Identification of Fatigue and Sleepiness in Immune and Neurodegenerative Disorders from Measures of Real-World Gait Variability.

Current assessments of fatigue and sleepiness rely on patient reported outcomes (PROs), which are subjective and prone to recall bias. The current study investigated the use of gait variability in the "real world" to identify patient fatigue and daytime sleepiness. Inertial measurement units were worn on the lower backs of 159 participants (117 with six different immune and neurodegenerative disorders and 42 healthy controls) for up to 20 days, whom completed regular PROs. To address walking bouts that were short and sparse, four feature groups were considered: sequence-independent variability (SIV), sequence-dependant variability (SDV), padded SDV (PSDV), and typical gait variability (TGV) measures. These gait variability measures were extracted from step, stride, stance, and swing time, step length, and step velocity. These different approaches were compared using correlations and four machine learning classifiers to separate low/high fatigue and sleepiness.Most balanced accuracies were above 50%, the highest was 57.04% from TGV measures. The strongest correlation was 0.262 from an SDV feature against sleepiness. Overall, TGV measures had lower correlations and classification accuracies.Identifying fatigue or sleepiness from gait variability is extremely complex and requires more investigation with a larger data set, but these measures have shown performances that could contribute to a larger feature set.Clinical relevance- Gait variability has been repeatedly used to assess fatigue in the lab. The current study, however, explores gait variability for fatigue and daytime sleepiness in real-world scenarios with multiple gait-impacted disorders.

Immune System Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Immune system dysfunction is poorly represented in pediatric organ dysfunction definitions. OBJECTIVE: To evaluate evidence for criteria that define immune system dysfunction in critically ill children and associations with adverse outcomes and develop consensus criteria for the diagnosis of immune system dysfunction in critically ill children. DATA SOURCES: We conducted electronic searches of PubMed and Embase from January 1992 to January 2020, using medical subject heading terms and text words to define immune system dysfunction and outcomes of interest. STUDY SELECTION: Studies of critically ill children with an abnormality in leukocyte numbers or function that is currently measurable in the clinical laboratory in which researchers assessed patient-centered outcomes were included. Studies of adults or premature infants, animal studies, reviews and commentaries, case series (≤10 subjects), and studies not published in English with inability to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted from eligible studies into a standard data extraction form along with risk of bias assessment by a task force member. RESULTS: We identified the following criteria for immune system dysfunction: (1) peripheral absolute neutrophil count <500 cells/µL, (2) peripheral absolute lymphocyte count <1000 cells/µL, (3) reduction in CD4+ lymphocyte count or percentage of total lymphocytes below age-specific thresholds, (4) monocyte HLA-DR expression <30%, or (5) reduction in ex vivo whole blood lipopolysaccharide-induced TNFα production capacity below manufacturer-provided thresholds. LIMITATIONS: Many measures of immune system function are currently limited to the research environment. CONCLUSIONS: We present consensus criteria for the diagnosis of immune system dysfunction in critically ill children.

Mouse Model of Critical Persistent Inflammation, Immunosuppression, and Catabolism Syndrome.

ABSTRACT: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a growing challenge in intensive care units (ICUs). PIICS causes a severe illness with high mortality. Currently, treatment is expensive, and the outcomes are dismal. Herein, we established a PIICS model to study the disease pathophysiology and its potential treatment. Using a modified sublethal cecal ligation and puncture (CLP) to induce sepsis (day 1) and the injection of lipopolysaccharide (LPS) to induce an aggravated inflammation response (day 11), CLP + LPS mice recapitulating PIICS features were successfully generated (day 14). Adult male mice were divided into CLP + LPS, CLP + daily chronic stress (DCS), CLP, DCS, LPS, and sham control groups. A survival curve was generated, and phenotypes were analyzed using markers for catabolism, inflammation, and immunosuppression. The CLP + LPS model showed two mortality peaks (after CLP and after LPS), whereas the CLP + DCS and CLP groups showed one peak. Surviving CLP + LPS mice exhibited significantly increased catabolism and inflammatory cytokine levels and aggravated inflammation, including organ inflammation. CLP + LPS mice exhibited strong immune suppression as evidenced by decreased splenic cluster of differentiation (CD)8+ and interferon-γ+CD8+ T cell counts and a concomitant and significant increase in the myeloid-derived suppressor cell population. This CLP+LPS-induced PIICS model differs from acute sepsis models, showing two mortality peaks and a protracted course of 14 days. Compared to previous PIICS models, ours shows a re-aggravated status and higher catabolism, inflammation, and immunosuppression levels. Our aim was to use the PIICS model to simulate PIICS pathophysiology and course in the ICU, enabling investigation of its mechanism and treatment.

Immunology 101: fundamental immunology for the practicing hematologist.

From an evolutionary perspective, the immune system developed primarily to protect the host from pathogens. In the continuous balance between killing pathogens and protecting host tissues, selective pressures have shaped the discriminatory functions of the immune system. In addition to protection against microbial pathogens, the immune system also plays a critical role in antitumor immunity. Immune dysfunction, either under- or overactivity, is found in a wide range of hematologic disorders. Here we review the fundamental features of the immune system and the key concepts critical to understanding the impact of immune dysfunction on hematologic disorders.

The impact of non-coding RNAs on macrophage polarization.

Macrophage polarization is a process through which macrophages attain unique functional features as a response to certain stimuli from their niche. Lipopolysaccharide and Th1 cytokines induce generation of M1 macrophages. On the other hand, IL-4, IL-13, IL-10, IL-33, and TGF-ß induce polarization of macrophages towards M2 phenotype. This process is also modulated by a number of miRNAs and lncRNAs. miR-375, miR-let7, miR-34a, miR-155, miR-124, miR-34a, miR-511-3p, miR-99a, miR-132 and miR-145-3p are among miRNAs that regulate macrophage polarization. Meanwhile, macrophage polarization is influenced by some lncRNAs such as H19, NRON, MEG3, GAS5, RN7SK, and AK085865. Macrophage polarization has functional significance in a wide range of human disorders particularly immune disorders and cancer. In addition, the effect of certain drugs in modulation of macrophage polarization is exerted through modulation of expression of non-coding RNAs. In the current manuscript, we provide a summary of studies aimed to identification of this aspect of non-coding RNAs.

Multi-Omics Approaches in Immunological Research.

The immune system plays a vital role in health and disease, and is regulated through a complex interactive network of many different immune cells and mediators. To understand the complexity of the immune system, we propose to apply a multi-omics approach in immunological research. This review provides a complete overview of available methodological approaches for the different omics data layers relevant for immunological research, including genetics, epigenetics, transcriptomics, proteomics, metabolomics, and cellomics. Thereafter, we describe the various methods for data analysis as well as how to integrate different layers of omics data. Finally, we discuss the possible applications of multi-omics studies and opportunities they provide for understanding the complex regulatory networks as well as immune variation in various immune-related diseases.

Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases.

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

Atypical late-onset severe gastritis in immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome: 2 case reports.

RATIONALE: The immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is a rare disorder that most often manifests in the early stages of life. IPEX syndrome with a late onset, presenting with severe gastritis has rarely been reported. PATIENT CONCERNS: Two male adolescents presented with recurrent vomiting, severe malnutrition, and growth retardation due to severe gastritis. DIAGNOSES: Esophagogastroduodenoscopy of the 2 patients revealed rare presentations of severe gastritis with multiple ulcers and stenosis of the pylorus. Next-generation sequencing revealed 2 novel variants in gene FOXP3 in the patients who were diagnosed with the IPEX syndrome. INTERVENTIONS: Both patients were treated with a high calorie formular enteral nutritional therapy. In addition, the pylorus of patient 1 was enlarged by balloon dilation, while patient 2 was treated with mercaptopurine and low dose prednisone. OUTCOMES: Symptoms and nutritional status of the patients improved after treatment. LESSONS: Chronic severe gastritis with stenosis of the pylorus could be an atypical manifestation of the IPEX syndrome. The use of next-generation sequencing is highly suitable for the diagnosis of atypical IPEX syndromes.

Immunopathogenesis of the feline atopic syndrome.

BACKGROUND: Feline diseases of possible allergic origin with similar clinical phenotypes can have a varied underlying pathogenesis. Clinical phenotype, precise aetiology and underlying immunopathogenesis all need to be considered if advances in this neglected area of dermatology are to be made. OBJECTIVES: To document the status of research into the immunopathogenesis of the diseases that fall within the spectrum of the feline atopic syndrome (FAS ), to summarize the conclusions, identify the limitations and recommend future research directions. METHODS AND MATERIALS: A search of the literature was undertaken. The strengths and validity of the data and the contributions to our current understanding of the immunopathogenesis were analysed. Skin diseases of presumed allergic aetiology and asthma were assessed separately, as was the role of antibodies, cells and cytokines in each. RESULTS: The research varied in its quality and its impact often was limited by a failure to employ strict criteria in case selection. This reflected the difficulties of skin reaction patterns associated with a number of inciting causes. Research into feline asthma was handicapped by the difficulties of investigating clinical material, and much of the useful information was derived from experimental models. CONCLUSIONS AND CLINICAL IMPORTANCE: The evidence reviewed was supportive of a role for immunoglobulin (Ig)E in the pathogenesis of both feline atopic skin syndrome (FASS) and asthma, albeit not strongly so. The inflammation noted in both FASS and asthma is accompanied by eosinophils and lymphocytes, and these findings, together with the cytokine expression, are suggestive in some (not all) cats of T-helper type 2 immune dysregulation.

Venoarterial extracorporeal membrane oxygenation induces early immune alterations.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections remain extremely frequent and increase mortality rate. Since immune dysfunctions have been described in both critically ill patients and after surgery with cardiopulmonary bypass, VA-ECMO initiation may be responsible for immune alterations that may expose patients to nosocomial infections (NI). Therefore, in this prospective study, we aimed to study immune alterations induced within the first days by VA-ECMO initiation. METHODS: We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients). RESULTS: Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine. CONCLUSION: VA-ECMO is associated with early immune changes that may be responsible for innate and adaptive immune alterations that could confer an increased risk of infection.

SNAREs and developmental disorders.

Members of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family mediate membrane fusion processes associated with vesicular trafficking and autophagy. SNAREs mediate core membrane fusion processes essential for all cells, but some SNAREs serve cell/tissue type-specific exocytic/endocytic functions, and are therefore critical for various aspects of embryonic development. Mutations or variants of their encoding genes could give rise to developmental disorders, such as those affecting the nervous system and immune system in humans. Mutations to components in the canonical synaptic vesicle fusion SNARE complex (VAMP2, STX1A/B, and SNAP25) and a key regulator of SNARE complex formation MUNC18-1, produce variant phenotypes of autism, intellectual disability, movement disorders, and epilepsy. STX11 and MUNC18-2 mutations underlie 2 subtypes of familial hemophagocytic lymphohistiocytosis. STX3 mutations contribute to variant microvillus inclusion disease. Chromosomal microdeletions involving STX16 play a role in pseudohypoparathyroidism type IB associated with abnormal imprinting of the GNAS complex locus. In this short review, I discuss these and other SNARE gene mutations and variants that are known to be associated with a variety developmental disorders, with a focus on their underlying cellular and molecular pathological basis deciphered through disease modeling. Possible pathogenic potentials of other SNAREs whose variants could be disease predisposing are also speculated upon.

Pretreatment with 6-Gingerol Ameliorates Sepsis-Induced Immune Dysfunction by Regulating the Cytokine Balance and Reducing Lymphocyte Apoptosis.

Sepsis is characterized by an initial net hyperinflammatory response, followed by a period of immunosuppression, termed immunoparalysis. During this immunosuppressive phase, patients may have difficulty eradicating invading pathogens and are susceptible to life-threatening secondary hospital-acquired infections. Due to progress in antimicrobial treatment and supportive care, most patients survive early sepsis. Mortality is more frequently attributed to subsequent secondary nosocomial infections and multiorgan system failure. 6-Gingerol is the major pharmacologically active component of ginger. Although it is known to exhibit a variety of biological activities, including anti-inflammation and antioxidation, the role of 6-gingerol in sepsis-induced immune dysfunction remains elusive. Thus, we investigated whether 6-gingerol improves septic host response to infections during sepsis. 6-Gingerol-treated mice showed significantly lower mortality in polymicrobial sepsis induced by cecal ligation and puncture LPS via enhanced bacterial clearance in the peritoneum, blood, and organs (liver, spleen, and kidney) and inhibited the production of TNF-α and IL-6 in TLR2 and/or TLR4-stimulated macrophages. In addition, we demonstrated that survival improvement of secondary infection following septic insult was associated with an initial response of enhanced neutrophil numbers and function at the infection site, reduced apoptosis of immune cells, and a shift from a T helper cell type 2 (Th2) to a T helper cell type 1 (Th1) cytokine balance in the hypoinflammation phase. Our overall findings suggest that 6-gingerol potentially restores sepsis-induced immune dysfunction by shifting the balance of Th1/Th2 and by regulating apoptosis of immune cells.

Approaching Shared Pathophysiology in Immune-Mediated Diseases through Functional Genomics.

Immune-mediated diseases (IMDs) are complex pathologies that are strongly influenced by environmental and genetic factors. Associations between genetic loci and susceptibility to these diseases have been widely studied, and hundreds of risk variants have emerged during the last two decades, with researchers observing a shared genetic pattern among them. Nevertheless, the pathological mechanism behind these associations remains a challenge that has just started to be understood thanks to functional genomic approaches. Transcriptomics, regulatory elements, chromatin interactome, as well as the experimental characterization of genomic findings, constitute key elements in the emerging understandings of how genetics affects the etiopathogenesis of IMDs. In this review, we will focus on the latest advances in the field of functional genomics, centering our attention on systemic rheumatic IMDs.

Single-cell analyses identify dysfunctional CD16+ CD8 T cells in smokers.

Tobacco smoke exposure contributes to the global burden of communicable and chronic diseases. To identify immune cells affected by smoking, we use single-cell RNA sequencing on peripheral blood from smokers and nonsmokers. Transcriptomes reveal a subpopulation of FCGR3A (CD16)-expressing Natural Killer (NK)-like CD8 T lymphocytes that increase in smokers. Mass cytometry confirms elevated CD16+ CD8 T cells in smokers. Inferred as highly differentiated by pseudotime analysis, NK-like CD8 T cells express markers characteristic of effector memory re-expressing CD45RA T (TEMRA) cells. Indicative of immune aging, smokers' CD8 T cells are biased toward differentiated cells and smokers have fewer naïve cells than nonsmokers. DNA methylation-based models show that smoking dose is associated with accelerated aging and decreased telomere length, a biomarker of T cell senescence. Immune aging accompanies T cell senescence, which can ultimately lead to impaired immune function. This suggests a role for smoking-induced, senescence-associated immune dysregulation in smoking-mediated pathologies.

Dysimmunity and inflammatory storm: Watch out for bone lesions in COVID-19 infection.

At the end of 2019, a new kind of pneumonia which was proven to be supported by novel coronaviruses named SARS-CoV-2 emerges and it seems to be more complicate in its clinical course and management. Related researches have demonstrated that SARS-CoV-2 serves roles in respiratory, intestinal and neuronal diseases. Given the growing cases of COVID-19, analyzing the relevance between COVID-19 and fragile patients who suffer from bone destruction is entirely indispensable. Accordingly, the recapitulatory commentary is necessary to advance our knowledge on COVID-19 and orthopedics. In this article, we particularly clarify the possible relationship between the newly COVID-19 infection and bone lesions from the standpoints of dysimmunity and inflammatory storm.

Role of miR-302/367 cluster in human physiology and pathophysiology.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate target mRNAs at the post-transcriptional level. Increasing evidence shows the involvement of miRNAs in diverse biological processes. miR-302/367 cluster is highly conserved among vertebrates and made up of five members, including miR-367, miR-302a, miR-302b, miR-302c and miR-302d. miR-302/367 cluster plays an important role in cell proliferation, differentiation and reprogramming, affecting the development of tumor, cardiovascular system, nervous system and immune system. In this review, we will summarize the role of miR-302/367 cluster in embryonic stem cells and induced pluripotent stem cells and try to point out its relationship with tumors, cardiovascular system, nervous system and immune system.

Immune memory limits human longevity: the role of memory СD4+ T cells in age-related immune abnormalities.

Introduction: With age, the proportion of memory T cells increases, while the proportion and number of naive T cell decreases. Memory T cells are more sensitive to antigenic stimulation and less dependent on co-stimulation signals, as compared to naïve T cells. Differentiation of naïve T cells into memory T cells is accompanied by an increase in T cell reactivity to self-peptide/MHC complexes, which allowed for positive selection of their naïve precursors in the thymus.Areas covered: We envisage that in geriatric age memory Th1-type autoreactivity leads to age-associated immune hyporeactivity, atherosclerosis, and degenerative neuropathology, such as Alzheimer's and Parkinson's diseases, whereas autoreactive memory Th2 cells could promote tumorigenesis.Expert option: Stimulation of adaptive immunoregulatory mechanisms by polyclonal T-cell vaccination could constrain the development of age-related T-cell autoreactivity surplus. Another approach to immune system 'rejuvenation' could involve adoptive cell transfer of naïve T cells with a view to restrain the expansion of pathological memory T cells and support immune responsiveness to novel antigenic challenges. The proposed concept conjectures the occurrence of a hard-wired immunological clock that could determine the duration of life, which theoretically could be subject to immune-based therapy.