Complement Components Research Articles

Dietary fiber consumption by sows during pregnancy has effects on gut microbial composition and immunity of offspring

Context Piglets encounter numerous challenges post-birth, and positive maternal influences can significantly aid their survival. Aims This study aimed to investigate the potential impact of dietary fiber (DF) consumption during pregnancy on the establishment of colonic flora and immunity in offspring. Methods Sixty-eight multiparous sows were randomly assigned to either a control diet lacking fiber sources or a diet supplemented with a fiber mixture. The study evaluated the developmental status, intestinal microecology, and immune indices, including the expression of Toll-like receptors and nuclear factor kappa-B, tumor necrosis factor α, interleukins 6 and 10, and interferon γ, as well as the concentrations of complement components 3 and 4, and immunoglobulins G and M in the offspring. Key results The findings revealed a significant reduction in Toll-like receptor 4 and nuclear factor kappa-B messenger RNA levels in the colon and tumor necrosis factor α levels in the serum of 21-day-weaned piglets from the fiber group, indicating a decrease in inflammation. Moreover, there was a notable increase in the abundance of Roseburia and Lactobacillus in the colons of weaned piglets from the fiber-supplemented group, whereas Odoribacter showed a substantial decrease. This indicates that sows transfer beneficial microorganisms to their piglets, and fiber supplementation further enhances these positive microbial changes. Conclusion This study highlights the positive impact on the microbiota profile and immunity of piglets of fiber supplementation in sow diets during pregnancy, using a 3% purified fiber mixture. These findings hold implications for the enhanced development of weaned piglets, providing valuable theoretical support.

Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.

Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain. We hypothesize the Schwann cells involvement in endometriotic pain. Here, we show that silencing the C5a receptor (C5aR1) in Schwann cells blocks the C5a-induced activation of the NLRP1 inflammasome and subsequent release of interleukin-1β (IL-1β). Macrophages, recruited to sciatic/trigeminal nerves by IL-1β from Schwann cells, increase oxidative stress, which activates the proalgesic TRPA1 pathway, resulting in widespread pain. These findings reveal a pathway involving Schwann cell C5aR1, NLRP1/IL-1β activation, macrophage recruitment, oxidative stress, and TRPA1 engagement, contributing to pain in a mouse model of endometriosis.

A new player in the game: identification of C1ql1 as a novel factor driving OPC differentiation.

Oligodendrocytes (OLGs) are the myelin-producing cells in the central nervous system (CNS). Following injury, these cells are prone to death, leading to demyelination and, eventually, axonal loss and neurodegeneration. Upon injury, the damaged CNS repopulates the lesion with oligodendrocyte precursor cells (OPCs) that consequently mature into OLGs to repair the myelin damage and prevent further axonal loss. In this issue, Altunay etal. identified that complement component 1, q subcomponent-like-1 (C1ql1), a factor known to play a role in neuron-neuron synapses, is also expressed by OPCs and drives their differentiation into OLGs. These data suggest that C1ql1 or other downstream factors could be therapeutic targets in the context of demyelinating disorders in which remyelination fails, such as in multiple sclerosis (MS).

Plant derived bioactive compounds for the treatment of neurodegeneration and neuroimmune disorders associated with the complement system

The complement system is a key component of the innate immune system that mediates the clearance of pathogens, apoptotic cells, and cellular debris. However, the complement system also has diverse roles in the central nervous system (CNS), where it regulates synaptic pruning, neural plasticity, and neuroinflammation. Dysregulation of the complement system has been implicated in various neurodegenerative disorders such as Alzheimer’s disease, multiple sclerosis, epilepsy, stroke, and traumatic brain injury. In these conditions, excessive or chronic activation of the complement system may lead to synaptic loss, neuronal damage, immune dysregulation, and inflammation, which leads to exacerbating the disease’s progression and severity. Moreover, the complement system may interact with infectious agents that invade the CNS, such as bacteria, viruses, fungi, and parasites, and modulate their pathogenicity and host response. Therefore, understanding the complex interplay between the complement system and the CNS is crucial for developing novel therapeutic strategies to prevent or treat neurodegenerative and neuroimmune disorders. Natural compounds, such as plant extracts, phytochemicals, and nutraceuticals, have emerged as promising candidates for modulating the complement system and its effects on the CNS. These compounds may exert anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory effects by regulating the expression of various complement components and pathways. In this review, we summarized the current knowledge on the roles of the complement system in human neurodegenerative disorders and the benefits of natural compounds for complement-targeted therapy.

Pioneering anti-inflammatory therapy: The path to precision therapy with C3aR peptide libraries

Abstract. Inflammation, a pervasive process with profound implications for tissue, joint, and vascular health, underscores the critical importance of immune system regulation in maintaining bodily homeostasis. Central to this regulatory network is the complement system, a complex array of proteins that orchestrate immune responses to infections and cellular damage. Among these proteins, the complement component 3a receptor (C3aR) serves as a pivotal mediator, triggering inflammatory cascades upon binding to the anaphylatoxin C3a. Targeting C3aR has emerged as a promising strategy for anti-inflammatory therapy, driven by recent advances in structural biology elucidating the complex architecture of the C3a-C3aR interaction. This study focuses on the design of high-affinity peptides targeting the C3aR receptor, leveraging ligand design and docking techniques to optimize binding interactions. Utilizing computational tools with sophisticated algorithms, we modeled the binding affinity of mutated ligands with the C3aR receptor, providing insights into the potential efficacy of peptide-based therapeutics. Our findings reveal that mutations at residues G74 and A76 enhance the binding affinity of the ligand with the C3aR receptor, offering a promising avenue for the development of novel anti-inflammatory agents. By elucidating the molecular determinants underlying peptide-receptor interactions within the C3a system, this study advances our understanding of inflammation biology and lays the groundwork for the rational design of targeted therapeutics. These insights hold potential for the development of potent and selective C3aR agonists/antagonists, offering new avenues for the treatment of inflammatory diseases and enhancing patient outcomes.

Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms.

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.

Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

New preclinical biomarkers for prion diseases in the cerebrospinal fluid proteome revealed by mass spectrometry

Current diagnostic methods for prion diseases only work in late stages of the disease when neurodegeneration is irreversible. Therefore, biomarkers that can detect the disease before the onset of clinical symptoms are necessary. High-throughput discovery proteomics is of great interest in the search for such molecules. Here we used mass spectrometry to analyse the cerebrospinal fluid proteome in an animal prion disease: preclinical and clinical sheep affected with natural scrapie, and healthy sheep. Interestingly, we found 46 proteins in the preclinical stage that were significantly altered (p < 0.01) compared to healthy sheep, mainly associated with biological processes such as stress and inflammatory responses. Five of them were selected for validation by enzyme-like immunosorbent assay: synaptotagmin binding, cytoplasmic RNA interacting protein (SYNCRIP), involved in nucleic acid metabolism; phospholipase D3 (PLD3) and cathepsin D (CTSD), both related to lysosomal apoptosis; complement component 4 (C4), an element of the classical immune response; and osteopontin (SPP1), a proinflammatory cytokine. These proteins significantly increased in the preclinical stage and maintained their levels in the clinical phase, except for CTSD, whose concentration returned to basal levels in the clinical group. Further research is ongoing to explore their potential as preclinical biomarkers of prion diseases.

A Thrilling Case of Anemia

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that presents with triad of peripheral blood cytopenias, hemolytic anemia and thrombosis. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is due to acquired somatic mutations in phosphatidylinositol glycan class A (PIGA) gene.Terminal complement inhibition with eculizumab and allogeneic bone marrow transplantation (BMT) are the only widely effective therapies for patients with classical PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3).

Evidence of a Lytic Pathway in an Invertebrate Complement System: Identification of a Terminal Complement Complex Gene in a Colonial Tunicate and Its Evolutionary Implications.

The complement system is a pivotal component of innate immunity, extensively studied in vertebrates but also present in invertebrates. This study explores the existence of a terminal complement pathway in the tunicate Botryllus schlosseri, aiming to understand the evolutionary integration of innate and adaptive immunity. Through transcriptome analysis, we identified a novel transcript, BsITCCP, encoding a protein with both MACPF and LDLa domains-a structure resembling that of vertebrate C9 but with a simpler organization. Phylogenetic reconstruction positions BsITCCP between invertebrate perforins and vertebrate terminal complement proteins, suggesting an evolutionary link. Localization studies confirmed that bsitccp is transcribed in cytotoxic morula cells (MCs), which are also responsible for producing other complement components like BsC3, BsMBL, BsMASP, and BsBf. Functional assays demonstrated that bsitccp transcription is upregulated in response to nonself challenges and is dependent on BsC3 activity; inhibition of BsC3 led to a significant reduction in BsITCCP expression. Electron microscopy revealed that MCs form contact with perforated yeast cells, indicating a possible mechanism of cell lysis similar to the immunological synapse observed in vertebrates. These findings suggest that a C3-governed lytic complement pathway exists in B. schlosseri, challenging the assumption that a C5 ortholog is necessary for such a pathway. This work enhances our understanding of the evolution of the complement system and suggests that invertebrates possess a terminal complement complex capable of mediating cell lysis, regulated by C3. Future studies will focus on confirming the pore-forming ability of BsITCCP and its role in the immunological synapse.

Transcriptomic Analysis of Non-Specific Immune Responses in the Rice Field Eel (Monopterus albus) Infected with Pallisentis (Neosentis) celatus

Parasitic infestations present significant threats to the physiological health and ecological stability of aquatic species, frequently compromising immune defenses and elevating mortality rates. This study was conducted to elucidate the non-specific immune responses induced by Pallisentis (Neosentis) celatus infection in Monopterus albus, with a focus on intestinal histopathology and transcriptome gene expression. A histopathological examination revealed minor alterations in intestinal villi under low-level infection. A transcriptome analysis, performed using Illumina sequencing technology, identified 347 upregulated and 298 downregulated genes involved in critical biological pathways, such as lipid metabolism, immune responses, and the regulation of inflammatory processes. GO and KEGG analyses indicated the upregulation of immune-related pathways, including the RIG-I-like and IL-17 signaling pathways, highlighting a robust intestinal immune response. Conversely, the complement pathway was found to be downregulated, with significant suppression of C9, suggesting that the parasite may engage in immune evasion. Fluorescein-labeled C9 antibody assays confirmed reduced complement C9 levels in the infected tissues. A real-time PCR analysis identified the differential expression of eight genes, including C5, maats1, CFI, and gmnc, which were consistent with the sequencing results. These findings suggest that Pallisentis (Neosentis) celatus infection compromises intestinal health, induces inflammation, and activates non-specific immune responses in Monopterus albus. However, Pallisentis (Neosentis) celatus appears to evade the host immune response by suppressing the activation of complement components, thereby facilitating its reproductive parasitism.

A bovine model of hypoxia-induced pulmonary hypertension reveals a gradient of immune and matrisome response with a complement signature found in circulation.

Pulmonary hypertension (PH) is a progressive vascular disease characterized by vascular remodeling, stiffening, and luminal obstruction, driven by dysregulated cell proliferation, inflammation, and extracellular matrix (ECM) alterations. Despite the recognized contribution of ECM dysregulation to PH pathogenesis, the precise molecular alterations in the matrisome remain poorly understood. In this study, we employed a matrisome-focused proteomics approach to map the protein composition in a young bovine calf model of acute hypoxia-induced PH. Our findings reveal distinct alterations in the matrisome along the pulmonary vascular axis, with the most prominent changes observed in the main pulmonary artery. Key alterations included a strong immune response and wound repair signature, characterized by increased levels of complement components, coagulation cascade proteins, and provisional matrix markers. Additionally, we observed upregulation of ECM-modifying enzymes, growth factors, and core ECM proteins implicated in vascular stiffening, such as collagens, periostin, tenacsin-C, and fibrin(ogen). Notably, these alterations correlated with increased mean pulmonary arterial pressure and vascular remodeling. In the plasma, we identified increased levels of complement components, indicating a systemic inflammatory response accompanying the vascular remodeling. Our findings shed light on the dynamic matrisome remodeling in early-stage PH, implicating a wound-healing trajectory with distinct patterns from the MPA to the distal vasculature. This study provides novel insights into the molecular underpinnings of PH pathogenesis and highlights potential biomarkers and therapeutic targets within the matrisome landscape.

Immune Markers and Inflammatory Cytokines in Granulomatous Lobular Mastitis: A Case-Control Study.

Granulomatous lobular mastitis (GLM) has seen a rising incidence, though its pathogenesis remains unclear, posing challenges for treatment and contributing to high recurrence rates with conventional therapies. While the role of inflammatory and immune factors in GLM has been recognized, a comprehensive clinical evaluation of these markers is still lacking. This study aims to identify potential diagnostic markers and therapeutic targets by comparing immune markers and cytokine levels in GLM patients and healthy controls. Conducted at Beijing Hospital of Traditional Chinese Medicine, Capital Medical University from July 2023 to May 2024, this study enrolled 30 GLM patients and 15healthy female controls in a 2:1 ratio. Serum levels of immune markers and cytokines were analyzed to explore their potential association with GLM. The study population comprised 30 GLM patients with a mean age of 33.40 ± 4.12 years and 15healthy female controls with a mean age of 32.13 ± 6.19 years. Significantly elevated levels of C-reactive protein (CRP), Immunoglobulin A (IgA), Complement Component 3 (C3), Complement Component 4 (C4), Compliment Component 1q (C1q), Alpha1-antit-rypsin (AAT), α1-acidglycoprotein (AGP), Anti-histone antibodies (Anti-HIS), Anti-Ro52 antibodies (Anti-Ro52), Anti-double stranded DNA antibodies (Anti-dsDNA), Interleukin-6 (IL-6), Interleukin-10 (IL-10), and Tumor Necrosis Factor-α (TNF-α) were observed in GLM patients compared to controls (all P < 0.05). Subgroup analysis revealed higher levels of CRP, C3, C1q, AAT, and AGP in patients with larger mass areas and those with erythema nodosum (all P < 0.05). No significant differences were found in subgroups based on disease duration or recurrence (both P > 0.05). Serum levels of CRP, IgA, AAT, AGP, Anti-HIS, Anti-Ro52, Anti-dsDNA, C3, C4, C1q, IL-6, IL-10, and TNF-α may serve as diagnostic and prognostic indicators for GLM, with CRP, AAT, AGP, and C1q being particularly indicative of disease severity. These markers offer potential therapeutic targets for GLM.

Function of immune cells and effector molecules of the innate immune system in the establishment and maintenance of pregnancy in mammals - A review.

In mammalian species, pregnancy is a complex process that involves the maternal recognition of pregnancy, implantation, decidualization, placentation, and parturition. The innate immune system is composed of cellular components, such as natural killer cells, neutrophils, monocytes, and macrophages, and effector molecules, such as cytokines, interferons, antimicrobial peptides, and complement components. The innate immune system plays a critical role as the first line of defense against infection or inflammation to maintain homeostasis and activate the adaptive immunity. During pregnancy, innate immune cells and effector molecules act on the regulation of innate immunity for host defense and processes such as embryo development, implantation, and placentation at the maternal-conceptus interface. In this review, we describe the components of the innate immune system and their functions at the maternal-conceptus interface to establish and maintain pregnancy in animal species that form hemochorial- or epitheliochorial-type placentas, including humans, rodents, ruminants, and pigs.

Hemostatic derangements associated with cardiopulmonary bypass predict outcomes in pediatric patients undergoing corrective heart surgery

BackgroundUnderstanding of the hemostatic and complement alterations associated with cardiopulmonary bypass (CPB) in pediatric patients and the impact of these alterations on outcome is limited. ObjectivesThe present study prospectively characterized these alterations and their association with postoperative outcomes in pediatric CPB. Patients/MethodsAll patients <21 years undergoing CPB at the authors’ institution between 2020 and 2021 that weighed >3 kg, were >36 weeks gestational age, and had no known prothrombotic or hemorrhagic disorders were eligible. Blood samples were analyzed for multiple hemostatic and complement biomarkers pre-, intra-, and 24 hours post-CPB. Biomarker levels were compared to clinical outcomes, including chest tube output (CTO). ResultsFifty consecutive patients were enrolled. CPB resulted in multiple significant alterations in hemostatic and complement components. Lower platelet counts (<80 x 109 platelets/L) at CPB termination were associated with increased postoperative CTO (p=0.003). Lower factor VIII levels (<60 IU/dl) at the end of CPB were associated with a longer hospital stay (p<0.001) and increased postoperative CTO (p<0.001). Patients undergoing staged single ventricle reconstruction were more likely to have lower platelet counts at CPB termination (p=0.009) and higher CTO postoperatively (p=0.001) than patients undergoing other types of surgical repair. These differences were not due to different preoperative platelet counts, increased incidences of circulatory arrest, or longer CPB times. ConclusionsThese data suggest that intraoperative alterations in hemostatic system components may predict postoperative outcomes in pediatric CPB. Further study is needed to determine if interventions targeting platelets or factor VIII could improve outcomes in pediatric CPB.

Features of changes in nonspecific factors of immunological reactivity in obesity

Introduction. The study of pathogenetic factors of obesity is an urgent task of modern medicine. The formation of obesity is characterized by changes in the activity of individual mechanisms of innate immunity. At the same time, the values of laboratory indicators that characterize them are often within the current boundaries of the reference values of laboratory indicators of the immunity of a healthy person. This complicates the pathogenetic assessment of the mechanisms of nonspecific immunological reactivity in obesity and determines the need for further study of the characteristics of nonspecific immune defense factors in this pathology.Aim. To identify the features of changes in cellular and humoral factors of nonspecific immunological reactivity in obesity.Materials and methods. A single-center cross-sectional, one-time controlled study was conducted with the participation of 118 people, of which 87 people were obese patients (BMI 37.2 [34.1; 42.05] kg/m2), 31 people had normal body weight (BMI 21.9 [ 20.2; 23.5] kg/m2) and were included in the control group. All patients underwent a study of lipid profile (total cholesterol, high-density lipoproteins, low-density lipoproteins, very low-density lipoproteins, triglycerides), carbohydrate metabolism (glucose, insulin, glycated hemoglobin), C-reactive protein, indicators of cellular and humoral factors of nonspecific immunity (leukogram, cytokine profile, C3-C4 complement components).Results. An increase in the total number of leukocytes was revealed, due to neutrophil granulocytes against the background of the development of a disproportion between the percentage and absolute value of the number of lymphocytes and monocytes, the concentration of C3 and C4 complement components, C-reactive protein, as well as an increase in the level of IL-6, which confirms the presence of low-grade chronic inflammation in obese patients. Statistically significant correlations of immunological parameters with anthropometric data, indicators of carbohydrate and lipid metabolism were revealed.Conclusion. The results of the study indicate that obesity causes activation of certain cellular and humoral mechanisms of nonspecific immune defense involved in the formation of the inflammatory process. Confirmation of the presence of a latent inflammatory process in obesity is an increase in the level of leukocytes and their individual cellular forms, C-reactive protein, C3 and C4 complement components, IL-6. A feature of the changes is the presence of fluctuations in the values of the studied indicators within the current boundaries of the reference values of laboratory indicators, which makes it difficult to timely diagnose chronic inflammation in obesity

The Difficulties of Treating Complement-3–Mediated Glomerulopathy

Background: C3 glomerulopathy (C3G) is a rare disease affecting the complement alternative pathway, categorized into dense deposit disease and C3 glomerulonephritis. Dense deposit disease predominantly affects younger individuals, while C3 glomerulonephritis tends to manifest in older populations. The diseases are characterized by dysregulation of the complement alternative pathway, leading to the deposition of complement components in the glomeruli and subsequent renal dysfunction. Notably, the incidence of C3G in the United States is low, with 1–3 cases per 1,000,000 and a prevalence of 5 cases per 1,000,000. Areas of Uncertainty: Numerous uncertainties persist in comprehending the etiology and pathophysiology of C3G. While biomarkers such as C3 nephritic factor, autoantibodies, and relevant genetic mutations have been identified, their pathogenicity and clinical utility remain unclear. Standard workups involve complement assays and autoantibody panels, yet the definitive diagnostic test remains a kidney biopsy. Nuanced challenges lie in deciphering the sensitivity and specificity of these diagnostic tools, especially in the presence of phenotypical variations among individuals. Therapeutic Advancement: Current therapeutic approaches, albeit lacking robust evidence, encompass a spectrum ranging from supportive care to targeted B-cell therapy and immunosuppression with mycophenolate mofetil and glucocorticoids. For severe and refractory cases, the monoclonal antibody eculizumab, targeting C5 in the complement cascade, is recommended. These treatments, while offering some relief, pose challenges related to their cost and obtaining insurance approval. Exploratory avenues delve into the potential of plasma exchange and innovative treatments such as oral complement inhibitors, reflecting the ongoing quest for effective therapeutic modalities. Trials investigating various complement inhibitors underscore the dynamic landscape of therapeutic advancements in C3G management. Conclusion: In conclusion, the article highlights the complexities of C3G management. The need for further understanding, large-scale trials, and ongoing investigations into disease etiology and pathophysiology is emphasized.

Astrocyte-TREM2 alleviates brain injury by regulating reactive astrocyte states following ischemic stroke.

Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to confer strong neuroprotective effects in acute ischemic stroke (AIS). However, as the vast majority of research findings to date are based on its functions in microglia, the precise role of TREM2 in astrocytes after AIS is unknown. Here, both loss- and gain-of-function experiments were employed to investigate how astrocytic TREM2 influences the pathogenesis of AIS in vivo and in vitro. Our results demonstrated that cerebral ischemia triggered induction of TREM2 expression on reactive astrocytes following AIS. In addition, astrocyte-specific TREM2 knockout mice exhibited much greater brain injury than TREM2 flox/flox controls following AIS, as evidenced by increased cerebral infarct volume, neuronal apoptosis and neurological deficit, which was associated with an increased expression of pro-inflammatory molecule complement component 3 (C3) on reactive astrocytes and activation of microglia/macrophages but decreased expression of S100 calcium binding protein A10 (S100A10) and arginase1 (Arg1) on reactive astrocytes. Mechanistic analyses revealed that astrocytic TREM2 alleviated brain injury by inhibiting detrimental actions of reactive astrocytes but promoting their neuro- and glioprotective actions via the kruppel-like transcription factor-4-nuclear factor-κB axis. Together, this study provides novel evidence for a critical protective role of astrocyte-derived TREM2 in AIS and highlights a potential therapeutic target for the treatment of AIS.

C3 glomerulonephritis with genetically confirmed C3 deficiency in a pediatric patient: a case report

Complement component 3 glomerulonephritis (C3GN) is a rare kidney disease characterized by complement dysregulation that results in prominent complement component 3 (C3) deposition in the kidneys. The clinical course of C3GN varies from mild hematuria to progressive chronic kidney disease. In most patients, C3GN is driven by acquired factors, namely, autoantibodies that target C3 or C5 convertases. Genetic variations in complement-related genes are less frequent. We report the case of a 9-yearold Korean boy who presented with microscopic hematuria and a persistently low C3 level and had biopsy findings of C3GN, with the presence of a C3 gene mutation: a frameshift mutation associated with C3 deficiency. However, the patient did not exhibit any other symptoms of complement deficiency. Direct DNA sequencing of his family members revealed the same genetic mutation in his father and older brother. This case report is significant because there are very few such reports worldwide concerning gene mutations related to C3 deficiency to be discovered in patients with C3GN. Explaining C3GN pathogenesis is challenging; therefore, additional research is required in the future.

The prognostic role of activation of the complement pathways in the progression of advanced IgA nephropathy to end-stage renal disease

IntroductionThe role of complement system in late stage of IgA nephropathy (IgAN) remains unknown. We therefore investigated the effects of complement system on worsening kidney function in advanced (stage 4 CKD) IgAN.MethodsRenal specimens of 69 IgAN patients who underwent renal biopsy during stage 4 CKD between 2010 and 2021, were stained using immunofluorescence (IF) and immunohistochemistry (IHC) for glomerular complement components. The primary outcome was progression to end-stage renal disease (ESRD). Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses.ResultsDuring a median follow-up of 18.0 months, 26 (37.7%) patients progressed to ESRD and none died. C1q and C3 deposition were detected in 12 and 66 patients, respectively. Higher eGFR [hazards ratio (HR), 0.852, 95% confidence interval (CI), 0.756–0.959; P = 0.008], higher C3 intensity (HR, 2.955, 95%CI, 1.063–8.220; P = 0.038) and T1-2 score (HR, 2.576, 95%CI, 1.205–5.576, P = 0.015) were predictive of time to ESRD in CKD 4 stage IgAN. Significant expressions of C1q (P = 0.005), C4d (P < 0.001), factor B (P < 0.001), C3 (P = 0.042) and C5b-9 (P = 0.004) were identified in ESRD group than in non-ESRD group by IHC, while MBL expression was low. Although they were not associated with baseline 24 h-UP, higher factor B and C1q expressions were both correlated with a lower baseline eGFR (P < 0.001 and = 0.04, respectively) and the deterioration of kidney function during follow-up (P = 0.046 and 0.015, respectively).ConclusionComplement deposition in IgAN patients with stage 4 CKD portends a faster deterioration of kidney function. Activation of classical and alternative complement pathways plays a major role in this stage.