Independently of CD146, the sSS patients exhibited increased CD31

Independently of CD146, the sSS patients exhibited increased CD31 expression on CD4 and CD8 cells; some showed loss of CD28 from CD4 cells (Supporting information, Fig. S8). Other memory,

adhesion and homing markers were similar to those in HDs. Thus, circulating T cells in the few CTD patients who exhibited phenotypic T cell activation had increased CD146 expression, associated with a broadened range of activation markers. We examined CD146 expression on circulating CD4 and CD8 T cells of HDs and patients with CTDs, and characterized the relationship of Selleck Cobimetinib CD146 with surface markers associated with activation, memory, adhesion and homing. As expected, CD146 expression correlated with some activation and memory markers, but unexpected differences between CD4 and CD8 T cells were observed. CD146 on T cells was increased in a small number of patients with sSS, all of whom exhibited systemic T cell activation, but not in patients with other CTDs, who did not. Previous work has shown CD146 induction by phytohaemagglutinin-activated T cells [3, 7]. We found that stimulation of HD T cells with anti-CD3/anti-CD28, a more physiological stimulus, up-regulated CD146 expression with slower kinetics and longer persistence than CD69, but similar to CD25. Both activated CD4 and CD8 T cells expressed

CD146. Ex vivo, however, the relationship of CD146 expression to T cell activation was more complex. Selleck BGB324 CD146-expressing CD4 T cells contained a greater proportion of activated-phenotype cells than bulk CD4 Cell press T cells (OX40+, CD69+ and low-level

CD25 expression). Within the CD4 subset, the CD146+ population comprised almost exclusively CD45RO+/RA–/CD28+ non-senescent memory cells, and was enriched in CD27− cells, suggesting repeated activation. Nevertheless, the correlation with activation was not absolute: most activated cells lacked CD146, and no single marker correlated perfectly with CD146 expression. Thus, CD4 T cell activation in vivo does not induce CD146 expression as uniformly as it does in vitro. This could partly reflect differences in the timing of expression of activation markers post-stimulation but suggests that physiological stimuli induce CD146 expression more selectively than is recapitulated in vitro. A few CD146+CD4 T cells are FoxP3+ CD25high, consistent with a Treg phenotype, but FoxP3 can be expressed by human activated effector T cells and additional markers would be required to address this definitively [33]. Previous work has reported similar findings, albeit with fewer markers analysed in individual donors [7]. Unexpectedly, the association of CD146 with activation and memory ex vivo was less marked in CD8 T cells. In HD CD8 cells, CD146-expressing cells were less frequent than in CD4 cells; of the activation markers studied, only CD69 was enriched significantly in CD146+ CD8 cells.

“Micafungin was non-inferior to liposomal amphotericin B (

“Micafungin was non-inferior to liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC) in a major clinical trial. The present study investigated the economic impact of micafungin vs. LAmB in treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using micafungin or LAmB as primary definitive therapy. The main outcomes were treatment success and treatment failure due to mycological persistence, or death. MI-503 price Outcome probabilities were derived from key published sources. Resource used was estimated by an expert panel and cost inputs were from the latest

Australian resources. The analysis was from an Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$61 426) had a lower total cost than LAmB (AU$72 382), with a total net cost-saving of AU$10 957 per patient. This was primarily due to the lower cost associated with initial

antifungal treatment and shorter length of stay for patients in the micafungin arm. Hospitalisation was the main cost driver for both arms. Results were robust over a wide range of variables. The uncertainty analysis demonstrated that micafungin had a 99.9% chance of being cost-saving compared with LAmB. Tigecycline order Micafungin was associated with cost-saving relative to LAmB in the treatment of candidaemia and IC in Australia. “
“Aspergillus tracheobronchitis (ATB) is considered as an unusual form of invasive aspergillosis and has a fatal outcome. There is little current information on several aspects of chronic obstructive pulmonary diseases (COPD) complicated by ATB, the frequency of which is expected to increase in the coming years. In a prospective study of invasive bronchial-pulmonary aspergillosis (IBPA) in a critically ill COPD population, three proven cases of ATB were identified. The three new cases, combined with eight previously

reported cases of COPD with ATB over a 30-year period (1983–2013), were analysed. Among 153 critically ill COPD patients admitted to the ICU, eight cases were complicated by Phosphoglycerate kinase ATB [23.5% of IBPA (8 of 34); and 5.2% of COPD (8 of 153)], and three cases were finally diagnosed as proven ATB by histopathological findings. Among the three new cases reported and the eight published cases, the overall mortality rate was 72.7% (8 of 11 cases), with a median of 11.5 days (range, 7–27 days) between admission to death. The mortality rate was significantly higher in patients with invasive pulmonary aspergillosis (IPA) [100% (8 of 8 patients)] than in patients without parenchyma invasion [0% (0 of 3 patient), P = 0.006]. Seven patients (77.8%) received systemic corticosteroid therapy and three patients (33.3%) inhaled corticosteroids before diagnosis with ATB. Dyspnoea resistant to corticosteroids (77.8%) was the most frequent symptom.

Quality is classically screened in terms of number of spermatozoa

Quality is classically screened in terms of number of spermatozoa present, their motility and morphological ‘normality’, the relative numbers of shed leucocytes (classically seen as signs of inflammatory changes) or of Belnacasan purchase immature germ cells (as signs of defective spermatogenesis), etc. The SP of humans, but not of other species, is also examined, albeit not routinely, for specific markers (neutral α-glucuronidase for epididymis fluid, phosphatases or zinc levels for prostate fluid, or fructose for seminal vesicles).3 The reluctance in examining SP is often related to the classical view that SP is a

vehicle for spermatozoa and even regarded as deleterious for some purposes, such as storage. For that reason, the SP is largely removed and replaced by extenders for further handling or freezing.4 However, growing evidence demonstrates that the SP plays other roles, including modulation of sperm function and of their ability to interact with the epithelia and the secretions of the female genital

tract and also as a carrier of signals for the female, its immune system in particular.5–7 Simple components of the SP seem to play important roles for sperm viability. Bicarbonate modulates sperm motility Tanespimycin cost and destabilizes the plasmalemma during capacitation8,9, while zinc modulates chromatin stability.10 Most peptides and proteins of the SP, which often make up to 40–60 g/L per ejaculate (human 25–55 g/L; boar 30–60 g/L), play major other roles. Interestingly, the roles of seminal fluid proteins appear to be highly conserved. In insects, transfer of seminal fluid, its proteins in particular, induces numerous physiological post-mating changes, ranging from enhancement of egg production, modulation of sperm storage and competition, mating plug-formation and the expression of antimicrobial peptides. Moreover, seminal fluids appear to induce behavioural changes, including decreased receptivity to remating and modified feeding behaviour, with clear changes in female gene expression isothipendyl post-mating for mating-dependent genes with predicted functions in metabolism,

immune defence and protein modification.11 Despite our filogenetical distance, mammals – including humans – also seem to ascribe exposure to SP proteins other roles than serving as a nutrient and vehicle for spermatozoa, such as the induction of both innate and adaptative immunological responses by the female. These phenomena include the cleansing of eventually introduced pathogens and redundant allogeneic spermatozoa, while calling for immunotolerance towards tubal spermatozoa, developing embryos and feto-placental tissues, i.e. all components essential for reproductive success.12 Proteomics (e.g. the study of protein products expressed by the genome) has dramatically expanded over the past decade, owing to multidisciplinary methodological and instrumental developments, but also attributed to the central role of protein interactions in cell function.

“Tumors of the Peripheral Nervous System’ is the 19th Fasc

“Tumors of the Peripheral Nervous System’ is the 19th Fascicle in the 4th series of Armed Forces Institute of Pathology (AFIP) Atlases of Tumor Pathology.

The book is divided into a total of 15 chapters. The first chapter is an overview of peripheral nerve tumours, including a historical background, a brief account of early investigators (such as Theodor Schwann, Rudolf Virchow and Santiago Ramon y Cajal), and a section describing specimen presentation, handling and assessment. The second provides an overview of the development, gross anatomy, MLN0128 nmr histology and ultrastructure of the peripheral nervous system. Chapters 3 through 6 (a total of almost 100 pages) cover a variety of non-neoplastic lesions which would be included in the differential diagnosis of peripheral nervous system tumours. These are subdivided into Dabrafenib reactive lesions; inflammatory and infectious lesions; hyperplastic lesions; and lipomatosis and neuromuscular choristoma of nerve. The remainder of the book is broken down into chapters dedicated to neoplastic entities including schwannoma, neurofibroma, perineurial cell tumours, miscellaneous benign neurogenic tumours, benign and malignant non-neurogenic tumours, malignant tumours of the peripheral nerves, tumours of the neural transmitting mesenchymal cell component of the peripheral nervous system, and secondary neoplasms. The final chapter is dedicated to neurofibromatosis

(types 1 and 2) and schwannomatosis. Each diagnostic entity is broken down into various subsections (the number of which vary depending on the type of lesion), but which typically include a definition, general features, clinical features, gross findings, microscopic findings, immunohistochemical findings, ultrastructural findings, differential diagnosis, and treatment and prognosis. Each chapter ends with an extensive selection of references for readers wishing to refer to the original papers. Within the chapter dedicated to neurofibroma additional subsections include ‘diagnostically confusing else microscopic features’ (including a review of features such as hypercellularity with and without epithelioid

cell change, densely aggregated small nuclei, melanin containing cells, and a variety of other histological appearances), ‘histological atypia and malignant change’ and ‘tumors of proposed neurofibromatous nature but unconfirmed’. As with all AFIP fascicles the book is lavishly illustrated throughout with well-annotated clinical pictures, radiology, macroscopic, microscopic and ultrastructural findings. The great strength of this book is its practical approach to diagnosis. This is the sort of book pathologists will keep by their microscope to refer to when reporting day-to-day work, as well as more challenging cases. The histological features are clearly illustrated and the differential diagnoses are particularly useful, providing a concise yet clear approach to dealing with problematic cases.

Alterations to the balance of angiogenic (i e , placental growth

Alterations to the balance of angiogenic (i.e., placental growth factor) and anti-angiogenic factors (i.e., soluble fms-like tyrosine kinase 1; soluble endoglin) X-396 order are highlighted as potential contributors to endothelial cell dysfunction. Notably, increased activation of inflammatory cells, with concomitant shifts in cytokine profiles, has been observed in women with preeclampsia. The authors describe these alterations and how they are linked with endothelial cell dysfunction. Investigations that have documented the effect of preeclampsia on altered vasoresponsiveness of both systemic and uterine resistance vessels

are summarized. Recent developments implicate not only circulating factors, but also endothelial-derived microparticles, as mediating the systemic vascular effects of preeclampsia. Endothelial dysfunction within the fetoplacental circulation also is a central feature of GDM. Guzmán-Gutiérrez et al. [6] describe the regulation of l-arginine transport within the macro- and microvascular endothelial cells of the placental circulation, and highlight the inherent phenotypic differences exhibited by these two types of endothelial cells. The authors summarize recent advances in understanding how the placental endothelial cell l-arginine/nitric oxide (NO) signaling pathway is subject to modulation by adenosine and insulin. They discuss a model of how imbalances in adenosine and insulin-mediated signals

may disrupt physiological function of the l-arginine/NO pathway within the placental circulation during GDM. As the rate of occurrence of the pathological condition of GDM grows in the population click here in parallel with rates of obesity and insulin resistance, this undoubtedly is a key area that warrants further investigation. “
“Please cite this paper as: Leach and Mann (2011). Consequences of Fetal Programming for Cardiovascular Disease in Adulthood. Microcirculation 18(4),

253–255. This Spotlight Issue of Microcirculation contains six current perspectives on the role of the intrauterine environment, especially maternal nutritional status and maternal diabetes, in influencing fetal growth and cardiovascular health in the offspring in later life. The reviews address issues such as the existence of a commonality PJ34 HCl of mechanism following both under-nutritional and over-nutritional states in utero; alterations in the placental fetal microcirculation in response to maternal and fetal changes; transmission of metabolic or nutritional perturbations affecting fetal endogenous antioxidant defense pathways; the presence of a disadvantageous microvascular phenotype resulting from perinatal priming; interactions between developmental programming and genetic variation in noncommunicable adult diseases such as hypertension and hypercholesterolemia; and unresolved questions on the independency and causal mechanisms for low birth weight/intrauterine growth restriction and the risk of developing the metabolic syndrome.

Another meta-analysis, by Boudville et al examined the effect of

Another meta-analysis, by Boudville et al. examined the effect of donation on blood pressure.29 This concluded that donors may have a 5 mmHg increase in blood pressure within 5–10 years of donation. Ibrahim et al. assessed the vital status and lifetime risk of end-stage kidney disease (ESKD), GFR, urinary albumin excretion, prevalence of hypertension, general health status and quality of life in 3698 kidney donors.30 Survival and risk of ESKD was not significantly different to those in the general population. Most donors had a preserved GFR, normal albumin excretion and an excellent quality of life. It is important to point out that the absence

of any large prospective, well-controlled, long-term follow-up studies on live donors is seen as a significant deficiency.27,31,32 Furthermore, long-term studies regarding live donors with isolated DNA Damage inhibitor abnormalities (e.g. hyperlipidaemia, mild hypertension, obesity) H 89 nmr are also lacking, and the long-term risks in these subjects remain particularly ill defined. It is hoped that the recently established ANZDATA Live Donor Registry will help in further

clarifying the true long-term donor outcomes in Australia and New Zealand. With regards to the short-term risks, these are predominantly related to the surgical procedure. The risk of perioperative mortality is generally regarded as being approximately 1 in 3000 – a figure derived from large American surveys33 and several Ribonucleotide reductase single centre reports. Although Australian and New Zealand registry data are currently lacking, of approximately 5000 live kidney donations that have occurred in Australia and New Zealand to date, the transplant community is currently aware of two perioperative deaths (anecdotal reports). The risk of non-fatal major perioperative complication is also generally felt to be low, approximating 2–4% in most published series (see later subtopics for a detailed account of the supporting literature). The majority of these complications have been haemorrhagic episodes, although a variety of other events have been reported including

bowel obstruction, bowel injury, thromboembolic events, pneumothoraces, hernia development and rhabdomyolysis. Prasad et al. performed an observational cohort study of 58 living donors to 6 months post-donation for changes in 24 h ambulatory blood pressure profile, kidney function, urine protein excretion, body mass index, glucose intolerance and fasting lipid profiles.34 No significant changes in blood pressure, protein excretion, body mass index, glucose and lipids were found. Estimated glomerular filtration rate declined significantly (P < 0.0001). Most of the data presented here comes from Registries and from large retrospective cohort studies. There is a lack of prospective long-term data regarding live donor safety, particularly in relation to consequences of donation in certain donor subgroups.

Despite comparably low levels

Despite comparably low levels GSK126 in vivo in Th1 cells, SOCS3 and SOCS5 also regulate Th1 differentiation. Indeed through binding to the IL-12Rβ2 chain, SOCS3 prevents STAT4 activation (Fig. 2) and constitutive expression of SOCS3 in CD4+

T cells was shown to hinder Th1 polarization.33 Consistent with these findings, up-regulation of SOCS3 by IL-2 was found to prevent acute graft-versus-host disease by inhibiting the Th1 response.34 However, SOCS3 deletion in T cells also resulted in decreased Th1 differentiation, although this was proposed to be indirect. Indeed, increased IL-10 and transforming growth factor (TGF-β) secretion was also observed in these cells, perhaps suggesting that SOCS3 may limit Treg see more cell development.35 The role of SOCS5 is more controversial. Indeed, despite being highly expressed in Th1 cells,36 disruption of the socs5 gene does not affect the ability of cells

to differentiate either towards Th1 or Th2.37 Over-expression of SOCS5 in T cells is associated with increased levels of IL-12, IFN-γ and tumour necrosis factor-α in a mouse model of septic peritonitis,38 but this could be indirectly the result of enhanced macrophage activity, possibly through increased IFN-γ secretion by T cells.36,39 Finally, Th1 differentiation does not seem to be affected by higher levels of SOCS5,36 and so the exact role of SOCS5 in Th1 differentiation remains unclear. By regulating IL-12-mediated STAT4 activation and IFN-γ-mediated STAT1 signals, SOCS1, VEGFR inhibitor SOCS3 and SOCS5 certainly modulate the development

of Th1 cells, although the role of individual SOCS is, even at this point, far from clear. Our current understanding is summarized in Table 2. The Th2 cells secrete large amounts IL-4, IL-5, IL-9 and IL-13, and consequently promote the humoral response but also drive IgE class switching and allergic disease.40 The commitment of Th2 cells is essentially driven by IL-4, which activates both JAK1 and JAK3 and the transcription factor STAT641 (Fig. 3). Not surprisingly, STAT6 plays a key role in the acquisition of the Th2 phenotype. In particular STAT6 directly controls the expression of Th2 lineage master regulator, GATA3,42 and enforced expression of STAT6 in Th1 cells re-establishes their ability to secrete IL-4 and IL-5, while repressing IFN-γ and IL-12Rβ2 expression.42 STAT6-deficient T cells fail to polarize towards Th2 in vitro and in vivo,43–45 but the absence of STAT6 does not affect the emergence of Th2 cells in response to Nippostrongylus brasiliensis or Schistosoma mansoni challenge,46–48 which probably reflects the fact that STAT6 does not directly regulate the il4 gene. Instead, induction of IL-4 is controlled by GATA-3, which suggests that STAT6 essentially acts by up-regulating GATA-3 levels, although STAT6 seems to modify the chromatin structure of the Rad50 gene, which may allow optimal transcription of the il4 and il13 genes.

Indeed, pneumolysin was found to be an essential and sufficient f

Indeed, pneumolysin was found to be an essential and sufficient factor in inducing the expression of IL-1β to a limited level (Fig. 3b and c). Pneumolysin is not a secretary protein because it does not have a typical secretion signal, but it can be released by the action of the cell-bound autolysin (Canvin et al., 1995). This explains how live bacterial

culture and the culture supernatant also displayed a limited induction of IL-1β expression Selleckchem LEE011 (Fig. 3a). Upregulated expression of proinflammatory cytokines represents an important innate defense response to facilitate the clearance of infectious agents by increasing leukocyte influx. A significant amount of neutrophil infiltration was observed in murine lung following NTHi

infection, indicating that NTHi may potently induce the expression of proinflammatory cytokines (Lim et al., 2007a, b). It was also reported that NTHi stimulated the early expressions of proinflammatory cytokines in epithelial cells (Clemans et al., 2000). Indeed, NTHi was shown to maximally induce the expression of IL-1β, TNF-α and cox2 at 3 h after treatment (Fig. 2), although the expression of IL-1β was gradually reduced by three- to fourfold at 7 h (Fig. 4). In comparison with this, a low level of cytokine expression was observed in response to either S. pneumoniae or pneumolysin at 3 h after treatment (Figs 2 and 3). In line with this result, S. pneumoniae-mediated lobar pneumonia in human patients does not have many PMNs at the early stage of infection (Lagoa et al., 2005; Ware et al., 2005). Additionally, less immune infiltration was histologically observed in murine lung during S. pneumoniae infection (Lim et al., 2007a, b). However, the expression gradually increased in a time-dependent manner, and peaked at 7 h after treatment (Fig. 4a and b). Streptococcus pneumoniae induced a low level of cytokine expression at the early stage of infection, suggesting that S. pneumoniae may have interfering mechanisms in inducing cytokine expression to a limited level compared with that by NTHi. Based on a previous report, the expression of cox2 induced by IL-1β appears

to be regulated by nuclear factor (NF)-κB and PI3K/AKT pathways (Chun & Surh, 2004). An NF-κB-dependent promoter assay revealed that NF-κB activity in response to S. pneumoniae was over 5 fold lower than that by NTHi triclocarban (Kweon et al., 2006), indicating that the low level of induction may involve interfering with this NF-κB pathway. In addition, IL-1β expression appears to be regulated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway (Baldassare et al., 1999). Inhibition of MAPK commonly occurs through the action of MAPK-phosphatase (MKP). Thus, it is highly possible that the increased expression of MKP was responsible for the low level of cytokine expression in response to S. pneumoniae. Consistent with this, we reported previously that S.

16–19 The innate A3G response

16–19 The innate A3G response learn more is surprisingly long-lasting following immunization in macaques20,21 and this has been attributed to A3G being expressed in CD4+ CD95+ CCR7− effector memory T cells.20 Up-regulation of A3G stimulated

by CD40L is mediated by ligation of CD40 cell-surface molecules on dendritic cells22 and this is also likely to account for A3G regulation in B cells expressing CD40. However, B-cell-derived A3G in vivo has not been studied previously. The signalling pathway following engagement of CD40 by CD40L elicits phosphorylation of IκB kinase complex followed by nuclear translocation of nuclear factor-κB (NF-κB), which initiates class switch recombination by binding to the κB site on IH promoters.23,24

CD40L-bound CD40 also activates extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase inducing A3G mRNA and protein expression.22 Interleukin-4 bound to IL-4 receptor induces phosphorylation of Jak1 and Jak3 kinases, followed by phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription (STAT6) leading to class switch recombination.24 Transforming growth factor-β is another B-cell agonist critical in switching IgM to IgA.25 We have pursued a report that appeared after we had completed the project that the AID encoding gene (Aicda) responds to activation with CD40L, IL-4 and TGF-β.26 We confirmed this using human B cells, which showed maximal activation of AID mRNA with the combined three agents selleck products (2665 ± 1150), compared with TGF-β alone (80·5 ± 18) and extended it to A3G mRNA from 118 ± 45 to 495 ± 88 (P = 0·030) (data not presented). selleck compound Flow cytometry studies also demonstrated a significant increase in AID expression by the combined TGF-β + CD40L + IL-4-stimulated B cells. The mechanism advanced26 was that region 4 of the AID encoding gene (Aicda) contains the functional binding sites for NF-κB, STAT6 and Smad

3/4, which are response elements to CD40L, IL-4 and TGF-β, respectively.26 This may lead to de-repression of silencers by B-lineage-specific and stimulation-responsive enhancers. Whether this mechanism might also apply to A3G, another deaminase belonging to the same family produced by B cells, needs to be verified. We postulate that A3G produced by B cells is transmitted to CD4+ T cells probably via exosomes, in which A3G is a major component.10 B cells are significant producers of exosomes following activation of cell-surface CD40 and IL-4 receptors27 or interaction with T cells via CD40–CD40L molecules.28 Inhibition of HIV replication has been demonstrated between monocyte-derived exosomes and CD4+ T cells.9 Alternatively, B cells might produce intercellular nanotubes which establish contact with CD4+ T cells.

40 These results are consistent with our own, as CatG is known to

40 These results are consistent with our own, as CatG is known to have a chymotrysin-like activity,

although digestion patterns of other substrates by these BAY 57-1293 in vivo two proteases are not always identical.38 The finding that cleavage of MHC II occurs after L is consistent with published data on CatG specificity, the preferred P1 amino acids for CatG cleavage being Y, F, R, L, and K.41,42 Both in vitro and ex vivo data initially suggested, but did not prove, that CatG might be involved in physiological MHC II turnover. The DR loop that harbours the cleavage site is physically close to the DM interaction site of DR, and a subset of adjacent mutations that impair DM interaction also confer resistance to CatG-mediated proteolysis. DM is known to stabilize empty Pictilisib nmr MHC II molecules against degradation during endosomal peptide exchange, and this protective effect might be attributable to protection of DM-associated empty DR molecules from CatG cleavage. We were unable to reproduce this effect with DM/DR complexes formed in vitro (data not shown), but this negative result might reflect the fact that these are reversible, non-covalent

complexes. Furthermore, the inverse relationships between changes in CatG activity and MHC II levels during immune cell activation were consistent with a role for CatG in MHC II turnover. Previous work has shown that CatG accumulates in endocytic compartments of primary APCs and contributes to endosomal processing of autoantigens,38,43 so its subcellular location would be compatible with participation of CatG in endosomal MHC II turnover. However, three independent experiments failed

to provide positive evidence that would implicate CatG in MHC II turnover in APCs. First, pharmacological inhibition of CatG for extended periods of time in primary human APCs failed to cause accumulation of HLA-DR molecules or of large degradation intermediates. In some preliminary Non-specific serine/threonine protein kinase experiments, we noticed that endogenous CatG activity appeared to cause DR degradation following detergent lysis of cells (data not shown); however, inclusion of the CatG inhibitor in the lysis buffer prevented this artifact, and this precaution was adopted in the experiments shown here. Similarly, genetic ablation of CatG in mice had no effect on steady-state levels of murine MHC II molecules. Collectively, our data suggest that CatG acts enzymatically upon detergent-solubilized, but not upon membrane-embedded native MHC II molecules. We considered two possible explanations for the lack of CatG cleavage in live APCs. One possibility is that the resistance of MHC II molecules to endosomal CatG cleavage reflected the neutral, rather than endosomal, pH optimum of CatG cleavage of MHC II.