Maladaptive Immune Responses Research Articles

Gut Microbiota Mediates Neuroinflammation in Alzheimer's Disease: Unraveling Key Factors and Mechanistic Insights.

The gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract, has emerged as a key player in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by progressive cognitive decline and neuronal loss, associated with the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation in the brain. Increasing evidence suggests that alterations in the composition and function of the gut microbiota, known as dysbiosis, may contribute to the development and progression of AD by modulating neuroinflammation, a chronic and maladaptive immune response in the central nervous system. This review aims to comprehensively analyze the current role of the gut microbiota in regulating neuroinflammation and glial cell function in AD. Its objective is to deepen our understanding of the pathogenesis of AD and to discuss the potential advantages and challenges of using gut microbiota modulation as a novel approach for the diagnosis, treatment, and prevention of AD.

Effect of physical activity in lymphocytes senescence burden in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is regarded as an accelerated-age disease in which chronic inflammation, maladaptive immune responses, and senescence cell burden coexist. Accordingly, cellular senescence has emerged as a potential mechanism involved in COPD pathophysiology. In this study, 25 stable patients with COPD underwent a daily physical activity promotion program for 6 mo. We reported that increase of physical activity was related to a reduction of the senescent cell burden in circulating lymphocytes of patients with COPD. Senescent T-lymphocyte population, characterized by absence of surface expression of CD28, was reduced after physical activity intervention, and the reduction was associated to the increase of physical activity level. In addition, the mRNA expression of cyclin-dependent kinase inhibitors, a hallmark of cell senescence, was reduced and, in accordance, the proliferative capacity of lymphocytes was improved postintervention. Moreover, we observed an increase in functionality in T cells from patients after intervention, including improved markers of activation, enhanced cytotoxicity, and altered cytokine secretions in response to viral challenge. Lastly, physical activity intervention reduced the potential of lymphocytes' secretome to induce senescence in human primary fibroblasts. In conclusion, our study provides, for the first time, evidence of the potential of physical activity intervention in patients with COPD to reduce the senescent burden in circulating immune cells.NEW & NOTEWORTHY For the first time, we identified in patients with COPD a relation between physical activity intervention with respiratory function improvement and cellular senescence burden in lymphocytes that improved the T cell functionality and proliferative capacity of patients. In addition, our experiments highlight the possible impact of T-cell senescence in other cell types which could be related to some of the clinical lung complications observed in COPD.

Integrated multi-omics analysis reveals molecular changes associated with chronic lipid accumulation following contusive spinal cord injury

Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet.In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion.We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m6A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI.By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage.

Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis.

Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens succeeding towards autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells. Using flow cytometry, high-throughput T cell receptor (TCR) sequencing and scRNA-seq of CD4+ Th cells isolated from the joints of European ARLA patients, we aimed at inferring antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs and connecting TCR specificity to transcriptional patterns. PD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCRβ motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in North American ARLA patients, were unexpectedly prevalent in our European cohort. The identified TCRβ motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-seq dataset, the TCRβ motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ. By inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of ARLA patients that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response. Supported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.

Abstract 1027: Mechanical Stress Is A Non-canonical Regulator Of Inflammatory Metabolism In Immune Cells Via Netrin-1

Atherosclerotic cardiovascular disease (CVD) is characterized by chronic inflammation of the artery wall triggered by lipoprotein deposition. Maladaptive immune responses, primarily mediated by macrophages (Mø), promote disease progression including extracellular matrix (ECM) remodeling. Emerging evidence suggests a relationship between cellular mechanics and metabolic programming, yet the role of ECM-induced mechanical stress on Mø immunometabolism remains unexplored. We hypothesized that mechanical stress induces cytoskeletal-mediated rewiring of cellular metabolism that fuels inflammation in plaque macrophages. To investigate the role of matrix-induced mechanical stress on Mø, we used an in vitro system that reproduces the elasticity parameters of the atherosclerotic plaque environment. Compared to stiff matrices, Mø cultured on soft matrices showed marked morphological changes, accompanied by increased inflammation and decreased mitochondrial function as assessed by RNA sequencing and flow cytometry analyses. Notably, cytoskeletal changes were associated with profound mitochondrial network reorganization and increased ROS generation. RNA-seq and ligand-receptor pairing analysis identified the neuroimmune guidance molecule netrin-1 ( Ntn1 ) and its receptor Unc5b as most upregulated in reponse to mechanical stress. Loss-of-function studies showed that netrin-1-deficiency protects from mechanical stress-induced metabolic changes observed in WT Mø, as measured by mitochondrial network remodelling and higher mitochondrial respiration. Importantly, incubation with recombinant netrin-1 reversed the effects of genetic loss of Ntn1 , but not Unc5b , suggesting receptor dependency. Mechanistically, we showed that netrin-1 controls cytoskeletal reorganization via the Rho-associated kinase (ROCK) pathway to alter mitochondrial function, and that ROCK inhibition recapitulated the effect of Ntn1 silencing on mitochondrial potential. Collectively, our data link Ntn1-Uncb mediated changes in cytoskeletal rearrangement to alterations in mitochondrial metabolism that dictate Mø inflammation, and implicate the ECM as a non-canonical regulator of immunometabolism that perpetuates inflammation in CVD.

Sepsis in surgical patients: Personalized medicine in the future treatment of sepsis

Sepsis results when a severe infection overwhelms the normal regulatory mechanisms of the immune system, resulting in a dysregulated host response characterized by new-onset organ failure. A wide range of infectious challenges can induce sepsis, resulting in an even wider range of maladaptive immune responses. This makes sepsis a syndromic diagnosis without a unifying, underlying molecular mechanism. The next step toward personalized medicine for sepsis is to resolve the heterogeneity across the universe of septic patients in order to establish pathobiologically homogenous sepsis “endotypes” that have uniformly defined changes in physiology and immunology. Defining the mechanisms of immune dysfunction within these endotypes will provide a roadmap for the application of immunomodulatory therapies for sepsis. This approach can drive in a paradigm shift in sepsis treatment, moving beyond supportive care and toward active efforts to restore normal immune function.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

Macrophages coordinate immune response to laser-induced injury via extracellular traps.

Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury. Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina. Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer. Our data offer novel insights into innate immunity's role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration.

Monocytic Phagocytes in the Immunopathogenesis of Cytokine Storm Syndromes.

Cytokine storm syndromes (CSSs) are caused by a dysregulated host immune response to an inciting systemic inflammatory trigger. This maladaptive and harmful immune response culminates in collateral damage to host tissues resulting in life-threatening multisystem organ failure. Knowledge of the various immune cells that contribute to CSS pathogenesis has improved dramatically in the past decade. Monocytes, dendritic cells, and macrophages, collective known as monocytic phagocytes, are well-positioned within the immune system hierarchy to make key contributions to the initiation, propagation, and amplification of the hyperinflammatory response in CSS. The plasticity of monocytic phagocytes also makes them prime candidates for mediating immunoregulatory and tissue-healing functions in patients who recover from cytokine storm-mediated immunopathology. Therefore, approaches to manipulate the myriad functions of monocytic phagocytes may improve the clinical outcome of CSS.

Abstract 18959: Glycosphingolipid-Mediated Cardiomyocyte and Immune Cell Dysfunction in Hypoplastic Left Heart Syndrome

Introduction: Hypoplastic Left Heart Syndrome (HLHS) is the leading indication for heart transplant and the most common cause of cardiovascular death in infants. However, the mechanisms associated with heart failure progression in HLHS are poorly understood. Glycosphingolipids (GSLs) have been implicated in a variety of biological and disease processes, however, the role of GSLs in the context of HLHS pathophysiology have not been explored. Here we test the hypothesis that aberrant GSLs drive maladaptive cardiac and immune cell responses and predispose HLHS patients to pathologic remodeling and eventual cardiac dysfunction. Methods: GSL content was measured by mass-spectrometry. To test the direct effect of the specific GSL species, lactosylceramide (LacCer), cardiac and peripheral immune cells (PBMCs) were treated with liposomes containing 3uM LacCer (C18:0 and C24:0). Mitochondrial respiration was assessed using the Seahorse Bioanalyzer (Agilent). Expression of metabolic proteins were assessed by western blot. Statistical analysis between 2 groups was performed using an unpaired T-test. Results: LacCer is significantly increased in heart tissue and in isolated PBMCs from patients with HLHS (A), and isolated mitochondria are highly enriched with LacCer. Moreover, exogenous LacCer is sufficient to impair cardiomyocyte mitochondrial fatty acid beta-oxidation (B), induce ROS generation, and decrease the expression of metabolic proteins Additionally, exogenous LacCer is sufficient to promote inflammation and decrease mitochondrial bioenergetics in PBMCs (C). Conclusions: These data highlight a novel role for LacCer in modulating cardiomyocyte and immune cell phenotypes and suggest aberrant GSLs contribute to the HLHS pathophysiology. Elucidation of the molecular mechanisms involved in impaired immune cell and cardiomyocyte responses in HLHS is crucial and these data suggest a unique avenue for therapeutic intervention in this population.

FRI131 Abrogation Of Transglutaminase 2 In Myeloid Cells Ameliorates Angiotensin II Induced Vascular Stiffness In Female Mice

Abstract Disclosure: H. Naz: None. A.R. Aroor: None. A.T. Whaley-Connell: None. J. Guanghong: None. J.L. Hulse: None. C.M. Manrique Acevedo: None. G. Lastra: None. Introduction: Chronic low-grade inflammation and vascular stiffening contribute to cardiovascular disease (CVD) in obese and insulin-resistant women. Under these conditions, inappropriate activation of the renin angiotensin aldosterone system (RAAS) stimulates Transglutaminase 2 (TG2), a ubiquitously expressed enzyme that promotes vascular stiffening and remodeling. Additionally, Th17 cells contribute to CVD development in the setting of RAAS activation. However, it is unclear how TG2 activation mediates maladaptive immune responses associated with vascular stiffening in women. In this study, we hypothesize that TG2 abrogation inhibits Ang II-induced vascular stiffness in females by modulating Th17 immunity. Methods: 12-week-old female mice lacking TG2 expression (MyTG2KO) in myeloid cells, and control littermates (LM) were infused with Ang-II (1.4 mg/kg/day) for 2 weeks (n=4-8 per group). Prior to sacrifice, systolic blood pressure (SBP) was measured by tail-cuff method. Aortic stiffness was assessed by atomic force microscopy of thoracic aorta explants, and TG2 activity was examined by Alexa FluorTM 488 cadaverine. Analysis of Th17 cells in blood, spleen and epididymal fat (epi-fat) was done by flow cytometry. Cytokine bead array was used to measure cytokine levels in serum, RT-PCR was used to analyze cytokines in aortic tissue and TG2 knockdown efficiency in myeloid cells. Immunohistochemistry was used to examine fibrosis in aorta. Results: SBP was decreased in MyTG2KO-Ang-II as compared to LM-Ang-II cohort (129.6±5.6 vs 152.5 ±2 mmHg; p=0.04). TG2 mRNA expression in macrophages was lower in MyTG2KO mice as compared to LM (p=0.002). TG2 activity in aortic tissue increased in LM-Ang-II as compared to LM-saline (p=0.004) but was significantly lower in MyTG2KO-Ang-II mice (p=0.02). Aortic stiffness was lower in MyTG2KO-Ang-II mice relative to LM-Ang-II (4.0±0.6 vs 10.3±2.4 kPa; p=0.02). Compared to LM-Ang-II, MyTG2KO-Ang-II mice also had decreased Th17 lymphocytes (CD4+IL-17A+) in blood (3.5±0.2 vs 5.8 ±0.4 %; p=<0.0001), spleen (4.7±0.4 vs 7.1 ±0.5 %; p=0.004) and epi-fat (4.7±0.6 vs 6.8 ±0.5 %; p=0.02). MyTG2KO-Ang II mice also had significant lower levels of proinflammatory cytokines (TNF-a, IL6, IL17A, INF-g) in serum and mRNA expression of proinflammatory cytokines compared to LM-Ang-II mice and decreased total macrophage infiltration (CD68+) in the aorta. Ang-II treated MyTG2KO mice group also exhibited reduced fibrosis in the aorta relative to LM-Ang-II (p=0.003). Conclusion: The results demonstrate that abrogating TG2 in myeloid cells in female mice substantially reduces blood pressure, proinflammatory cytokines, and Th17 immune responses induced by Ang-II. Our findings have potential clinical implications for the prevention and management of CVD in women. Presentation: Friday, June 16, 2023

The good or the bad: an overview ofautoantibodies in traumatic spinal cord injury.

Infections remain the most common cause of death after traumatic spinal cord injury, likely due to a developing immune deficiency syndrome. This, together with a somewhat contradictory development of autoimmunity in many patients, are two major components of the maladaptive systemic immune response. Although the local non-resolving inflammation in the lesioned spinal cord may lead to an antibody formation against autoantigens of the injured spinal cord tissue, there are also natural (pre-existing) autoantibodies independent of the injury. The way in which these autoantibodies with different origins affect the neuronal and functional outcome of spinal cord-injured patients is still controversial.

Airway Epithelial-Derived Immune Mediators in COVID-19.

The airway epithelium, which lines the conducting airways, is central to the defense of the lungs against inhaled particulate matter and pathogens such as SARS-CoV-2, the virus that causes COVID-19. Recognition of pathogens results in the activation of an innate and intermediate immune response which involves the release of cytokines and chemokines by the airway epithelium. This response can inhibit further viral invasion and influence adaptive immunity. However, severe COVID-19 is characterized by a hyper-inflammatory response which can give rise to clinical presentations including lung injury and lead to acute respiratory distress syndrome, viral pneumonia, coagulopathy, and multi-system organ failure. In response to SARS-CoV-2 infection, the airway epithelium can mount a maladaptive immune response which can delay viral clearance, perpetuate excessive inflammation, and contribute to the pathogenesis of severe COVID-19. In this article, we will review the barrier and immune functions of the airway epithelium, how SARS-CoV-2 can interact with the epithelium, and epithelial-derived cytokines and chemokines and their roles in COVID-19 and as biomarkers. Finally, we will discuss these immune mediators and their potential as therapeutic targets in COVID-19.

The Role of Renin-Angiotensin System in Diabetic Cardiomyopathy: A Narrative Review.

Diabetic cardiomyopathy refers to myocardial dysfunction in type 2 diabetes, but without the traditional cardiovascular risk factors or overt clinical atherosclerosis and valvular disease. The activation of the renin-angiotensin system (RAS), oxidative stress, lipotoxicity, maladaptive immune responses, imbalanced mitochondrial dynamics, impaired myocyte autophagy, increased myocyte apoptosis, and fibrosis contribute to diabetic cardiomyopathy. This review summarizes the studies that address the link between cardiomyopathy and the RAS in humans and presents proposed pathophysiological mechanisms underlying this association. The RAS plays an important role in the development and progression of diabetic cardiomyopathy. The over-activation of the classical RAS axis in diabetes leads to the increased production of angiotensin (Ang) II, angiotensin type 1 receptor activation, and aldosterone release, contributing to increased oxidative stress, fibrosis, and cardiac remodeling. In contrast, Ang-(1-7) suppresses oxidative stress, inhibits tissue fibrosis, and prevents extensive cardiac remodeling. Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers improve heart functioning and reduce the occurrence of diabetic cardiomyopathy. Experimental studies also show beneficial effects for Ang-(1-7) and angiotensin-converting enzyme 2 infusion in improving heart functioning and tissue injury. Further research is necessary to fully understand the pathophysiology of diabetic cardiomyopathy and to translate experimental findings into clinical practice.

Association of Persistent Symptoms after Lyme Neuroborreliosis and Increased Levels of Interferon-α in Blood.

Patients who have Lyme neuroborreliosis (LNB) might experience lingering symptoms that persist despite antibiotic drug therapy. We tested whether those symptoms are caused by maladaptive immune responses by measuring 20 immune mediators in serum and cerebrospinal fluid (CSF) in 79 LNB patients followed for 1 year. At study entry, most mediators were highly concentrated in CSF, the site of the infection. Those responses resolved with antibiotic therapy, and associations between CSF cytokines and signs and symptoms of LNB were no longer observed. In contrast, subjective symptoms that persisted after use of antibiotics were associated with increased levels of serum interferon-α (IFN-α), which were already observed at study entry, and remained increased at each subsequent timepoint. Highest IFN-α levels corresponded with severe disease. Although the infection serves as the initial trigger, sequelae after antibiotic therapy are associated with unremitting systemic IFN-α levels, consistent with the pathogenic role of this cytokine in interferonopathies in other conditions.

Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis.

To identify differentially expressed lipid metabolism-related genes (DE-LMRGs) responsible for immune dysfunction in sepsis. The lipid metabolism-related hub genes were screened using machine learning algorithms, and the immune cell infiltration of these hub genes were assessed by CIBERSORT and Single-sample GSEA. Next, the immune function of these hub genes at the single-cell level were validated by comparing multiregional immune landscapes between septic patients (SP) and healthy control (HC). Then, the support vector machine-recursive feature elimination (SVM-RFE) algorithm was conducted to compare the significantly altered metabolites critical to hub genes between SP and HC. Furthermore, the role of the key hub gene was verified in sepsis rats and LPS-induced cardiomyocytes, respectively. A total of 508 DE-LMRGs were identified between SP and HC, and 5 hub genes relevant to lipid metabolism (MAPK14, EPHX2, BMX, FCER1A, and PAFAH2) were screened. Then, we found an immunosuppressive microenvironment in sepsis. The role of hub genes in immune cells was further confirmed by the single-cell RNA landscape. Moreover, significantly altered metabolites were mainly enriched in lipid metabolism-related signaling pathways and were associated with MAPK14. Finally, inhibiting MAPK14 decreased the levels of inflammatory cytokines and improved the survival and myocardial injury of sepsis. The lipid metabolism-related hub genes may have great potential in prognosis prediction and precise treatment for sepsis patients.

Single-cell analysis reveals novel clonally expanded monocytes associated with IL1β–IL1R2 pair in acute inflammatory demyelinating polyneuropathy

Guillain–Barré syndrome (GBS) is an autoimmune disorder wherein the composition and gene expression patterns of peripheral blood immune cells change significantly. It is triggered by antigens with similar epitopes to Schwann cells that stimulate a maladaptive immune response against peripheral nerves. However, an atlas for peripheral blood immune cells in patients with GBS has not yet been constructed. This is a monocentric, prospective study. We collected 5 acute inflammatory demyelinating polyneuropathy (AIDP) patients and 3 healthy controls hospitalized in the First Affiliated Hospital of Harbin Medical University from December 2020 to May 2021, 3 AIDP patients were in the peak stage and 2 were in the convalescent stage. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from these patients. Furthermore, we performed cell clustering, cell annotation, cell–cell communication, differentially expressed genes (DEGs) identification and pseudotime trajectory analysis. Our study identified a novel clonally expanded CD14+ CD163+ monocyte subtype in the peripheral blood of patients with AIDP, and it was enriched in cellular response to IL1 and chemokine signaling pathways. Furthermore, we observed increased IL1β–IL1R2 cell–cell communication between CD14+ and CD16+ monocytes. In short, by analyzing the single-cell landscape of the PBMCs in patients with AIDP we hope to widen our understanding of the composition of peripheral immune cells in patients with GBS and provide a theoretical basis for future studies.

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.

Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane. This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored. Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier. This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes.

CFTR deficiency increases Th2 cytokine production and allergic airway inflammation in mice

The adaptive immune system is increasingly appreciated for contributions to the exuberant and maladaptive immune response in Cystic Fibrosis (CF). We hypothesized that 1) CFTR-deficiency in mouse Th2 cells increases Th2 cytokine production, 2) CF mice have increased allergic inflammation when challenged with inhaled allergen, and 3) GATA-3 expression is increased in murine CFTR-deficient Th2 cells.