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Gao, Kim, and colleagues recently reported that clonal populations of CD4 + T cells could be detected in mice that underwent spinal cord injury (SCI). A subset of clones mediated enhanced motor recovery and suppressed inflammation. Further studies may point towards novel cell therapies for SCI, for which care is presently supportive only., Competing Interests: Declaration of interests R.M.R. is a venture partner at Third Rock Ventures. He is co-founder and clinical advisor with equity in Abata Therapeutics, a company producing regulatory T cell therapies for autoimmune conditions., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We investigated the immunological outcome predictors in patients with antibody-mediated autoimmune encephalitis. A severe disability on admission, a low lymphocyte count, including T, B, and T + B + NK (TBNK) cells, an elevated neutrophil (%) and neutrophil to lymphocyte ratio (NLR) could predict poor prognoses. The increased neutrophils (%) and NLR with the decreased eosinophil percent and count were sensitive (>0.8) in predicting severe disabilities, while the declined total T cell count, lymphocyte percent and count were specific (>0.9). TBNK cell count had a balanced sensitivity and specificity (both>0.8). Patients with autoimmune encephalitis with poor outcomes are immunologically distinct from those with good recoveries., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur due to ischemia-induced cerebral pathology. Mounting evidence indicates that the robust recruitment of immune cells plays a central role in the acute stage of stroke. Infiltrating peripheral immune cells and resident microglia mediate neuronal cell death and blood-brain barrier disruption by releasing inflammation-associated molecules. Nevertheless, profound immunological effects in the context of the subacute and chronic recovery phase of stroke have received little attention. Early attempts to curtail the infiltration of immune cells were effective in mitigating brain injury in experimental stroke studies but failed to exert beneficial effects in clinical trials. Neural tissue damage repair processes include angiogenesis, neurogenesis, and synaptic remodeling, etc. Post-stroke inflammatory cells can adopt divergent phenotypes that influence the aforementioned biological processes in both endothelial and neural stem cells by either alleviating acute inflammatory responses or secreting a variety of growth factors, which are substantially involved in the process of angiogenesis and neurogenesis. To better understand the multiple roles of immune cells in neural tissue repair processes post stroke, we review what is known and unknown regarding the role of immune cells in angiogenesis, neurogenesis, and neuronal remodeling. A comprehensive understanding of these inflammatory mechanisms may help identify potential targets for the development of novel immunoregulatory therapeutic strategies that ameliorate complications and improve functional rehabilitation after stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ma, Yang, He, Zhang and Chang.)

Immune cell infiltration to the injured brain is a key component of the neuroinflammatory response after ischemic stroke. In contrast to the large amount of proinflammatory immune cells, regulatory T cells, are an important subgroup of T cells that are involved in maintaining immune homeostasis and suppress an overshooting immune reaction after stroke. Numerous previous reports have consistently demonstrated the beneficial role of this immunosuppressive immune cell population during the acute phase after experimental stroke by limiting inflammatory lesion progression. Two recent studies expanded now this concept and demonstrate that regulatory T cells-mediated effects also promote chronic recovery after stroke by promoting a proregenerative tissue environment. These recent findings suggest that boosting regulatory T cells could be beneficial beyond modulating the immediate neuroinflammatory response and improve chronic functional recovery.

While traumatic brain injury (TBI) is the leading cause of death and disability in children, we have yet to identify those pathogenic events that determine the extent of recovery. Neutrophils are best known as "first responders" to sites of infection and trauma where they become fully activated, killing pathogens via proteases that are released during degranulation. However, this activational state may generate substantial toxicity in the young brain after TBI that is partially due to developmentally regulated inadequate antioxidant reserves. Neutrophil degranulation is triggered via a downstream signaling pathway that is dependent on spleen tyrosine kinase (Syk). To test the hypothesis that the activational state of neutrophils is a determinant of early pathogenesis and long-term recovery, we compared young, brain-injured conditional knockouts of Syk (syk f/f MRP8-cre + ) to congenic littermates (syk f/f ). Based upon flow cytometry, there was an extended recruitment of distinct leukocyte subsets, including Ly6G + /Ly6C - and Ly6G + /Ly6C int , over the first several weeks post-injury which was similar between genotypes. Subsequent assessment of the acutely injured brain revealed a reduction in blood-brain barrier disruption to both high and low molecular weight dextrans and reactive oxygen species in syk f/f MRP8-cre + mice compared to congenic littermates, and this was associated with greater preservation of claudin 5 and neuronal integrity, as determined by Western blot analyses. At adulthood, motor learning was less affected in brain-injured syk f/f MRP8-cre + mice as compared to syk f/f mice. Performance in the Morris Water Maze revealed a robust improvement in hippocampal-dependent acquisition and short and long-term spatial memory retention in syk f/f MRP8-cre + mice. Subsequent analyses of swim path lengths during hidden platform training and probe trials showed greater thigmotaxis in brain-injured syk f/f mice than sham syk f/f mice and injured syk f/f MRP8-cre + mice. Our results establish the first mechanistic link between the activation state of neutrophils and long-term functional recovery after traumatic injury to the developing brain. These results also highlight Syk kinase as a novel therapeutic target that could be further developed for the brain-injured child., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDIndividuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.METHODSWe performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.RESULTSSixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53).CONCLUSIONSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingNational Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Enterovirus 71 (EV71) is a positive single-stranded RNA virus from the enterovirus genus of the Picornaviridae family. Most young children infected with EV71 develop mild symptoms of hand, foot and mouth disease, but some develop severe symptoms with neurological involvement. Limb paralysis from EV71 infection is presumed to arise mainly from dysfunction of motor neurons in the spinal cord. However, EV71 also targets and damages skeletal muscle, which may also contribute to the debilitating symptoms. In this study, we have delineated the impacts of EV71 infection on skeletal muscle using a mouse model. Mouse pups infected with EV71 developed limb paralysis, starting at day 3 post-infection and peaking at day 5-7 post-infection. At later times, mice recovered gradually but not completely. Notably, severe disease was associated with high levels of myositis accompanied by muscle calcification and persistent motor end plate abnormalities. Interestingly, macrophages exhibited a dynamic change in phenotype, with inflammatory macrophages (CD45 + CD11b + Ly6C hi ) appearing in the early stage of infection and anti-inflammatory/restorative macrophages (CD45 + CD11b + Ly6C low/- ) appearing in the late stage. The presence of inflammatory macrophages was associated with severe inflammation, while the restorative macrophages were associated with recovery. Altogether, we have demonstrated that EV71 infection causes myositis, muscle calcification and structural defects in motor end plates. Subsequent muscle regeneration is associated with a dynamic change in macrophage phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Lin, Kuo, Chuang, Wang and Liao.)

Objectives: Olfactory and gustatory dysfunction (OD/GD) are now recognized as typical symptoms of COVID-19 infection. However, their pathogenesis remains unclear and no clear prognostic factors have been identified. We have analyzed a cohort of mild/moderate hospitalized patients to identify possible clinical or immunological predictors of recovery from OD/GD., Methods: Clinical and biological parameters were reviewed along with associated comorbidities. Chemosensory Complaint Score was administered on admission and 30 days after the first negative swab. Unpaired Wilcoxon and chi-squared tests were used to compare the variables in the patients who recovered versus those who did not., Results: From a cohort of 119 hospitalized patients, 43 (36%) reported OD/GD on admission. 60.6% had a full recovery from OD and 69.2% from GD. Only the concentration of IL-10 on admission emerged as significantly associated with recovery of taste (p = 0.041) while allergic respiratory disease was more prevalent in the group who did not recover from OD (p = 0.049) and GD (p = 0.007)., Conclusion: These findings suggest that COVID-19 associated OD/GD is an inflammatory-mediated condition and that clinical and immunological parameters could predict the evolution of these symptoms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by multiple cellular and molecular dysfunctions of the innate and adaptive immunity. Cytotoxic function of NK cells is compromised in patients with SLE. Herein, we characterized the phenotypic alterations of SLE NK cells in a comprehensive manner to further delineate the mechanisms underlying the cytotoxic dysfunction of SLE NK cells and identify novel potential therapeutic targets. Therefore, we examined PBMC from SLE patients and matched healthy controls by single-cell mass cytometry to assess the phenotype of NK cells. In addition, we evaluated the cell function of NK cells (degranulation and cytokine production) and the killing of B cell subpopulations in a B cell-NK cell in vitro co-culture model. We found that SLE NK cells expressed higher levels of CD38 and were not able to adequately upregulate SLAMF1 and SLAMF7 following activation. In addition, ligation of SLAMF7 with elotuzumab or of CD38 with daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK cells and primed them to kill circulating plasma cells in an in vitro co-culture system. Overall, our data indicated that dysregulated expression of CD38, SLAMF1 and SLAMF7 on SLE NK cells is associated with an altered interplay between SLE NK cells and plasma cells, thus suggesting their contribution to the accumulation of (auto)antibody producing cells. Accordingly, targeting SLAMF7 and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell function and promoting elimination of circulating plasma cell., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Humbel, Bellanger, Fluder, Horisberger, Suffiotti, Fenwick, Ribi and Comte.)

Background: Persistent inflammation is an important driver of disease progression and affects prognosis. Some indicators of inflammation predict short-term outcomes. The relationship between prognosis, especially mortality, and persistent inflammation in massive stroke has not been studied, and this has been the subject of our research., Methods: From April 1, 2017 to February 1, 2020, consecutive patients were prospectively enrolled. Clinical data, laboratory data, imaging data and follow-up infections morbidity were compared between 2 groups according to modified Rankin scale (mRS) scores (mRS < 3 and ≥ 3) at 1 month. The binomial logistic analysis was used to determine independent factors of 1-month prognosis. Short-term functional outcome, mortality and infection rates in massive stroke with and without persistent inflammation were compared., Results: One hundred thirty-nine patients with massive stroke were included from 800 patients. We found that admission blood glucose levels (p = 0.005), proportions of cerebral hemispheric (p = 0.001), posterior circulatory (p = 0.035), and lacunar (p = 0.022) ischemia were higher in poor outcome patients; neutrophil-to-lymphocyte ratio (odd ratio = 1.87, 95%CI 1.14-3.07, p = 0.013) and blood glucose concentrations (odd ratio = 1.34, 95%CI 1.01-1.79, p = 0.043) can independently predict the short-term prognosis in massive stroke patients. We also found that the incidence of pulmonary infection (p = 0.009), one-month mortality (p = 0.003) and adverse outcomes (p = 0.0005) were higher in patients with persistent inflammation., Conclusions: This study suggested that persistent inflammation is associated with poor prognosis, 1-month mortality and the occurrence of in-hospital pulmonary infection and that higher baseline inflammation level predicts short-term poor outcomes in massive stroke.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD) in most seropositive subjects. IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over 3 months. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells may play an important role in SARS-CoV-2 immunity., Competing Interests: The authors have declared that no competing interests exist.

Background: Acute traumatic spinal cord injury (SCI) induces a systemic immune response involving circulating white blood cells (WBCs). How this response is influenced by overall trauma severity, the neurological level of injury and/or correlates with patient outcomes is poorly understood. The objective of this study was to identify relationships between early changes in circulating WBCs, injury characteristics and long-term patient outcomes in individuals with traumatic SCI., Methods: We retrospectively analysed data from 161 SCI patients admitted to Brisbane's Princess Alexandra Hospital (exploration cohort). Logistic regression models in conjunction with receiver operating characteristic (ROC) analyses were used to assess the strength of specific links between the WBC response, respiratory infection incidence and neurological outcomes (American Spinal Injury Association Impairment Scale (AIS) grade conversion). An independent validation cohort from the Trauma Hospital Berlin, Germany (n = 49) was then probed to assess the robustness of effects and disentangle centre effects., Results: We find that the extent of acute neutrophilia in human SCI patients is positively correlated with New Injury Severity Scores but inversely with the neurological outcome (AIS grade). Multivariate analysis demonstrated that acute SCI-induced neutrophilia is an independent predictor of AIS grade conversion failure, with an odds ratio (OR) of 4.16 and ROC area under curve (AUC) of 0.82 (P < 0.0001). SCI-induced lymphopenia was separately identified as an independent predictor of better recovery (OR = 24.15; ROC AUC = 0.85, P < 0.0001). Acute neutrophilia and increased neutrophil-lymphocyte ratios were otherwise significantly associated with respiratory infection presentation in both patient cohorts., Conclusions: Our findings demonstrate the prognostic value of modelling early circulating neutrophil and lymphocyte counts with patient characteristics for predicting the longer term recovery after SCI., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.

The regenerative capacity of the peripheral nervous system is closely related to the role that Schwann cells (SCs) play in construction of the basement membrane containing multiple extracellular matrix proteins and secretion of neurotrophic factors, including laminin (LN) and brain-derived neurotrophic factor (BDNF). Here, we developed a self-assembling peptide (SAP) nanofiber hydrogel based on self-assembling backbone Ac-(RADA) 4 -NH 2 (RAD) dual-functionalized with laminin-derived motif IKVAV (IKV) and a BDNF-mimetic peptide epitope RGIDKRHWNSQ (RGI) for peripheral nerve regeneration, with the hydrogel providing a three-dimensional (3D) microenvironment for SCs and neurites. Methods: Circular dichroism (CD), atomic force microscopy (AFM), and scanning electron microscopy (SEM) were used to characterize the secondary structures, microscopic structures, and morphologies of self-assembling nanofiber hydrogels. Then the SC adhesion, myelination and neurotrophin secretion were evaluated on the hydrogels. Finally, the SAP hydrogels were injected into hollow chitosan tubes to bridge a 10-mm-long sciatic nerve defect in rats, and in vivo gene expression at 1 week, axonal regeneration, target muscular re-innervation, and functional recovery at 12 weeks were assessed. Results: The bioactive peptide motifs were covalently linked to the C-terminal of the self-assembling peptide and the functionalized peptides could form well-defined nanofibrous hydrogels capable of providing a 3D microenvironment similar to native extracellular matrix. SCs displayed improved cell adhesion on hydrogels with both IKV and RGI, accompanied by increased cell spreading and elongation relative to other groups. RSCs cultured on hydrogels with IKV and RGI showed enhanced gene expression of NGF, BDNF, CNTF, PMP22 and NRP2, and decreased gene expression of NCAM compared with those cultured on other three groups after a 7-day incubation. Additionally, the secretion of NGF, BDNF, and CNTF of RSCs was significantly improved on dual-functionalized peptide hydrogels after 3 days. At 1 week after implantation, the expressions of neurotrophin and myelin-related genes in the nerve grafts in SAP and Autograft groups were higher than that in Hollow group, and the expression of S100 in groups containing both IKV and RGI was significantly higher than that in groups containing either IKV or RGI hydrogels, suggesting enhanced SC proliferation. The morphometric parameters of the regenerated nerves, their electrophysiological performance, the innervated muscle weight and remodeling of muscle fibers, and motor function showed that RAD/IKV/RGI and RAD/IKV-GG-RGI hydrogels could markedly improve axonal regeneration with enhanced re-myelination and motor functional recovery through the synergetic effect of IKV and RGI functional motifs. Conclusions: We found that the dual-functionalized SAP hydrogels promoted RSC adhesion, myelination, and neurotrophin secretion in vitro and successfully bridged a 10-mm gap representing a sciatic nerve defect in rats in vivo . The results demonstrated the synergistic effect of IKVAV and RGI on axonal regrowth and function recovery after peripheral nerve injury., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Microglia play essential roles in neuroinflammatory responses after traumatic brain injury (TBI). Our previous studies showed that phenotypes of microglia, as well as infiltrating macrophages, altered at different stages after CNS injury, which was correlated to functional outcomes. IL-13 is an anti-inflammatory cytokine that has been reported to protect against demyelination and spinal cord injury through immunomodulation. The effects of IL-13 in microglia/macrophage-mediated immune responses after TBI remain unknown. In this study, we showed that intranasal administration of IL-13 in male C57BL/6J mice accelerated functional recovery in the controlled cortical impact model of TBI. IL-13 treatment increased the time to fall off in the Rotarod test, reduced the number of foot faults in the foot fault test, and improved the score in the wire hang test up to 28 d after TBI. Consistent with functional improvement, IL-13 reduced neuronal tissue loss and preserved white matter integrity 6 d after TBI. Furthermore, IL-13 ameliorated the elevation of proinflammatory factors and reduced the number of proinflammatory microglia/macrophages 6 d after TBI. Additionally, IL-13 enhanced microglia/macrophage phagocytosis of damaged neurons in the peri-lesion areas. In vitro studies confirmed that IL-13 treatment inhibited the production of proinflammatory cytokines in rat primary microglia in response to LPS or dead neuron stimulation and increased the ability of microglia to engulf fluorophore-labeled latex beads or dead neurons. Collectively, we demonstrated that IL-13 treatment improved neurologic outcomes after TBI through adjusting microglia/macrophage phenotypes and inhibiting inflammatory responses. IL-13 may represent a potential immunotherapy to promote long-term recovery from TBI., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Innate and adaptive immune systems participate in the pathogenesis of acute kidney injury (AKI). Considerable data from different research teams have shown the importance of T lymphocytes in the pathophysiology of AKI and, more recently, prevention and repair. T cells can generate or resolve inflammation by secreting specific cytokines and growth factors as well as interact with other immune and stromal cells to induce kidney injury or promote tissue repair. There also are emerging data on the role of T cells in the progression of AKI to chronic kidney disease and organ cross-talk in AKI. These data set the stage for immunomodulatory therapies for AKI. This review focuses on the major populations of T lymphocytes and their roles as mediators for AKI and repair., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The regulatory mechanisms affecting the modulation of the immune system accompanying the progressive effort to exhaustion, particularly associated with T cells, are not fully understood. We analysed the impact of two progressive effort protocols on T helper (Th) cell distribution and selected cytokines., Methods: Sixty-two male soccer players with a median age of 17 (16-29) years performed different protocols for progressive exercise until exhaustion: YO-YO (YYRL1) and Beep. Blood samples for all analyses were taken three times: at baseline, post-effort, and in recovery., Results: The percentage of Th1 cells increased post-effort and in recovery. The post-effort percentage of Th1 cells was higher in the Beep group compared to the YYRL1 group. Significant post-effort increase in Th17 cells was observed in both groups. The post-effort percentage of regulatory T cells (Treg) increased in the Beep group. An increased post-effort concentration of IL-2, IL-6, IL-8 and IFN-γ in both groups was observed. Post-effort TNF-α and IL-10 levels were higher than baseline in the YYRL1 group, while the post-effort IL-17A concentration was lower than baseline only in the Beep group. The recovery IL-2, IL-4, TNF-α and IFN-γ levels were higher than baseline in the YYRL1 group. The recovery IL-4, IL-6, IL-8, TNF-α and IFN-γ values were higher than baseline in the Beep group., Conclusion: The molecular patterns related to cytokine secretion are not the same between different protocols for progressive effort. It seems that Treg cells are probably the key cells responsible for silencing the inflammation and enhancing anti-inflammatory pathways., Competing Interests: The authors have declared that no competing interests exist.

The inflammatory processes following traumatic brain injury (TBI) have not been fully characterized. We hypothesize that differences in systemic cytokine/chemokine (CC) levels are associated with TBI clinical outcomes. To test this hypothesis, we examined systemic levels of CCs and their relationship with patient outcomes. Plasma from acute TBI subjects was collected at 24-48 h, and the CC levels were measured using a multiplex 41-plex-kit. Clinical outcomes were assessed using the modified Rankin scale (mRS) with good outcomes defined as mRS ≤ 3 and poor outcome as mRS ≥ 4. The differences in CC concentrations between groups were then compared using the Mann-Whitney U test. Seventy-six acute TBI subjects were included in this study. In the mRS ≥ 4 group, interleukin-6 (IL-6) and interleukin-10 (IL-10) were elevated, indicating early activation of immune reaction and modulation. Simultaneously, PDGFAA and RANTES were lower in the mRS ≥ 4 group. Poor outcomes after TBI were associated with elevated levels of IL-6 and IL-10 and lower levels of PDGFAA and RANTES within 24-48 h after injury., (Published by Elsevier Ltd.)

The role of suppressive anti-retroviral therapy (ART) in eliciting restoration of dysregulated immune function remains unclear in HIV-1 infection. Also, due to tailoring of therapeutic regimens towards HIV-1, this possible impairment of therapy may be even more pronounced in HIV-2 and dual (HIV-D) infection. Thus, we evaluated the impact of ART on immune restoration by assessing T cell functions, including HIV specific responses in HIV-1-, HIV-2- and HIV-D-infected individuals. Both ART-treated and naive infected subjects showed persistently altered frequency of CD4 + T cell subsets [regulatory T cells (T reg ), naive/central memory, effector memory], increased immune activation, cytoxicity and decreased frequency of natural killer T (NKT)- like cells and T helper type 17 (Th17)/T reg ratio with elevated microbial translocation. Further, HIV-specific responses were dominated by gag-specific CD4 + T cells in virologically suppressed HIV-D individuals, suggesting retention of T cell memory for both viruses. Increased antigen-specific responses, including dual-functional interleukin (IL)-2/interferon (IFN)-γ CD4 + T cells, were detected in therapy receiving HIV-2-infected individuals indicative of a greater and more functionally diverse T cell memory repertoire. We delineated immune signatures specific to therapy-naive single HIV infection, as well as a unique signature associated with HIV-2 disease progression and immune restoration. Circulating T reg frequency, T cell activation and microbial translocation levels correlated with disease progression and immune restoration among all types of HIV infection. Also, memory responses negatively correlated, irrespective of type of infection, in ART receiving infected individuals, with CD4 rebound and decreased pan T cell activation. Our data highlight the need for adjunct immunomodulatory therapeutic strategies to achieve optimal immune restoration in HIV infection., (© 2019 British Society for Immunology.)

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

Initial studies suggest that increased age is associated with worse outcomes after traumatic brain injury (TBI), though the pathophysiological mechanisms responsible for this remain unclear. Immunosenescence (i.e., dysregulation of the immune system due to aging) may play a significant role in influencing TBI outcomes. This study therefore examined neurological outcomes and immune response in young-adult (i.e., 10 weeks old) compared to middle-aged (i.e., 1 year old) rats following a TBI (i.e., fluid percussion) or sham-injury. Rats were euthanized at either 24 h or one-week post-injury to analyze immune cell populations in the brain and periphery via flow cytometry, as well as telomere length (i.e., a biomarker of neurological health). Behavioral testing, as well as volumetric and diffusion-weighted MRI, were also performed in the one-week recovery rats to assess for functional deficits and brain damage. Middle-aged rats had worse sensorimotor deficits and shorter telomeres after TBI compared to young rats. Both aging and TBI independently worsened cognitive function and cortical volume. These changes occurred in the presence of fewer total leukocytes, fewer infiltrating myeloid cells, and fewer microglia in the brains of middle-aged TBI rats compared to young rats. These findings indicate that middle-aged rats have worse sensorimotor deficits and shorter telomeres after TBI than young rats, and this may be related to an altered neuroimmune response. Although further studies are required, these findings have important implications for understanding the pathophysiology and optimal treatment strategies in TBI patients across the life span., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The innate immune response plays a critical role in traumatic brain injury (TBI), contributing to ongoing pathogenesis and worsening long-term outcomes. Here we focus on neutrophils, one of the "first responders" to TBI. These leukocytes are recruited to the injured brain where they release a host of toxic molecules including free radicals, proteases, and pro-inflammatory cytokines, all of which promote secondary tissue damage. There is mounting evidence that the developing brain is more vulnerable to injury that the adult brain. This vulnerability to greater damage from TBI is, in part, attributed to relatively low antioxidant reserves coupled with an early robust immune response. The latter is reflected in enhanced sensitivity to cytokines and a prolonged recruitment of neutrophils into both cortical and subcortical regions. This review considers the contribution of neutrophils to early secondary pathogenesis in the injured developing brain and raises the distinct possibility that these leukocytes, which exhibit phenotypic plasticity, may also be poised to support wound healing. We provide a basic review of the development, life cycle, and granular contents of neutrophils and evaluate their potential as therapeutic targets for early neuroprotection and functional recovery after injury at early age. While neutrophils have been broadly studied in neurotrauma, we are only beginning to appreciate their diverse roles in the developing brain and the extent to which their acute manipulation may result in enduring neurological recovery when TBI is superimposed upon brain development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Alterations in immunological homeostasis induced by acute exercise have been frequently reported. In view of the growing amount of repetitive exercise stimuli in competitive sports, quick recovery plays a superior role. Therefore, we examined whether aqua cycling affects cellular immunological recovery., Methods: After performing 300 countermovement jumps with maximal effort male sport students (n = 20; 24.4 ± 2.2 years) were randomized into either an aqua cycling (AC) or a passive recovery (P) group. AC pedaled in chest-deep water without resistance, while P lay in a supine position. Each recovery protocols lasted 30 min. Blood samples were taken at Baseline, Post-exercise, Post-recovery and 1 h (h), 2 h, 4 h, 24 h, 48 h and 72 h after recovery. Outcomes comprised white blood cell (WBC) counts, lymphocyte (LYM) counts and LYM subsets (CD4/CD8 ratio). Additionally, cellular inflammation markers (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII)) were calculated., Results: In both groups, WBC, NLR and SII were significantly increased compared to Baseline up to and including 4 h after recovery. Significant interaction effects were found for WBC (Post-recovery, 2 h and 4 h), NLR (Post-recovery), SII (Post-recovery) and CD4/CD8 ratio (2 h) with values of AC being higher than of P., Conclusions: Interestingly, AC provoked a stronger but not prolonged immunological disturbance than P. NLR and SII may present simple, more integrative markers to screen exercise-induced alterations in immune homeostasis/recovery in athletes and clinical populations. More research is warranted to elucidate the clinical and practical relevance of these findings.

Nogo-66 receptor (NgR) and paired immunoglobulin-like receptor B (PirB) are two common receptors of various myelin-associated inhibitors (MAIs) and, thus, play an important role in MAIs-induced inhibitory signalling of regeneration following spinal cord injury (SCI). Based on the concept of protective autoimmunity, vaccine approaches could induce the production of antibodies against inhibitors in myelin, such as using purified myelin, spinal cord homogenates, or MAIs receptor NgR, in order to block the inhibitory effects and promote functional recovery in SCI models. However, due to the complication of the molecules and the mechanisms involved in MAIs-mediated inhibitory signalling, these immunotherapy strategies have yielded inconsistent outcomes. Therefore, we hypothesized that the choice and modification of self-antigens, and co-regulating multiple targets, may be more effective in repairing the injured spinal cord and improving functional recovery. In this study, NgR and PirB were selected to construct a double-targeted granulocyte-macrophage colony stimulating factor-NgR-PirB (GMCSF-NgR-PirB) nucleic acid vaccine, and investigate the efficacy of this immunotherapy in a spinal cord injury model in rats. The results showed that this vaccination could stimulate the production of antibodies against NgR and PirB, block the inhibitory effects mediated by various MAIs, and promote nerve regeneration and functional recovery after spinal cord injury. These findings suggest that nucleic acid vaccination against NgR and PirB can be a promising therapeutic strategy for SCI and other central nervous system diseases and injuries.

Ophthalmoplegia, ataxia and areflexia characterise the clinical triad of Miller-Fisher Syndrome (MFS). When the disease presents acutely, it can mimic posterior circulation stroke. We describe a case of an adult patient presenting with sudden dizziness, diplopia, vomiting, and loss of balance. She was initially managed as a case of a brainstem stroke, but the progression of craniopathies without deterioration in sensorium coupled with areflexia clinched the diagnosis of MFS two days into her admission. On the third day, her MFS progressed rapidly to acute motor and sensory axonal neuropathy (AMSAN) variant of Guillain-Barre Syndrome, a rare occurrence in patients with MFS, with only four reported cases including our own. Among the four cases, ours is the only one still non-ambulatory eight months after the initial onset of symptoms. The case highlights the importance of early recognition of MFS in patients with ophthalmoplegia and ataxia despite initially normal reflexes., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of (non) malignant conditions. GvHD is a severe complication with high morbidity and mortality. The pathogenesis remains unclear. We studied dendritic cell (DC) reconstitution to detect potential differences, which may improve our knowledge in the development of chronic GvHD (cGvHD)., Procedure: We examined immune reconstitution (T, B, and NK cells and dendritic cells) at defined time points in a pediatric cohort who underwent 61 allogeneic HSCTs., Results: Regarding DC reconstitution we found a fast reconstitution of the DC compartment negatively correlated with age. After HSCT, both myeloid DC (mDC) and plasmacytoid DC (pDC) counts recover to pre-HSCT levels within 2 months. Higher CCR7 positive cell counts were found in patients receiving TBI during engraftment and during the whole posttransplant period we found a correlation with an improved outcome. In cGVHD patients decreased total DC counts and increased pDCs were found after day+100. No relevant correlation was achieved regarding to HLA-matching, stem cell manipulation of the graft as well as HSCT-indication compared with different DC counts., Discussion: Pathogenesis of cGvHD remains complex. Our data suggest an influence of dendritic cells, which may contribute to the clinical picture and should be further investigated in future studies.

Objective: The aim of this study was to explore the specific role of miR-219-5p in spinal cord injury (SCI), and to investigate its underlying mechanism., Materials and Methods: The SCI model was first constructed in mice, and the motor function of each mouse was evaluated by the Basso Beattie Bresnahan (BBB) method. The protein and mRNA expression levels of miR-219-5p and NEUROD2 in SCI mice were detected by Western blot and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), respectively. Subsequently, all mice were assigned into 3 groups, including the sham operation group, the SCI group and the SCI+miR-219-5p group. The levels of inflammatory factors (TNF-α, IL-1β and IL-6) were detected by Western blot and qRT-PCR. Meanwhile, reactive oxygen species (ROS) were detected by flow cytometry. Target genes of miR-219-5p were predicted by TargetScan and verified by Luciferase reporter gene assay. For in vitro experiments, the possible molecule mechanism of miR-219-5p in regulating NEUROD2 was detected by Western blot., Results: MiR-219-5p was significantly downregulated after SCI. The expression level of miR-219-5p was decreased in the SCI group than that of the sham operation group in a time-dependent manner, which reached the lowest level on the 7th day. Besides, the mRNA and protein levels of NEUROD2 in the SCI group were both remarkably increased in a time-dependent manner, which reached a peak on the 7th day. The levels of inflammatory factors (TNF-α, IL-1β and IL-6) and ROS were significantly higher in the SCI group, which could be reversed by miR-219-5p mimics transfection in SCI mice. Meanwhile, the BBB score in the SCI group was remarkably lower than that of the SCI + miR-219-5p group from the 4th day after SCI. TargetScan predicted that NEUROD2 was the target gene of miRNA-219-5p. In addition, Western blot results indicated that miR-219-5p could regulate NEUROD2, eventually promoting the recovery of SCI., Conclusions: Overexpressed miR-219-5p promotes SCI recovery and motor function elevation via alleviating NEUROD2-regulated inflammation and oxidative stress.

Objective: The aim of this research is to explore the possible role of miR-152 in spinal cord injury and its underlying mechanism., Materials and Methods: After a mouse model of spinal cord injury (SCI) was developed, Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was used to detect the expression of miR-152 and c-jun in the mouse. In addition, the expression levels of interleukin-1b (IL-1b), interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Subsequently, miR-152 was overexpressed and the levels of inflammation and c-jun after spinal cord injury were detected by Western blot. Furthermore, the grip strength of double forelimb, left forelimb or right forelimb of the mice was detected using a grip force test after miR-152 was overexpressed in the injured area of each group., Results: By constructing a mouse model of spinal cord injury, we found that the expression of miR-152 in the injured area decreased with time; meanwhile, the inflammatory relative genes including IL-1b, IL18, TNF-α, and c-jun were significantly increased. However, miR-152 overexpression significantly reduced the levels of inflammation genes as well as the expression of c-jun. Besides, the strength of the forelimbs in the spinal cord injury mice was restored., Conclusions: MiR-152 could inhibit inflammatory responses and promote the recovery of the spinal cord injury through the c-jun N-terminal kinase pathway and it can be a target molecular for treating spinal cord injury.

Background: The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP)., Methods: This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers., Results: Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers., Conclusion: Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose of Review: In adult mammals, a traumatic spinal cord injury (SCI) elicits a chronic unregulated neuroinflammatory response accompanied by seemingly paradoxical suppression of systemic immunity. These SCI-induced changes in immune function contribute to poor neurological outcomes and enhanced morbidity or mortality. Nonspecific anti-inflammatory or proinflammatory therapies are ineffective and can even worsen outcomes. Therefore, recent experimental SCI research has advanced the understanding of how neuroimmune cross-talk contributes to spinal cord and systemic pathology., Recent Findings: It is now appreciated that the immune response caused by injury to the brain or spinal cord encompasses heterogeneous elements that can drive events on the spectrum between exacerbating pathology and promoting tissue repair, within the spinal cord and throughout the body. Recent novel discoveries regarding the role and regulation of soluble factors, monocytes/macrophages, microRNAs, lymphocytes and systemic immune function are highlighted in this review., Summary: A more nuanced understanding of how the immune system responds and reacts to nervous system injury will present an array of novel therapeutic opportunities for clinical SCI and other forms of neurotrauma.

Outcomes for patients with high-risk neuroblastoma (HR-NBL) are significantly improved with the addition of immunotherapy (dinutuximab + cytokines) following autologous hematopoietic stem cell transplantation (auto-HSCT). We hypothesized that the immune system is not fully reconstituted at the initiation of immunotherapy. To test this hypothesis, we evaluated hematologic and immune subsets in 34 patients with HR-NBL before and after auto-HSCT. We found that absolute T, B, and NK cell counts at the time of immunotherapy were below normal in 80% of patients. Patients with residual disease at the time of transplantation had significantly lower absolute lymphocyte counts (ALC; P = .008), lower CD16 + cell counts (P = .009), and an abnormal ratio of cytokine-releasing to cytotoxic NK cells at the time of dinutuximab treatment. In addition, the preparative regimen used for auto-HSCT predicted immune recovery. Finally, higher total white blood cell count (P = .013) and ALC (P = .013) at 3 months after completion of therapy were measured in patients who remained in remission compared with those who relapsed. Our results indicate that most patients with HR-NBL do not have full immune reconstitution at the time of dinutuximab treatment after auto-HSCT, and that immune recovery may correlate with disease-related outcomes in patients with high-risk disease., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Human placenta-derived mesenchymal stem cell (hPMSC) transplantation has been demonstrated to be an effective way of recovering ovarian function in mice with autoimmune induced premature ovarian failure (POF). But the exact mechanism remains unclear. The goal of the present study is to investigate the role of immune factors (T-helper 17 (Th17), cytotoxic T (Tc17) and regulatory T (Treg) cells) in the recovery of ovarian function and whether the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway is involved in the regulation., Methods: The inhibitor of PI3K/Akt was administered to observe its effect on ovarian function recovery and immune regulation. Serum levels of estradiol (E 2 ), follicle stimulation hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH)) and anti-Zona pellucida antibody (AZPAb) were measured by ELISA to evaluate ovarian function. The morphological changes of ovaries were observed by HE staining. Apoptosis of granular cells (GCs) was determined by detecting the expression of capase-3. Expression of p-Akt protein was detected by immunohistochemistry and western blot assay in ovarian tissues. The MTT assay was performed to assess GC proliferation. GC apoptosis was performed using flow cytometry analysis. Percentages of Th17, Tc17 and Treg cells were detected by flow cytometry. Expression of interleukin (IL)-17 in serum was measured by ELISA., Results: LY294002 administration decreased serum levels of E 2 and AMH, while the levels of FSH, LH and AZPAb in serum were increased compared with mice in the hPMSC transplantation group. The ovarian morphology presented as atrophy and fibrosis, with functional follicles exhausted. The expression of p-Akt in ovarian tissue was significantly decreased. Also, LY294002 administration significantly decreased proliferation and increased cell apoptosis in GCs, and for immune factors the ratios of Th17/Tc17 and Th17/Treg cells were significantly increased, as well as the serum levels of IL-17., Conclusions: Our data suggest that the PI3K/Akt signal pathway is involved in the recovery of ovarian function by changing the ratios of Th17/ Tc17 and Th17/Treg cells in POF mice following hPMSC transplantation.

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

Hydrogen sulfide (H 2 S) is an endogenous gasotransmitter that has vasodilatory properties. It may be a novel therapy for intestinal ischemia-reperfusion (I/R) injury. We hypothesized that 1 ) H 2 S would improve postischemic survival, mesenteric perfusion, mucosal injury, and inflammation compared with vehicle and 2 ) the benefits of H 2 S would be mediated through endothelial nitric oxide. C57BL/6J wild-type and endothelial nitric oxide synthase knockout (eNOS KO) mice were anesthetized, and a midline laparotomy was performed. Intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using laser Doppler. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery. Following ischemia, the clamp was removed, and the intestines were allowed to recover. Either sodium hydrosulfide (2 nmol/kg or 2 µmol/kg NaHS) in PBS vehicle or vehicle only was injected into the peritoneum. Animals were allowed to recover and were assessed for mesenteric perfusion, mucosal injury, and intestinal cytokines. P values < 0.05 were significant. H 2 S improved mesenteric perfusion and mucosal injury scores following I/R injury. However, in the setting of eNOS ablation, there was no improvement in these parameters with H 2 S therapy. Application of H 2 S also resulted in lower levels of intestinal cytokine production following I/R. Intraperitoneal H 2 S therapy can improve mesenteric perfusion, intestinal mucosal injury, and intestinal inflammation following I/R. The benefits of H 2 S appear to be mediated through endothelial nitric oxide-dependent pathways. NEW & NOTEWORTHY H 2 S is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear whether H 2 S works through nitric oxide-dependent pathways in the intestine. We appreciate that H 2 S was able to improve postischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of H 2 S appear to be mediated through endothelial nitric oxide-dependent pathways., (Copyright © 2017 the American Physiological Society.)

Objective: To study disease severity and response to therapy in a large cohort of patients with anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-associated myositis., Methods: Muscle strength, creatine kinase levels and treatments were assessed in anti-HMGCR-positive patients at each clinical visit. Univariate and multivariate analyses were used to analyse the influence of clinical characteristics on strength and the change in strength over time. Whole exome sequencing was performed in a subset of patients., Results: . Among 50 patients followed for ⩾2 years, only 22 (44%) reached full strength with immunosuppressive therapy; even among those with full strength, 55% continued to have CK levels in excess of 500 IU/l and only three could be tapered off immunosuppressive therapy. Both univariate and multivariate analysis showed that patients who were older at disease onset were stronger at all time points (P < 0.001) and improved faster (P < 0.008) than younger patients; a history of statin exposure was not independently associated with the improvement rate. Younger patients were more likely to have refractory disease (P = 0.02) than older patients. Among eight refractory patients with DNA available for testing, whole exome sequencing did not reveal pathogenic mutations in known dystrophy genes. The risk of cancer was not increased in anti-HMGCR myositis patients compared with the general population., Conclusions: Anti-HMGCR myositis is usually a chronic disease requiring long-term immunosuppression. Although younger patients had more severe disease and a worse prognosis than older patients, they did not have evidence of a known co-existing muscular dystrophy to explain their persistent, and sometimes progressive, muscle weakness., (© Published by Oxford University Press British Society for Rheumatology 2017. This work is written by US Government employees and is in the public domain in the United States.)

Background: The effect of hepatitis C virus (HCV) coinfection on CD4 T cell recovery in treated HIV-infected children is poorly understood., Objective: To compare CD4 T cell recovery in HIV/HCV coinfected children with recovery in HIV monoinfected children., Method: We studied 355 HIV monoinfected and 46 HIV/HCV coinfected children receiving antiretroviral therapy (ART) during a median follow-up period of 4.2 years (interquartile range: 2.7-5.3 years). Our dataset came from the Ukraine pediatric HIV Cohort and the HIV/HCV coinfection study within the European Pregnancy and Paediatric HIV Cohort Collaboration. We fitted an asymptotic nonlinear mixed-effects model of CD4 T cell reconstitution to age-standardized CD4 counts in all 401 children and investigated factors predicting the speed and extent of recovery., Results: We found no significant impact of HCV coinfection on either pre-ART or long-term age-adjusted CD4 counts (z scores). However, the rate of increase in CD4 z score was slower in HIV/HCV coinfected children when compared with their monoinfected counterparts (P < 0.001). Both monoinfected and coinfected children starting ART at younger ages had higher pre-ART (P < 0.001) and long-term (P < 0.001) CD4 z scores than those who started when they were older., Conclusions: HIV/HCV coinfected children receiving ART had slower CD4 T cell recovery than HIV monoinfected children. HIV/HCV coinfection had no impact on pre-ART or long-term CD4 z scores. Early treatment of HIV/HCV coinfected children with ART should be encouraged.

Objective: To investigate the effects of resuscitation with normal saline (NS), hypertonic saline (HTS), and hydroxyethyl starch (HES) on regulatory T cells (Tregs), helper T 1 (Th1)/Th2 and cytotoxic T 1 (Tc1)/Tc2 profiles in the treatment of hemorrhagic shock., Methods: Rats subjected to severe hemorrhagic shock were resuscitated for 30 min with NS (n=8), HTS (n=8), or HES (n=8); sham (n=8) and naive control (n=8) groups were used for comparison. Following fluid resuscitation, the whole shed blood was reinfused for 30 min, and the rats were observed with continuous hemodynamic monitoring for 120 min. CD4 + CD25 + Foxp3 + Treg proportions, Th1/Th2 and Tc1/Tc2 profiles in spleen were analyzed by three-color flow cytometry., Results: The proportion of CD4 + CD25 + Foxp3 + Tregs and ratios of Th1/Th2 and Tc1/Tc2 did not differ among control, sham, and HTS groups, but were significantly lower in NS and HES groups (both P<0.05 vs. sham); NS and HES levels were similar. The level of Tc1 was significantly increased in HTS (P<0.05 vs. sham), and levels of Tc2 were increased in NS, HES, and HTS groups compared to sham (all P<0.05), but did not differ from each other., Conclusions: HTS resuscitation has a greater impact on immune system recovery than NS or HES by preserving the proportion of Tregs and maintaining the balance between Th1/Th2 and Tc1/Tc2 cells in the spleen. Thus, HTS resuscitation provides potential immunomodulatory activity in the early stage after hemorrhagic shock.

Background: Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A 4 (LXA 4 ) is an anti-inflammatory, pro-resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML-111. We hypothesized that post-ischemic, intravenous treatment with BML-111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML-111 on the post-stroke molecular and cellular profile., Methods: A total of 133 male Sprague-Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML-111 administration was started at the time of reperfusion. Two methods of week-long BML-111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 μg μl -1  hr -1 ), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML-111 and characterized an optimal dose and a dosing schedule for the administration of BML-111., Results: One week of BML-111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post-ischemic treatment with BML-111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro-inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti-inflammatory M2 microglia/macrophage cell populations in the post-ischemic brain., Conclusion: These data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long-term protection.

Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery ( day 10 ). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at day 10 During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bε but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser 555 -phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2α and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis., (Copyright © 2017 the American Physiological Society.)

Unaccustomed exercise consisting of eccentric (i.e., lengthening) muscle contractions often results in muscle damage characterized by ultrastructural alterations in muscle tissue, clinical signs, and symptoms (e.g., reduced muscle strength and range of motion, increased muscle soreness and swelling, efflux of myocellular proteins). The time course of recovery following exercise-induced muscle damage depends on the extent of initial muscle damage, which in turn is influenced by the intensity and duration of exercise, joint angle/muscle length, and muscle groups used during exercise. The effects of these factors on muscle strength, soreness, and swelling are well characterized. By contrast, much less is known about how they affect intramuscular inflammation and molecular aspects of muscle adaptation/remodeling. Although inflammation has historically been viewed as detrimental for recovery from exercise, it is now generally accepted that inflammatory responses, if tightly regulated, are integral to muscle repair and regeneration. Animal studies have revealed that various cell types, including neutrophils, macrophages, mast cells, eosinophils, CD8 and T-regulatory lymphocytes, fibro-adipogenic progenitors, and pericytes help to facilitate muscle tissue regeneration. However, more research is required to determine whether these cells respond to exercise-induced muscle damage. A large body of research has investigated the efficacy of physicotherapeutic, pharmacological, and nutritional interventions for reducing the signs and symptoms of exercise-induced muscle damage, with mixed results. More research is needed to examine if/how these treatments influence inflammation and muscle remodeling during recovery from exercise., (Copyright © 2017 the American Physiological Society.)

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1-associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART., Competing Interests: The authors have declared that no conflict of interest exists.

Mushroom nutriceutical components have lately attracted interest for developing immunonutritional support. However, there is relatively little information pertaining to the use of mushroom preparations for modulating the metabolic and immunological disorders associated to malnutrition. This study was aimed to evaluate the effects of oral administration of an aqueous extract (CW-P) from Pleurotus ostreatus on the recovery of biochemical and immunological functions of malnourished mice. 8-week old female BALB/c mice were starved for 3days and then refed with commercial diet supplemented with or without CW-P (100mg/kg) for 8days. Regardless of the diet used during refeeding, animal body weights and serum protein concentrations did not differ between groups. Oral treatment with CW-P normalized haemoglobin levels, liver arginase and gut mucosal weight. CW-P increased total liver proteins and also DNA and protein contents in gut mucosa. Pleurotus extract provided benefits in terms of macrophages activation as well as in haemopoiesis, as judged by the recovery of bone marrow cells and leukocyte counts. Moreover, CW-P stimulated humoral immunity (T-dependent and T non-dependent antibodies responses) compared to non-supplemented mice. CW-P extract from the oyster mushroom can be used to develop specific food or nutritional supplement formulations with potential clinical applications in the immunotherapy., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Our first ever Open Highlights explores recent Open Access research into the complex relationship between host and pathogen during the course of an infection, and the factors that determine its eventual outcome.

High-mobility group box 1 (HMGB1), a ligand of receptor for advanced glycation endproducts (RAGE), functions as a proinflammatory factor. It is mainly involved in inflammatory activation and contributes to the initiation and progression of stroke. By using a model of transient middle cerebral artery occlusion (MCAo) in type 2 diabetic rats, we investigated the changes of pro-inflammation mediators, blood-brain barrier (BBB) leakage and functional outcome after stroke. Type 2 diabetic rats did not show an increased lesion volume, but exhibited significantly increased expression of HMGB1 and RAGE, BBB leakage, as well as decreased functional outcome after stroke compared with control rats. Injection of bone marrow stromal cells (BMSCs) into type 2 diabetic rats significantly reduced the expression of HMGB1 and RAGE, attenuated BBB leakage, and improved functional outcome after stroke. BMSCs-treated type 2 diabetic rats inhibited inflammation and improved functional outcome after stroke. Furthermore, in vitro data support the hypothesis that BMSCs-induced reduction of HMGB1 and RAGE in T2DM-MCAo rats contributed to attenuated inflammatory response in the ischemic brain, which may lead to the beneficial effects of BMSCs treatment. Further investigation of BMSCs treatment in type 2 diabetic stroke is warranted., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

NK cell cytotoxicity against residual leukemic cells is crucial for immune system reconstitution after hematopoietic stem cell transplantation (HSCT). Since immune recovery after transplant still remains a major concern, we studied the counterbalance of NK cell receptors after HSCT and its importance in NK cell functional recovery. We investigated NK cell reconstitution in 27 acute leukemia patients at different time points following HLA-matched allogeneic HSCT compared to those of donors. NK cells were evaluated for their cytotoxicity in a standard (51)Cr-release assay against target cells and also analyzed for their receptors expression using flow cytometry. Early after transplant, we found higher percentage of CD56(bright) NK cells, increased levels of NKG2A and NCRs as well as decreased levels of KIRs expression on NK cells associated with an impaired cytotoxicity of these cells. All the abnormalities were normalized by one year after HSCT when CD56(bright) NK cells gradually differentiated into CD56(dim) subset. Collectively, we confirmed a gradual increase of CD56(dim) NK cells expressing NCRs with the significant decrease in NKG2A expression on NK cells. This finding was also associated with the recovery of NK cell cytotoxicity that suggests an important role for the kinetics of NK cell receptors during cell maturation in HSCT outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Basophils are the smallest population of granulocytes found in the circulation. They have crucial and nonredundant roles in allergic disorders, in protection from parasite infections, in autoimmunity, and in the regulation of type 2 immunity. They share phenotypic and functional properties with mast cells, which exert substantial protective effects after traumatic brain injury and spinal cord injury, although they are considered one of the most proinflammatory cell types in the body. In contrast, the in vivo functions of basophils in central nervous system trauma are still obscure and not well studied. In this study, we show that by comparing spinal cord injury in wild type vs. basophil-deficient Mcpt8Cre transgenic mice, the locomotor recovery is not affected in mice depleted in basophils. In addition, no substantial differences were observed in the lesion size and in the astrocytic and macrophage/microglia reaction between both mouse strains. Hence, despite the multiple properties shared with mast cells, these data show, for the first time, to our knowledge, that basophils are dispensable for the functional recovery process after hemisection injury to the spinal cord in mice., (© Society for Leukocyte Biology.)

Background: X-linked hyper-IgM syndrome (X-HIGM) due to mutations in the gene encoding CD40 ligand results in failure of Ig class switching and an increased propensity for recurrent sinopulmonary and other infections, and thus decreased life expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is curative, but long-term follow-up data are limited., Procedures: We conducted a retrospective analysis of seven patients who have undergone allogeneic HSCT for HIGM syndrome at Duke University Medical Center., Results: Median age at transplant was 5.2 years (range 0.7-19.3). None of the patients had active hepatic or pulmonary disease immediately prior to transplant, but all had a history of serious infections. Five patients received myeloablative conditioning, and two patients received reduced intensity conditioning. Graft sources included bone marrow, peripheral blood, and unrelated umbilical cord blood. Post-transplantation complications included veno-occlusive disease, hemorrhagic cystitis, adenoviremia, and cryptosporidium recurrence in one patient each. Two patients developed acute GVHD grades II-IV that resolved promptly with treatment and none developed extensive chronic GVHD. All patients are intravenous IgG-independent and 6/7 have normal antibody titers. Immunoglobulin (Ig) A levels normalized in all but one patient and T and B cell numbers and function are otherwise normal in all. All patients are alive at a median follow-up of 9.7 (range 9.7-16.1) years post-transplantation with predominantly donor chimerism and no recurrent infections., Conclusions: Allogeneic HSCT results in excellent survival and sustained immune reconstitution in patients with CD40 ligand deficiency using both myeloablative and reduced intensity conditioning approaches and various graft sources, including bone marrow, peripheral blood, and umbilical cord blood., (© 2015 Wiley Periodicals, Inc.)

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.