3A). The MFG-E8 transcript that included the cryptic exon encoded an MFG-E8 protein that was truncated at the C2 domain (designated as C2del) (Fig. 3A). Studies on mouse and bovine MFG-E8 show that the C1/C2-homologous domains are required for binding to phosphatidylserine 7, 20. To characterize C2del, we prepared human rMFG-E8 using HeLa cell transformants that produced the transgene in a tetracycline-dependent manner. On SDS-PAGE, the purified C2del ran as a smeared band of approximately 50 kDa, which was significantly bigger than the 46-kDa wild-type MFG-E8 (Fig. 3B). This was unexpected considering that C2del had a truncation of 96 amino acids and contained

only one of three N-linked glycosylation sites present in the wild-type protein. The treatment of C2del with PNGase selleck chemicals llc F reduced its molecular weight to 32.6 kDa (Fig. 3C), and a mutation of the remaining N-glycosylation site (Asn238) also reduced its molecular weight (data not shown). Neuraminidase treatment significantly reduced C2del’s molecular weight (Fig. 3D), indicating that it was sialylated. These results suggested that this C-terminal NVP-BEZ235 truncation of human MFG-E8 caused it to be aberrantly glycosylated. We next examined the

ability of C2del to recognize apoptotic cells. As shown in Fig. 3E, C2del dose-dependently bound to phosphatidylserine. The dissociation constants (Kd) determined by Biacore for the wild-type and C2del MFG-E8 Ribose-5-phosphate isomerase were 1.1 and 8.0 nM, respectively. C2del supported phagocytosis with a bell-shaped dosage effect and the same dose dependency as the wild-type molecule (Fig. 3F). However, the ability of C2del to enhance the engulfment at the optimum concentration was consistently lower than that observed with the wild-type MFG-E8. As described above, C2del was aberrantly glycosylated, and in particular, sialylated. The sialylation of proteins is known to prolong their half-life in vivo21, 22. To examine whether this was true for C2del, the wild-type MFG-E8

and C2del proteins were injected into C57BL/6 mice, and their levels in serum were monitored by ELISA. As shown in Fig. 4A, when 12 pmol of the wild-type or mutant MFG-E8 was injected into the tail vein, about 20 pM wild-type MFG-E8 was found in the serum after 60 min, whereas the concentration of C2del was more than 1 nM at the same time point. These results suggested that C2del was sustained longer than the wild-type protein in the blood. We previously showed that excess MFG-E8 prevents the efficient engulfment of apoptotic cells and that some SLE patients carry a significantly increased level of MFG-E8 in their blood 15. Accordingly, the injection of wild-type MFG-E8 into mice induced the development of autoimmune diseases 16. Since C2del lasted longer in vivo than wild-type MFG-E8, we hypothesized that the administration of C2del might cause autoimmune disease in mice at a lower dose than the wild-type molecule. As shown in Fig.

[118, 119] Similar to Copanlisib some of the EAE models, stimulation of type I NKT cells with αGalCer results in disease exacerbation associated with a Th1 cytokine release profile.[118-121] In the latter cases, type I NKT cell activation by αGalCer or its analogues may lead to the tolerization of APC populations. In turn, this outcome may inhibit the activity of most Th1/Th17/Th2 secreting effector cells and thereby lead to protection from autoimmune disease. Generally, activation of type II NKT cells with self-glycolipid

sulphatide may control both antigen-induced and spontaneously arising autoimmune disease. During EAE, sulphatide-reactive type II NKT cells, but not type I NKT cells, are increased several fold in the CNS. This greater abundance of type II NKT cells in the CNS inverts the usual ratio of type II : type I NKT cells (type II NKT cells, 3–4%; and type I NKT cells, 0·6–0·9%) and affords INCB024360 in vitro protection from EAE.[27, 61] Furthermore, administration of sulphatide to activate type II NKT cells decreases the number of IFN-γ- and IL-17-secreting myelin basic protein and proteolipid protein-reactive encephalitogenic CD4+

T cells. The net outcome is protection from EAE via a CD1d-dependent regulatory pathway (Maricic et al., submitted). This type II NKT-mediated immunoregulatory pathway results in (i) inactivation of type I NKT cells that now function as regulatory T cells, (ii) tolerization

of conventional DCs, (iii) tolerization of microglia in the CNS and (iv) inhibition of the effector clonidine functions of pathogenic MHC-restricted CD4+ T cells. As APCs that activate pathogenic Th1 and Th17 cells in lymphoid organs and the CNS are tolerized following sulphatide administration, activation of type II NKT cells induced by sulphatide is much more potent in the regulation of autoimmune demyelination than only the inactivation of type I NKT cells by αGalCer (Maricic et al., submitted). Activation of type II NKT cells by sulphatide was recently reported to protect NOD mice from type 1 diabetes.[28, 89] Pre-treatment of NOD mice with the C24:0 but not C18:0 sulphatide analogue was found to protect against the transfer of type 1 diabetes.[89] These data suggest that the longer C24:0 sulphatide analogue should be examined for its therapeutic value in clinical trials in human subjects at risk for or newly diagnosed with type 1 diabetes. Our preliminary studies suggest that activation of type II NKT cells following administration of sulphatide significantly prevents lupus nephritis in (NZB × NZW) F1 mice, indicating that the protective capacity of sulphatide activated type II NKT cells can counteract potentially pathogenic type I NKT cells.

In a 1964 review lecture, Renkin [15] analyzed the available data on the transport of macromolecules Fulvestrant supplier between plasma and lymph and considered how well they could be accounted for by ultrafiltration through Grotte’s large pores and by transcytosis by vesicles. By so doing, he showed that if vesicular transport were responsible for macromolecular permeability, it could be described in quantitative terms and these terms placed restrictions on the numbers and behavior of the vesicles. Renkin’s review stimulated considerable experimental work by both physiologists and electron microscopists in the late 1960s and throughout the 1970s. Trans-endothelial channels were reported to be formed by a chain of fused

vesicles [23], and some analyses selleck kinase inhibitor suggested both convective and non-convective mechanisms of macromolecular transport

operated in parallel. Convective transport and non-convective transport were interpreted in terms of large pores and transcytosis, respectively. In 1979, however, Rippe et al. [16], working on isolated perfused rat hind limb preparations, published a definitive set of experiments providing strong evidence that, in this preparation, the movement of serum albumin from plasma to tissue occurred entirely by convection. In the same year, Bundgaard et al. [3] published the first of a series of papers in which electron micrographs showed that all the vesicles in capillary endothelium were arranged in fused clusters, which communicated with caveolae at either the luminal or abluminal surface of the cells, but never at both. In their later papers, they [9] reconstructed three-dimensional models of the vesicle clusters from TEMs of ultra-thin Methamphetamine serial sections. It was argued [2,6] that the vesicle clusters

were static structures incompatible with transcytosis because single unattached vesicles were never present, and this was inconsistent with the simple model of transcytosis. It was not, however, inconsistent with the later fusion–fission model [5]. Furthermore, they found no evidence of channels formed as connections between chains or clusters of vesicles opening on to both luminal and abluminal cell surfaces. To account for the appearance of a blood-borne label in abluminal vesicles, it was proposed that the label had entered the abluminal vesicles from the interstitial fluid, having crossed the endothelium by a nearby intercellular cleft, which lay just out of the plane of section. A few years later, direct evidence rebutting this last argument was reported. Wagner and Chen [24] used terbium as a tracer of transport from blood to tissue in the rete mirabile of the eel. By making TEMs from serial sections, they showed that the tracer reached the abluminal surface via vesicles when no intercellular clefts were in the vicinity. Furthermore, the terbium density decreased with distance from a discharging caveola.

Evidence suggests that the level of TCR mispairing is also affected by the variable region of the endogenous TCR chains (Fig. 3).12 An additional approach to prevent TCR mispairing, as demonstrated by Voss et al.,26 was the identification and inversion of a pair of specifically interacting amino acids in the TCR-α and TCR-β constant-domain interface. Mutational inversion of these two amino acids changed a ‘knob-into-hole’ configuration into a charged ‘hole-into-knob’ configuration and by so doing increased the preferential pairing of the transduced mutated TCRs. This approach was effective in both human and murine TCR gene-transfer

systems. An alternative method to completely abolish TCR mispairing is the development of chimeric antigen receptors (CARs), which consist of a single chain Fv fused to CD3 signalling elements. However, the functional activity of CARs is dependent on TAM Receptor inhibitor the sensitivity of the signalling elements, which in some constructs contain additional costimulatory molecules and/or cytokines. Early Everolimus research with CAR-expressing T cells suggested that they were less sensitive to peptide than T cells expressing αβ TCR heterodimers.27,28 It is possible that the described modified TCRs will be immunogenic in an immunocompetent

host, resulting in reduced persistence or elimination of the transduced T cells. Whilst the lymphodepleting regimens currently used before adoptive T-cell transfer are likely to permit T-cell engraftment, it is still necessary to consider strategies to minimize the possible immunogenicity of the modified TCRs. An alternative and novel method of eliminating TCR mispairing is to transduce TCR-αβ genes into γδ T cells. Using this system, T cells must either be transduced with CD8 or CD4 co-receptor independent TCRs, or TCRs and co-receptors must be co-transferred together. These TCR-transduced γδ T cells demonstrate peptide-specific lysis and cytokine release in vitro and also peptide-specific proliferation, persistence and recall responses in vivo.29–31 Achieving

T cells with a high functional avidity is one of the major Reverse transcriptase challenges in current TCR gene-therapy protocols. One means of attaining T cells capable of recognizing and effectively killing tumour cells is to confer the manipulated T cells with TCRs with a high affinity. As the majority of currently available tumour-associated antigens (TAAs) are self-antigens that are expressed at elevated levels in tumours, T cells expressing high-affinity TCRs to tumour antigens may be deleted in the thymus or rendered unresponsive by central or peripheral tolerance. As a result, TAA-specific T cells identifiable within the autologous repertoire are often of low frequency and low-to-moderate functional avidity.

CAT-354 has recently been shown to be safe for use in humans in a phase I clinical trial but its real clinical efficacy remains to be proven [148]. Over the past few years, some evidence suggests that the most effective approaches may be combination therapies interfering with several cytokines and pathways involved in asthma

pathogenesis, since anti-IL-4 treatment alone appears to be ineffective and similarly antagonizing IL-13 in mice requires additional suppression of eosinophillic inflammation [149]. IL-4 and IL-13 both use the IL-4R-α chain, and blocking this receptor has been developed as a therapeutic strategy. A human monoclonal anti-IL-4Rα antibody (AMG317) was developed but showed no clinical efficacy [150], whereas another fully humanized anti-IL-4R-α antibody (Dupilumab REGN668) showed clinical

efficacy in patients with high peripheral blood eosinophilia upon tapering of inhaled Cobimetinib datasheet steroids and bronchodilators [151]. Initial proof of concept studies in human asthmatics with anti-IL-5-specific antibody therapies, such as mepolizumab and reslizumab, showed an effective reduction of eosinophil numbers in the blood and sputum of both mild and severe asthmatics, but late allergen responses and BHR were not improved [152, 153]. However, improved efficacy was noticed in specific subgroups CP-673451 mw of patients with frequent asthma exacerbation and in these patients mepolizumab treatment significantly reduced blood and sputum eosinophil levels and allowed lower corticosteroid doses to be used to control the inflammation [12, 13]. It seems, however, that for the majority of asthmatic patients, the anti-IL-5 treatment will need to be administered in combination with other therapies that suppress asthma features through other mechanisms. Results of clinical trials targeting the IL-5R-α subunit to obtain long-term depletion of eosinophils and basophils are eagerly awaited [154]. Currently, clinical data on anti-IL-9 therapeutics are modest and larger clinical

trials are eagerly awaited to conclude whether this form of therapy can be used in the treatment of asthma [155]. Similarly, studies on the neutralization of IL-17 and/or IL-23 and the effect of such MG-132 cell line neutralization on asthma still need to be reported in humans. Could ILC2s constitute a therapeutic target? Certainly, given the character of the ROR-α nuclear receptor, it might be a target amenable to modification by selective antagonists. Also the precise contribution of ILC2s to asthma pathogenesis in human asthma or in mice with a fully functional adaptive immune system has not been thoroughly explored, as strategies to selectively deplete these cells without affecting other cells of the innate and adaptive immune system have not yet been developed.

Apoptosis of the secretory epithelium as a triggering factor of early dysfunction and autoimmune response has been explored in SS patients and models [32–34] and the potential of certain TNF-α superfamily members, as SS susceptibility biomarkers has emerged from microarray studies in a transgenic mice model of SS [35]. Remarkably, local over-expression of TNF-αR1 in murine glands was shown to reduce saliva secretion [36], while TNF-α has been reported as a potent BVD-523 cell line inducer of acinar apoptosis and TNF-αR1 expression in prediabetic

NOD mice [16]. However, TNF-α/TNF-αR1effects are also commonly associated with cytokine synthesis and cell survival in immune cells, being the final cellular fate determined primarily by a pivotal factor such as NF-κB [28]. NF-κB is dysregulated in autoimmune disorders and, particularly in SS patients but not in other autoimmune disorders, a lack of a proteasome subunit – multi-functional peptidase 2 – in immune cells could result in a lower NF-κB activity

[37]. Finally, macrophage high functional plasticity guarantees ABT-888 in vitro the silent clearance of apoptotic cells that involves the synthesis of anti-inflammatory mediators IL-10, PGE2 and TGF-β to maintain tissue homeostasis [38]. While NOD macrophages expressed an inflammatory profile in resting conditions, a shift to a regulatory phenotype of NOD macrophages was seen when faced to apoptotic acinar cells. Interestingly, NOD macrophages presented lower phagocytosis of acinar apoptotic cells. A lower avidity and efficacy to engulf apoptotic thymocytes has been reported previously for NOD macrophages [39–41]. In contrast to results presented herein, phagocytosis of apoptotic thymocytes elicited an inflammatory profile in NOD macrophages, suggesting that selective suppressor mechanisms PFKL might be involved in the clearance of apoptotic acinar cells. Evidence presented here also suggests that VIP might contribute to the homeostatic surveillance function of macrophages in the glands by stabilizing a regulatory phenotype for

silent phagocytic clearance. This work was funded by the National Agency of Sciences and Technology ANPCyT (PICT 1971 and 2165) and University of Buenos Aires (20020100100505 and X172). The authors declare that they have no competing interests. “
“Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin (MTg)-sensitized splenocytes activated with MTg and interleukin (IL)-12. Our previous studies showed that, when used as donors and recipients, interferon (IFN)-γ−/− and wild-type (WT) DBA/1 mice both develop severe G-EAT. Thyroid lesions in IFN-γ−/− mice have many eosinophils and few neutrophils, while those in WT mice have extensive neutrophil infiltration and few eosinophils.

© 2014 Wiley Periodicals, Inc. Microsurgery 34:421–424, 2014. “
“Perineal wound complications following abdominoperineal resection (APR) are still frequent and most troublesome

Selleckchem CHIR-99021 complications. We report the case of a 79-year-old male found to have the huge precoccygeal defect with infection after APR for rectal carcinoma. Before surgery, the patient received a complete course of chemoradiation therapy to treat for downgrade staging of the rectal malignancy. Extensive debridement of the perianal wound was performed for three times, followed by perianal reconstruction and packing and augmentation of the precoccygeal dead space with free latissimus dorsi (LD) muscle flap. Although persisted wound infection was still observed after reconstruction, the patient still led a good result after one time of further debridement and split-thickness skin graft. We selected free LD

muscle flap to fill and seal off the large pelvic dead space without the needs to change the jackknife position of the patient after debridement. To the best of our knowledge, this is the first case reported in the literature with the radiation-associated perianal wound infection after Alvelestat solubility dmso APR reconstructed successfully by free LD muscle flap. © 2011 Wiley-Liss, Inc. Microsurgery, 2011. “
“The peroneus brevis flap can be used as either proximally or distally based flap for Nintedanib (BIBF 1120) coverage of small to medium-sized defects in the lower leg. The purpose of this study was to clarify the vascular anatomy of the peroneus brevis muscle. An anatomical dissection was performed on 17 fixed adult cadaver lower legs. Altogether, 87 segmental branches (mean 5.1 ± 1.6 per leg) either from the fibular or anterior tibial artery

to the muscle were identified. Sixty-two were branches from the fibular artery (mean 3.4 ± 1.1 per fibular artery), whereas 25 (mean 1.4 ± 0.9 per anterior tibial artery) originated from the anterior tibial artery. The distance between the most distal vascular branch and the malleolar tip averaged 4.3 ± 0.6 cm. An axial vascular bundle to the muscle could be identified in all cadavers; in one leg two axial supplying vessels were found. Their average length was 5.5 ± 2.4 cm and the average arterial diameter was 1.1 ± 0.5 mm, the average venous diameter was 1.54 ± 0.7 mm. The constant blood supply to the peroneus brevis muscle by segmental branches from the fibular and tibial artery make this muscle a viable option for proximally or distally pedicled flap transfer. The location of the most proximal and distal branches to the muscle and conclusively the pivot points for flap transfer could be determined. Furthermore, a constant proximal axial vascular pedicle to the muscle may enlarge the clinical applications. Perfusion studies should be conducted to confirm these findings. © 2014 Wiley Periodicals, Inc. Microsurgery, 2014.

The average values at diagnosis in this cohort and the control group were age of 65 vs. 37 years, eGFR of 47 vs. 77 ml/min/1.73 m2, and urinary protein excretion (UPE) of 1.8vs. 1.3 g/day, respectively. Glomerulosclerosis or interstitial fibrosis/tubular atrophy were more advanced see more than the control group, whereas the frequency of the patients with cellular/fibrocellular crescents was comparable to that of the control group (35% vs. 25%). In comparative analyses of the 46 patients treated with corticosteroids (S) and the 75 patients with conventional therapies including RAS blockades (C), UPE at one year after diagnosis significantly decreased in both groups (S: 2.4  0.5 g/day, C: 1.5 g  0.9 g/day).

During the observation periods, 9 patients in the S group (20%, 3.4 years on average) and 21 patients in the C group (28%, 5.4 years on average) showed a 50% decrease in their eGFRor reached ESRD. Frequency of newly

diagnosed diabetes was higher in the S group, whereas other extra-renal complications were not different between the groups. Conclusion: In elderly IgAN patients, clinicopathological features at diagnosis are severe than the younger patients. However, therapeutic interventions that are suitable for the stage and grade of the disease may lead to better renal outcomes. IHARA KATSUHITO, IIMORI BEZ235 SOICHIRO, OKADO TOMOKAZU, RAI TATEMITSU, UCHIDA SHINICHI, SASAKI SEI Tokyo Medical and Dental University Introduction: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. Previous studies identified that histopathologic findings could predict renal prognosis; however, defining the predictors of renal prognosis by clinical data and pathological findings at biopsy have been controversial. We retrospectively investigated the association between renal functional

change and clinicopathological factors, and aimed to detect the predictors of renal prognosis at renal biopsy. Methods: We collected data Anidulafungin (LY303366) among patients of initially biopsy-proven IgAN from January 2005 to December 2010, and who were followed for three years. Primary outcome was chronic kidney disease (CKD) progression as assessed by progression to the next CKD stage. We investigated the association of CKD progression with the following factors; gender, Body Mass Index, pathological findings by Oxford classification, hypertension, proteinuria, hematuria, baseline values of IgA, baseline estimated glomerular filtration rate (GFR), use of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), use of corticosteroid, tonsillectomy, and antiplatelet therapy. Results: Fifty seven patients were eligible for participation in our study. Twenty eight patients were female gender, and mean age was 36.7 ± 14.1 years old. Thirteen patients progressed to the next CKD stage (progression group).

The small leucine-rich proteoglycans (SLRPs) are a group belonging to the leucine-rich repeat (LRR) superfamily of proteins.

This includes decorin and biglycan (Figure 1C), which have a central region of 10 leucine residues flanked by cysteine residues [73]. Decorin is the best characterized SLRP member and is traditionally associated with ‘decorating’ collagen fibrils. The core protein is 40 kDa and has a single GAG chain attached to a serine residue near the N-terminus. Biglycan is structurally similar, click here with a core protein of 45 kDa and two GAG chains. SLRPs evoke a number of signalling pathways and are implicated in multiple interactions including modulation of collagen I and II fibrillogenesis [74]. Decorin expression may have positive effects on repair. It is known to inhibit activity of TGFβ [75] and EGFR [76,77], which have ICG-001 price regulatory effects on synthesis of inhibitory CSPGs [78,79]. Biglycan also binds TGFβ, and soluble glycosylated biglycan acts as an endogenous ligand of the innate immunity

receptors TLR4 and TLR2 in macrophages (reviewed in [80]). Thus, the CSPGs comprise a complex family of molecules that are key components of the ECM. The multiple interactions of CSPGs with other ECM molecules as well as their binding affinity for a diverse array of growth factors, cytokines and receptors all suggest that they are crucial players in the CNS response to injury and that ECM modification will be an important therapeutic target. In addition to specific targeting of individual CSPGs (such as the function blocking NG2 antibody), global targeting of CSPGs has been a widely used strategy in experimental studies, for example by enzymatic digestion of CS-GAG chains to reduce the growth inhibitory properties of CSPGs. These approaches will be discussed

in detail later in this review. Many of the above ECM molecules have been targeted in repair strategies, often in an attempt to recapitulate developmental processes, where they play an important role in cell proliferation, migration, axon guidance and plasticity. Below we will discuss some of these many processes. Correct wiring of the nervous system requires the precise distribution and connectivity of millions of cells during development. The ECM plays a key role, conferring many of the properties required to form intricate networks with specificity and reliability. During embryogenesis, neural induction and neural tube formation are followed by rapid cell proliferation, migration and differentiation of cells to neurones and glia to form the CNS. Subsequent to regionalization of neurones, connections form between them. Connections form when a differentiated neurone sends out an axon, tipped by a growth cone which responds to multiple sources of extracellular cues to reach its target.

Our results demonstrate that CD4+ T cells from Irf5+/+ mice produce negligible amounts of IL-4;

in contrast, a fraction of CD4+ T cells from Irf5−/− mice produced IL-4 (Fig. 4A). Both Th1 (IFN-γ+IL-4−) and Th2 (IFN-γ−IL-4+) cells, but not Th0 (IFN-γ+IL-4+), exist in Irf5−/− mice, whereas only Th1 cells could be detected in Irf5+/+ mice. The frequency of IFN-γ producing CD4+ T cells from Irf5−/− mice was comparable selleck products with those from Irf5+/+ (Fig. 4A). Together, these data support a critical role for IRF5 in the regulation of Th1/Th2 polarization contributing to pristane-induced lupus pathogenesis. Since IFN-γ production was not impaired in T cells from Irf5−/− mice, the emergence of Th2 cells in Irf5−/− mice is not solely due to a lack of Th1 polarization in this model. In SLE, activated T and B cells can infiltrate tissues to cause organ damage. Recent data in the Yaa murine lupus model [[23]] indicated that IRF5 was critical for T-cell activation. In a similar manner, we investigated whether loss of Irf5 affects lymphocyte activation. At 6 months postpristane, selleck chemicals llc we found that expression of the early activation marker

CD69, in splenic CD4+ T cells of Irf5−/− mice, was significantly reduced (Fig. 4B). Because IRF5 regulates type I IFN production [[15, 42]] and type I IFN signaling is central to the pathogenesis of pristane-induced SLE [[25]], we examined the contribution of IRF5 to pristane-induced type I IFN production. Levels of serum IFN were determined by the type I IFN reporter cell assay that measures the ability of sera to cause IFN-induced gene expression [[43]]. Anidulafungin (LY303366) A significant decrease in

mRNA levels of the IFN stimulated gene (ISG) IRF7 was observed in L929 cells stimulated with sera from pristane-injected Irf5−/− mice as compared with Irf5+/+ (Fig. 5A). No increase in surface expression of the ISG Sca-1 [[44, 45]] was observed on CD19+ B cells from the PB of Irf5−/− mice 2 weeks postpristane injection (Fig. 5B). Similar results were found at 6 months postinjection in different cellular compartments of Irf5−/− mice (Fig. 5C) and decreased mRNA expression of the ISGs — MCP-1 (ccl2) and MX1 (myxoma response protein) — was also observed in the bone marrow (BM) of Irf5−/− mice (Supporting Information Fig. 2). Ly6Chi monocytes, which are recruited rapidly to the peritoneal cavity (PC) in response to pristane, are thought to be the major source of type I IFN in this model [[44]]. As such, Ly6Chi monocytes were isolated from the PC [[45]] and quantitative PCR (qPCR) performed to determine IRF7 and MX1 mRNA levels. Expression of IRF7 and MX1 were significantly decreased in Irf5−/− mice (Fig. 5D).