Involvement of Peripheral Monocytes with IL-1β in the Pathogenesis of West Syndrome

Neuroinflammation has been implicated in the pathogenesis of West syndrome (WS). Inflammatory cytokines, including interleukin-1β(IL-1β), have been reported to be associated with epilepsy. However, the assessment of cytokine changes in humans is not always simple or deterministic. This study aimed to elucidate the immunological mechanism of WS. We examined the intracellular cytokine profiles of peripheral blood cells collected from 13 patients with WS, using flow cytometry, and measured their serum cytokine levels. These were compared with those of 10 age-matched controls. We found that the WS group had significantly higher percentages of inter IL-1β, interleukin-1 receptor antagonist (IL-1RA)-positive monocytes, and interferon gamma (IFN-γ) in their CD8+ T cells than the control group. Interestingly, the group with sequelae revealed significantly lower levels of intracellular IFN-γ and IL-6 in their CD8+ T and CD4+ T cells, respectively, than the group without sequelae. There was no correlation between the ratios of positive cells and the serum levels of a particular cytokine in the WS patients. These cytokines in the peripheral immune cells might be involved in the neuroinflammation of WS, even in the absence of infectious or immune disease. Overall, an immunological approach using flow cytometry analysis might be useful for immunological studies of epilepsy.

Immune Checkpoint Inhibitor Therapy for Bone Metastases: Specific Microenvironment and Current Situation

The treatment of bone metastases is a thorny issue. Immunotherapy may be one of the few hopes for patients with unresectable bone metastases. Immune checkpoint inhibitors are the most commonly used immunotherapy drugs currently. In this review, the characteristics and interaction of bone metastases and their immune microenvironment were systematically discussed, and the relevant research progress of the immunological mechanism of tumor bone metastasis was reviewed. On this basis, we expounded the clinical application of immune checkpoint inhibitors for bone metastasis of common tumors, including non-small-cell lung cancer, renal cell carcinoma, prostate cancer, melanoma, and breast cancer. Then, the deficiencies and limitations in current researches were summarized. In-depth basic research on bone metastases and optimization of clinical treatment is needed.

Therapeutic Effect of Schistosoma japonicum Cystatin on Atherosclerotic Renal Damage

Atherosclerosis is a chronic inflammation of the arterial vessel wall driven by lipid metabolism disorders. Although helminthic infection and their derivatives have been identified to attenuate the chronic inflammatory diseases, the immunomodulatory effect of recombinant Schistosoma japonicum cystatin (rSj-Cys) on metabolic diseases and atherosclerosis has not been reported. In this study, we investigated the therapeutic efficacy of rSj-Cys on atherosclerotic renal damage and explored the related immunological mechanism. The results demonstrated that treatment with rSj-Cys significantly reduced body weight gain, hyperlipidemia, and atherosclerosis induced by the high-fat diet in apoE–/– mice. The treatment of rSj-Cys also significantly improved kidney functions through promoting macrophage polarization from M1 to M2, therefore inhibiting M1 macrophage–induced inflammation. The possible mechanism underlying the regulatory effect of rSj-Cys on reducing atherosclerosis and atherosclerotic renal damage is that rSj-Cys stimulates regulatory T cell and M2 macrophage polarization that produce regulatory cytokines, such as interleukin 10 and transforming growth factor β. The therapeutic effect of rSj-Cys on atherosclerotic renal damage is possibly through inhibiting the activation of TLR2/Myd88 signaling pathway. The results in this study provide evidence for the first time that Schistosoma-derived cystatin could be developed as a therapeutic agent to treat lipid metabolism disorder and atherosclerosis that threats million lives around the world.

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

ARCADIA study protocol: a phase II, randomised, double-blind, placebo-controlled clinical trial to assess the safety and efficacy of AZD1656 in patients with diabetes hospitalised with suspected or confirmed COVID-19

IntroductionCOVID-19, caused by SARS-CoV-2, remains a global pandemic that has affected more than 100 million people worldwide with over 4.8 million deaths as of October 2021. Patients with diabetes have both an increased susceptibility to SARS-CoV-2 infection, enhanced disease severity and increased risk of mortality. The challenge presented in these patients is both to improve glycaemic control—which itself may confer a survival advantage—and to help maintain or restore immunological homeostasis. The specific glucokinase activator AZD1656 may address both of these challenges via its glucose-lowering effect and its immunological mechanism of action. The aim of the Alleviation of cardioRespiratory complications in patients with COVID-19 And DIAbetes (ARCADIA) trial is to investigate this hypothesis and determine whether AZD1656 can improve clinical outcomes for these patients.Methods and analysisARCADIA is a double-blind, placebo-controlled, interventional study of AZD1656 in 150 patients with either type 1 or type 2 diabetes who have been admitted to hospital with COVID-19. Eligible, consented patients will be randomised in a 1:1 manner to receive either active drug or matched placebo tablets while they are in hospital. All patients will receive the usual and current standard of care for patients with COVID-19 in that hospital. Clinical and laboratory data will be collected and assessed at baseline and throughout their participation in the study. Data will be captured in the case report form, which will be electronically archived at the end of the trial in the trial master file. The WHO 8-point Ordinal Scale for Clinical Improvement will be used to measure clinical outcome for the primary endpoint of the trial.Ethics and disseminationEthical approval has been obtained from the East Midlands-Leicester South Ethics Committee (REC 20/EM/0198) in the UK, from the National Bioethics Committee of Medicines and Medical Devices in Bucharest, Romania, and from the Ethics Committee IKEM a TN in Prague, Czech Republic. All study-related data will be used by the sponsor in accordance with local data protection law. In the UK, all patient identifiable data will be stored on a password-protected National Health Service N3 network with full audit trail. Anonymised data will be stored in an ISO27001 certificated data warehouse.Trial registration numberEudraCT 2020-002211-21, NCT04516759.

Differential Diagnosis of Latent Tuberculosis Infection and Active Tuberculosis: A Key to a Successful Tuberculosis Control Strategy

As an ancient infectious disease, tuberculosis (TB) is still the leading cause of death from a single infectious agent worldwide. Latent TB infection (LTBI) has been recognized as the largest source of new TB cases and is one of the biggest obstacles to achieving the aim of the End TB Strategy. The latest data indicate that a considerable percentage of the population with LTBI and the lack of differential diagnosis between LTBI and active TB (aTB) may be potential reasons for the high TB morbidity and mortality in countries with high TB burdens. The tuberculin skin test (TST) has been used to diagnose TB for &gt; 100 years, but it fails to distinguish patients with LTBI from those with aTB and people who have received Bacillus Calmette–Guérin vaccination. To overcome the limitations of TST, several new skin tests and interferon-gamma release assays have been developed, such as the Diaskintest, C-Tb skin test, EC-Test, and T-cell spot of the TB assay, QuantiFERON-TB Gold In-Tube, QuantiFERON-TB Gold-Plus, LIAISON QuantiFERON-TB Gold Plus test, and LIOFeron TB/LTBI. However, these methods cannot distinguish LTBI from aTB. To investigate the reasons why all these methods cannot distinguish LTBI from aTB, we have explained the concept and definition of LTBI and expounded on the immunological mechanism of LTBI in this review. In addition, we have outlined the research status, future directions, and challenges of LTBI differential diagnosis, including novel biomarkers derived from Mycobacterium tuberculosis and hosts, new models and algorithms, omics technologies, and microbiota.

Immunological Manifestations of Hepatitis E-Associated Acute and Chronic Liver Failure and Its Regulatory Mechanisms

Hepatitis E virus (HEV) is a common cause of viral hepatitis in developing countries, most commonly transmitted through the fecal-oral route. The virus is mainly of genotypes (GT) 1 and GT2 genotypes, and patients usually show symptoms of acute hepatitis. Due to the rising trend of HEV serological prevalence in global population, HEV has become an important public health problem in developed countries. Severe hepatitis caused by HEV includes acute and chronic liver failure (ACLF). ACLF frequently occurs in developed countries and is caused by overlapping chronic liver diseases of HEV with genotypes GT3 and GT4. Because the onset of hepatitis E is closely associated with immunity, it is critical to understand the immunological mechanism of hepatitis E associated with acute and chronic liver failure (HEV-ACLF). This review discusses the immunological manifestations and mechanisms of HEV-ACLF, intrahepatic immune microenvironment and treatment, and raises outstanding questions about the immunological mechanism and treatment of the disease.

Acquired Idiopathic Generalized Anhidrosis (AIGA) and Its Complications: Implications for AIGA as an Autoimmune Disease

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.