“
“Multiple Sclerosis (MS) is a common and heterogeneous CNS inflammatory demyelinating disease. The HLA-DRB1 locus may influence clinical outcome. MS cortical pathology is frequent and correlates with measures of clinical disability, including motoric dysfunction that is a predominant feature of disease progression. The influence of HLA-DRB1*15 on motor AZD2014 datasheet cortical pathology is unknown. A pathologically confirmed age- and sex-matched HLA-DRB1*15+ (n=21)

and HLA-DRB1*15- (n=26) MS post-mortem cohort was used for detailed pathologic analyses. For each case, adjacent sections of motor cortex were stained for myelin and inflammation, to evaluate the extent and distribution of motor cortical pathology. A subset of MS cases (n=42) had spinal cord (SC) pathologic outcome data available for comparison. Motor cortical demyelination was more pronounced in younger cases (r =-0.337, p < 0.05), with MS cases carrying the HLA-DRB1*15 allele driving this effect (r=-0.612, p < 0.01). HLA-DRB1*15+ MS cases had more severe motor cortical parenchymal (p < 0.05), perivascular (p < 0.05), and meningeal (p < 0.05) T-cell inflammation compared to HLA-DRB1*15- cases. HLA-DRB1*15 status significantly influenced the extent of motor cortical microglial burden Selleck Ku-0059436 in both NAGM (p < 0.0001) and lesions

(p < 0.01) in MS cases. Relationships between the extent of motor cortical and SC pathology were limited, but when present were primarily driven by HLA-DRB1*15+ cases. HLA-DRB1*15 status has a significant

association with the extent of inflammation in the MS motor cortex, the extent of demyelination in younger MS cases, and influences relationships between motor cortical and SC pathology. “
“Rhabdoid glioblastoma is a recently described entity in which a glioblastoma is associated with a rhabdoid component. Although rhabdoid glioblastoma has not Acetophenone appeared in the new World Health Organization classification of tumors of the CNS, it has a specific morphological feature and highly aggressive clinic process. Up to now, there have been six cases of rhabdoid glioblastoma reported in the literature. We report rhabdoid glioblastoma in the right front temporal lobe from a 31-year-old Chinese man. This tumor consisted of rhabdoid tumor cells with an eccentric nucleus and an eosinophilic cytoplasm. The tumor had an area appearing to be glioblastoma with microvascular proliferation and necrosis, and lacked a primitive neuroectodermal tumor component, and a mesenchymal component. Vimentin, epithelial membrane antigen, GFAP and integrase interactor (INI-1) expression were found in the tumor cells. Genetic abnormalities which include monosomy or a deletion of chromosome 22 were not found in this tumor. After 3 months post-surgery, the tumor was widespread in leptomeningia and the patient died.

Localized CL is the most frequent clinical form of ATL [18,36,39]. It can be caused by all pathogenic Leishmania species with dermal tropism, including L. braziliensis and L. amazonensis[18]. Clinical and histopathological differences have been described between human infections with these two species: L. braziliensis causes mucosal leishmaniasis, a clinical form associated with the up-regulation of Th1-type responses [15–18], whereas L. amazonensis is the aetiological agent of anergic diffuse cutaneous NVP-LDE225 leishmaniasis, a condition associated with specific impairment of the

cell-mediated immune response [3,10,18,37,40]. Furthermore, a respectable amount of data in the murine model indicates impairment in multiple immune functions after L. amazonensis infection [41–47]. Taken together, these observations suggest major differences in cell-mediated immunity against these Leishmania species, and that the mechanisms responsible for susceptibility to L. amazonensis are complex and deserve more

thorough investigation. In the present study, we were able to show that crude promastigotes extracts obtained from MLN0128 datasheet L. braziliensis and L. amazonensis induce a different magnitude and quality of the Th1 response in PBMCs from healed CL patients. To our knowledge, this is the first time that multifunctional click here CD4+T cells have been evaluated in human leishmaniasis. Corroborating previous data [48], in this study we confirmed that LbAg induces higher levels of IFN-γ than LaAg, and are now able to demonstrate that this fact was related not to a higher percentage of cytokine-producing cells, but to a higher

amount of protein produced by individual CD4+T cells (Fig. 1a and b). Furthermore, using multiparametric flow cytometry approach, we were also able to indicate that it might be associated to differences in the quality of Th1 CD4+T cells induced by both antigen extracts (Fig. 2). Because the same results regarding IFN-γ levels induced by LbAg and LaAg were observed in PBMCs obtained from ATL patients before therapy [48], and that parasites isolated from patients of the former and current studies were characterized as L braziliensis, it could be expected that their T cells would respond more strongly to antigens from the homologous species with which they have been infected than to antigens from species belonging to a different subgenus. Conversely, it has been demonstrated that LbAg is a more potent stimulator of T cell response than LaAg in individuals infected with L. amazonensis, as well as in individuals infected with parasites from the Viannia subgenus, before and after therapy [49]. It has also been shown that LaAg or live L.

g., delineating what is and what is not vasculature), measurement (e.g., the diameter of vessel interbranch segments or the hierarchical structure of the entire vascular tree), and modeling (e.g., comparing measurements to theoretical predictions based on optimization criteria, or computing perfusion territories and local shear stresses through fluid dynamic simulations).

We summarize the current state of micro‐CT microcirculation research RAD001 nmr and suggest possible directions for future research investigations. “
“Please cite this paper as: Yang, Aragon and Murfee (2011). Angiogenesis in Mesenteric Microvascular Networks from Spontaneously Hypertensive Versus Normotensive Rats. Microcirculation 18(7), 574–582. Objective:  Elevated blood pressure during hypertension has been associated with microvascular rarefaction, defined

as a loss of microvessels. However, whether rarefaction is a result of impaired angiogenesis remains unclear. The objective of this study was to compare angiogenesis across the time course of mesenteric microvascular network remodeling in adult spontaneously hypertensive versus normotensive rats. Methods:  Angiogenic responses in 15- to 16-week-old SHR and Wistar rats at 0, 3, 5, 10 or 25 days post 20-minute exteriorization of the mesentery were quantified. Results:  Consistent with the phenomenon of rarefaction, vascularized area in unstimulated SHR was decreased compared to Wistar. By 25 days, SHR vascular area had increased to MK-1775 concentration the Wistar level and vascular length

density and capillary sprouting were comparable. At 3 and 5 days, SHR and Wistar tissues displayed an increase in the capillary sprouting and vascular density relative to their unstimulated controls. At 10 days, capillary sprouting in the SHR remained elevated. The percent change in vascular density was elevated in the SHR compared to the Wistar group at 3 and 5 days and by 25 days the rate of change was more negative. Conclusions:  Our results suggest Oxalosuccinic acid that SHR networks undergo an increased rate of growth followed by an increased rate of pruning. “
“Please cite this paper as Nagaraja S, Kapela A, Tsoukias NM. Intercellular communication in the vascular wall: a modeling perspective. Microcirculation 19: 391-402, 2012. Movement of ions (Ca2+, K+, Na+, and Cl−) and second messenger molecules like inositol 1, 4, 5-trisphosphate inside and in between different cells is the basis of many signaling mechanisms in the microcirculation. In spite of the vast experimental efforts directed toward evaluation of these fluxes, it has been a challenge to establish their roles in many essential microcirculatory phenomena. Recently, detailed theoretical models of calcium dynamics and plasma membrane electrophysiology have emerged to assist in the quantification of these intra and intercellular fluxes and enhance understanding of their physiological importance.

The bone marrow (BM) and, to a lesser extent, the spleen represent the major homing sites of PCs, notably long-lived ones 4. Additionally, a substantial number of PCs can be found in the mucosa, especially in the gut 5. Antibody-secreting cells (ASCs) are also located in inflamed tissues, for instance within the nephritic kidneys of lupus mice and of SLE-patients 6–9 as well as in the synovial tissue of patients with rheumatoid arthritis 10. Cassese et al. reported that after immunization of New Zealand black/white (NZB/W) F1 lupus mice with ovalbumin (OVA), OVA-specific antibody producing cells were initially found in

the spleen 6. Within weeks, Small molecule library they disappeared from the spleen and could then be detected in the BM and also within the inflamed kidneys. Hence, inflamed tissues may synthesize chemokines such as CXCL10, which recruit migratory plasmablasts to sites of inflammation. Apart from recent reports identifying cells secreting antibodies to histone H2B 8 and dsDNA 13, respectively, little is known about the antigen-specificity of ASCs within inflamed tissues. Also, it remained elusive whether inflammatory lesions can solely harbor short-lived PCs, or if they can also support the survival of long-lived PCs. Non-dividing long-lived PCs play a critical role in maintaining protective antibody concentrations and may account for the majority of serum IgG 4. These long-lived PCs may be located in niches providing survival factors such

as APRIL or PR-171 purchase BAFF, stroma-derived factor-1 (SDF-1), IL-6, TNF-α, CD44 signaling, etc. to maintain continuous antibody production over time 11. Here, we further characterize the renal ASCs in the course of experimental lupus. Remarkably, we not only identified short-lived, but also long-lived, PCs within the inflamed kidneys of NZB/W F1 mice, a mouse model resembling many features of SLE 12. Moreover, we show that the frequencies of cells secreting IgG autoantibodies against dsDNA and nucleolin were significantly increased within nephritic kidneys when compared with those of the spleen PtdIns(3,4)P2 and BM. PCs can be detected within

the inflamed kidneys of SLE patients and lupus mice; however, these ASCs have not yet been thoroughly characterized. Immunohistochemical staining on paraffin-sections of perfused kidneys from nephritic NZB/W F1 mice using anti-CD138 (Supporting Information Fig. 1A and B) showed PCs located within the renal tubulointerstitial tissue of medulla as well as cortex and often formed small clusters, similar to previous observations 6, 13. Next we investigated if nephritic kidneys can harbor both short- as well as long-lived PCs. As shown in Fig. 1A, CD138+ intracellular κ and λ light chain+ PCs were detected at significantly increased numbers in aged lupus mice when compared with young, still healthy NZB/W F1 (8-wk-old) mice and >30-wk-old C57BL/6 mice. These results confirm the presence of significant numbers of PCs within the inflamed renal tissue in accordance to recently published data 8, 13.

Mice were sacrificed on week 18 after inducing diabetes after collecting urinary and serum samples, and kidneys were obtained

for the following examination. Results: Renal dysfunction and glomerular alterations were not observed in the non-diabetic VASH-2−/− mice. Although hyperglycemia, mild reduction Dinaciclib of body weight, blood pressure and glomerular hyperfiltration (elevation of creatinine clearance) were not significantly different between the diabetic VASH-2+/+ and VASH-2−/− mice, albuminuria (6–16 weeks after disease induction) was significantly suppressed in the diabetic VASH-2−/− mice compared with the diabetic VASH-2+/+ mice. Histologically, glomerular hypertrophy was not altered, but mesangial matrix index was mildly decreased in the diabetic VASH-2−/− mice compared with the diabetic VASH-2+/+ mice. The thickening of glomerular basement membrane and decrease in the density of the slit membrane was significantly suppressed in the diabetic VASH-2−/− mice compared with the diabetic wild-type littermates (electron microscopy). CB-839 clinical trial Conclusion: Taken together, these results suggest that endogenous VASH-2 may exacerbate albuminuria in type 1 diabetic nephropathy, partly via inducing podocyte

injuries. SHI SEN, KANASAKI MEGUMI, NAGAI TAKAKO, SRIVASTAVA SWAYAM PRAKASH, KANASAKI KEIZO, KOYA DAISUKE Kanazawa Adenosine triphosphate Medical University Introduction: Kidney fibrosis is the final common pathway of progressive kidney

diseases. It is caused by prolonged injury associated with the dysregulation of the normal wound healing process and an excess accumulation of extracellular matrix. Kidney fibroblasts play an important role in this fibrotic process and endothelial-to-mesenchymal transition (EndMT) has emerged as one of such origins of matrix-producing fibroblasts. MicroRNA 29s exhibit anti-fibrotic effects. Methods: Streptozotocin(STZ)-induced diabetic CD1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 after 24 weeks on the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. All mice were sacrificed 24 weeks after the induction of diabetes. Kidney tissues of control, STZ and linagliptin-treated STZ mice were analyzed for EndMT detection, morphological evaluation, immunohischemistry, immunofluorescence and western blot. At the same time, mRNA and microRNA array were analyzed. qPCR for microRNA 29s was performed in vivo and in vitro. In vitro, HMVEC was utilized for EndMT detection, migration, wound healing assay, immunofluorescence, western blot, and microRNA 29s transfection. 3′-UTR reportor analysis was performed in HMVEC. Results: Linagliptin-treated diabetic mice exhibited an amelioration of kidney fibrosis associated with the inhibition of EndMT.

A statistical comparison is presented in Table 2. When compared with sialolithiasis (non-autoimmune control), VH clones of SS were frequently unmutated (P = 0.0005) as they were with IgG4-related sclerosing sialadenitis (P < 0.0001). For VH3 family clones, rates of unmutated clones in cases of SS and IgG4-related sclerosing sialadenitis were significantly higher than in the sialolithiasis cases (P = 0.002 and P < 0.0001, respectively). In contrast, there were no significant differences in non-VH3 family clones. In our study, we retrieved typical

clinical cases of SS, IgG4-related sclerosing sialadenitis and sialolithiasis. Selleck AZD1208 We then analysed VH fragments of B cells infiltrating these three types of lesions. After PCR amplification of rearranged IgH genes, at least 50 clones per case and more than 500 clones in total were sequenced for VH fragments, and the data obtained showed that VH fragments of SS and IgG4-related

sclerosing sialadenitis cases were frequently unmutated. We employed sialolithiasis tissues as a non-autoimmune control and observed chronic inflammation together with many mature lymphoid and plasma cells. In previous VH analyses [17, 18], peripheral blood B cells have been used as a control. However, as about 70% of peripheral blood B cells are naïve or unmutated [19], we consider that local non-specific inflammatory lesions (e.g. those of sialolithiasis) would be a more appropriate control in analysing local inflammation in autoimmune diseases. Hansen et al. reported that the VH3 family was preferentially used in a patient with SS (VH3 > VH1 ≥ VH4 > others) [18]. In this study, a similar VH usage was observed in SS selleck chemical and IgG4-related sclerosing sialadenitis cases: the VH3 family was the most frequently used and VH3-23 was the most often used among VH3 fragments. However, this usage of the VH3 family and a tendency towards use of VH3-23 was also found in the sialolithiasis controls, suggesting that the VH usage patterns observed in SS and IgG4-related sclerosing sialadenitis were not specific. Most interestingly, VH clones Loperamide were often unmutated in SS

and IgG4-related sclerosing sialadenitis and the percentage ratios of unmutated/total clones were 30% and 39%, respectively. These rates were significantly higher than that of sialolithiasis clones (14%). In addition, the unmutated clones appeared to be derived mainly from the VH3 family because VH3 family clones were often unmutated in SS (36%) and IgG4-related sclerosing sialadenitis (48%), when compared with those in sialolithiasis (15%). In contrast, when non-VH3 family fragments were analysed, the unmutation ratios were uniformly low (11–16%) in all three lesions. Unfortunately, owing to the small number of clones analysed, we were unable to determine which fragment of the VH3 family contributed most to the higher rates of unmutated clones in SS and IgG4-related sclerosing sialadenitis cases.

The rat Poziotinib nmr myeloid cell line RMW [5] and BWN3G [27] were generated in our laboratory. 293T cells were obtained from ATCC. Resident peritoneal macrophages were collected by peritoneal lavage, left to adhere to plastic dishes for 2 h, and washed. Remaining adherent cells were cultured overnight in either M-CSF (20 ng/mL), IL-4 (20 ng/mL), or IFN-γ (20 ng/mL) plus LPS (10 ng/mL) (cytokines from PeproTech and LPS from InvivoGen). Cells were analyzed by flow cytometry the next day. Expression constructs consisting of the full-length

open reading frames of rat Mincle, DCIR-1, or KLRH1 followed by a C-terminal FLAG epitope tag; rat FcεRI-γ with an N-terminal HA tag; or rat MCL without tag were generated. 293T cells were transiently transfected using polyethylenimine “Max” (m.w. 25 000, Polysciences) [28]. A rat Mincle-Fcγ2b Fc fusion protein was used to immunize female BALB/c mice by i.p. injections. Hybridomas were generated using standard techniques. One clone of IgG1 isotype, WEN43,

was selected and shown by flow cytometry to react specifically with cells transfected with rat Mincle, and not other APLEC-encoded receptors (Fig. 1). WEN42 (anti-MCL), WEN43 (anti-Mincle), and OX-42 (anti-CD11b/c) were produced in-house; STOK9 (anti-KLRH1) was a gift from Bent Rolstad; commercial antibodies were OX-41 (anti-CD172a/SIRP-α, Accurate Chemical & Scientific Co.), OX-22 (anti-CD45RC, BioLegend), and OX6 (anti-MHC class II, AbD Serotec). Data were acquired using a FACSCanto II (BD Biosciences) and analyzed using FlowJo software (Tree Star). Transfected 293T cells were lysed in 1% digitonin (Calbiochem) lysis AZD3965 order buffer. Lysates were immunoprecipitated with Protein G Dynabeads (Invitrogen), separated by SDS-PAGE, and detected by ECL as detailed previously [5]. For immunoprecipitation, mAbs used were: anti-MCL (WEN42), Florfenicol isotype control (W6/32, IgG2a), or anti-FLAG (M2, Sigma-Aldrich). Immunoblotting: anti-FLAG-biotin (M2, Sigma-Aldrich), anti-MCL-biotin (WEN42), or rabbit anti-FcεRI-γ (Upstate Biotechnology) were used as primary antibodies, followed by streptavidin-HRP or HRP-conjugated anti-rabbit IgG

(Jackson ImmunoReseach Laboratories). 293T cells were incubated with Ab-coated yellow-green fluorescent 1-μm microspheres, counterstained with streptavidin-DyLight594, and analyzed by imaging flow cytometry on an ImageStream X (Amnis) as described previously [5]. For blocking, a cocktail of three mAbs specific for rat MCL was used. To compare efficiency of phagocytosis, data are expressed as phagocytic ratio: (fraction of bead-binding cells with internalized beads)/(fraction of bead-binding cells with no internalized beads). Statistical analysis was performed using one-way ANOVA with Tukey’s multiple comparison posttest (GraphPad InStat). We would like to thank Wendi Jensen for her technical assistance. This work was supported by grants from the University of Oslo (to M.R.D.) and the Norwegian Research Council, Norway (to M.R.D., S.F.

In the validation cohort of nine

patients, six had PGD grade 1, and for the remaining three there was no evidence to suggest PGD. All patients were extubated in the first 24 hr and none qualified for a PGD grade 2 or higher. A nearest centroid classifier18 was constructed from the 17 differentially reactive proteins identified (Fig. 2a), and was used to predict the PGD grades of the nine patients in this validation cohort (Fig. 2b). Here, five out of six patients check details having had PGD were correctly identified (83% sensitivity), and all three patients without PGD were classified as such (100% specificity), giving an overall classification accuracy of 89% (P = 0·048 by Fisher’s exact test). This is comparable to the classification accuracy in the test set (85%). Two recent studies have investigated gene expression differences

in donor lungs developing PGD9,10 Differential gene expression in each study was evaluated using Student’s t-test. Out of the 17 differentially reactive proteins identified, 15 proteins could be paired with gene expression in the first study,9 and six with expressions from the second study10 (Table 2). Comparing differences in IgM reactivity with differences in gene expression levels in the first study (study GSE8021 in Table 2), 12 out of 15 change in the find protocol same direction (80% concordance, P = 0·04 by Fisher’s Exact Test), i.e. increased expression is significantly associated with increased reactivity and vice versa. The same conclusion is reached when calculating Pearson’s product–moment correlation (r = 0·63, P = 0·011), see Fig. 3(a). For IgG reactivity, no significant correlation with gene expression changes was observed (r = − 0·01, P = 0·98). Inspection of the P-values for the

differential expressions (study GSE8021 in Table 2) showed that none of them had P < 0·05, which is usually a standard threshold of significance. Still, five out of six genes displayed the same direction as well as magnitude of change when compared with the Ureohydrolase second gene expression study (GSE9102 in Table 2), which is a significant correlation (r = 0·91, P = 0·013), see Fig 3(b). This study demonstrates that lung transplant recipients manifest widespread IgG and IgM autoantibody reactivity, and that specific patterns of reactivity to self-antigens discriminate between patients with and without PGD. It has been speculated that PGD may induce or accelerate chronic rejection in the form BOS, although conflicting results have been published.2 We observed no significant correlation between BOS and PGD grades among the 39 patients included in this study (Table 1). However, six (35%) out of the 17 informative proteins were also observed to be informative with respect to BOS.8 A two-factor analysis of variance including both BOS and PGD as factors in general confirms the significant differential reactivity with respect to both factors (Table 3 and Fig. S2).

We observed no significant change in this measurement (Fig. 2c, P = 0·4691). Plasma TGF-β levels were relatively stable over time in both groups (Fig. 2d). We next measured plasma cytokine and chemokine levels in both groups using multiplex assays. Twenty-seven analytes were measured, and no significant differences were found GSK-3 inhibitor in the change from baseline between the placebo and sitagliptin groups at any of the time-points. The levels of cytokines and chemokines in both the drug and placebo groups at day 3 are shown in Fig. 2e. Similar results were obtained at other time-points (data not shown). The

percentage of lymphocyte subsets in PBMCs were measured by flow cytometry. The frequency of major lymphocyte subsets (B cells, T cells: both CD4+ and CD8+, NK, NKT cells and monocytes) was measured, and no significant differences were found between groups (data not shown). https://www.selleckchem.com/products/LY294002.html In addition, numbers of regulatory T cells (CD4+CD25+FoxP3+) were assessed. In mice, increases in regulatory

T cells with DPP-4 inhibition have been reported [18]. However, we observed no significant changes in the percentage of regulatory T cells with sitagliptin treatment (Fig. 3a,b). A small increase in neutrophil and total white blood cell count after sitagliptin treatment was reported to the Federal Drug Administration. In our study, CBC values were also measured, and no significant differences were found between groups in any measure, including white blood cells (WBC) and neutrophils (data not shown and Supporting information, Fig. S1). CD26/DPP-4

is expressed differentially on naive (CD45RA+) and memory (CD45RO+) T cells [25]. Therefore, we measured the percentage of naive and memory T cells in both the CD4+ and CD8+ T cell compartment. The percentage of CD8+CD45RO+ cells increased significantly on day 3 in the sitagliptin group compared to the placebo (P = 0·0104) and was also higher on day 14 (P = 0·0351) (Table 1). We also measured CD26 expression, gating on three populations: CD26– cells defined by fluorescence-1 controls, CD26lo cells, corresponding to the low level found on most naive CD45RA+ cells and CD26hi cells found primarily among the memory CD45RO+ population ID-8 (Fig. 3c). We observed changes consistent with an increase in CD26 expression early after sitagliptin treatment compared to placebo treatment, including increases in the percentages of CD4+CD45RO+CD26hi and CD8+CD26hi cells, and in the fluorescence levels of CD26 on CD4+CD26hi, CD3+CD26hi and CD3+CD45RO+CD26hi populations (Fig. 3d and Table 1). A significant decrease in the percentage of CD8+CD26lo cells was also observed in sitagliptin-treated individuals compared to placebo, which is consistent with increased CD26, as these cells probably shifted to the CD8+CD26hi population.

“
“The NACHT, LRR and PYD domains containing protein (NALP3) inflammasome is a key regulator of interleukin-1β (IL-1β) secretion. As there is strong evidence for a pro-inflammatory role of IL-1β in rheumatoid arthritis (RA) and in murine models of arthritis, we explored the expression of the different components of the NALP3 inflammasome as well as other nucleotide oligomerization domain (NOD)-like receptors (NLRs) in synovium obtained from patients with RA. The expression of NLRs was also

studied in fibroblast lines derived from joint tissue. By immunohistology, NALP3 and apoptosis-associated speck-like protein containing a CARD domain (ASC) were expressed in myeloid and endothelial cells and B cells. T cells expressed ASC but lacked NALP3. In synovial fibroblast lines, NALP3 expression Opaganib in vitro was not detected at the RNA and protein

levels and stimulation with known NALP3 agonists failed to induce IL-1β RAD001 cell line secretion. Interestingly, we were unable to distinguish RA from osteoarthritis synovial samples on the basis of their basal level of RNA expression of known NLR proteins, though RA samples contained higher levels of caspase-1 assayed by enzyme-linked immunsorbent assay. These results indicate that myeloid and endothelial cells are the principal sources of inflammasome-mediated IL-1β production in the synovium, and that synovial fibroblasts are unable to activate caspase-1 because they lack NALP3. The NALP3 inflammasome activity does not account for the difference in level of inflammation between RA and osteoarthritis. Clinical and experimental studies point to a key role for interleukin-1β (IL-1β) in the pathophysiology of rheumatoid arthritis (RA) and inhibition of IL-1 reduces signs and symptoms of ADP ribosylation factor RA as well as radiological damage. Animal models of RA, such as collagen-induced arthritis and antigen-induced arthritis, also respond to IL-1 inhibition.1,2 Interleukin-1β is produced as an inactive pro-molecule

by immune cells such as macrophages, monocytes and dendritic cells; as well as by other cell types such as keratinocytes. The pro-molecule (p35) must be cleaved into active IL-1β (p17), which is then released from the cell. Cleavage of pro-IL-1β is catalysed by the enzyme caspase-1 (also known as IL-1-converting enzyme) and therefore the biological activity of IL-1β is directly dependent on the activity of caspase-1. Recent work established that caspase-1 activation requires the recruitment and dimerization of the enzyme within a molecular platform known as the inflammasome. Briefly, the inflammasome is a cytoplasmic complex formed by the intracellular receptor NACHT, LRR and PYD domains containing protein (NALP), the apoptosis-associated speck-like protein containing a CARD domain (ASC) adapter protein and pro-caspase-1.