We confirmed that residual catalytic activity of dnRAG1 could not account for this accumulation as dnRAG1 mice bred to a RAG1-deficient background Gamma-secretase inhibitor show no

evidence of B-cell or T-cell development beyond what is observed in RAG1−/− mice (see Supplementary material, Fig. S1). Follow-up studies on one of these lines, no. 15, show that in 12-week-old mice, the percentage and absolute number of B220lo CD19+ B cells is significantly higher in dnRAG1 mice than in wild-type (WT) mice in spleen, bone marrow (BM), lymph node (LN), peritoneal cavity (PC), and peripheral blood (PB), but the relative abundance of these cells compared with more conventional B220hi CD19+ B cells varies depending on tissue origin (Fig. 1c; see Supplementary material, Fig. S2a). The abundance and distribution of T-cell

subsets is not significantly different between WT and dnRAG1 animals in the thymus or spleen (see Supplementary material, check details Fig. S2b,c). In lymph nodes, CD4+ T cells show a modest, but statistically significant increase in dnRAG1 mice compared with WT mice (see Supplementary material, Fig. S2b,c). As the B220lo CD19+ B-cell phenotype in dnRAG1 mice was so striking, we focused our efforts to characterize the accumulation of these cells and did not investigate T-cell subsets further. Examining the ontogeny of these cells demonstrated that the frequency of B220lo CD19+ B cells steadily increases with age, with significant differences detected in the spleen by 4 weeks of age, eventually comprising ∼ 35% of splenic lymphocytes by about 12 months CHIR-99021 order of age (Fig. 1d). Other than a mild splenic hyperplasia, older dnRAG1 exhibited no obvious indications of disease that would distinguish them from their normal littermates, suggesting that B220lo CD19+ B-cell accumulation has no significant impact on the health of the animals. Because

peritoneal B1 B cells display a B220lo CD19+ phenotype,27 we speculated that splenic B220lo CD19+ B cells in dnRAG1 mice may express other surface markers indicative of a B1 B cell. A hallmark of the B1a B cell is the expression of CD5.27 Extensive flow cytometric analysis revealed that splenic B220lo CD19+ cells in dnRAG1 mice also express CD5, and have a surface phenotype characterized as sIgMhi sIgDint CD21− CD23− CD24−CD43lo AA4.1− CD11b− (Fig. 1e, and data not shown). This immunophenotype is quite similar to peritoneal B1a B cells, except that the peritoneal subset expresses slightly lower levels of sIgD and also expresses CD11b (Fig. 1e). The lack of CD11b expression is also consistent with the reported phenotype of splenic B1 cells from wild-type BALB/cByJ mice reported by others.28 To determine whether dnRAG1 mice exhibit defects in B-cell maturation, we stained bone marrow and spleen with antibodies to differentiate the various stages of B-cell development.

This was confirmed by the observation that α-GalCer presentation to the DN32.D3 NKT cell clone occurs mainly in the lung and to a lesser extent in the lung-draining lymph node up to 5 days after intranasal administration. However, it is unclear as to how NKT cells and DCs are activated in more distal tissues, such as the

spleen and liver, after a primary intranasal immunization with α-GalCer. It is possible that either activated DCs and/or activated LY2157299 NKT cells migrate from the lung after stimulation with α-GalCer, or alternatively the cytokine milieu resulting from NKT cell stimulation with α-GalCer may induce activation of these cell types in other tissues. In this regard it has been reported that a decrease in NKT cell populations in the liver

coincided with an increase in the blood NKT cell levels after intraperitoneal immunization with α-GalCer, suggesting potential trafficking of NKT cells 16. It has been observed that multiple LY2606368 solubility dmso administrations of DCs pulsed ex vivo with α-GalCer, as opposed to free α-GalCer, do not induce NKT cell anergy 5, 8. On the other hand, it has also been shown that injection of B cells pulsed ex vivo with α-GalCer does induce NKT cell anergy 5, 17. Here we have shown that after intranasal administration, CD11c+ cells, not B220+ cells, more efficiently present α-GalCer in the lung, suggesting that the intranasal route of immunization preferentially targets α-GalCer presentation to DCs. Interestingly,

Hermans et al. 18 showed that presentation of both α-GalCer and peptide antigen by the same DC was required for the strong activation Chlormezanone of antigen-specific T-cell responses. Futhermore, Ko et al. 14 showed that the responding DC-presenting antigen in the lung-draining LNs also expresses a CD8α− phenotype. This suggests that the DCs presenting α-GalCer in the lung should show a similar phenotype, which would be intriguing to pursue in the future. In addition to the potential influence of the phenotype of cells presenting α-GalCer to induce NKT cell anergy, recently it has been reported that expression levels of the cell surface marker PD-1 on NKT cells may also be an important factor for anergy induction. In T cells, higher levels of PD-1 expression were observed to be associated with functional exhaustion resulting from interactions with either of its ligands, PD-L1 or PD-L2, which are both commonly expressed on APCs including B cells, DCs, and macrophages 19–21. It has also been observed that PD-1 expression is up-regulated on the ‘exhausted’ CD8+ T cells in HIV-infected patients and blocking of the PD-1/PD-L1 interaction could rescue the exhausted T cells in terms of restoring functional properties 22, 23.

For the triple regimens, analyses of the challenge virus loads were carried not only in splenocytes, where respective 2.7- and 5.5-fold decreases were detected for the DCM and DMC regimens (Fig. 4D), but also in the pooled superficial cervical and

MLNs and thymus. In all of these nonsplenic sites, a considerable clearance of the EcoHIV/NDK virus was detected (Fig. 4E). At 42 days postvaccination, in vivo killing of AMQ peptide-pulsed Saracatinib and re-infused splenocytes showed close to 100% killing efficiency by T cells elicited by both triple regimens (Fig. 4F). Finally, to assess the longevity of the triple vaccine-induced responses, the third subgroup of animals receiving either the DCM or DMC regimens was rested for 115 days prior to the late surrogate virus challenge. Collected pooled PBMCs maintained polyfunctionality upon the AMQ peptide restimulation and the IFN-γ+-cell frequencies remained at respective 5.6 and 2.2% of total CD8+ cells for the DCM and DMC regimens (Fig. 5A). After challenge and measured in spleen, these frequencies rose to means of 9.6 and 6.7%, respectively (Fig. 5B). In the same animals, the DCM- and DMC-induced memory T cells decreased the EcoHIV/NDK DNA copy numbers 3.5-

and 5.2-fold, respectively. Using ANOVA analysis, the means of the challenge virus loads among individual treatments were significantly different, but in pairwise comparisons, this significance was lost after the Bonferroni adjustment (Fig. 5C). Thus, a sequential combination of three different vaccine modalities into a single regimen induced robust, durable, and polyfunctional CD8+ Tanespimycin research buy T-cell responses. It remains that the real benefit of triple regimens may only become apparent in more challenging situations such as protection of humans against HIV-1. Finally, we assessed the AMQ-specific,

IFN-γ-producing CD8+ T cells for expression of proliferation-promoting IL-2, L-selectin CD62L, memory marker MycoClean Mycoplasma Removal Kit IL-7 receptor α-chain CD127 and CD27, which is required for generation and maintenance of T-cell immunity and is lost from terminally differentiated effector cells. Central memory (TCM), but not effector memory (TEM), T cells possess ability to express high levels of CD62L, have a high proliferative potential, and are primarily found in lymphoid tissue. Thus in spleen for both DCM and DMC regimens, the AMQ-specific postchallenge responses increased from the peak to the memory phase for IL-2 production and CD62L and CD127 expression (Fig. 6A). Memory PBMCs prior to the challenges differed from immune splenocytes the most in lower levels of IL-2 and higher expression of CD62L and CD27 (Fig. 6B). In addition to memory markers, vaccine-elicited CD8+ T cells were also analyzed for expression of the α4β7 adhesion molecule linked to migration of lymphoytes to the GALT. Vaccine-induced T-cell population expressing low level of α4β7 was found among immune splenocytes (Fig. 6C), but not PBMCs (Fig. 5D).

2G and H). However, in the absence of T cells, addition of exogenous

IL-2 up to 100 IU/mL was unable to rescue IFN-γ production by NK cells (Fig. 2H). Thus, IL-2 contributes to, but find more alone is insufficient for NK IFN-γ production against PfRBC. Possibly, the unique immunological characteristics of PfRBC, i.e. a protozoan pathogen residing within a host cell without MHC class-I molecules, might explain the requirement of further activation signals. One potentially interesting candidate in this regard might be the IL-2 family member IL-21, which is produced by activated T cells 20 and enhances IFN-γ production by NK cells 21. Nonetheless, if T-cell help is required for NK-cell activation, this clearly suggests that it is in fact the immunological memory residing within the T-cell population, rather than intrinsic NK memory, that underlies the observed recall responses by NK cells against PfRBC. Finally, we investigated the

relative contribution of different lymphocyte subpopulations to the total IFN-γ production against PfRBC (Fig. 3A). Depletion of NK and NKT cells from PBMC with anti-CD56 beads prior to stimulation with PfRBC resulted in a reduction of learn more IFN-γ production by approximately 60%. Thus, although these two cell types together form only around 20% of IFN-γ-producing cells following exposure (Fig. 1H), their contribution to total cytokine secretion is much greater, presumably in part due to a positive

feedback effect on T cells (Fig. 2A). Once more, however, Quisqualic acid anti-CD3 depletion of all T cells resulted in the total abrogation of IFN-γ secretion into the supernatant by remaining PBMC, including NK (Fig. 3A). Thus NK cells are incapable of producing even small amounts of IFN-γ in response to PfRBC in the absence of T cells. In order to understand whether such patterns are representative of naturally acquired immunity to malaria, we performed similar experiments with PBMC from representative samples of three other groups: unexposed Caucasian donors (Fig. 3B), Caucasians exposed by visiting malaria-endemic areas (Fig. 3C) and semi-immune African adults living in an area of intense seasonal transmission (Fig. 3D). Although relative contributions of CD56+ cells varied slightly between individual volunteers, the overall pattern was remarkably similar in all, confirming the generality of our findings. Of particular note, two out of the six malaria-naïve donors responded to PfRBC with considerable IFN-γ production (Fig. 3B), a well-known phenomenon 4, 22–24, yet even in these “innate” responders depletion of CD3+ cells but not CD56+ cells resulted in total abrogation of IFN-γ production. In these donors, “memory” is presumably provided by cross-reacting T cells 22, 23, 25.

Adverse effects were recorded concurrently to evaluate the safety of the treatment. Of all 168 patients, 107 were males and 61 were females, with an average age of 33.8±8.79 years. Baseline characteristics were comparable among the four groups (p>0.05) prior to the experimental treatment.

There was a significant (p<0.05) decrease in 24h urinary check details protein excretion after 4 months of experimental treatment. At the end of the 24 months, group 3 and 4 showed a respective 62.35% and 69.47% reduction in proteinuria. The serum creatinine was significantly higher (p<0.05) in group 1 and 2 at the end of the follow-up, and their respective eGFR was significantly lower. The incidence of cardiovascular complication was 11.9% and 9.5% for group 1 and 3 respectively. The treatment with Valsartan combined with Clopidogrel and Leflunomide can reduce the urinary proteins

loss and renal function deterioration for IgA nephropathy patients and cause minimal adverse reactions. Our study suggests a new clinical treatment option for IgA find more nephropathy. “
“Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and muscle wasting, arising from numerous factors associated with declining renal function and lifestyle factors. Exercise has the ability to impact beneficially on the comorbidities associated with CKD and is accepted as an important intervention in the treatment, prevention and rehabilitation of other chronic diseases, however, the role of exercise

in CKD is overlooked, with the provision of rehabilitation programmes well behind those of cardiology and respiratory services. Whilst there is now a large evidence base demonstrating the efficacy and safety of exercise training interventions in patients receiving dialysis, and this is now becoming incorporated into clinical guidelines for treatment of dialysis patients, there is a paucity of research evaluating the effectiveness of exercise in patients with CKD who are not on dialysis. Despite this, existing studies indicate that exercise can improve physical functioning and impact positively on the mediators of co-morbid diseases aminophylline and upstream factors associated with progression of renal disease. Although preliminary evidence appears positive, more research is required to identify the best modes, frequency and intensities of exercise in order to optimise exercise prescription in pre-dialysis CKD patients. This review summarizes what is known about the main effects of exercise in pre-dialysis CKD patients, discusses the potential of exercise in the rehabilitation and treatment of disease and highlights the need for further research. Chronic kidney disease (CKD) has many heterogeneous causes, but is always associated with increased morbidity and mortality.

Still, these findings indicate that the migration of Treg cells from the gut or other peripheral tissues back into the draining LN might be a general feature of Treg-cell trafficking and have a profound role on the function of these cells. This is supported by findings suggesting that CCR7 is crucial to permit relocation of tissue-residing Treg cells to the draining LN [35]. There are compelling data supporting an important function of iTreg cells in intestinal tolerance since oral tolerance this website against OVA does not require nTreg cells [22] but rather iTreg cells [23, 36]. Thus, at least in

the OVA model, iTreg cells but not nTreg cells are essential. However, it is conceivable that nTreg cells also survey the gut tissue as part of their body-wide task to protect the host from T-cell driven autoimmune responses. Beyond

this surveillance role, why should not nTreg cells participate in establishing tolerance to the gut-specific antigenic load in the form of food and microbial antigens? At least in an inflammatory context, this is indeed the case. In models of experimental colitis where Treg cells need to keep immune responses to a broad heterogeneity of ITF2357 cost antigens in check, both nTreg- and iTreg-cell populations contribute in a nonredundant manner to protect from fatal disease outcomes [4, 5]. Therefore, the local condition and the nature of the antigenic compound — ranging from food constituents and self-antigen to PAMPs — may preferentially require either iTreg or nTreg cell-borne protection Aspartate and in many cases, successful Treg-cell responses might rely on the involvement of both Treg-cell subsets. Given that nTreg and iTreg

cells differ in their TCR repertoire and may also diverge in the mode/efficacy of their suppressive mechanisms [6], one advantage of recruiting both cell types to participate in immune inhibition would be the availability of a combined and thus broader repertoire of TCRs, as well as broader inhibitory tools. We hypothesize that both iTreg and nTreg cells can acquire LN- and tissue-specific homing patterns upon antigen contact, even at the subinflammatory levels that characterize the daily (nondiseased) situation [8, 23]. Typically, these migration patterns are not too restrictive but also permit organism-wide dissemination of Treg cells in order to communicate (and possibly coordinate) immune activities. The intestine stands out with respect to the load and diversity of antigens encountered by immune cells. Along the road to fully appreciate Treg-cell contributions to intestinal homeostasis, it will be important to collect data regarding the identity of antigenic epitopes recognized by nTreg and/or iTreg cells. Moreover, the importance of recirculation between LNs and the drained extra-lymphatic tissue for the shaping and function of Treg cells deserves more attention.

2 ± 2.9 kg (P < 0.001). Total-cholesterol decreased (P < 0.05). LDL-cholesterol also decreased (P < 0.05) but only in males. This study provides level IV evidence to support the use of the AHA Step One diet and weight loss for reducing total- and LDL-cholesterol. While dyslipidaemia is known to be a common problem after renal transplantation, there are currently

few studies that consider the management of the issue in kidney transplant recipients. The small number of studies identified have considered the effects of diet rich in wholegrain, low glycaemic index and high fibre carbohydrates as well as rich sources of vitamin E and monounsaturated fat as well as weight loss in adult kidney transplant recipients with elevated serum total cholesterol, LDL-cholesterol and triglycerides. The findings of these studies are consistent with Ferroptosis inhibitor cancer similar studies in the general population and indicate favourable outcomes with respect to dyslipidaemia. Kidney Disease FK228 chemical structure Outcomes Quality Initiative:10 These guidelines are based on recommendations for the general population with some modifications. They do not conflict with the recommendations above. Patients with triglycerides ≥500 mg/dL (≥5.65 mmol/L) should be treated with therapeutic lifestyle changes, including diet, weight reduction, increased physical activity, abstinence from alcohol, and treatment of hyperglycaemia (if present). Patients with triglycerides ≥1000 mg/dL (≥11.29 mmol/L), should

follow a very low fat diet (<15% total calories), with medium-chain triglycerides and fish oils to replace some long-chain triglycerides. The diet should be used judiciously, if at all, in individuals who are malnourished. Patients with elevated LDL-cholesterol should be treated with a diet containing <7% energy from saturated fat, up to 10% calories from polyunsaturated Molecular motor fat, up to 20% calories from monounsaturated fat, giving a total fat of 25–35% of total calories. The diet should contain complex carbohydrates (50–60% of total calories) and 20–30 g fibre per day. Dietary cholesterol should be kept under 200 mg/day. For patients with LDL-cholesterol 100–129 mg/dL

(2.59–3.34 mmol/L), it is reasonable to attempt dietary changes for 2–3 months before beginning drug treatment. However, kidney transplant recipients often have a number of other nutritional concerns and it is important to consult a dietitian experienced in the care of these patients. UK Renal Association: No recommendation. Canadian Society of Nephrology: No recommendation. European Best Practice Guidelines:39 Hyperlipidaemia risk profiles should be identified by regular screening (at least once a year) for cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride blood levels in renal transplant patients. In renal transplant patients, hyperlipidaemia must be treated in order to keep the cholesterol/lipid levels within recommended limits according to the number of risk factors.

We attempted to define the exact requirements for signalling through BTLA to exert an effect on lymphocyte proliferation. We found that neither the HVEM-Fc ligand nor any of the anti-BTLA mAbs had any significant effect on B cell proliferation in Palbociclib mw vitro. We found that the ligand and some of the antibodies inhibited T cell proliferation, but only when they were cross-linked with an anti-Fc reagent; this was consistent with several different published studies. We used the beads-based system to separate the stimulus and the test agent physically and found that T

cell proliferation could be inhibited only when the test agent was juxtaposed immediately to the stimulus, and we have proposed a model for how this might occur. Other evidence in support of this hypothesis is shown by studies that demonstrate localization of BTLA to the immunological synapse during

T cell activation [32]. None of the anti-BTLA reagents tested had any significant effect on the observed in vitro T cell proliferation in other commonly used experimental systems such as the MLR or the OVA antigen-induced system. In our opinion, this observation is a reflection of our hypothesis that an anti-BTLA reagent can act to inhibit T cell proliferation only when it is juxtaposed immediately to the activating stimulus. In the MLR and DO11.10 in vitro systems, the activating stimulus U0126 to the T cell is either a polymorphic MHC molecule on another cell or the OVA peptide presented by an MHC molecule on another cell, respectively. Hence, the anti-BTLA test agent is physically unable to interdict the signalling complex that drives TCR signalling mafosfamide and the subsequent T cell activation and proliferation. Indeed, as the stimulus is inherent to the cell–cell interaction, it would not be possible to mitigate the target T cell activation successfully with an exogenous anti-BTLA reagent in this experimental system. Based on our current understanding

of BTLA biology, in the frame of our current hypothesis, one would have to engineer genetically the cell that presents the stimulus to the target cell with an appropriate anti-BTLA reagent, such as the HVEM ligand, in order to interdict successfully the target T cell activation. Indeed, this was described by Sedyet al. [9], whereby the presentation was made by CHO cells transfected with the MHC IAd molecule that presented the OVA antigen to the target DO11.10 T cell, causing T cell activation. This was mitigated by transfection of the same CHO cell with the HVEM molecule, i.e. the BTLA ligand. We extended these studies to look at the effect of a BTLA-specific reagent in vivo. Of the various options for in vivo models, and bearing in mind the lack of any in vivo exposure data for any of these reagents, the most strongly indicated for T cell antagonism was judged to be the DO11.10 T cells syngeneic transfer with in vivo trapping of IL-2.

Lu et al. have suggested that recipient-derived MCs are crucial for Treg-mediated peripheral tolerance [11], indicating that the function of mast cells in suppressing immune responses was related to Tregs. Our study showed that CD4+CD25+ FoxP3+ cells could be induced by BMMCs. This finding may supply a new mechanism suggesting that MCs are crucial for Treg-mediated transplant tolerance [11]. This method may also become a new method for the induction of Tregsin vitro. Our results showed that the highest percentage of Tregs was found in the highest ratio (2:1) of BMMCs to T cells. TGF-β1 expression in BMMCs was determined in our experimental

groups. Jahanyar et al. concluded that mast cell-derived TGF-β may serve as important mediators for Treg activation in allografts [21], and other studies reported that the percentage of Tregs increased with the higher level of added TGF-β1 [22]. Therefore, it seems that the increase of Tregs with a higher ratio of BMMCs STA-9090 in vitro may be related to more BMMCs-derived TGF-β1. Consistent with previous studies, and in order to test whether BMMC-derived TGF-β1 is involved in BAY 80-6946 manufacturer the generation of Tregs, TGF-β1

neutralizing antibody was added to the co-culture system [4]. The conversion of Tregs was reduced significantly by the TGF-β1 neutralizing antibody, but the TGF-β1 neutralizing antibody could not reverse Treg induction completely. The percentages of Tregs were still higher than control, even with the application of TGF-β1 neutralizing antibody. Whether there were some other mediators derived from BMMCs which also had the potential to induce Tregs is debatable. Metz considered that IL-4 may be related to the suppression function of MC in the immune response [6]. Therefore, IL-4 neutralizing antibody was applied to block the function of IL-4, but there were no significant differences after the application of IL-4 neutralizing antibody.

Although this study did not provide direct evidence for BMMCs as the main source of TGF-β1, it suggests that BMMC-derived TGF-β1 is involved in the regulation of Treg cell generation in vitro. Our experiment concerned mainly the relationship between mast cells and Tregsin vitro. Huang et al. showed that tumour-infiltrating mast cells may promote tumour growth through one way of increasing Treg cells in vivo[23]. isothipendyl This leads us to conclude that perhaps Tregs can be induced by mast cells in vivo. More studies will be conducted to clarify this phenomenon. In conclusion, our experiments demonstrate that Tregs can be induced by BMMCs in vitro, and secreting TGF-β1 by BMMCs is one of the principal factors for the effect. This finding may provide new evidence that mast cells have the ability to suppress immune responses by way of Treg induction. Furthermore, the study may supply new data for identifying clearly the role of mast cells in immune systems. This work was funded by National Natural Science Foundation of China (no.

For example, Casp-1 mRNA levels correlate with disease severity in MS patients,[30] and caspase-1 protein is highly abundant in MS plaques.[31] Further, expression of caspase-1 and IL-18 in peripheral mononuclear cells

from MS patients has been found at increased levels compared with those in cells from healthy controls.[32] High IL-1β and low IL-1 receptor antagonist (IL-1RA) production has been hypothesized as a predisposition of increased susceptibility and disease progression SCH772984 cost of MS.[33] Patients with MS are also known to express high levels of purine compounds and uric acid in cerebrospinal fluid,[34] as well as high serum uric acid levels.[35] Increased activity of cathepsin B, which is known to induce NLRP3 inflammasome activation by leaking out from lysozomes,[10] was also reported in peripheral blood mononuclear cells, as well as brain cells of MS patients.[36, 37] The NLRP3 inflammasome is activated by triggering the P2X7 receptor (P2X7R) signalling by extracellular ATP. Sustained activation of P2X7R during EAE Tyrosine Kinase Inhibitor Library concentration appears to cause MS plaque-like lesions, and treatment with P2X7R antagonists ameliorates EAE.[38] The same study also suggested that P2X7R signalling is enhanced in normal-appearing axonal tracts of the CNS in MS patients.[38] Further, expression of the P2x7r gene is increased in the

optic nerve region of MS patients.[39] Single nucleotide polymorphisms in the P2x7r locus were found more frequently in MS patients compared with healthy controls.[40] Because MS is a multifactorial and heterogeneous disease, the NLRP3 inflammasome may not be involved in the development of

all forms of MS. However, these studies strongly suggest the general involvement of the NLRP3 inflammasome in MS progression. The critical role of the NLRP3 inflammasome in EAE has recently become clear.[41-44] NLRP3 inflammasome induces demyelination as indicated using the chemically induced demyelinating disease and EAE models.[42] A subsequent study showed that the NLRP3 inflammasome induces EAE progression by enhancing chemotactic migration of T helper cells, and antigen-presenting cells (APCs) into Glycogen branching enzyme the CNS.[43] Nlrp3−/− mice were characterized by being resistant to EAE and to reduction in both Th1 and Th17 cells in the peripheral lymphoid tissues, as well as in the spinal cord.[41, 43] It appears that the NLRP3 inflammasome has the most critical impact on EAE among all inflammasomes, because of a similar phenotype between Nlrp3−/− and Asc−/− mice in their resistance to EAE.[43] Caspase-1-deficient mice (which may have also been lacking caspase-11[18]) are resistant to EAE, supporting the involvement of inflammasomes (most probably, NLRP3 inflammasome) in EAE pathogenicity.