It has been reported that the immunosuppressive effects of ASC are mediated via soluble factors, and enhanced further if direct cell–cell contact between ASC and immune cells was allowed [14]. Different studies have attributed the immunosuppressive effect of MSC to different immunosuppressive factors. These include indoleamine

2,3-dioxygenase (IDO) [15–17], prostaglandin E2[18], transforming growth factor (TGF)-β and hepatocyte growth factor (HGF) [5], HLA-G [19], nitric oxide [20], interleukin (IL)-10 [21] and haem oxygenase [22]. In addition, there is evidence that cell–membrane interactions between MSC and immune cells via the adhesion molecules intercellular adhesion molecule (ICAM)-1 or vascular cell adhesion molecule (VCAM)-1 play a crucial role in the immunomodulatory www.selleckchem.com/products/dabrafenib-gsk2118436.html capacity of MSC [14,23]. Thus, the immunomodulatory capacity of MSC is a multi-factorial process. The activity of these processes may depend upon local immunological conditions. It has been demonstrated that in the absence

of inflammation, MSC can stimulate lymphocyte survival and proliferation [24]. Under inflammatory conditions a high production of cytokines, see more such as interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-6, are largely produced and MSC may respond to these factors by changing their immunomodulatory function [25–27]. Exposure of MSC to IFN-γ has been reported to up-regulate the expression of IDO, TGF-β and HGF [25,28] and it was demonstrated recently that IFN-γ-activated MSC are more effective for the treatment of graft-versus-host disease [29]. Effective application of MSC in organ transplantation may require potent and immediate immunosuppressive effects. In vitro activation of MSC could therefore be beneficial for clinical effectiveness of MSC in organ Carbohydrate transplantation. In the present study, we investigated whether different inflammatory conditions affected the gene expression,

phenotype and function of adipose tissue-derived mesenchymal stem cells (ASC). ASC were cultured with alloactivated peripheral blood mononuclear cells (PBMC) (mixed lymphocyte reaction, MLR) or with a cocktail of proinflammatory cytokines containing IFN-γ, TNF-α and IL-6, while their functions and full genome expression were examined. ASC were isolated and expanded from perirenal adipose tissue of four living healthy kidney donors, as described previously [30,31]. These donors (three males, one female, mean age 46 ± 7 years) were approved to donate their kidney after routine screening. They did not use immunosuppressive medication. In brief, perirenal fat was minced and digested with 0·5 mg/ml collagenase type IV (Invitrogen, Paisley, UK) in RPMI-1640 (Invitrogen) for 30 min at 37°C.

The cells in a volume of 50 μl were added to 96-well plates and stimulated in triplicates with heat-killed M. tuberculosis H37Rv, and cell wall (CW), and culture filtrate (CF) of M. tuberculosis [18], and purified proteins of PE35, PPE68, EsxA, EsxB and EsxV [13], at an optimal concentration of 5 μg/ml [19]. The cultures were pulsed on day 3 with 1 μCi 3H-Thymidine (Amersham Life Science, Amersham, UK), harvested 4 h later with a cell harvester and the amount of incorporated methyl-[3H] thymidine was determined using liquid scintillation counting [20]. The proliferation of spleen cells was considered positive with stimulation index (SI) > 5.0; which is defined

as: SI = average cpm in triplicate wells with antigen/average cpm in triplicate wells without antigen. Ethical approval.  Mice were immunized and handled according to established IACUC-approved protocols EPZ-6438 in vitro at Kuwait University, Kuwait. DNA fragments suitable for cloning and expression of PE35, PPE68, EsxA, EsxB and EsxV genes in DNA vaccine vectors pUMVC6 and pUMVC7 Autophagy activator were PCR amplified from genomic DNA of M. tuberculosis

using gene-specific primers suitable for cloning in each vector (Tables 1 and 2). The amplified DNA corresponding to the size of PE35, PPE68, EsxA, EsxB and EsxV genes were purified and ligated to pGEM-T Easy vector DNA yielding recombinant plasmids pGEM-T/PE35, pGEM-T/PPE68, pGEM-T/EsxA, pGEM-T/EsxB and pGEMT/EsxV, respectively. The analysis of DNA fragments released from the recombinant plasmids after digestion with EcoRI showed that the cloned DNA corresponded to the expected molecular size of PE35, PPE68, EsxA, EsxB of RD1 and EsxV of RD9 genes (data not shown). The very DNA corresponding to PE35, PPE68, EsxA, EsxB and EsxV genes from the recombinant plasmids pGEM-T/PE35, pGEM-T/PPE68, pGEM-T/EsxA,

pGEM-T/EsxB and pGEM-T/EsxV were released by restriction digestion with BamH I for pUMVC6 and BamH I and Xba I for pUMVC7, and ligated to appropriately digested pUMVC6 and pUMVC7 plasmid DNA to give rise to recombinant plasmids pUMVC6/PE35, pUMVC6/PPE68, pUMVC6/EsxA, pUMVC6/EsxB, pUMVC6/EsxV and pUMVC7/PE35, pUMVC7/PPE68, pUMVC7/EsxA, pUMVC7/EsxB and pUMVC7/EsxV, respectively. The identity of each cloned gene was confirmed by restriction digestion of recombinant plasmids with the restriction enzymes BamH I for pUMVC6; and BamH I and Xba I for pUMVC7, which released the cloned DNA corresponding to the size expected for each gene (data not shown). To study the immunogenicity of the RD1 PE35, PPE68, EsxA, EsxB and RD9 EsxV proteins in mice, studies were performed with the recombinant DNA vaccine constructs of pUMVC6 and pUMVC7 expressing the RD1 and RD9 proteins.

36,41 Therefore, while intracellular bacterial pathogens like Listeria and Salmonella are capable of in utero fetal invasion,39,42,43 infection susceptibility during pregnancy is not simply the result of the presence of fetal tissue that is susceptible to direct invasion, and instead more likely reflects systemic defects in host defence dictated by expanded maternal Treg cells. These findings with experimental Listeria

infection in mice are also consistent with the epidemiological features of this infection in humans where a significant portion of disseminated maternal infection www.selleckchem.com/products/Romidepsin-FK228.html cases occur without evidence of fetal direct invasion.38 Hence, the physiological

expansion of maternal Foxp3+ Treg cells during pregnancy compromises host defence, and these immune defects are exploited by pathogens like Listeria and Salmonella with a predisposition for prenatal infection. Importantly, since the expansion of maternal Treg cells is blunted during syngeneic LEE011 pregnancy, where the only potential sources of antigen heterogeneity between maternal and fetal antigens are those encoded on the Y chromosome, the importance of expanded maternal Treg cells in host defence for other prenatal pathogens may have been overlooked in previous studies, and deserve re-investigation using allogeneic pregnancy. The impacts on host defence dictated by the physiological expansion

of immune suppressive Treg cells also have broader implications beyond this instance of prenatal infection susceptibility. For example, the progressive expansion of Treg cells among peripheral CD4+ T cells occurs with aging throughout the lifespan of humans and mice.44–47 In particular, individuals over 60 years have a threefold increased proportion of Treg cells compared with CHIR-99021 molecular weight individuals less than 40 years.44,45 In turn, when pregnancy-associated cases are excluded, individuals over 60 years are also markedly more susceptible to disseminated Listeria infection compared with those < 60 years.48 Reciprocally following natural West Nile virus infection, symptomatic infection is more common in younger than older individuals, and these findings are consistent with the protective role provided by Treg cells in this infection.23,49 However, the expansion of Treg cells with aging alone does not explain other epidemiological data for this infection where individuals over 70 years compared with those aged 20–69 years have fivefold increased mortality with West Nile virus infection.

The inability to regulate cytokine production is likely a major contributor to the mortality in PKO mice since treatment with neutralizing anti-IFN-γ antibodies prevents mortality in vaccinated BALB/c-PKO as well as in naïve C57BL/6-PKO mice after LCMV infection [[16, 18]]. The discrepancy in survival in mice containing NP118- versus GP273-specific memory CD8+ T

cells could be explained by the extent to which Ag-specific CD8+ T cells can regulate cytokine production. To test this notion, we examined the IFN-γ production and the phenotype of CD8+ T cells post-LCMV challenge NU7441 in vaccinated as well as in control mice. Five and seven days after LCMV infection, a substantial percentage of total splenic CD8+ T cells exhibited IFN-γ production in the absence of exogenous peptide stimulation (no peptide) in the DC-NP118-vaccinated mice (Fig. 6A, middle row) while there was little difference in the DC-GP283-vaccinated or nonvaccinated mice (Fig. 6A, top and bottom rows). This resulted in significantly (p = 0.0017) higher number of total splenic CD8+ T cells

(∼10-fold) producing IFN-γ directly www.selleckchem.com/products/bay-57-1293.html ex vivo at day 5 post-LCMV in DC-NP118-vaccinated mice (Fig. 6B). In addition, stimulation of splenic CD8+ T cells isolated from DC-NP118-vaccinated mice at 5 and 7 days post-LCMV infection with GP283 peptide did not increase the frequency of IFN-γ-producing cells over the baseline (no peptide), suggesting that most of these IFN-γ-producing CD8+ T cells are NP118-specific (Fig. 6A, middle row). Finally, the GP283-specific secondary effector CD8+ T cells from DC-GP283-vaccinated mice had lower expression of programmed death 1 receptor (PD-1) and higher fraction of these cells producing TNF when compared with NP118-specific CD8+ T cells from DC-NP118-vaccinated

mice (Fig. 6C and D). While PD-1 is upregulated in effector cells, sustained expression requires continued antigen-stimulation [[38, 39]]. This phenotype suggested a lesser degree of functional exhaustion in the GP283-specific CD8+ T cells since increased PD-1 expression and loss of TNF production have been shown to correspond Low-density-lipoprotein receptor kinase to exhaustion of antigen-specific CD8+ T cells in chronic viral infection model [[38, 39]]. These results demonstrated that CD8+ T-cell epitope specificity impacts both functional exhaustion and the ability to tightly regulate CD8+ T-cell-derived cytokine secretion, rather than the absolute number or magnitude of CD8+ T-cell expansion. Memory CD8+ T cells provide enhanced resistance to reinfection by the same pathogen. Moreover, the number of memory CD8+ T cells correlates strongly with the level of protection in experimental models of infection [[1, 3]]. The ultimate goal of any vaccine regimen is to induce protective immunity against the targeted pathogens.

In order to assess the relation between CT60 cytotoxic T lymphocyte antigen-4 (CTLA-4)

gene polymorphism and thyroid autoantibody production, we investigated 180 consecutive newly diagnosed patients with two forms of AITD, 105 with Hashimoto’s thyroiditis (HT) and 75 with postpartum thyroiditis (PPT). We evaluated thyroid function, measured antibodies against thyroid PD98059 supplier peroxidase (TPO) and thyroglobulin (Tg), and determined CT60 CTLA-4 gene polymorphism. In HT, TPO antibody median value was significantly lower in the AA compared to the AG and GG genotypes (65, 122 and 319 U/ml, P < 0·005), while the Tg antibody median value was lower in the AA compared to the AG genotype (91 and 189 U/ml, P < 0·02). In PPT, the frequency of thyroid autoantibody-positive patients was higher among G-allele-carrying

genotypes (P < 0·04). Similar Compound Library clinical trial to HT, the TPO antibody median value was lower in the AA compared to the AG and GG genotypes (12, 130 and 423 U/ml, P < 0·006). Hypothyroid PPT patients were more often thyroid autoantibody-positive (P < 0·005) and the TPO antibody median value was higher compared to hyperthyroid PPT patients (500 and 32 U/ml, P < 0·0001). The frequency of the G-allele was significantly higher among hypothyroid patients (P < 0·05). Our data suggest that in both HT and PPT, the CT60 CTLA-4 gene polymorphism contributes importantly to thyroid autoantibody production. In PPT, the genotype also seems to influence thyroid function, as patients with the polymorphous allele are more prone to develop hypothyroid form of PPT. The presence of circulating autoantibodies against major thyroid antigens is the hallmark of thyroid autoimmunity, which comprises several different clinical forms, including Hashimoto's thyroiditis (HT) and postpartum thyroiditis (PPT). In HT, the antibodies against thyroid peroxidase or thyroglobulin (Tg) appear characteristically in the patients' sera, while tissue damage due to T cell-mediated cytotoxicity usually contributes to gradual development of hypothyroidism [1]. In PPT, where the re-establishment of immune responsiveness

after delivery leads to thyroid dysfunction in the first year postpartum, two-thirds of females present with Adenosine triphosphate positive thyroid peroxidase antibodies, putting them at risk for developing a hypothyroid form of PPT and permanent hypothyroidism. Thyroid peroxidase antibody-negative PPT patients are more likely to experience only a phase of transient hyperthyroidism and 1 year postpartum the euthyroid state is usually restored [2]. Similar to autoimmune thyroid disease (AITD), strong genetic susceptibility is required for the production of thyroid autoantibodies [3]. According to an estimation based on Danish twin pairs, the genetic background contributes 73% to the predisposition to thyroid autoantibody production [4].

Eculizumab treatment has raised the special concern of meningococcal infections [27]. Data on specific biomarkers for most of the agents described are widely lacking. Repopulation of B cells via GSK126 in vitro detection of CD19+ and CD20+ cells is sometimes used to determine reinfusion intervals for rituximab treatment, as it may be correlated with disease activity [103]. FTY entails peripheral immunomodulatory effects and direct interactions within the CNS resulting from modulation of sphingosin-phosphate receptors (S1PR) [104]. Approval of Gilenya® for treatment of RRMS differs substantially between FDA and EMA [105, 106], reflecting divergent evaluations of its risk–benefit

profile. Whereas, APO866 cost in the United States, FTY is approved as first-line therapy, in the European Union it is considered second-line therapy predominantly after a failure of IFN-beta or glatirameracetate. This approach is supported, at least in part, by subgroup

analyses of the TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS) study, especially for patients with high disease activity on IFN-beta therapy [107]. Ongoing studies investigate the use of FTY in PPMS (ClinicalTrials.gov NCT00731692), in paediatric MS (ClinicalTrials.gov NCT01892722) and in CIDP (ClinicalTrials.gov NCT01625182). Siponimod, a specific modulator of S1PR subtypes 1 and 5, [108] is being evaluated in a trial in SPMS patients (ClinicalTrials.gov NCT01665144). Specific risk populations comprise patients with predisposing conditions for the development of macula oedema such as diabetes mellitus and (recurrent) uveitis. Patients with pre-existing

cardiac arrhythmia, negative dromo- and chronotropic co-medication and pre-existing pulmonary disease should be evaluated closely. In addition, assessment of varizella zoster (VZV) immune status is mandatory [106]. FTY is administered orally as a 0·5-mg capsule once daily. Before treatment Nintedanib in vitro initiation, laboratory investigations including differential blood count, liver enzymes, pregnancy test and VZV status have to be performed. VZV-IgG-negative patients should be vaccinated. Electrocardiography (ECG) and continuous ECG monitoring are recommended during first-dose administration and selectively afterwards. Ophthalmological and dermatological screening are recommended as routine pretreatment investigation, most importantly in risk populations (see Patient selection). Routine laboratory testing, especially for lymphopenia, is required at close intervals; dermatological, opthalmological and pneumological check-up should be implied in bigger, but regular, intervals or by clinical indication [106]. Because FTY can moderately raise blood pressure, especially in hypertensive patients, blood pressure measurements should be performed regularly.

To this end we used an NF-κB inhibitor (Bay11) and the mTOR inhibitor rapamycin. TLR-triggered IL-10 production was significantly reduced after treatment with Bay11 or rapamycin alone and nearly absent after combined inhibitor usage (Fig. 5C). As expected for NF-κB inhibition, TLR2/4-induced TNF and IL-12 secretion levels were decreased under Bay11 treatment, but only TNF production remained unaffected by rapamycin, thus, confirming its selective regulation via NF-κB (Supporting Information Fig. 2D). Altogether, these findings suggested

a possible involvement of the PKB/Akt and p38 MAPK pathways in LPS-induced IL-10 regulation Luminespib clinical trial and provided the notion that IRAK4 might serve as a differential regulator of PKB/Akt and/or p38 learn more MAPK signaling and could thereby determine the IL-10/IL-12 ratio. Furthermore, IL-10 secretion is partially dependent on NF-κB, but is additionally driven by the PKB/Akt/mTOR pathway in an NF-κB-independent manner.

Based on these results we subsequently focused on the PKB/Akt pathway. Analysis of mRNA expression by quantitative real time RT-PCR showed that expression of IL-10 in response to LPS stimulation is markedly reduced in the presence of rapamycin, Akt inhibitor or wortmannin (Fig. 6A). This indicated that interference with PI3K/PKB/Akt/mTOR signaling negatively regulates- IL-10 synthesis at a transcriptional level. Confirming our hypothesis, western blot analysis demonstrated increased phosphorylation of the Akt kinase on Thr308 in IRAK4-silenced monocytes Carbohydrate stimulated with LPS (Fig. 6B). This effect was specific as this was not observed under MyD88 knockdown conditions, which, by contrast, decreased phospho-Akt levels to those measured in unstimulated cells (Fig. 6B). Thus, this experiment

highlighted the selective role of IRAK4 in the quantitative regulation of PKB/Akt activation. Also in line with these findings we detected enhanced phosphorylation of the PKB/Akt-mTOR-dependent transcription factor FoxO3a in IRAK4-silenced monocytes (Fig. 6C). As a last step we wanted to assess the functional impact of IRAK4-silencing on T-cell responses. To this end we used co-cultures of monocytes and allogenic CD8+ or CD4+ T cells. The results demonstrated that IRAK4-silenced monocytes represent weaker inducers of CD8+ as well as CD4+ T-cell proliferation than monocytes transfected with control siRNA (Fig. 7A). Notably, flow cytometric analysis of expression of monocyte activation markers, for example, CD14, CD80, CD86, PDL-1, MHCII, and ICOS-L was not affected by IRAK4 knockdown (not shown). But, suppressive monocyte function was found to be IL-10-dependent, as full T-cell stimulatory capacity was restored via neutralization of IL-10 in the co-cultures (Fig. 7B).

caninum (9). Despite the fact that protective measures to prevent infection have been sought, there is no nonlive vaccine capable of inducing complete protective immunity against neosporosis in cattle. selleck chemicals In contrast,

live vaccines such as attenuated strains of N. caninum have been shown to elicit protective immunity in cattle and mice (10,11). Despite this efficacy, live vaccines are generally not considered to be an economically viable option, because of logistic problems in production and handling, short-shelf life and the risk of reverting to a more virulent phenotype. The commercialized nonviable vaccine (Neoguard™) based on tachyzoite extracts, which is currently marketed in the Unites States of America, exhibits ambiguous results (12,13), and was shown to provide only partial protectivity (14). This could be because of the fact that a crude lysate contains immunoprotective, but possibly also immunomodulatory or even immunosuppressive, components. Thus, other approaches have been focussing on recombinant antigens,

which allow researchers to work with defined subsets of proteins that represent interesting targets. Most of the research on Neospora vaccines has been carried out employing murine models of cerebral infection (acute disease model) or models of foetal infection during pregnancy. One group of proteins/targets that is of interest for the development Y 27632 of a N. caninum vaccine are proteins that are secreted by the parasite at the onset of host cell adhesion and/or invasion. By targeting such molecules, one could possibly interfere in the vital mechanisms that lead to increased replication of the parasite within infected tissues. One of these antigens,

recombinant NcPDI (recNcPDI) (a protein disulphide isomerase), is localized in the parasite micronemes and the parasite surface. This is related to a protein found in the endoplasmic reticulum, functioning as a chaperone by interacting with S–S bridges and/or thiol groups, thus ensuring proper protein folding. Recombinant NcPDI was earlier shown to be involved in interactions between N. caninum Cyclic nucleotide phosphodiesterase tachyzoites and host cells (15) and represents a target for thiazolide drugs, which have a profound impact on N. caninum tachyzoites (16–18). Subsequently, Debache et al. (19) found that vaccination with recNcPDI protected mice from cerebral infection by experimental N. caninum infection when applied intranasally, but not when applied intraperitoneally. We have here exploited these unusual features of recNcPDI and used this protein as a model antigen to investigate its properties whether delivered entrapped in a nanosized delivery system, consisting of chitosan-based nanogels surface decorated with alginate or alginate-mannose. Chitosan, a copolymer of d-glucosamine and N-acetyl-d-glucosamine is a derivative of chitin, one of the most abundant polysaccharides in nature.

Hence, the defects in immunological development in the Ts65Dn mice seem to be limited to immature haematopoietic progenitors, particularly T-lineage precursors, although the mechanisms and potential biochemical effects in DS remain to be tested. Hence, these data demonstrate significant defects in immature and mature T-lymphocyte populations of Ts65Dn mice, with changes in

both the composition and function of the cells of the thymus and spleen. The data suggest that decreased IL-7Rα expression may underlie this dysfunction, causing decreased proliferation and function. Taken together with the haematopoietic stem and progenitor defects in previous studies,[6] the data indicate an overall dysfunction of adaptive

immune system development in Ts65Dn mice. The authors wish to thank Ian M. Kaplan for helpful discussions and Regina Harley for Opaganib check details expert assistance in cell sorting. This work was supported by funding from the US Public Health Service (AI070823) (MSW) and the LeJeune Foundation (PJY). The authors declare that they have no competing interests. “
“Highly protective intestinal cell membrane antigens have been prepared from Haemonchus contortus, an important blood feeding nematode which parasitizes sheep and goats. One such antigen, H-gal-GP, is a glycoprotein complex containing predominantly digestive proteases. This study showed that H-gal-GP readily digested ovine haemoglobin and albumin, the two most abundant proteins in the parasite’s blood meal. It was found that adding protective antibodies from H-gal-GP immunized sheep to the H-gal-GP catalysed haemoglobin digestion reaction, reduced the rate by 70–90% at pH 5·0. This reduction was only 30% when nonprotective IgG from sheep immunized with denatured H-gal-GP was added and IgG from worm-free sheep had no effect. These

results support the theory that the mechanism of protection in sheep vaccinated with H-gal-GP is by specific antibodies impairing the parasites ability to digest its blood meal. The blood feeding parasitic nematode Haemonchus contortus causes severe anaemia, loss of condition Quisqualic acid and, in the worst cases, death in small ruminants (1). Currently, it is controlled by pasture management and anthelmintic drugs. However, the increasing prevalence of worm strains resistant to the current drugs (2,3) demands alternative approaches for control, one of which could be by vaccination. To meet this goal, Smith et al. (4) have pursued the hidden antigen approach. Hidden antigens are ones to which the host does not normally mount an immune response over the course of natural infection, but which are accessible to antibodies ingested by the parasite (5). Their work has led to the isolation of a highly protective antigen called Haemonchus galactose-containing glycoprotein complex (H-gal-GP) from detergent extracts of Haemonchus intestinal cell membranes (6).

The culture supernatants were analyzed for the inflammatory mediator IL-1β (Fig. 5E), and we found that while both GlyAg and LPS stimulated IL-1β production, the response in WT and CGD cells were indistinguishable, even with 1400W present. Finally, we tested the efficacy of 1400W in reducing abscess incidence in CGD mice. Using the four-fold dilution challenge (50 μg GlyAg and 1:4 SCC), we found that 1400W treatment significantly reduced the number of CGD animals that developed abscesses from 93 to 57% (Fig. 5F). Moreover, the abscesses found in 1400W-treated CGD animals were also significantly Belinostat clinical trial reduced in clinical score as judged by size (1.9 mm average diameter)

compared with those found in CGD animals without 1400W (3.6 mm average diameter; Fig.

5F and G). These data show that modulation of iNOS activity via 1400W decreases NO production in vivo compared with that seen in Selleck LDE225 WT animals, resulting in the reduced incidence and severity of GlyAg-mediated abscess formation in CGD. We show that the gp91phox mutation in CGD results in the upregulation of NO production, leading to increased T-cell-mediated abscess formation in response to GlyAg. We further demonstrate that inhibition of iNOS in vivo with 1400W decreases abscess incidence and severity in CGD without increasing risk of bacterial sepsis, raising the possibility of iNOS inhibition as a clinical approach for CGD patients. CGD is characterized by recurring abscess and granuloma formation 7–9. While granulomas are usually sterile and result from chronic inflammation 7, 11, abscesses tend to form in response to microbial stimuli 13. For example, S. aureus, a GlyAg-expressing pathogen 16, is commonly associated with liver and brain abscesses 8, 11, 13, 32. Although abscesses are an important response to contain microbes and prevent sepsis, once formed, they preclude antibiotic effectiveness and require surgical drainage 7, 8. As a result, attenuation of abscess formation could provide a significant reduction in

infection morbidity and possibly even mortality through improving antibiotic efficacy and reducing surgical intervention. CGD has traditionally been viewed as a neutrophil-mediated Phosphoribosylglycinamide formyltransferase disease since neutrophils are early responders to infection and produce high bactericidal oxidant concentrations. In addition, apoptosis of responding neutrophils is known to be abnormal through multiple mechanisms including deficient surface expression of phosphatidylserine (PS) 27, 28, 33, or diminished production of the apoptosis-inducers TGFβ and prostaglandin D234. However, an emphasis on the involvement of other cell populations (e.g. macrophages, DCs, and even T cells) in CGD has more recently challenged the neutrophil-centered model.