Immunological predictors for the outcome in patients with antibody-mediated autoimmune encephalitis.

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.

Coming to the Rescue: Regulatory T Cells for Promoting Recovery After Ischemic Stroke.

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.

Innate Lymphoid Cells Promote Recovery of Ventricular Function After Myocardial Infarction.

BACKGROUND: Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development. OBJECTIVES: ILC2s also reside in the pericardium but their role in postischemic injury is unknown. METHODS: We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS). RESULTS: We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine. CONCLUSIONS: ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.

Muscle Tissue Damage and Recovery After EV71 Infection Correspond to Dynamic Macrophage Phenotypes.

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+Ly6Chi) appearing in the early stage of infection and anti-inflammatory/restorative macrophages (CD45+CD11b+Ly6Clow/-) 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.

Neutrophil-specific deletion of Syk results in recruitment-independent stabilization of the barrier and a long-term improvement in cognitive function after traumatic injury to the developing brain.

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 (sykf/fMRP8-cre+) to congenic littermates (sykf/f). Based upon flow cytometry, there was an extended recruitment of distinct leukocyte subsets, including Ly6G+/Ly6C- and Ly6G+/Ly6Cint, 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 sykf/fMRP8-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 sykf/fMRP8-cre+ mice as compared to sykf/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 sykf/fMRP8-cre+ mice. Subsequent analyses of swim path lengths during hidden platform training and probe trials showed greater thigmotaxis in brain-injured sykf/f mice than sham sykf/f mice and injured sykf/fMRP8-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.

Immunofibrotic drivers of impaired lung function in postacute sequelae of SARS-CoV-2 infection.

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.

Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke.

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.

Restoration of NK Cell Cytotoxic Function With Elotuzumab and Daratumumab Promotes Elimination of Circulating Plasma Cells in Patients With SLE.

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.

The prognostic role of IL-10 in non-severe COVID-19 with chemosensory dysfunction.

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.

Persistent inflammation worsens short-term outcomes in massive stroke patients.

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.

Switched and unswitched memory B cells detected during SARS-CoV-2 convalescence correlate with limited symptom duration.

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.

Prognostic value of early leukocyte fluctuations for recovery from traumatic spinal cord injury.

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.

The Role of Immune Cells in Post-Stroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown.

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.

Microenvironment-responsive immunoregulatory electrospun fibers for promoting nerve function recovery.

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.

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration.

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-NH2 (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.

T Lymphocytes in Acute Kidney Injury and Repair.

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.

IL-13 Ameliorates Neuroinflammation and Promotes Functional Recovery after Traumatic Brain Injury.

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.

T helper cell-related changes in peripheral blood induced by progressive effort among soccer players.

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.

Elevated inflammation and decreased platelet activity is associated with poor outcomes after traumatic brain injury.

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.

T cell functionality in HIV-1, HIV-2 and dually infected individuals: correlates of disease progression and immune restoration.

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 (Treg ), 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)/Treg 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 Treg 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.