT and PAO1SCV isolates showed similar levels of violacein induction as the parental strains, while all of the 18ASTY isolates showed a larger zone of violacein production in the monitor strain (Fig. 4c). Thus, for the 18A variants, there was a clear correlation between the observed AHL signal production and elastase production (Figs 3a and 4a, c). For the PAO1 isolates, there was no similar correlation between reduction in QS signal production (Figs 3c and 4b) and elastase activity (Figs 3d and 4b, c). When the mutation frequencies for both strains 18A and PAO1 were determined using the rifampicin-resistant method (Oliver et al., 2002), the parental strains of 18A and PAO1 had mutation frequencies of 3.10 × 10−8 (SD ± 7.53 × 10−9) and 9.18 × 10−9 (SD ± 1.

Crosses with 3-83μδ and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca2+ mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM+ plasma cells in spleen and BM and significantly elevated serum

IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are HER2 inhibitor essential for appropriate regulation of B-cell activation. Signals transmitted by the B-cell receptor (BCR) control the antigen response of B cells and are Cisplatin chemical structure also essential regulators of survival, tolerance and differentiation (reviewed in 1, 2). Inducible and stage-specific targeting experiments demonstrated that mature B cells undergo apoptosis upon in vivo BCR ablation or mutation of one of its signaling units, Ig-α, and consequently disappear from the circulation 3, 4. A critical survival signal is provided by PI3K 5, but how this signaling is initiated in resting mature B cells is not fully understood. BCR signal strength is also a key factor in deciding between the three

functionally distinct mature B-cell compartments of follicular, marginal zone (MZ) and B-1 B cells. Increases in BCR signaling strength, induced by low-dose self-antigen, direct maturation of naive immature B cells from the follicular into the much B-1 or MZ B-cell fate 6, 7. In mature B cells, BCR engagement induces phosphorylation of Ig-α and Ig-β and the formation of a lipid raft-associated calcium-signaling module. In this complex Syk phosphorylates the adapter molecule Slp65, thereby providing docking sites for Bruton’s tyrosine kinase

(Btk) and phospholipase Cγ2 (Plcγ2). Activation of Plcγ2 by Btk results in the generation of the Ca2+-releasing factors inositol-1,4,5-trisphosphate and diacylglycerol (reviewed in 8, 9). During these events various co-receptors modulate BCR signaling either positively or negatively 10. Deficiencies of BCR signaling molecules, such as Btk, Slp65 or Plcγ2 or the excitatory co-receptor CD19 result in a hyporesponsive phenotype, mainly characterized by defects in the maturation of splenic follicular B cells, impaired MZ B-cell survival, absence of CD5+ B-1 B cells and impaired T–cell independent antibody responses 11. Conversely, a complex B-cell phenotype characterized by reduced numbers of follicular B cells, elevated numbers of B-1 B cells and to some extent MZ B cells, B-cell hyper-responsiveness and auto-antibody formation is found in genetic changes that increase BCR signaling.