TNF-α can certainly produce local and downstream endothelial acti

TNF-α can certainly produce local and downstream endothelial activation and inhibition of NO production in small vessels. In rats, TNF-α elevation concomitantly impairs insulin-mediated muscle capillary

recruitment and glucose uptake [124]. Moreover, in isolated skeletal muscle resistance arteries, TNF-α impairs the vasodilator effects, but not the vasoconstrictor effects of insulin through activation of intracellular check details enzyme JNK and impairment of insulin-mediated activation of Akt (Figure 3) [30]. This selective inhibition of the vasodilator effects of insulin results in insulin-mediated vasoconstriction in the presence of TNF-α. JNK has been shown to regulate whole-body insulin sensitivity as well as insulin-mediated cell signaling [40]. In cultured bovine aortic endothelial cells, TNF-α induces insulin resistance in the PI3K/Akt/eNOS pathway and enhances ERK1/2 and AMPK phosphorylation [72]. In humans, the TNF-α gene locus contributes to

the determination of obesity and obesity-associated hypertension [89]. Recent interesting evidence is that insulin sensitivity is improved by treatment through neutralizing TNF-α with the monoclonal antibody, infliximab, in patients with ankylosing spondylitis [63], indicating that TNF-α is indeed an important adipokine that may be at least partially responsible for an insulin-resistant state. Notably, compared with healthy controls, patients with ankylosing spondylitis had impaired microvascular endothelium-dependent vasodilatation and capillary recruitment, Opaganib order which was normalized following anti-TNF-α treatment [110]. Morphological studies reveal substantial differences in inflammation between subcutaneous and intra-abdominal (visceral) fat depots. STK38 Abdominal adipose tissue contains more monocytes and macrophages, and expresses more TNF-α than subcutaneous adipose tissue in obesity [8,42]. In accordance, increased visceral adipose tissue

and trunk/extremity skinfold ratio were shown to be associated with an increased inflammation score, which combined information on concentrations of C-reactive protein, IL-6, and TNF-α. However, levels of circulating TNF-α are associated with capillary recruitment in some [45], but not in all studies [20]. This may be explained by the fact that TNF-α may not be a good candidate as a systemic fat-derived signal, due to its low circulating concentration [41]. A new source of TNF-α, which has recently been identified, is perivascular adipose tissue around coronary arteries [13,81]. This implies that TNF-α is produced in the vicinity of the vascular endothelium, and may mean that circulating levels of TNF-α underestimate the biologically relevant concentrations of this cytokine.

Concerningly, 10% said the amputation could be stored directly on

Concerningly, 10% said the amputation could be stored directly on ice. Checking tetanus immunity status was only mentioned by 10% of respondents. Use of inappropriate solutions for cleaning/storage and transfer was reported by 4% of respondents. A wide variation was still observed in the perception of ischaemia with the time range of 1–12 hours, click here with a mode of 3 hours.

This data is a cause for concern especially considering the relatively high proportion of middle/senior medical grade respondents (36%). While the limitations on inference and generalization from such a small descriptive study are well-established, this study affirms the onus on plastic surgeons to educate and collaborate with referring departments. In the majority of cases, decisions determining Epigenetics Compound Library purchase viability of the replant (direct storage on ice/use of abrasive/cytotoxic solutions) are actuated before contact is made with the receiving plastic surgeon. Data reported in this study suggest that, applied

alone, educational engagement of referring centers reported in previous centers may be ineffective.[3] While educational engagement may benefit the staff cohort present during a training cycle, high staff turnover in the trainee medical sector would decrease long-term effectiveness. Therefore, this data suggests that a pre-emptive interventional tool to increase the proportion of salvageable amputations for replantation, aimed at staff with lower turn-over rates, may be more beneficial. Based on these findings, a procedural chart was formulated for pre-emptive pheromone “fax/email on-demand” as an effective and low-cost interventional tool. Current service reconfigurations within the UK National Health Service may result in gradual centralization of reconstructive services into larger teaching facilities which have been associated with higher replantation rates and successful procedures.[5] However, unless effective intervention, engagement, teaching, and leadership can be brought to bear, these advantages may not be exploited to their full potential. Anokha Oomman, M.B.B.S.,

Tomas Tickunas, M.D., M.R.C.S., Muhamad Javed, M.B.B.S., B.Sc., M.R.C.S., Jeremy Yarrow, M.B., Ch.B., B.Sc., M.R.C.S. The authors would like to thank Dr James Hankin (Morriston Hospital, Swansea) for his help with data collection. “
“In this report, we present a case of a giant cell tumor of the second metacarpal bone. The tumor was treated by en bloc resection of the distal portion of the second metacarpal with adjacent interosseus muscle. Reconstruction was achieved using a free vascularized scapular bone flap with nonvascularized free osteocartilagineous grafts from both second toes. Structural integrity and metacarpophalangeal joint motion were preserved with good functional result. A brief review of literature is presented. © 2010 Wiley-Liss, Inc. Microsurgery, 2011.

We compared the allograft function, severity of tissue injury, an

We compared the allograft function, severity of tissue injury, and clinical outcome between the two groups. In the IL-17 high group, allograft function was significantly decreased compared with the FOXP3 high group (P < 0·05). The severity of interstitial and tubular injury in the IL-17 high group was higher than the FOXP3 high group (P < 0·05). The proportions of steroid-resistant rejection, incomplete recovery and recurrent ATCMR were higher in the IL-17 high group than in the FOXP3 high group (all indicators, P < 0·05). The IL-17 high group showed lower 1-year (54% versus 90%, P < 0·05) and 5-year (38% versus 85%, P < 0·05) allograft survival

rates compared with the FOXP3 high group. Multivariate analysis revealed that the FOXP3/IL-17 ratio was a significant predictor for allograft outcome. The FOXP3/IL-17 ratio is a useful indicator for representing the severity of tissue injury, allograft dysfunction and for PLX4032 predicting the clinical outcome of ATCMR. FOXP3+ regulatory T cells (Treg) play a critical role in suppressing the immune responses of recipients to allografts.1,2 Therefore, high infiltration of FOXP3+ Treg in allograft tissue is expected to have significant associations

with a favourable allograft outcome. Indeed, the higher numbers of FOXP3+ Treg in a protocol biopsy are associated with the donor-specific hyporesponsiveness.3 In other studies, they were associated with favourable outcomes in subclinical rejection or chronic inflamed fibrotic tissue.4,5 In contrast, Glutamate dehydrogenase the detection of FOXP3+ Treg in acute T-cell-mediated rejection (ATCMR) did not suggest a favourable outcome. Veronese et al.6 observed that the presence of Treg had no significant association with the allograft outcome in patients undergoing biopsy-proven ATCMR. In another study, FOXP3 expression in allograft tissue with ATCMR did not correlate with a favourable outcome, and they concluded that the effect of inflammation could mask the benefits of FOXP3+ Treg in biopsies with ATCMR.7 Interleukin-17 (IL-17) is pro-inflammatory cytokine that has an important role in both autoimmune disorders

and alloimmune reactions in solid organ transplantation.8 Even though it is a pro-inflammatory mediator, it has close connections to FOXP3+ Treg.9,10 For example, T helper type 17 (Th17) cells, the major source of IL-17, developed from a common precursor with FOXP3+ Treg and it can interconvert with Treg according to the microenvironment.11–13 In addition, FOXP3+ Treg can differentiate into IL-17-producing cells under certain circumstances.14,15 Therefore, the interplay between IL-17 and Treg is an important mechanism for modulating the immune responses in various immunological disorders.16–19 In previous reports, the ratio between FOXP3+ Treg and IL-17-secreting T cells was associated significantly with the disease activity in autoimmune disease, graft-versus-host disease after haematopoietic stem cell transplantation, and the atherosclerotic inflammatory condition.

, 2010) They also reported that combination of bacteriophage and

, 2010). They also reported that combination of bacteriophage and ciprofloxacin efficiently kills K. pneumonia biofilm cells and restricts the formation of resistant variants when compared

with individual treatments (Verma et al., 2009). It is well known that environmental cues such as oxygen and carbon substrate concentration can trigger biofilm dispersion (Applegate & Bryers, 1991; Thormann et al., 2005; Gjermansen et al., 2010; Newell et al., 2011). Biofilm dispersion often coincides Selleck Ku-0059436 with alteration of the biofilm EPS components. Understanding the modulation of biofilm EPS components and transduction of the dispersion signals would greatly facilitate the development of dispersion-based strategies to control biofilm formation. In recent years, genetic regulators and

signal transduction pathways for biofilm dispersion have been identified from a number of microorganisms. Gjermansen et al. (2010) selleck chemicals reported that overexpression of a plasmid-born EAL domain protein reduces intracellular c-di-GMP level and activates the LapG cysteine proteinase in biofilms formed by Pseudomonas putida (Gjermansen et al., 2010). The activated LapG proteinase can digest the LapA protein, which functions both as a surface adhesin and as a biofilm matrix component, and cause dispersion of P. putida biofilms (Gjermansen et al., 2010). Three two-component systems, BfiSR, BfmSR and MifSR, are reported to be essential for regulating P. aeruginosa biofilm development (Petrova & Sauer, 2009). Inhibiting the expression of bfiS, bfmR and mifR genes in mature biofilms leads to biofilm architectural collapse and biomass loss (Petrova & Sauer, 2009). Boles & Horswill (2008) reported that activation of the agr quorum-sensing system of S. aureus by autoinducing peptide addition or glucose depletion can trigger biofilm dispersion via a protease-mediated mechanism (Boles & Horswill, 2008). Genetically engineered regulators are used to Ureohydrolase manipulate biofilm formation and dispersion. Uppuluri et al. (2010) demonstrated that modulation of NRG1 gene expression

affects biofilm formation and dispersion by Candida albicans (Uppuluri et al., 2010). Hong et al. (2010a) used random mutagenesis to obtain variants of the global transcriptional regulator Hha, which controls biofilm formation of E. coli probably by activation of proteases (Hong et al., 2010a). One of the obtained Hha variants, Hha13D6 (D22V, L40R, V42I and D48A), causes nearly complete biofilm dispersion by increasing apoptosis (Hong et al., 2010a). The same authors also engineered another global regulator H-NS of E. coli to control its biofilm formation (Hong et al., 2010a b). Analysis of signal transduction molecules involved in biofilm dispersion has led to identification of a series of biofilm dispersion-inducing agents.

Our study is the first to evaluate the percentage of blood monocy

Our study is the first to evaluate the percentage of blood monocytes in CRPS patients. Although the percentage of total monocytes Temsirolimus manufacturer (CD14+ peripheral blood mononuclear cells) remained unchanged in CRPS, the percentage of the CD14+CD16+ monocyte subgroup was elevated significantly (P < 0·01) in individuals afflicted with CRPS compared to healthy controls. Previous studies have

determined that these cells represent a potent antigen-presenting and proinflammatory subpopulation of monocytes [28] that has been shown to be expanded in inflammatory conditions [34]. Although there was no correlation between the increased number of CD14+CD16+ monocytes in the CRPS group and the patients’ overall pain level, there was a correlation between increased numbers of CD14+CD16+ monocytes in CRPS patients demonstrating cold allodynia. This finding

suggests that the increased percentage of CD14+CD16+ monocytes may be associated with central sensitization. As reported previously, there was no difference in plasma levels of TNF-α, IL-10, IL-8, IL-6 and IL-1β between CRPS patients and controls [35,36]. However, individuals with high levels of CD14+CD16+ monocytes demonstrated a significantly lower (P < 0·05) plasma level of IL-10 compared to individuals with low levels of CD14+CD16+. This is consistent with a study showing that CD14+CD16+ monocytes produce similar levels of the proinflammatory cytokines TNF-α, IL-6 and IL-1β and lower levels of the anti-inflammatory cytokine IL-10 [26]. This study also showed that the percentage of lymphocytes (T helper cells, T cytotoxic cells, NK cells or B cells) did not differ between CRPS patients and healthy control individuals. These results are in agreement with the study of Ribbers and colleagues that reported no association between lymphocyte subpopulations and patients with reflex sympathetic dystrophy (currently referred to as CRPS-type 1) [37]. A subsequent study by Kaufmann and colleagues also found no changes in the percentage of T cytotoxic cells, NK cells and B cells in CRPS patients [38]. However, they reported a reduction

of T helper cells (CD8+ lymphocytes) as well as an increase in the CD4/CD8 ratio [38] in CRPS patients compared to healthy controls. Although our study also many found a small reduction of CD8+ lymphocytes and an increase in the CD4/CD8 ratio, these changes were not statistically significant (P > 0·05). The elevation in the percentage of CD14+CD16+ monocytes seen in CRPS patients in this study could be due to the syndrome itself or may result from other factors. Factors such as physical inactivity, morbid obesity and sleep have been shown to alter the percentage of CD14+CD16+ monocytes [39–41]. Morbidly obese individuals have been reported to show elevated levels of the CD14+CD16+ monocyte subset [39]. The percentage of obese individuals (BMI > 30) in both the CRPS and control groups was approximately 20%.

“Allergen-specific immunotherapy (SIT) is the only treatme

“Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic

T lymphocyte antigen 4–immunoglobulin (CTLA-4–Ig) selleck has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4–Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4–Ig acts as an adjuvant for experimental SIT. We evaluated

click here the adjuvant effects of CTLA-4–Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4–Ig. Co-administration of CTLA-4–Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4–Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4–Ig is independent of IDO expression. We show that CTLA-4–Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4–Ig is independent

of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation. Atopic T helper type 2 (Th2) immune responses against innocuous environmental antigens are the cause of allergic diseases that impair the quality of life of a significant proportion of the world’s population [1, 2]. Currently, allergen-specific immunotherapy (SIT) is the only remedy for allergic diseases that modifies the dominant Th2 response and causes long-lasting relief of symptoms [3]. Classically, SIT is performed by repeated administration of high doses of the sensitizing allergen for a Ergoloid period of 3–5 years, after an initial gradual increase of administered allergen to avoid anaphylaxis [3]. SIT not only induces a sustained relief of allergic symptoms; it can also prevent the development of new allergen sensitizations [4, 5] and the progression of allergic rhinitis to allergic asthma [6]. Currently, there are concerns about the safety of using high doses of allergen and the required long-term duration of treatment [7, 8]. Therefore, improvement of SIT is highly required by using clinically applicable adjuvants that achieve optimal efficacy at lower doses of allergen and lead to a safer therapy in possibly a shorter time-frame [9].

To identify specific antigens against AECA, biotinylated

To identify specific antigens against AECA, biotinylated Rapamycin molecular weight CSPs were incubated with sera from LN patients with high titers of IgG-AECA, immunoprecipitated with immobilized protein G followed by immobilized avidin, and blotted with NeutrAvidin. A 150-kDa protein band that shifted to a 55-kDa protein band under reducing conditions was detected in

patients with LN, but not in HC. Conclusion: IgA-AECA was observed to be associated with pathological activity in LN. These EC membrane components recognized by AECA may be linked with the pathogenesis of LN. NAKAZAWA DAIGO1, SHIDA HARUKI1, TOMARU UTANO2, YOSHIDA MASAHARU3, NISHIO SAORI1, ATSUMI TATSUYA1, ISHIZU AKIHIRO4 1Department of Internal Medicine II, Hokkaido University Graduate School of Medicine; 2Department of Pathology, Hokkaido University Graduate School of Medicine; 3Renal Unit of Internal Medicine, Hachioji Medical Center, Tokyo Medical University; 4Faculty of Health Sciences, Hokkaido University Introduction: MPO-ANCA-associated vasculitis (MPO-AAV) is closely related to neutrophil extracellular traps (NETs). The aim of this study is to elucidate the enhanced formation and disordered regulation of NETs in patients with MPO-AAV.

Methods: Patients enrolled in this study included 38 MPO-AAV and 23 SLE patients diagnosed and MK 2206 treated in Hokkaido University Hospital. NETs induction rate was evaluated by reaction of patient-IgG with healthy neutrophils primed by TNF-α. Furthermore, to analyze the mechanism of NETs induction by patient-IgG, ANCA

affinity was determined by the competitive inhibitory ELISA method. DNase I and NETs degradation abilities were evaluated by ELISA and the incubation of patients’ serum with phorbol CYTH4 myristate acetate-induced NETs, respectively. Results: MPO-AAV patient-IgG induced NETs. The induction rate was 16.6 ± 9.7% and significantly higher than those of SLE patients (7.0 ± 3.5%) and healthy controls (3.2 ± 1.4%). Moreover, the NETs induction rate was correlated with vasculitis activity and ANCA affinity. On the other hand, activity of DNase I, the important regulator of NETs in the serum, was generally low in MPO-AAV patients and majority of them showed impaired degradation of NETs. Furthermore, the impaired degradation of NETs in some MPO-AAV patients was improved by removal of IgG and the presence of anti-NETs antibodies, which could interfere with the degradation of NETs by DNase I, were demonstrated. Conclusion: These findings clearly demonstrated that the feature of MPO-AAV serum could cause the excessive formation and persistence of NETs. Since such dysregulation of NETs could induce NETs producers, including MPO-ANCA, and NETs degradation inhibitors, including anti-NETs antibodies, it is considered that a vicious cycle through NETs and MPO-ANCA, namely “NETs-ANCA vicious cycle,” is critically involved in the pathogenesis of MPO-AAV.

but can be applied to other helminths and may contribute signific

but can be applied to other helminths and may contribute significantly to vaccine development against parasitic diseases in general. Bearing in mind the considerable potential of schistosomula as a source of effective vaccine antigens, techniques that overcome the difficulties of working with this developmental stage are required. One such

method, termed the ‘ASC-probe technique’ find more developed by Meeusen and Brandon (69,70), is particularly amenable to studying migrating larval helminths and has been used in a number of infections (70–76). In this technique, cells obtained from lymph nodes draining a particular infection site are cultured, which allows the in vivo-primed ASCs to secrete antibodies into the culture media. These antibodies,

present in the culture supernatants (ASC-probes), are specific for the pathogen infecting that tissue region and are only present in an active infection. ASC-probes obtained from lymph nodes draining different tissues from the same animal were shown to produce antibodies that can recognize distinct stage-specific antigens (70). Hence, these ASC probes can be considered to be a snapshot of the local antibody response, which is specific for (i) the tissue region, and (ii) the developmental stage of the pathogen within that tissue region. These tissue-specific ASC probes can be used for the discovery of their target antigens and can therefore be considered to be a more Org 27569 relevant and directed tool for immunomic analysis compared to the complexity and nonspecificity of serum antibody probes. The ASC-probe technique was used to identify a surface antigen specific to the infective larval stage of H. contortus (termed Hc-sL3) (71), which was later found to be protective in a vaccine

trial (25). In this study, ASC-probes were produced from the lymph nodes draining the abomasum, the site of parasite infection, during the rejection response and identified by Western blotting an antigenic region at 70–83 kDa, which localizes to the larval surface (71). Because the ASC-probe response profile was much simpler than that obtained with immune serum, it enabled a more manageable and targeted approach for larval-specific antigen identification. Similarly, Jungersen et al. (73) and Meeusen and Brandon (70) used the technique to show that particular larval-specific antigens are recognized in distinct tissue compartments during Ascaris suum and Fasciola hepatica migration, respectively. Once again, antibodies against these antigens were not always detectable in serum. For schistosomes, as for other pathogens, antigen identification has long been performed using serum antibodies obtained from infected individuals and has enabled the discovery of various candidates (see Table 1) that are often the most immunogenic (27).

Methods: Tubular epithelial cell line NRK cells were exposed to n

Methods: Tubular epithelial cell line NRK cells were exposed to nephrotoxic agents. The generation of ROS was detected by using a Total ROS/Superoxide Detection Kit. Cell viability was evaluated by cell shape change, calcein/ propidium iodide staining, cleavage of caspase 3 and WST

assay. The expression, selleck inhibitor function and role of GJs were evaluated through scrape-loading dye transfer, Western blot analysis and modulation of gap junctions with chemical and genetic approaches. Results: 1) Exposure of renal tubular cells to aminoglycosides caused the loss of cellular viability, which was preceded by an elevated level of ROS generation, connexin43 (Cx43) phosphorylation and gap junctional intercellular communication. 2) The cell injury induced by aminoglycosides was significantly attenuated by antioxidant GSH and NAC.

The protective action of these antioxidants was associated with a reduced level of gap junction protein Cx43. 3) Dysfunction of gap junctions with chemical inhibitors or downregulation of Cx43 with siRNA protected the cells from aminoglycoside-induced cell injury. 4) Treatment of cells with GJ inhibitors or Cx43 siRNA resulted in an increased phosphorylation of Akt. Inhibition of AKT exaggerated aminoglycoside-induced tubular cell injury and abolished the protective effect of GJ inhibitors. Conclusion: We characterized GJs as a presently unrecognized factor controlling renal tubular cell susceptibility to nephrotoxic drugs, possibly through modulation of cellular response to oxidative stress. Modulation of GJs could Cobimetinib mouse be developed as a novel therapeutic approach for prevention and treatment of drug-induced renal tubular cell injury. Nabilone HWANG SEON DEOK, YU JI HYUN, CHUNG BYUNG HA, YANG CHUL WOO, KIM YONG-SOO, PARK CHEOL WHEE, CHOI BUM SOON Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea Introduction: Aging is a multifactorial process characterized

by a progressive decline in physiological function. Decreased kidney function is associated with cardiovascular disease and mortality. Therefore, increasing our insight into kidney aging by understanding the anatomic, physiologic, and pathologic changes of aging in the kidney is important to prevent disastrous outcomes in elderly people. Methods: Male 2-, 12-, and 24-month-old C57/BL6 mice were used in this study. We measured histological change, oxidative stress, aging-related protein expression in the kidneys. Results: Twenty-four-month-old mice displayed increased albuminuria. Creatinine clearance decreased with aging, although this was not statistically significant. There were increases in mesangial volume and tubulointerstitial fibrosis in 24-month-old mice. There were also increases in F4/80 expression groups (0.11 ± 0.06% vs. 0.4 ± 0.11%, 2.5 ± 0.52%; **p < 0.01 vs. 2 M) and in apoptosis detected by TUNEL (p < 0.01 vs. 2 M) assay. Urine isoprostane (7.4 ± 0.3% vs. 19.4 ± 0.78%, 21.9 ± 1.9%; *p < 0.05 vs. 2 M, **p < 0.01 vs.

Crosses with 3-83μδ and VH81X BCR Tg mice showed that constitutiv

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 MAPK Inhibitor Library cost 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 GS 1101 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 Amine dehydrogenase 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.