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BackgroundAbnormal expanded GGC repeats within theNOTCH2HLCgene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features ofNOTCH2NLC-related NIID in China.MethodsPatients withNOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.ResultsIn the 247 patients withNOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=−0.196, pConclusionsNIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum ofNOTCH2NLC-related NIID.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin-4 antibodies (AQP4-IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed.In an open-label, dose-escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end-points were safety and tolerability. Secondary end-points included pharmacodynamics and efficacy, with key efficacy assessment at week 4.In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add-on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4-IgG was undetectable in six of seven subjects whose baseline AQP4-IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0).Batoclimab add-on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

Abnormal expanded GGC repeats within thePatients withIn the 247 patients withNIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of

Candida albicans is the most common cause of fungal infections in humans, and disseminated candidiasis has become one of the leading causes of hospital-acquired bloodstream infections with a high mortality rate. However, little is known about the host–pathogen interactions and the mechanisms of antifungal immunity. Here, we report that Nedd4 (neuronal precursor cell–expressed developmentally downregulated 4) is essential for signaling through Dectin-1 and Dectin-2/3. We showed that mice that lack Nedd4 globally or only in the myeloid compartment are highly susceptible to systemic C. albicans infection, which correlates with heightened organ fungal burden, defective inflammatory response, impaired leukocyte recruitment to the kidneys, and defective reactive oxygen species expression by granulocytes. At the molecular level, Nedd4−/− macrophages displayed impaired activation of TGF-β–activating kinase-1 and NF-κB, but normal activation of spleen tyrosine kinase and protein kinase C-δ on C. albicans yeast and hyphal infections. These data suggest that Nedd4 regulates signaling events downstream of protein kinase C-δ but upstream of or at TGF-β–activating kinase-1.

BackgroundSince September 2012, when teriflunomide was approved as a disease-modifying treatment for relapsing multiple sclerosis, real-world observational studies on teriflunomide in Chinese patients are limited.MethodsWe collected demographic characteristics and peripheral blood samples at different time points. Clinical symptoms, magnetic resonance imaging data, and concentrations of neurofilament light chains and multiple cytokines at different time points were compared to assess the efficacy. Moreover, the safety was assessed by blood routine, liver and kidney function, and a questionnaire to report adverse reactions.ResultsTeriflunomide significantly reduced serum levels of neurofilament light chains and several inflammatory cytokines. After accepting teriflunomide treatment, many clinical symptoms improved, scores of the expanded disability status scale decreased from 2.0 to 1.75, and annualized relapse rates decreased from 1.45 to 0.31. 29 (80.56%) and 15 (78.95%) patients achieved the no evidence of disease activity-3 status after 6 months and 12 months treatment, respectively. Teriflunomide was associated with mild or moderate discomfort, and discontinuation rates due to adverse events were low.ConclusionSerum neurofilament light chain protein is sensitive to teriflunomide treatment, suggesting that it has the potential to be used as an indicator to assess the efficacy of teriflunomide. Teriflunomide can significantly reduce the concentrations of inflammatory cytokines, indicating that teriflunomide may regulate neuroinflammation through the inhibitory effect on a variety of immune cells and their cytokines. Teriflunomide can improve clinical symptoms and disease severity in MS patients in southern China, and patients have good compliance.

Neuromyelitis optica spectrum disorders (NMOSDs) are uncommon antibody-mediated autoimmune diseases of the central nervous system (CNS), mainly occurring in optic nerves and spinal cord, which can cause visual impairment, paralysis, and occasionally bulbar dysfunction. Such neurological deficits can adversely affect pulmonary functions and increase complicated infection risk. Besides, most NMOSD patients undergo immunosuppressive therapy. All these factors make NMOSD patients the potential high-risk group under the current pandemic of coronavirus disease 2019 (COVID-19). Meanwhile, COVID-19 infection has already been demonstrated as a risk factor for NMOSD relapses. This review discusses the basic immunology of vaccination and common problems, including immunogenicity, safety, and efficacy of vaccination on NMOSD patients. Additionally, we offered vaccination recommendations, health care and treatment advice for NMOSD patients under the background of COVID-19.

E3 ubiquitin ligase Cbl-b is involved in the maintenance of a balance between immunity and tolerance. Mice lacking Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis (EAE), a Th17-mediated autoimmune disease. However, how Cbl-b regulates Th17 cell responses remains unclear. In this study, utilizing adoptive transfer and cell type-specific

Objects: To investigate the impact of COVID-19 epidemic on adult myasthenia gravis (MG) patients, in order to provide better medical advice for special patient population during the quarantine period.Methods: Adult MG patients were randomly recruited to participate. The survey consisted of self-designed questionnaires and the revised 15-item Myasthenia Gravis Quality of Life Questionnaire (MGQOL15r). Participation was strictly voluntary and remained anonymous.Results: A total of 214 adult MG patients (84 males and 130 females) gave valid replies. There were 49.53% patients reported they had the fear of COVID-19 outbreak at different levels. And female patients had a significant higher level of fear to COVID outbreak (p=0.009). It was found that the adult MG patients are more likely to be influenced by the COVID-19 epidemic compared to the general population. During the COVID-19 outbreak, 36.45% patients reported they got an improvement of MG disease severity. 57.01% patients reported they felt no change. 6.54% patients reported their condition got worse. The average of MGQOL15r score was 7.38±6.22. The higher level of the fear of COVID-19 outbreak, the higher score of MGQOL15r (p=0.029), the poorer quality of life. 96.73% patients hoped the specialist physicians could provide online consult. In addition, 64.95% patients would go to the tertiary hospital without hesitation if the Outpatients Department was opened even during the COVID-19 epidemic.Conclusions: The COVID-19 epidemic has significant impact on the quality of life and psychological status in the adult MG patients. Compared to the general population, the adult MG patients are more likely to be influenced by the COVID-19 epidemic. Hence, it is important for health care organizations to provide professional therapeutic advice and psychosocial support in time.*, Contributed to this work equally.

Background MicroRNA-19b (miR-19b) is essential in determining oligodendroglia proliferation. Phosphatase and tensin homologue on chromosome 10 (PTEN) is considered the target of miR-19b and participates in oligodendrocyte differentiation and proliferation. Methods Murine EAE was induced by myelin oligodendrocyte glycoprotein (MOG35- 55). For EAE reversal, artificially synthesized agomiR-19b was intravenous injected after immunization. Results We found that the expression of miR-19b is significantly reduced in an experimental autoimmune encephalomyelitis (EAE) mouse model. This downregulation, which is associated with the neurological scores, can be dramatically ameliorated by agomiR-19b. Our results show that agomiR-19b increases the expression of myelin basic protein (MBP) and cyclic nucleotide phosphodiesterase (CNP), which are regularly utilized as molecular markers of oligodendrocytes. Furthermore, our study also revealed that miR-19b probably affects the expression of PTEN in the EAE model. Conclusion These results indicate that the restoration of miR-19b probably exerts its therapeutic effect by affecting PTEN in the pathogenesis of EAE.

To investigate the value of MoCA and auditory P300 as a cognitive assessment tool in chinese idiopathic inflammatory-demyelinating diseases (IIDDs), eighty three consecutive patients with IIDDs and thirteen sex- and age-matched healthy controls were recruited in the study. MMSE, MoCA and auditory P300 potential were administrated to each participant. The percentage of cognitive impairment in IIDDs patients was 24.1% by using MMSE, while the percentage was 81.9% by using MoCA. The majority of IIDDs participants had MMSE scores in the normal range. In contrast, few IIDDs participants scored in the normal range on the MoCA. Age, EDSS and depression correlated negatively with the total score of MoCA and MMSE. Years of education correlated positively with MoCA and MMSE. ADEM patients scored lower on all MoCA subtests. Prolonged latency P300 which negatively correlated with MoCA and reduced P300 amplitude which positively correlated with MoCA were detected in IIDDs patients. Thus MoCA is superior to the MMSE as a cognitive impairment scan tool and P300 is useful for detecting cogntive deficiency in chinese IIDDs.

E3 ubiquitin ligase Cbl-b is involved in the maintenance of a balance between immunity and tolerance. Mice lacking Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis (EAE), a Th17-mediated autoimmune disease. However, how Cbl-b regulates Th17 cell responses remains unclear. In this study, utilizing adoptive transfer and cell type-specific Cblb knockout strains we show that Cbl-b expression in macrophages, but not T cells or dendritic cells (DCs), restrains the generation of pathogenic Th17 cells and the development of EAE. Cbl-b inhibits the production of IL-6 by macrophages induced by the signaling derived from C-type lectin receptors, which directs T cells to generate pathogenic Th17 cells. Therefore, our data are the first to unveil a previously unappreciated function for Cbl-b in the regulation of pathogenic Th17 responses.

Background Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic autoimmune disease characterized by immune-mediated demyelination and neurodegeneration of the central nervous system (CNS). Here, we investigated the role of LRRC4 in the pathological process of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS.Methods LRRC4 was detected in the CNS of EAE mice by the use of real-time PCR and western blotting. LRRC4 -/- mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG) 35–55 . Pathological changes in spinal cords of LRRC4 -/- and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4 -/- mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE.Results We discovered that the level of LRRC4 decreases in the spinal cords of the EAE mice. Deletion of LRRC4 accelerates infiltration of leukocytes into the spinal cords and disease exacerbation in vivo. We further showed that LRRC4 deletion disrupts the balance between Th1 cells and Treg cells and causes a shift toward Th1 cells and that the disrupted balance may be attributed to up-regulation of IL-6, IFN-γ and down-regulation of TNF-α in EAE mice. At a mechanistic level, we found that deficiency of LRRC4 induces elevated NF-κB p65 expression and does so by up-regulating Rab7b, while ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the CNS from immune damages.Conclusions We establish a critical role of LRRC4 in the progression of EAE and provide novel mechanistic insights into EAE development. Our findings also suggest that LRRC4 may be used as a potential target for therapeutic treatment of MS.

Recently, microRNAs (miRNAs) have been reported to play crucial roles in immune responses and other biological processes, but the role of miR-181a in myasthenia gravis (MG) has been relatively less studied. We found that miR-181a was downregulated in the peripheral blood mononuclear cells (PBMCs) of MG patients and was associated with QMGs and anti-AChR Ab levels. In vitro experiments indicated that miR-181a was involved in the modulation of CD4+ T cell activation and plasticity and that miR-181a decreased the expression level of the Th1-related transcription factor T-bet and the Th17-related transcription factor RORγt. In the in vivo experiment, miR-181a treatment alleviated experimental autoimmune myasthenia gravis (EAMG) symptoms and affected both CD4+ T cell differentiation and the production of anti-AChR antibodies. Moreover, in this study, we also found that IL-2 was regulated by miR-181a and that its expression level showed a strong negative correlation with miR-181a levels in MG patients. To illustrate that the expression levels of both IL-2 and miR-181a were sensitive to immunomodulatory therapy treatment in MG, we found that IL-2 and miR-181a were correlated with clinical severity. These findings demonstrate that miR-181a can contribute to the pathogenesis of MG by regulating IL-2 expression. This article is protected by copyright. All rights reserved.

The pathophysiologic significance of the CD16+ monocyte subset has been demonstrated by its expansion in various autoimmune disorders. To date, the characteristics and roles of monocyte subpopulations in patients with neuromyelitis optica (NMO) have been poorly defined. We measured the percentages of the monocyte subsets in the peripheral blood, the levels of IL-1β and TNF-α mRNA in monocyte subsets and the concentrations of IL-1β and TNF-α in plasma and CSF from NMO patients. Our results showed that nonclassical monocytes were up-regulated in NMO patients and significantly elevated IL-1β and TNF-α expression was detected in it. In addition the increased nonclassical monocytes could be selectively suppressed by GC in patients with NMO.

Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.

MiR-15a is likely to be associated with autoimmunity. Here, we aimed to examine the expression of miR-15 cluster in PBMCs from myasthenia gravis (MG) patients and investigate the potential roles of miR-15a in MG. We found that the expression of all miR-15 cluster was decreased in MG, furthermore, miR-15a levels in ocular MG (oMG) were much lower, while CXCL10 production was increased in MG. We display that CXCL10 was a functional target gene of miR-15a in MG. Increasing miR-15a expression could reduce CXCL10 expression and alleviate the abnormal T cells activation in immune response, while decreasing miR-15a expression could activate immune response abnormally. Moreover, miR-15a expression was significantly decreased after stimulation, and prednisone treatment could upregulate miR-15a expression in steroid-responsive MG patients. Take together, our data suggest that decreased miR-15a expression facilitates proinflammatory cytokines production and contributes to immune response at least in part via regulating CXCL10 expression in MG.

E3 ubiquitin ligase Cbl-b is involved in the maintenance of a balance between immunity and tolerance. Mice lacking Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis (EAE), a Th17-mediated autoimmune disease. However, how Cbl-b regulates Th17 cell response remains unclear. In this study, utilizing adoptive transfer and cell type-specific Cblb knockout strains we show that Cbl-b expression in macrophages but not T cells or dendritic cells (DCs) restrains the generation of pathogenic Th17 cells and the development of EAE. Cbl-b inhibits the production of IL-6 by macrophages induced by the signaling derived from C-type lectin receptors, which directs T cells to generate pathogenic Th17 cells. Therefore, our data are the first to unveil a previously-unappreciated function for Cbl-b in the regulation of pathogenic Th17 response.

Osteosarcoma (OS) is the most common primary malignant bone tumour among adolescents and young adults; however, its molecular pathogenesis has not been completely elucidated. Ubiquitin‑specific protease 7 (USP7), a member of the deubiquitinating enzyme family, plays a role in the malignancy process of various cancer types by targeting the key oncoprotein; however, its biological function and mechanism in OS have not been elucidated. The present study demonstrated that USP7 expression in OS tumour tissues was markedly higher than that in the paired surrounding tissues, and high USP7 expression was positively correlated with the TNM stage and metastasis in patients with OS. Next, biological function assays demonstrated that USP7 knockdown markedly inhibited OS cell migration and invasion, whereas USP7 overexpression enhanced it. Notably, USP7 can directly bind with β‑catenin to activate the Wnt/β‑catenin signalling pathway and induce epithelial‑mesenchymal transition (EMT) of OS cells. Overall, USP7 overexpression could promote OS cell metastasis by activating the Wnt/β‑catenin signalling pathway by inducing EMT, suggesting that USP7 is a potential therapeutic target for OS.

Akt isoforms play key roles in multiple cellular processes; however, the roles of Akt-1 and Akt-2 isoforms in the development of T cell–mediated autoimmunity are poorly defined. In this study, we showed that Akt1−/− mice develop ameliorated experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, whereas Akt2−/− mice develop exacerbated EAE, compared with wild-type mice. At the cellular level, Akt-1 appears to inhibit proliferation of thymus-derived regulatory T cells (tTregs), which facilitates Ag-specific Th1/Th17 responses. In a sharp contrast to Akt-1, Akt-2 potentiates tTreg proliferation in vitro and in vivo and suppresses Ag-specific Th1/Th17 responses. Furthermore, treating mice with established EAE with a specific Akt-1 inhibitor suppressed disease progression. Our data demonstrate that Akt-1 and Akt-2 differentially regulate the susceptibility of mice to EAE by controlling tTreg proliferation. Our data also indicate that targeting Akt-1 is a potential therapeutic approach for multiple sclerosis in humans.

Guillain-Barre syndrome (GBS) is an autoimmune disease of the nervous system and is the most common acute polyneuropathy. Both cellular and humoral immunity are believed to be involved in the pathogenesis of GBS, and various types of activated CD4+ T cells are thought to orchestrate the onset and progression of GBS. Lymphoplasma exchange (LPE) filtering out activated lymphocytes while exchanging plasma has been used for GBS treatment for years. However the treatment is still not yet optimal. In order to assess the efficacy of this treatment, we evaluate the effect of LPE and determine the appropriate frequency of LPE treatments for GBS patients through comparing the neurological deficit scores and the changes in related immunology indicators of GBS patients before and after LPE treatment. Twenty-four patients with GBS who received LPE were evaluated for immunologic indicants before treatment, on the second day, and the fourth day after the treatment. The immunoglobulin complement and CD4+ T lymphocyte subsets were tested by flow cytometry. The patients' Medical Research Council sum scores were increased from 25.7±10.4 up to. 36.7±10.4 (P=0.019) and their Hughes scores decreased from 3.7±0.76 to 3.1±0.73 (P=0.027) at 7 days after LPE. In the peripheral blood from patients received LPE treatment, the levels of immunoglobulin, complement, monocytes and fibrinogen were significantly reduced. The percentages of Th1 and Th17 cells in the CD4+ T lymphocyte subsets were significantly decreased, whereas the Th2 and Treg cells were increased in patients after treatment. The changes in CD4+T lymphocyte subsets were correlated with patient MRC score changes. Our data indicate that LPE is effective in treating GBS patients by directly removing immunoglobulin, complement, monocytes, and fibrinogen as well as regulating lymphocyte subsets in the peripheral blood.

Myasthenia gravis (MG) is a neurological autoimmune disease characterized by fluctuating weakness of certain voluntary muscles. Current treatments for MG are largely directed at suppressing the whole immune system by using immunosuppressants or glucocorticoids and often cause several side effects. The ideal therapeutic methods for MG should suppress aberrant immunoactivation specifically, while retaining normal function of the immune system. In this study, we first produced exosomes from microRNA-146a overexpressing dendritic cells (DCs). Then, we observed suppressive effects of those exosomes in experimental autoimmune myasthenia gravis (EAMG) mice. Results showed that exosomes from microRNA-146a overexpressing DCs expressed decreased levels of CD80 and CD86. In experimental autoimmune MG, exosomes from microRNA-146a overexpressing DCs suppressed ongoing clinical MG in mice and altered T helper cell profiles from Th1/Th17 to Th2/Treg both in serum and spleen, and the therapeutic effects of those exosomes were antigen-specific and partly dose dependent. All the findings provide experimental basis for antigen-specific therapy of MG.

The present study aimed to summarize the clinical features, alterations in cerebrospinal fluid (CSF), imaging characteristics, diagnostic methods, treatment regimens and outcomes of adult Chinese patients with tuberculous meningitis (TBM). Clinical data of 189 cases with 4 cases confirmed with definite TBM, 65 cases of probable (diagnostic score, ≥12 with imaging or ≥10 without imaging) and 120 cases of possible (diagnostic score, 6-11 with imaging or 6-9 without imaging) TBM admitted to Xiangya Hospital of Central South University between January 2009 and January 2015 were investigated retrospectively. Data on the clinical, laboratory and demographic characteristics of patients, as well as the results of radiological investigations and the clinical outcome, were collected for all patients. A total of 89.9% patients illustrated symptoms of acute or sub-acute TBM. The most frequent symptoms and signs were fever (78.3%), headache (89.2%), decreased level of consciousness (48.1%), meningeal irritation (73%), impairment of cranial nerve function and increased intracranial pressure (60%). The CSF protein concentration was significantly elevated and CSF glucose was greatly decreased in these cases. Imaging data were available for 144 cases, with 66 cases presenting abnormal chest X-ray or computed tomography findings, and 127 cases presenting abnormal brain magnetic resonance imaging findings among the 144 patients examined. All patients received anti-tuberculosis (TB) therapy, while 7 patients underwent neurosurgical drainage due to hydrocephalus and 3 patients succumbed to the disease. Among the survivors, 87% presented significant improvement. In conclusion, the diagnosis of TBM should combine clinical manifestations, CSF examination and the effect of anti-TB therapy. Differential diagnosis and trial anti-TB therapy may be of help for diagnosis. Positive CSF smear, CSF culture and biopsy of the brain, or biopsy of meninges are golden standards for the diagnosis of TBM. Early diagnosis and treatment are very important for improving the outcome.

The pathophysiologic significance of the CD16

Candida albicans is the most common cause of fungal infections in humans, and disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with 45% to 75% mortality rate. The understanding of the host–pathogen interactions and the mechanisms of immune regulation against fungal spread is critical for developing immune-based strategies to combat candidemia. Nedd4 (neuronal precursor cell-expressed developmentally down-regulated 4) is a HECT-type E3 ubiquitin ligase which has been shown to positively regulate T cell activation and proliferation. However, the role of Nedd4 in innate immunity is completely unknown. To elucidate the role of Nedd4 in innate immune response against fungal infection, we generated the mice bearing LoxP-flanked alleles encoding Nedd4 with Rosa26-Cre-ERT2 mice to generate Nedd4fl/flRosa26-Cre-ERT2 mice (called ‘Nedd4CreER mice’ here). We also generated mice deficient for Nedd4 in dendritic cells (DC) (Cd11c Cre.Nedd4f/f) or macrophages (LysM Cre.Nedd4f/f). We found that although Nedd4 might not regulate the signaling via TLRs and Dectin-1, Rosa26-Cre-ERT2 mice treated with tamoxifen or mice deficient for Nedd4 in the myeloid cell lineages (macrophages and dendritic cells) are highly susceptible to systemic C. albicans infection, which correlates with defective pro-inflammatory cytokines in the sera, impaired leukocyte recruitment to the kidneys, defective ROS expression by the granulocytes in the kidneys, and heightened kidney fungal burden. Therefore, our data suggest that Nedd4 expression in the myeloid cells is crucial for C-type lectin receptor (CLR)-mediated innate immune response against systemic C. albicans infection.

Akt-1 and -2 are major members of serine/threonine Akt family kinases that play a key role in multiple cellular processes. Previously, we have shown that Akt-2 but not Akt-1 is involved in the inhibition of inducible regulatory T cell development. However, the role of both isoforms of Akt in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is completely unknown. In this study, we showed that while Akt1−/− mice develop ameliorated EAE, Akt2−/− mice develop severe disease. At the cellular levels, Akt-1 appears to inhibit proliferation of thymic-derived CD4+CD25+Foxp3+ regulatory T cells (tTregs), but facilitates antigen-specific TH1/TH17 responses during EAE induction. In a sharp contrast to Akt-1, Akt-2 potentiates tTreg proliferation, and suppresses antigen-specific TH1/TH17 responses. Our data demonstrate Akt-1 and Akt-2 differentially regulates the susceptibility of mice to EAE possibly by controlling tTreg proliferation in the periphery, thus controlling TH1/TH17 responses during EAE development.