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Simple Summary: Pangolins, the only mammals covered in scales, play a crucial role in forest ecosystems as they specialize in myrmecophagy. Unfortunately, all eight pangolin species are critically endangered and susceptible to various pathogenic microorganisms, causing mass mortality, especially in captive Manis pentadactyla. However, information regarding the function of the immune system is lacking, which limits the development of effective rescue methods and subsequently hinders population rejuvenation. This study aimed to investigate the differences in the immunity of Manis javanica and Manis pentadactyla through proteomics and microbiotas conjoint analysis. Our findings revealed that Manis pentadactyla owned more pathogenic bacteria and neutralized through a powerful transferrin system. Manis javanica possessed stronger anti-inflammatory ability, which might be due to the structural deficiency of C5a. This study elucidates the distinct immune factors and microbiomes in Manis javanica compared to Manis pentadactyla, offering a foundational understanding for future immunotherapy research. All eight pangolin species, especially captive Manis pentadactyla, are critically endangered and susceptible to various pathogenic microorganisms, causing mass mortality. They are involved in the complement system, iron transport system, and inflammatory factors. M. pentadactyla exhibited a higher abundance of opportunistic pathogens, Moraxella, which potentially evaded complement-mediated immune response by reducing C5 levels and counteracting detrimental effects through transferrin neutralization. In addition, we found that the major structure of C5a, an important inflammatory factor, was lacking in M. javanica. In brief, this study revealed the differences in immune factors and microbiome between M. javanica and M. pentadactyla, thus providing a theoretical basis for subsequent immunotherapy. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that activation of complement system leading to the formation of the membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3−/−; 2. C7−/−; and 3. Cd59ab−/−) to evaluate the role of complement in severe COVID-19 pathogenesis. C3 deficient mice lack a key common component of all three complement activation pathways and are unable to generate C3 and C5 convertases. C7 deficient mice lack a complement protein needed for MAC formation. Cd59ab deficient mice lack an important inhibitor of MAC formation. We also used anti-C5 antibody to block and evaluate the therapeutic potential of inhibiting MAC formation. We demonstrate that inhibition of complement activation (in C3−/−) and MAC formation (in C3−/−. C7−/−, and anti-C5 antibody) attenuates severe COVID-19; whereas enhancement of MAC formation (Cd59ab−/−) accelerates severe COVID-19. The degree of MAC but not C3 deposits in the lungs of C3−/−, C7−/− mice, and Cd59ab−/− mice as compared to their control mice is associated with the attenuation or acceleration of SARS-CoV-2-induced disease. Further, the lack of terminal complement activation for the formation of MAC in C7 deficient mice protects endothelial dysfunction, which is associated with the attenuation of diseases and pathologic changes. Our results demonstrated the causative effect of MAC in severe COVID-19 and indicate a potential avenue for modulating the complement system and MAC formation in the treatment of severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Methods: Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Results: Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Conclusion: Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma. [ABSTRACT FROM AUTHOR]

Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity. [ABSTRACT FROM AUTHOR]

Aim: The availability of disease-modifying therapies and newborn screening programs for spinal muscular atrophy (SMA) has generated an urgent need for reliable prognostic biomarkers to classify patients according to disease severity. We aim to identify cerebrospinal fluid (CSF) prognostic protein biomarkers in CSF samples of SMA patients collected at baseline (T0), and to describe proteomic profile changes and biological pathways influenced by nusinersen before the sixth nusinersen infusion (T302). Methods: In this multicenter retrospective longitudinal study, we employed an untargeted liquid chromatography mass spectrometry (LC-MS)-based proteomic approach on CSF samples collected from 61 SMA patients treated with nusinersen (SMA1 n=19, SMA2 n=19, SMA3 n=23) at T0 at T302. The Random Forest (RF) machine learning algorithm and pathway enrichment analysis were applied for analysis. Results: The RF algorithm, applied to the protein expression profile of naïve patients, revealed several proteins that could classify the different types of SMA according to their differential abundance at T0. Analysis of changes in proteomic profiles identified a total of 147 differentially expressed proteins after nusinersen treatment in SMA1, 135 in SMA2, and 289 in SMA3. Overall, nusinersen-induced changes on proteomic profile were consistent with i) common effects observed in allSMA types (i.e. regulation of axonogenesis), and ii) disease severity-specific changes, namely regulation of glucose metabolism in SMA1, of coagulation processes in SMA2, and of complement cascade in SMA3. Conclusions: This untargeted LC-MS proteomic profiling in the CSF of SMA patients revealed differences in protein expression in naïve patients and showed nusinersen-related modulation in several biological processes after 10 months of treatment. Further confirmatory studies are needed to validate these results in larger number of patients and over abroader timeframe. [ABSTRACT FROM AUTHOR]

Abstract\nPLAIN LANGUAGE SUMMARYThe occurrence of incidents involving radiation-combined burn injuries (RCBI) poses a significant risk to public health. Understanding the immunological and physiological responses associated with such injuries is crucial for developing care triage to counter the mortality that occurs due to the synergistic effects of radiation and burn injuries. The core focus of this narrative review lies in unraveling the immune response against RCBI. Langerhans cells, mast cells, keratinocytes, and fibroblasts, which induce innate immunity, have been explored for their response to radiation, burns, and combined injuries. In the case of adaptive immune response, exploring behavioral changes in T regulatory (Treg) cells, T helper cells (Th1, Th2, and Th17), and immunoglobulin results in delayed healing compared to burn and radiation injury. The review also includes the function of complement system components such as neutrophils, acute phase proteins (CRP, C3, and C5), and cytokines for their role in RCBI. Combined insults resulting in a reduction in the cell population of immune cells display variation in response based on radiation doses, burn injury types, and their intrinsic radiosensitivity. The lack of approved countermeasures against RCBI poses a significant challenge. Drug repurposing might help to balance immune cell alteration, resulting in fast recovery and decreasing mortality, which gives it clinical significance for its implication on the site of such incidence. However, the exact immune response in RCBI remains insufficiently explored in pre-clinical and clinical stages, which might be due to the non-availability of in vitro models, standard animal models, or human subjects, warranting further research.In the realm of public health, RCBI presents significant risks and obstacles. This hazard is quite serious, and it might get worse in the future as evidenced by incidents like nuclear meltdowns and medical mistakes. Diagnosis and treatment become more challenging when serious injuries, particularly burns, are combined with radiation exposure. Features like early shock, poor wound healing, and hematopoietic instability call for advancements in both diagnosis and therapy. Furthermore, the immune system’s response to RCBI is complicated and involves changes in cytokine concentrations, immune cell activity, and adaptive immune responses compared to single injuries. Immune cell radiosensitivity varies depending on the type of cell, radiation dose, and length of exposure, so it’s important to understand. Repurposing drugs is one of the potential techniques to reduce mortality and speed up healing which are discussed in the manuscript. Still, more research is needed. To effectively tackle RCBI, more investigation into molecular processes, treatment strategy optimization, and information gap closure are essential. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) plays a crucial role in the diagnosis and monitoring of the non-specific acute phase response in humans. In contrast, rat CRP (rCRP) is an atypical acute-phase protein that possesses unique features, such as a possible incapacity to trigger the complement system and markedly elevated baseline plasma concentrations. To facilitate in vitro studies on these unique characteristics, obtaining high-quality pure rCRP is essential. Here we explored various strategies for rCRP purification, including direct isolation from rat plasma and recombinant expression in both prokaryotic and eukaryotic systems. Our study optimized the recombinant expression system to enhance the secretion and purification efficiency of rCRP. Compared to traditional purification methods, we present a streamlined and effective approach for the expression and purification of rCRP in the Pichia pastoris system. This refined methodology offers significant improvements in the efficiency and effectiveness of rCRP purification, thereby facilitating further structural and functional studies on rCRP. [ABSTRACT FROM AUTHOR]

Background: Complement activation in atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) may be associated with rare genetic variants. Here we describe gene variants in the Swedish and Norwegian populations. Methods: Patients with these diagnoses (N=141) were referred for genetic screening. Sanger or next-generation sequencing were performed to identify genetic variants in 16 genes associated with these conditions. Nonsynonymous genetic variants are described when they have a minor allele frequency of <1% or were previously reported as being disease-associated. Results: In patients with aHUS (n=94, one also had IC-MPGN) 68 different genetic variants or deletions were identified in 60 patients, of which 18 were novel. Thirty-two patients had more than one genetic variant. In patients with C3G (n=40) 29 genetic variants, deletions or duplications were identified in 15 patients, of which 9 were novel. Eight patients had more than one variant. In patients with IC-MPGN (n=7) five genetic variants were identified in five patients. Factor H variants were the most frequent in aHUS and C3 variants in C3G. Seventeen variants occurred in more than one condition. Conclusion: Genetic screening of patients with aHUS, C3G and IC-MPGN is of paramount importance for diagnostics and treatment. In this study, we describe genetic assessment of Nordic patients in which 26 novel variants were found. [ABSTRACT FROM AUTHOR]

This article, titled "My lifetime in IgA nephropathy: An unexpected journey," recounts the author's personal and professional experiences with IgA nephropathy, a kidney disease. The author's journey began in 1975 when they pursued medical training at the University of Kentucky. Through their work in nephrology, they encountered many patients with IgA nephropathy and eventually discovered a familial connection to the disease in southeastern Kentucky. Over the years, the author collaborated with researchers worldwide to unravel the pathogenesis of IgA nephropathy, leading to the identification of genetic loci associated with the disease. The article also discusses the author's involvement in the IgA Nephropathy Club and the development of the Oxford Classification of the histology of IgA nephropathy. The author has since retired from academia but continues to participate in clinical research and work on diagnostic tools for IgA nephropathy. [Extracted from the article]

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end‐stage kidney disease within their lifetime. The mechanisms responsible for the presentation and development of IgAN are required for the development of highly targeted therapies for this disease. In this review, we first demonstrate the current treatment strategy of IgAN recommended by the 2021 KDIGO guideline. Then, we update the new insights into disease pathogenesis based on the well acknowledged 'multiple‐hit hypothesis' and provide the potential therapeutic targets involved in the upstream production of pathogenic IgA1 and the downstream complement activation. Finally, the recent large randomized controlled trials focusing on these novel targets have been summarized, among which Nefecon and Sparsentan have received approval and Telitacicept have been used off‐label for IgAN. In the future, emerging treatment approaches for IgAN is likely to evolve, which will signify a shift in the management of the IgAN from traditional immunosuppressive approaches to an era of targeted treatment based on the understanding of the pathogenic mechanisms. Summary at a glance: IgA nephropathy (IgAN) is a heterogeneous disease with complex underlying pathophysiology. The evolving understanding of pathogenic pathways of IgAN has led the development of new treatments for more targeting therapies, signifying a shift in the management of IgAN from traditional immunosuppressive approaches to an era of targeted treatment. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease and the most common cause of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor 1 (PLA2R1) as the first target antigen in patients with MN 15 years ago has led to a paradigm shift in the pathobiological understanding of this disease. Autoantibodies against PLA2R1 as well as thrombospondin type-1 domain-containing 7A, the second identified antigen in adults, were shown to be disease-causing and act through local activation of the complement system, primarily via the classical and lectin pathways. These findings indicate that both plasma cells, the main source of antibodies and autoantibodies, as well as the complement system, the main pathogenic effector mechanism in MN, are rational and pathogenesis-based treatment targets in MN. This review summarizes pathomechanistic and clinical evidence for and against plasma cell– and complement-targeted treatments in MN. [ABSTRACT FROM AUTHOR]

Ticks are notable vectors of diseases affecting both humans and animals, with Hyalomma anatolicum being of particular significance due to its wide distribution and capability to transmit a variety of pathogens, including Theileria annulata and Crimean–Congo haemorrhagic fever virus. This study aimed to investigate the inhibitory effects of H. anatolicum salivary gland extract (HaSGE) and the identification of its key component on the complement system of the host’s innate immune defense. We demonstrated that HaSGE exerts a dosedependent inhibition on the complement activation in a hostspecific manner. Mechanistic studies revealed that HaSGE interferes with deposition and cleavage of complement proteins C3 and C5, thus preventing the formation of the membrane attack complex. Further, we identified a serine protease inhibitor, Hyalomma anatolicum serpin-1 (HAMpin-1), from the HaSGE through proteomic analysis and characterized its structure, function, and interaction with complement proteins. HAMpin-1 exhibited potent inhibitory activity against chymotrypsin and cathepsin-G, and notably, it is the first serpin from ticks shown to inhibit the classical and lectin pathways of the complement system. The expression of HAMpin-1 was highest in the salivary glands, suggesting its crucial role in blood feeding and immune evasion. Our findings revealed one of the potential mechanisms used by H. anatolicum to modulate host immune responses at the interface, offering new insights into tick–host interactions. [ABSTRACT FROM AUTHOR]

Microglia, the immune cells of the central nervous system, are dynamic and heterogenous cells. While single cell RNA sequencing has become the conventional methodology for evaluating microglial state, transcriptomics do not provide insight into functional changes, identifying a critical gap in the field. Here, we propose a novel organelle phenotyping approach in which we treat live human induced pluripotent stem cell‐derived microglia (iMGL) with organelle dyes staining mitochondria, lipids, lysosomes and acquire data by live‐cell spectral microscopy. Dimensionality reduction techniques and unbiased cluster identification allow for recognition of microglial subpopulations with single‐cell resolution based on organelle function. We validated this methodology using lipopolysaccharide and IL‐10 treatment to polarize iMGL to an "inflammatory" and "anti‐inflammatory" state, respectively, and then applied it to identify a novel regulator of iMGL function, complement protein C1q. While C1q is traditionally known as the initiator of the complement cascade, here we use organelle phenotyping to identify a role for C1q in regulating iMGL polarization via fatty acid storage and mitochondria membrane potential. Follow up evaluation of microglia using traditional read outs of activation state confirm that C1q drives an increase in microglia pro‐inflammatory gene production and migration, while suppressing microglial proliferation. These data together validate the use of a novel organelle phenotyping approach and enable better mechanistic investigation of molecular regulators of microglial state. [ABSTRACT FROM AUTHOR]

Background: A complement imbalance in lung alveolar tissue can play a deteriorating role in COVID-19, leading to acute respiratory distress syndrome (ARDS). CD55 is a transmembrane glycoprotein that inhibits the activation of the complement system at the intermediate cascade level, blocking the activity of the C3 convertase. Objective: In our study, lung specimens from COVID-19 and ARDS-positive COVID+/ARDS+ patients were compared with COVID-19 and ARDS-negative COVID–/ARDS– as well as COVID–/ARDS+ patients. Methods: Histochemical staining and immunolabeling of CD55 protein were performed. Results: The COVID–/ARDS– specimen showed higher expression and homogeneous distribution of glycosaminoglycans as well as compactly arranged elastic and collagen fibers of the alveolar walls in comparison to ARDS-affected lungs. In addition, COVID–/ARDS– lung tissues revealed stronger and homogenously distributed CD55 expression on the alveolar walls in comparison to the disrupted COVID–/ARDS+ lung tissues. Conclusions: Even though the collapse of the alveolar linings and the accumulation of cellular components in the alveolar spaces were characteristic of COVID+/ARDS+ lung tissues, evaluating CD55 expression could be relevant to understand its relation to the disease. Furthermore, targeting CD55 upregulation as a potential therapy could be an option for post-infectious complications of COVID-19 and other inflammatory lung diseases in the future. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) can present a variety of clinical presentations and has high inter-individual heterogeneity. Multiple studies have suggested various subtype models related to symptoms, etiology, sex, and treatment response. Employing different regimens is common when treating MDD, and identifying effective therapeutics requires time. Frequent treatment attempts and failures can lead to a diagnosis of treatment resistance, and the heterogeneity of treatment responses among individuals makes it difficult to understand and interpret the biological mechanisms underlying MDD. Aim: This study explored the differentially expressed proteins and commonly altered protein networks across drug treatments by comparing the serum proteomes of patients with MDD treated with drug regimens (T-MDD, n = 20) and untreated patients (NT-MDD, n = 20). Methods: Differentially expressed proteins were profiled in non-drug-treated and drug-treated patients with depression using liquid chromatography-mass spectrometry. The common protein networks affected by different medications were studied. Results: Of the proteins profiled, 12 were significantly differentially expressed between the T-MDD and NT-MDD groups. Commonly altered proteins and networks of various drug treatments for depression were related to the complement system and immunity. Conclusions: Our results provide information on common biological changes across different pharmacological treatments employed for depression and provide an alternative perspective for improving our understanding of the biological mechanisms of drug response in MDD with great heterogeneity in the background of the disease. [ABSTRACT FROM AUTHOR]

The complement system and neutrophils play crucial roles in innate immunity. Neutrophils release neutrophil extracellular traps (NETs), which are composed of decondensed DNA entangled with granular contents, as part of their innate immune function. Mechanisms governing complement-mediated NET formation remain unclear. In this study, we tested a two-step NETosis mechanism, as follows: classical complement-mediated neutrophil activation in serum and subsequent NET formation in serum-free conditions, using neutrophils from healthy donors, endothelial cells, and various assays (Fluo-4AM, DHR123, and SYTOX), along with flow cytometry and confocal microscopy. Our findings reveal that classical complement activation on neutrophils upregulated the membrane-anchored complement regulators CD46, CD55, and CD59. Additionally, complement activation increased CD11b on neutrophils, signifying activation and promoting their attachment to endothelial cells. Complement activation induced calcium influx and citrullination of histone 3 (CitH3) in neutrophils. However, CitH3 formation alone was insufficient for NET generation. Importantly, NET formation occurred only when neutrophils were in serum-free conditions. In such environments, neutrophils induced NADPH oxidase-dependent reactive oxygen species (ROS) production, leading to NET formation. Hence, we propose that complement-mediated NET formation involves a two-step process, as follows: complement deposition, neutrophil priming, calcium influx, CitH3 formation, and attachment to endothelial cells in serum. This is followed by NADPH-dependent ROS production and NET completion in serum-free conditions. Understanding this process may unveil treatment targets for pathologies involving complement activation and NET formation. [ABSTRACT FROM AUTHOR]

There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer's disease (AD)—the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks of this disease—β-amyloid plaques and neurofibrillary tangles—failed, showed discrete clinical effects, or were accompanied by concerning side effects. There has been an ongoing search for novel therapeutic targets. Neuroinflammation, now widely recognized as a hallmark of all neurodegenerative diseases, has been proven to be a major contributor to AD pathology. Here, we summarize the role of neuroinflammation in the pathogenesis and progression of AD and discuss potential targets such as microglia, TREM2, the complement system, inflammasomes, and cytosolic DNA sensors. We also present an overview of ongoing studies targeting specific innate immune system components, highlighting the progress in this field of drug research while bringing attention to the delicate nature of innate immune modulations in AD. [ABSTRACT FROM AUTHOR]

Arteriogenesis is an inflammatory driven mechanism, describing the growth of a natural bypass from pre-existing collateral arteries to compensate for an occluded artery. The complement system component C3 is a potent natural inflammatory activator. Here, we investigated its impact on the process of collateral artery growth using C3-deficient (C3 −/−) and wildtype control mice in a murine hindlimb model of arteriogenesis. Induction of arteriogenesis by unilateral femoral artery ligation resulted in decreased perfusion recovery in C3 −/− mice on day 7 as shown by Laser Doppler imaging. Immunofluorescence staining revealed a reduced vascular cell proliferation in C3 −/− mice. Gene expression analysis displayed a significant reduction in monocyte chemoattractant protein-1 (MCP-1) expression in C3 −/− mice. Interestingly, 3 days after induction of arteriogenesis, the number of macrophages (CD68+) recruited to growing collaterals was not affected by C3 deficiency. However, a significant reduction in inflammatory M1-like polarized macrophages (CD68+/MRC1−) was noted. Forced mast cell activation by Compound 48/80 as well as exogenous MCP-1 application rescued the number of M1-like polarized macrophages along with perfusion recovery in C3 −/− mice. In summary, this study demonstrates that complement C3 influences arteriogenesis by mediating MCP-1 expression, which is essential for the induction and enhancement of sterile inflammation. [ABSTRACT FROM AUTHOR]

Two-thirds of published patients with anti-leucine rich, glioma inactivated 1 (LGI1) encephalitis develop hippocampal sclerosis (HS). It is likely that this contributes to residual cognitive long-term deficits and the risk of epilepsy. Almost all patients harbor anti-LGI1-immunoglobulin G-(IgG-) subclass 4, which is considered a "benign", non-destructive subclass. In contrast, neuropathological case studies have suggested that the classical complement cascade may contribute to mediotemporal cell death in patients with LGI1 antibodies. IgG subclasses 1, 2, or 3 are required to initiate this cascade. We hypothesized that patients with these anti-LGI1-IgG1/2/3 in addition to IgG4 have a higher risk of developing HS than patients with anti-LGI1-IgG4 alone. We retrospectively assessed all anti-LGI1 encephalitis patients from this center with anti-LGI1-IgG-subclass information and follow-up MRI available. Nine out of 20 patients had developed HS (45%). Volumetric FreeSurfer analysis confirmed the visual HS diagnoses. HS and a lower hippocampal volume were associated with anti-LGI1-IgG1/2/3. All six patients with this IgG subclass status developed HS. There was no association with older or younger age at onset, female sex, longer latency from disease onset to start of immunotherapy, less intense immunotherapy, higher serum titers of LGI1 antibodies, LGI1 antibodies in CSF or higher LGI1-specific antibody indices. There was no association between anti-LGI1-IgG1/2/3 status and neuropsychological performance, epilepsy, or general neurological performance. This confirms our hypothesis that anti-LGI1-IgG1/2/3 in serum puts patients at risk of developing HS. If these findings can be confirmed and clinically corroborated, patients with anti-LGI1-IgG1/2/3 might become candidates for anti-complement-directed immunological treatments. [ABSTRACT FROM AUTHOR]

MBL is critical in activating the lectin pathway of the complement system. MBL deficiency remains a contentious issue in clinical practice, mainly because low MBL levels may present in completely asymptomatic individuals. However, in some cases, symptomatic patients may present with susceptibility to infections and even immune dysregulation. Infections may range from mild to severe, and may even be life-threatening and fatal. A significant number of patients may remain undiagnosed, merely because interrogating complement function is often postponed until after presumably more common immune problems have been excluded in patients with severe, recurrent or unusual infections. In addition, clinicians are less familiar with the clinical recognition and appropriate choice of special investigations necessary to diagnose MBL and other complement deficiencies. Our case report describes a young girl with a serious underlying inborn error of immunity. She initially presented with recurrent 'innocent' and mild infections. We illustrate that clinically relevant MBL deficiency, if undiagnosed, may have disastrous consequences. We also stress the importance of careful interpretation of MBL quantitative laboratory values and the urgent need for access to more specialised complement-component and genetic testing, especially for patients attending state healthcare facilities. [ABSTRACT FROM AUTHOR]

Background: During the COVID‐19 pandemic, novel nanoparticle‐based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined. Methods: To understand COVID‐19 vaccine‐mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure. Results: Vaccine‐mediated complement activation correlated with anti‐polyethelyne glycol (PEG) IgG (but not IgM) levels while anti‐PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine‐mediated basophil activation. Single‐cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll‐like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL‐13 and IL‐1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions. Conclusion: These findings provide insights into the mechanisms underlying allergic reactions to COVID‐19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy. [ABSTRACT FROM AUTHOR]

Background & Aims: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF‐associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non‐cirrhotic portal hypertension, recently classified as porto‐sinusoidal vascular disorders (PSVD). Methods: Since endothelial cells (ECs) are an important component in PSVD, we performed single‐cell RNA sequencing (scRNA‐seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA‐seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues. Results: We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs—coined CF LSECs—upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs. Conclusions: Our work showed novel aspects of human liver ECs at the single‐cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases. [ABSTRACT FROM AUTHOR]

Objective and design: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. Methods: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. Results: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. Conclusion: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD. [ABSTRACT FROM AUTHOR]

Lipedema is an adipose tissue disease with a massive expansion of subcutaneous fat tissue. Its etiology is poorly understood. We suggest that a major driving force of the disease is an enrichment of bacterial lipopolysaccharide (endotoxin) in lower-body fat depots (gluteofemoral white adipose tissue; gfWAT). Endotoxin, combined with a malfunctioning complement system, can induce low-grade inflammation in gfWAT and prompt massive depot expansion. The components of the terminal stage of the alternative complement pathway (ACP) are widely expressed in adipocytes and characterized by the production of the membrane attack complex that can lyse host cells as well, including adipocytes. In lipedema patients, a suppression of the ACP is observed, ultimately leading to an expansion of that fat mass. Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here, we propose that the underlying cause for lipedema could be triggered by a selective accumulation of bacterial lipopolysaccharides (LPS; also known as endotoxin) in gluteofemoral WAT. Together with a malfunctioning complement system, this induces low-grade inflammation in the depot and raises its uncontrollable expansion. Correspondingly, more attention should be paid in future research to the endotoxemia prevalent in patients with lipedema. We would like to propose that proper management of endotoxemia can reduce the progression and even improve the state of disease in patients with lipedema. [ABSTRACT FROM AUTHOR]

The complement system is an important component of innate and adaptive immunity that consists of three activation pathways. The classic complement pathway plays a role in humoral immunity, whereas the alternative and lectin pathways augment the innate response. Impairment, deficiency, or overactivation of any of the known 50 complement proteins may lead to increased susceptibility to infection with encapsulated organisms, autoimmunity, hereditary angioedema, or thrombosis, depending on the affected protein. Classic pathway defects result from deficiencies of complement proteins C1q, C1r, C1s, C2, and C4, and typically manifest with features of systemic lupus erythematosus and infections with encapsulated organisms. Alternative pathway defects due to deficiencies of factor B, factor D, and properdin may present with increased susceptibility to Neisseria infections. Lectin pathway defects, including Mannose-binding protein-associated serine protease 2 (MASP2) and ficolin 3, may be asymptomatic or lead to pyogenic infections and autoimmunity. Complement protein C3 is common to all pathways, deficiency of which predisposes patients to severe frequent infections and glomerulonephritis. Deficiencies in factor H and factor I, which regulate the alternative pathway, may lead to hemolytic uremic syndrome. Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9). Diagnosis of complement deficiencies involves screening with functional assays (i.e., total complement activity [CH50], alternative complement pathway activity [AH50], enzyme-linked immunosorbent assay [ELISA]) followed by measurement of individual complement factors by immunoassay. Management of complement deficiencies requires a comprehensive and individualized approach with special attention to vaccination against encapsulated bacteria, consideration of prophylactic antibiotics, treatment of comorbid autoimmunity, and close surveillance. [ABSTRACT FROM AUTHOR]

Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host‐protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement‐targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance. [ABSTRACT FROM AUTHOR]

The origination of graphs with neutrosophic type where membership of indeterminacy expels the vague results, by increasing the accuracy is used to extend application through the graphical environment. Since it is an extension of the intuitionistic type, there comes an immediate need to extend its findings and application to the neutrosophic type. Reversing the conditions of neutrosophic graphs by introducing the anti-behavior properties will produce an adequate number of new results and data, breaking the backlog in approaching decision-making problems and other real-world applications. This research aims to recognize the complementation concept in the Pythagorean co-neutrosophic graph, which has not been dealt with yet. The co-neutrosophic graph is the reversal concept of neutrosophic graphs, where the vertex and edge membership conditions are reversed, but the total sum of these memberships remains the same. Here, the discussion about complementation, cocomplementation, and its properties are carried out on a Pythagorean co-neutrosophic Graph. As a result, an application with improved accuracy result will be obtained as an outcome. [ABSTRACT FROM AUTHOR]

Ferumoxytol injection, also known as Feraheme®, is an approved IV injectable iron supplement and an experimental MRI contrast agent. Initially, it was approved as an IV bolus agent, but its use was later limited to a slow infusion drip due to high levels of infusion reactions. We collected various batches of ferumoxytol with expiration dates ranging from 2010 to 2025 and compared their size and zeta potential. Since nanoparticle surface properties can affect infusion reactions, we conducted a dot blot immunoassay to measure complement C3 opsonization with ferumoxytol preparations. We observed differences in nanoparticle size and zeta potential between batches and a 2.5-fold variation in complement activation. Interestingly, older batches from 2010 showed more uniform size distribution and lower complement activation than some of the newer batches. This finding may be valuable to the nanomedicine community and regulatory authorities. [ABSTRACT FROM AUTHOR]

PEGylation technology confers stability and modulates the biological performance of a broad range of preclinical and clinical nanopharmaceuticals. However, the emerging PEG immunogenicity in the general population is thought to impact the efficacy and safety of PEGylated medicines. Despite this, the clinical significance of PEG immunogenicity is still not clear and remains debatable. By considering the strategic importance of the PEGylation technology in nanopharmaceutical engineering, we raise a number of critical questions and briefly discuss gaps in the knowledge of PEG immunogenicity and its clinical significance. [ABSTRACT FROM AUTHOR]

Background: To explore whether IgG4 is involved in the pathogenesis of IgG4 HT. Methods: Serum TgAb IgG4 and TPOAb IgG4 were measured in IgG4 HT and non-IgG4 HT. C1q, mannose-binding lectin (MBL), Bb, C3d, C4d, and membrane attack complex (MAC) in thyroid tissues from IgG4 HT, non-IgG4 HT, and controls were examined by immunohistochemistry. We assessed IgG4 and MAC deposition in mouse thyroid by immunohistochemistry after injecting purified IgG4 into mice. The glycosylation patterns of TgAb IgG4 from IgG4 HT were identified by MALDI-TOF-MS. The ability of IgG4 to bind to MBL before and after deglycosylation was assessed by ELISA. MBL and MAC fluorescence were detected in thyrocytes after the addition of IgG4 or deglycosylated IgG4. Results: Serum TgAb IgG4 and TPOAb IgG4 levels were significantly higher in the IgG4 HT group. MBL, Bb, C3d, C4d, and MAC levels were significantly higher in the thyroid tissues of IgG4 HT than in non-IgG4 HT (all P < 0.001). IgG4 colocalized with MBL by immunofluorescence. In mice, follicular cell structure disruption was observed after the injection of IgG4 from IgG4 HT, as well as the colocalization of IgG4 with MAC. High levels of TgAb IgG4 glycosylation patterns, including monogalactose glycan (G1F), galactose-deficient glycan (G0F), and high-mannose glycan (M5), were detected in IgG4 HT. After deglycosylation, IgG4 reduced its ability to bind to MBL, and there was low MBL and MAC activation in thyrocytes. Conclusion: High levels of IgG4 glycosylation patterns, including G1F, G0F, and M5, may activate the complement lectin pathway, thereby participating in the pathogenesis of IgG4 HT.

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by the absence of complement regulatory proteins on the surface of erythrocytes, leading to intravascular hemolysis and thrombosis. Managing PNH during pregnancy poses significant challenges due to increased risks of morbidity and mortality. This case report describes the detailed obstetric course of a 44‐year‐old woman with PNH and additional hereditary protein C deficiency who had previously experienced multiple thrombotic events and adverse pregnancy outcomes (two early miscarriages and one stillbirth at 25 weeks gestation [WG]), treated with eculizumab (terminal C5 inhibitor) and optimal anticoagulation management. Close monitoring of hemolysis and hemostasis parameters was conducted throughout the gestation period together with increased obstetrical surveillance. The pregnancy progressed without thrombotic complications or breakthrough hemolysis, and the patient delivered a healthy newborn at 36 WG after induction of labor due to restricted fetal growth. To the best of our knowledge, this is the first reported case of a positive pregnancy outcome despite PNH in conjunction with hereditary thrombophilia. This case report highlights the importance of a multidisciplinary approach involving hematologists and obstetricians in the management of pregnant women with PNH. Tailored therapy, close monitoring, and comprehensive care are crucial to minimize risks and optimize outcomes.

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs. [ABSTRACT FROM AUTHOR]

Previous studies have highlighted the significant role of complement activation in kidney injuries induced by rhabdomyolysis, intravascular hemolysis, sepsis, and ischemia-reperfusion. Nevertheless, the specific role and mechanism of complement activation in acute kidney injury (AKI) caused by wasp venom remain unclear. The aim of this study was to elucidate the specific complement pathway activated and investigate complement activation in AKI induced by wasp venom. In this study, a complement-depleted mouse model was used to investigate the role of complement in wasp venom-induced AKI. Mice were randomly categorized into control, cobra venom factor (CVF), AKI, and CVF + AKI groups. Compared to the AKI group, the CVF + AKI group showed improved pathological changes in kidneys and reduced blood urea nitrogen (BUN) levels. The expression levels of renal complement 3 (C3), complement 5 (C5), complement 1q (C1q), factor B (FB), mannose-binding lectin (MBL), and C5b-9 in AKI group were upregulated compared with the control group. Conversely, the renal tissue expression levels of C3, C5, C1q, FB, MBL, and C5b-9 were decreased in the CVF + AKI group compared to those in the AKI group. Complement activation occurs through all three pathways in AKI induced by wasp venom. Furthermore, complement depletion by CVF attenuates wasp venom-induced nephrotoxicity, suggesting that complement activation plays a primary role in the pathogenesis of wasp venom-induced AKI. [ABSTRACT FROM AUTHOR]

Abstract Autoimmune related kidney diseases (ARKDs), including minimal change nephropathy (MCN), membranous nephropathy (MN), IgA nephropathy (IgAN), and lupus nephritis (LN), significantly affect renal function. These diseases are characterized by the formation of local immune complexes and the subsequent activation of the complement system, leading to kidney damage and proteinuria. Despite the known patterns of glomerular injury, the specific molecular mechanisms that contribute to renal tubular damage across ARKDs remain underexplored. Laser capture microdissection and liquid chromatography–tandem mass spectrometry (LC–MS/MS) were used to conduct a comparative proteomic analysis of renal tubular tissues from formalin-fixed paraffin-embedded samples. The cohort comprised of 10 normal controls (NC), 5 MCN, 4 MN, 17 IgAN, and 21 LN patients. Clinical parameters and histopathological assessments were integrated with proteomic findings to comprehensively investigate underlying pathogenic processes. Clinical evaluation indicated significant glomerular damage, as reflected by elevated urinary protein levels and reduced plasma albumin levels in patients with ARKD. Histological analyses confirmed varying degrees of tubular damage and deposition of immune complexes. Proteomic analyses identified significant changes in protein expression, particularly in complement components (C3, C4A, C4B, C8G, CFB, and SERPINA1) and mitochondrial proteins (ATP5F1E and ATP5PD), highlighting the common alterations in the complement system and mitochondrial proteins across ARKDs. These alterations suggest a novel complement–mitochondrial–epithelial–mesenchymal transition (EMT) pathway axis that contributes to tubular damage in ARKDs. Notably, significant alterations in CFB in tubular ARKD patients were revealed, implicating it as a therapeutic target. This study underscores the importance of complement activation and mitochondrial dysfunction in the pathogenesis of ARKDs, and proposes CFB as a potential therapeutic target to inhibit complement activation and mitigate tubular damage. Future research should validate the complement-mitochondrial-EMT pathway axis and explore the effects and mechanisms of CFB inhibitors in alleviating ARKD progression.

Background: Respiratory diseases seriously threaten human health worldwide, and lung injury is an important component of respiratory disease. Complement activation is an important function of the innate immune system. Complement activation helps the body defend against invasion by external microorganisms, whereas excessive complement activation can exacerbate tissue damage or lead to unwanted side effects. Ficolins are a class of immune-related proteins in the lectin pathway that play important roles in the body’s immune defense. Although individual ficolins are not well understood, current information suggests that ficolins may play an important regulatory role in lung injury. Summary: Several studies have shown that ficolins are involved in the immune response in the lung, particularly in the response to infectious and inflammatory processes. Key Messages: This review summarizes the role of ficolins in lung injury. Ficolins may influence the development and repair of lung injury by recognizing and binding pathogenic microorganisms, modulating the inflammatory response, and promoting the clearance of immune cells. In addition, ficolins are associated with the development and progression of lung diseases (such as pneumonia and ARDS) and may have an important impact on the pathophysiological processes of inflammatory diseases.

Diabetic kidney disease (DKD) is the most common cause of kidney failure, characterized by chronic inflammation and fibrosis. The complement system is increasingly implicated in the development and progression of diabetic nephropathy. The important complement anaphylatoxins C3a and C5a are key mediators of the innate immune system, which regulates cellular inflammation, oxidative stress, mitochondrial homeostasis and tissue fibrosis. This review summarizes the involvement of anaphylatoxins in the pathogenesis of diabetic kidney disease, highlights their important roles in the pathophysiologic changes of glomerulopathy, tubulointerstitial damage and immune cell infiltration, and discusses the modulatory effects of new anti‐diabetic drugs acting on the complement system. Based on available clinical data and findings from the preclinical studies of complement blockade, anaphylatoxin‐targeted therapeutics may become a promising approach for patients with DKD in the future. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%-50% of patients progress to kidney failure. The pathogenesis is incompletely understood. Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage. Diagnosis requires a biopsy interpreted by the Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, and C4d staining. Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology. Acceptable surrogate endpoints for therapeutic trials include ongoing proteinuria and rate of eGFR decline. The significance of persisting hematuria remains uncertain. The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric). Immunosuppression should be considered for those at high risk after maximal supportive care. Corticosteroids are controversial with the most positive results observed in Chinese. They carry a high risk of serious side effects. Similarly, mycophenolate may be most effective in Chinese. Other immunosuppressants are of uncertain benefit. Tonsillectomy appears efficacious in Japanese. Active areas of investigation include B-cell inhibition with agents targeting the survival factors BAFF and APRIL and complement inhibition with agents targeting the alternate pathway (Factors B and D), the lectin pathway (MASP-2), and the common pathway (C3 and C5). Hopefully soon, the who and the how of immunosuppression will be clarified, and kidney failure can be forestalled. [ABSTRACT FROM AUTHOR]

The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy. [ABSTRACT FROM AUTHOR]

Humoral immunity is a major waypoint towards chronic allograft dysfunction in lung transplantation (LT) recipients. Though allo-immunization and antibody-mediated rejection (AMR) are well-known entities, some diagnostic gaps need to be addressed. Morphological analysis could be enhanced by digital pathology and artificial intelligence-based companion tools. Graft transcriptomics can help to identify graft failure phenotypes or endotypes. Donorderived cell free DNA is being evaluated for graft-loss risk stratification and tailored surveillance. Preventative therapies should be tailored according to risk. The donor pool can be enlarged for candidates with HLA sensitization, with strategies combining plasma exchange, intravenous immunoglobulin and immune cell depletion, or with emerging or innovative therapies such as imlifidase or immunoadsorption. In cases of insufficient pre-transplant desensitization, the effects of antibodies on the allograft can be prevented by targeting the complement cascade, although evidence for this strategy in LT is limited. In LT recipients with a humoral response, strategies are combined, including depletion of immune cells (plasmapheresis or immunoadsorption), inhibition of immune pathways, or modulation of the inflammatory cascade, which can be achieved with photopheresis. Altogether, these innovative techniques offer promising perspectives for LT recipients and shape the 21st century's armamentarium against AMR. [ABSTRACT FROM AUTHOR]

Knowledge about the molecular mechanisms underlying the systemic inflammation observed in psoriasis remains incomplete. In this study, we applied mass spectrometry-based proteomics to compare the plasma protein levels between patients with psoriasis and healthy individuals, aiming to unveil potential systemically dysregulated proteins and pathways associated with the disease. Plasma samples from adult patients with moderate-to-severe psoriasis vulgaris (N = 59) and healthy age- and sex-matched individuals (N = 21) were analyzed using liquid chromatography–tandem mass spectrometry. Patients did not receive systemic anti-psoriatic treatment for four weeks before inclusion. A total of 776 protein groups were quantified. Of these, 691 were present in at least 60% of the samples, providing the basis for the downstream analysis. We identified 20 upregulated and 22 downregulated proteins in patients with psoriasis compared to controls (p < 0.05). Multiple proteins from the complement system were upregulated, including C2, C4b, C5, and C9, and pathway analysis revealed enrichment of proteins involved in complement activation and formation of the terminal complement complex. On the other end of the spectrum, periostin was the most downregulated protein in sera from patients with psoriasis. This comprehensive proteomic investigation revealed significantly elevated levels of complement cascade proteins in psoriatic plasma, which might contribute to increased systemic inflammation in patients with psoriasis. [ABSTRACT FROM AUTHOR]

The characteristic feature of chronic peritoneal damage in peritoneal dialysis (PD) is a decline in ultrafiltration capacity associated with pathological fibrosis and angiogenesis. The pathogenesis of peritoneal fibrosis is attributed to bioincompatible factors of PD fluid and peritonitis. Uremia is associated with peritoneal membrane inflammation that affects fibrosis, neoangiogenesis, and baseline peritoneal membrane function. Net ultrafiltration volume is affected by capillary surface area, vasculopathy, peritoneal fibrosis, and lymphangiogenesis. Many inflammatory cytokines induce fibrogenic growth factors, with crosstalk between macrophages and fibroblasts. Transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF)-A are the key mediators of fibrosis and angiogenesis, respectively. Bioincompatible factors of PD fluid upregulate TGF-β expression by mesothelial cells that contributes to the development of fibrosis. Angiogenesis and lymphangiogenesis can progress during fibrosis via TGF-β–VEGF-A/C pathways. Complement activation occurs in fungal peritonitis and progresses insidiously during PD. Analyses of the human peritoneal membrane have clarified the mechanisms by which encapsulating peritoneal sclerosis develops. Different effects of dialysates on the peritoneal membrane were also recognized, particularly in terms of vascular damage. Understanding the pathophysiologies of the peritoneal membrane will lead to preservation of peritoneal membrane function and improvements in technical survival, mortality, and quality of life for PD patients. [ABSTRACT FROM AUTHOR]

Background: Factor H (FH) is a major soluble inhibitor of the complement system and part of a family comprising five related proteins (FHRs 1-5). Deficiency of FHR1 was described to be linked to an elevated risk of systemic lupus erythematosus (SLE). As FHR1 can partially antagonize the functionality of FH, an altered FHR1/FH ratio could not only enhance SLE vulnerability but also affect the disease expression. This study focuses on the analysis of FH and FHR1 at a protein level, and the occurrence of anti-FH autoantibodies (anti-FH) in a large cohort of SLE patients to explore their association with disease activity and/or expression. Methods: We assessed FH and FHR1 levels in plasma from 378 SLE patients compared to 84 healthy controls (normal human plasma, NHP), and sera from another cohort of 84 healthy individuals (normal human serum, NHS), using RayBio® CFH and CFHR1 ELISA kits. Patients were recruited by the Swiss SLE Cohort Study (SSCS). Unmeasurable FHR1 levels were all confirmed by Western blot, and in a subgroup of patients by PCR. Anti-FH were measured in SLE patients with non-detectable FHR1 levels and matched control patients using Abnova's CFH IgG ELISA kit. Results: Overall, FH and FHR1 levels were significantly higher in healthy controls, but there was no significant difference in FHR1/FH ratios between SLE patients and NHPs. However, SLE patients showed a significantly higher prevalence of undetectable FHR1 compared to all healthy controls (35/378 SLE patients versus 6/168 healthy controls; p= 0.0214, OR=2.751, 95% CI = 1.115 - 8.164), with a consistent trend across all ethnic subgroups. Levels of FH and FHR1, FHR1/FH ratios and absence of FHR1 were not consistently associated with disease activity and/or specific disease manifestations, but absence of FHR1 (primarily equivalent to CFHR1 deficiency) was linked to the presence of anti-FH in SLE patients (p=0.039). Conclusions: Deficiency of FHR1 is associated with a markedly elevated risk of developing SLE. A small proportion of FHR1-deficient SLE patients was found to have autoantibodies against FH but did not show clinical signs of microangiopathy. [ABSTRACT FROM AUTHOR]

Blood transfusions save lives and improve health every day. Despite the matching of blood types being stricter than it ever has been, emergency transfusions among incompatible blood types are still inevitable in the clinic when there is a lack of acceptable blood types for recipients. Here to overcome this, a counter measure nanoplatform consisting of a polymeric core coated by a red blood cell (RBC) membrane is developed. With A‐type or B‐type RBC membrane camouflaging, the nanoplatform is capable of specifically capturing anti‐A or anti‐B IgM antibodies within B‐type or A‐type whole blood, thereby decreasing the corresponding IgM antibody levels and then allowing the incompatible blood transfusions. In addition to IgM, the anti‐RBC IgG antibody in a passive immunization murine model can likewise be neutralized by this nanoplatform, leading to prolonged circulation time of incompatible donor RBCs. Noteworthily, nanoplatform made by expired RBCs (>42 days stored hypothermically) and then subjected to lyophilization does not impair their effect on antibody neutralization. Most importantly, antibody‐captured RBC‐NP do not exacerbate the risk of inflammation, complement activation, and coagulopathy in an acute hemorrhagic shock murine model. Overall, this biomimetic nanoplatform can safely neutralize the antibody to enable incompatible blood transfusion. [ABSTRACT FROM AUTHOR]

Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice. [ABSTRACT FROM AUTHOR]

Many kidney diseases are associated with proteinuria. Since proteinuria is independently associated with kidney function loss, anti-proteinuric medication, often in combination with dietary salt restriction, comprises a major cornerstone in the prevention of progressive kidney failure. Nevertheless, complete remission of proteinuria is very difficult to achieve, and most patients with persistent proteinuria slowly progress toward kidney failure. It is well-recognized that proteinuria leads to kidney inflammation and fibrosis via various mechanisms. Among others, complement activation at the apical side of the proximal tubular epithelial cells is suggested to play a crucial role as a cause of progressive loss of kidney function. However, hitherto limited attention is given to the pathophysiological role of tubular complement activation relative to glomerular complement activation. This review aims to summarize the evidence for tubular epithelial complement activation in proteinuric kidney diseases in relation to loss of kidney function. [ABSTRACT FROM AUTHOR]

Early-onset systemic lupus erythematous (SLE) is a distinct clinical entity characterized by the onset of disease manifestations during childhood. Despite some similarities to patients who are diagnosed during adulthood, early-onset SLE typically displays a greater disease severity, with aggressive multiorgan involvement, lower responsiveness to classical therapies, and more frequent flares. Lupus nephritis is one of the most severe complications of SLE and represents a major risk factor for long-term morbidity and mortality, especially in children. This review focuses on the clinical and histological aspects of early-onset lupus nephritis, aiming at highlighting relevant differences with adult patients, emphasizing long-term outcomes and discussing the management of long-term complications. We also discuss monogenic lupus, a spectrum of conditions caused by single gene variants affecting the complement cascade, extracellular and intracellular nucleic acid sensing and processing, and occasionally other metabolic pathways. These monogenic forms typically develop early in life and often have clinical manifestations that resemble sporadic SLE, whereas their response to standard treatments is poor. [ABSTRACT FROM AUTHOR]

Iron (Fe) is a crucial mineral for the health of fish. The investigation explored the effects of two different sources of iron (organic and inorganic) and two levels (60 and 85 mg/kg) of Fe on the innate immunity, antioxidant capacity, and hematological responses of Nile tilapia. Fish with an average weight of 16.57 ± 2.25 g were fed three times a day for a duration of seven weeks. A total of 400 fish were distributed among 20 tanks, each with a capacity of 240 L and housing 20 fish. The experiment comprised five treatments, and the experimental design employed was a completely randomized design, which included the following treatments: a basal diet (BD) with no addition of Fe in the premix, 60 mg/kg Inorganic Fe, 60 mg/kg Organic Fe, 85 mg/kg Inorganic Fe, and 85 mg/kg Organic Fe. The results indicated that the use of organic Fe significantly improved the hematocrit levels and mean corpuscular hemoglobin. Conversely, the values of lysozyme decreased in fish that were fed with the organic Fe source. However, the hemolytic activity of the complement system and the production of the superoxide anion test exhibited an increase with the use of organic Fe. Furthermore, the fish that were fed with the 85 mg/kg organic diet demonstrated superior antioxidant responses. In conclusion, the inclusion of organic Fe at a concentration of 85 mg/kg was found to be more efficient for the growth of juvenile Nile tilapia. [ABSTRACT FROM AUTHOR]

Antibodies to Ebola virus glycoprotein (EBOV GP) represent an important correlate of the vaccine efficiency and infection survival. Both neutralization and some of the Fc-mediated effects are known to contribute the protection conferred by antibodies of various epitope specificities. At the same time, the role of the complement system remains unclear. Here, we compare complement activation by two groups of representative monoclonal antibodies (mAbs) interacting with the glycan cap (GC) or the membrane-proximal external region (MPER) of GP. Binding of GC-specific mAbs to GP induces complement-dependent cytotoxicity (CDC) in the GP-expressing cell line via C3 deposition on GP in contrast to MPER-specific mAbs. In the mouse model of EBOV infection, depletion of the complement system leads to an impairment of protection exerted by one of the GC-specific, but not MPER-specific mAbs. Our data suggest that activation of the complement system represents an important mechanism of antiviral protection by GC antibodies. An analysis of the complement activation by human monoclonal antibodies to Ebola virus glycoprotein suggests the distinct mechanisms for antibodies targeting the glycan cap versus antibodies against the membrane-proximal external region. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a widespread muscle pain disorder that primarily affects females. Osteoarthritis (OA) is another common chronic condition. This study utilized sequential window acquisition of all theoretical mass spectra (SWATH)‐based proteomic analysis on the urine of patients with FM and OA. The study identified 54 differentially expressed proteins (DEPs) in the FM group compared to the healthy control (HC) group; 17 DEPs in the OA group compared to the HC group; and 47 DEPs in the FM group compared to the OA group, with a p‐value <0.05 and a fold change >1.5 or <0.67. The DEPs in both FM and OA groups were primarily involved in pathways related to coagulation and the complement system, as well as serotonin, dopamine, glutamate pathways, and acute phase reactions. The study suggests that FM and OA induce inflammatory reactions, significantly altering the expression of acute phase proteins and notably decreasing the expression of GNB2. This distinction between health and disease, and the differentiation between FM and OA, is facilitated through the coagulation and complement systems, with SERPING1 and EPCR being key markers. Through these pathways, a better understanding of the impact of FM and OA on the human proteome is achieved. [ABSTRACT FROM AUTHOR]

Complement mediated interference with the detection of antibodies targeting HLA is a known limitation of the single antigen bead (SAB) Luminex assay. Ethylenediaminetetraacetic acid (EDTA) is currently the serum treatment of choice in most histocompatibility laboratories to block complement activation by chelating calcium. The purpose of this study was to investigate a serum with an antibody reactivity to HLA‐DQ6, 7, 8 and 9 molecules, in the Luminex SAB assay, that was inhibited by treatment with EDTA. Serum was from a 55‐year‐old highly sensitised female renal transplant candidate that contained, among others, antibodies to an epitope containing the 74EL eplet, shared by HLA‐DQ6, DQ7, DQ8 and DQ9 molecules. Serum samples were treated with EDTA, dithiothreitol (DTT), or heat prior to testing by SAB assay. EDTA‐treated serum was also tested after the addition of calcium chloride (CaCl2). HLA‐DQ‐specific antibodies were isolated by adsorption/elution method using three informative donor cells and were tested in the absence or presence of EDTA. The antibody reactivity against HLA‐DQ6, DQ7, DQ8 and DQ9 in the SAB assay was significantly inhibited by treating serum and eluates with EDTA and was restored by addition of CaCl2. The study represents the first description of a calcium‐dependent epitope in HLA molecules. The relevance of this finding is that the treatment of sera with EDTA could lead to false‐negative reactions in the SAB assay, which may compromise virtual crossmatching. [ABSTRACT FROM AUTHOR]