The serum complement system is a cornerstone element of the innate immune response. Bacterial resistance to this system is a multifaceted process involving various proteins and molecular mechanisms. Here, we report several genes required for the growth of Yersinia pestis in serum. Among them, we found that ypo0337 encodes an outer-membrane-associated lectin that recruits factor H, C4BP and hemopexin, conferring resistance to the serum complement system. YPO0337 displays high sequence similarity with the SubB subunit of the AB5 toxin from Escherichia coli, as well as other SubB-like proteins, and subB from E. coli restores the ability of Y. pestis Δypo0337 mutant to resist to serum complement. Altogether, the data suggest that at least two members of the SubB protein family function as virulence factors, conferring resistance to serum complement through a unique mode of action.

Vascular dementia (VaD) is the second most common cause of dementia. Few bioinformatic analysis has been done to explore its biomarkers. This study aimed to excavate potential biomarkers for VaD using bioinformatic analysis and validate them at both animal and patient levels. Based on microarray data of GSE122063, bioinformatic analysis revealed 502 DEGs in the frontal and 674 DEGs in the temporal cortex of VaD patients. Afterward, the hub genes between two regions, including C1QA, C1QB, C1QC, and C5AR1, were dugout. Interestingly, compared with sham mice or controls, the above four complements were highly expressed in the cortices of VaD animals and in the peripheral serum of VaD patients. Moreover, receiver operating characteristic curve analysis conformed to good diagnostic powers of these complements, with C1QB having the most prominent capacity (AUC = 0.799, 95%CI 0.722-0.875). That means the complements, especially subunits of C1Q, might be used as specific early VaD diagnostic biomarkers.

Cytokines are crucial regulators of the immune system that orchestrate interactions between cells and, when dysregulated, contribute to the progression of chronic inflammation, cancer, and autoimmunity. Numerous biologic-based clinical agents, mostly monoclonal antibodies, have validated cytokines as important clinical targets and are now part of the standard of care for a number of diseases. These agents, while impactful, still suffer from limitations including a lack of oral bioavailability, high cost of production, and immunogenicity. Small-molecule cytokine inhibitors are attractive alternatives that can address these limitations. Although targeting cytokine-cytokine receptor complexes with small molecules has been a challenging research endeavor, multiple small-molecule inhibitors have now been identified, with a number of them undergoing clinical evaluation. In this review, we highlight the recent advancements in the discovery and development of small-molecule inhibitors targeting soluble cytokines. The strategies for identifying these novel ligands as well as the structural and mechanistic insights into their activity represent important milestones in tackling these challenging and clinically important protein-protein interactions.

With the approval of mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lipid nanoparticles (LNP) have emerged as a powerful tool for nucleic acid delivery. Modification of LNP with polyethylene glycol (PEG)-lipids contributes to their in vitro and in vivo stability by reducing aggregation of the particles. Despite the general acknowledgement of the low immunogenicity of PEG, there are numerous reports of the occurrence of anti-PEG antibodies in the blood of healthy individuals. Furthermore, there are reports that pre-existing anti-PEG IgM antibodies attenuated the efficacy of PEG-modified drugs administered systemically. Skeletal muscles, the administration site for mRNA vaccines, are highly vascularized by a network of blood vessels to provide them with nutrients and oxygen. Since skeletal muscles can contain circulating anti-PEG antibodies or the administered mRNA-LNP extravasate into bloodstream, the purpose of this study was to evaluate the effects of pre-existing anti-PEG IgM on the protein translation, biodistribution, and humoral responses to mRNA-loaded LNP (mRNA-LNP) administered intramuscularly (i.m.) in mice. We found that the presence of anti-PEG IgM in blood has only a minor effect on the translation and distribution of mRNA-LNP in the localized muscle area where the mRNA-LNP were administered. Circulating anti-PEG IgM did not increase the total accumulation of mRNA-LNP in the liver, but did markedly diminish its protein translation because the mRNA-LNP were delivered primarily to Kupffer cells rather than to hepatocytes. Binding of anti-PEG IgM to mRNA-LNP, and subsequent complement activation, suppressed mRNA translation loaded in LNP in the liver. Repeated intramuscular injections of SARS-CoV-2 Spike protein mRNA-LNP elicited a robust immune response. Our results indicate that the presence of circulating anti-PEG IgM does not interfere with the efficiency of mRNA vaccines administered i.m. in mice. We can speculate that non-specific translation of mRNA vaccines in somatic cells may be inhibited in vivo by circulating anti-PEG IgM, reducing adverse effects such as hepatitis and myocarditis that are caused by immune responses against translated antigen proteins.

Type 2 (Th2) allergic diseases are chronic conditions characterized by a Th2-polarized immune response to allergens. These diseases can be categorized by affected barrier sites: skin (atopic dermatitis, allergic contact dermatitis), gut (food allergy), and respiratory tract (e.g., asthma, chronic rhinosinusitis). The global prevalence of Th2 allergic diseases has increased the need for a deeper understanding of their pathophysiology. Several associations have been identified between genetic variants in the genes encoding components of the complement system and allergic disease. Moreover, levels of several complement proteins are elevated in patients with allergy. Experimental evidence demonstrates that the complement system plays a critical role in the development of these diseases across barrier sites. While site-specific differences exist in the complement components involved, key pathways, particularly C3 and C5, are prominent across the skin, gut, and lung.

Around one-quarter of all patients undergoing cardiac procedures, particularly those on cardiopulmonary bypass, develop cardiac surgery-associated acute kidney injury (CSA-AKI). This complication increases the risk of several serious morbidities and of mortality, representing a significant burden for both patients and the healthcare system. Patients with diminished kidney function before surgery, such as those with chronic kidney disease, are at heightened risk of developing CSA-AKI and have poorer outcomes than patients without preexisting kidney injury who develop CSA-AKI. Several mechanisms are involved in the development of CSA-AKI; injury is primarily thought to result from an amplification loop of inflammation and cell death, with complement and immune system activation, cardiopulmonary bypass, and ischemia-reperfusion injury all contributing to pathogenesis. At present there are no effective, targeted pharmacological therapies for the prevention or treatment of CSA-AKI, although several preclinical trials have shown promise, and clinical trials are under way. Progress in the understanding of the complex pathophysiology of CSA-AKI is needed to improve the development of successful strategies for its prevention, management, and treatment. In this review, we outline our current understanding of CSA-AKI development and management strategies and discuss potential future therapeutic targets under investigation.

Epidermolysis Bullosa Acquisita (EBA) is an autoimmune blistering dermatosis characterized by autoantibodies (AAbs) against type VII collagen (COL7) located at the dermal epidermal junction (DEJ). Local complement activation drives C5a generation associated with neutrophil recruitment and activation resulting in skin lesions and inflammation. Here we tested the impact of C5a/C5adesArg, C5 or combined C5 and alternative pathway (AP) targeting on disease development and skin inflammation in a preclinical mouse model mimicking the effector phase of EBA.

C57BL/6 mice were treated subcutaneously with purified rabbit anti-mouse-COL7 IgG in the presence of IgG1 mAbs directed against murine C5a/C5adesArg (M031), C5 (mBB5.1), a bifunctional protein comprising mBB5.1 fused to an active fragment of the AP inhibitor factor H (M014) or an IgG1 isotype control mAb. Formation of skin lesions was evaluated 12 days every other day. On day 12, DEJ separation, IgG AAb and C3b deposition and neutrophil infiltration was assessed.

Isotype IgG1-treated mice developed first skin lesions on day 4 peaking on day 12. Prophylactic treatment with either M031 or M014 markedly reduced the development of skin lesions, the dermal/epidermal separation and neutrophil recruitment. Surprisingly, C5 or combined AP/C5 inhibition by M014 but not C5a/C5adesArg-targeting by M031 reduced the development of skin lesions and dermal/epidermal separation in the setting of therapeutic treatment. IgG and C3b deposition was not affected by either treatment. Importantly, direct comparison of isolated C5 targeting by mBB5.1 vs. combined AP/C5 inhibition by M014 revealed that M014 reduced the development of skin lesions earlier and more pronounced than mBB5.1.

Our findings identify combined C5/AP targeting as a novel therapeutic option for autoimmune blistering dermatoses.

Extracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72-80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in discovery (n = 32) and validation (n = 16) datasets with areas under receiver operating characteristic curves (AUCs). Longevity-associated large EV (LEV) plasma subpopulations were mainly related to immune cells (HLA-ABC+, CD9+, and CD31+) and muscle cells (MCAD+ and RyR2+). Of 7960 identified plasma EV peptides (519 proteins), 46.4% were related to the immune system and 10.1% to muscle. Compared with short-lived older adults, 756 EV peptides (131 proteins) had a higher abundance, and 130 EV peptides (78 proteins) had a lower abundance in long-lived adults. Among longevity-associated peptides, 437 (58 proteins) were immune system related, and 12 (2 proteins) were muscle related. Using just three to five plasma EV peptides (mainly complement components C2-C6), we achieved high predictive accuracy for longevity (AUC range 0.91-1 in a hold-out validation dataset). Our findings suggest that immune cells produce longevity-associated plasma EVs and elucidate fundamental mechanisms regulating aging and longevity. EV longevity predictors suggest there may be merit in targeting complement pathways to extend lifespan, for instance, with any one of the multiple complement inhibitors currently available or in clinical development.

Aortic disease encompasses life-threatening conditions such as aortic aneurysm and dissection, which are associated with high prevalence, morbidity, and mortality. The complement system, a key component of innate immunity, not only defends against pathogens but also maintains tissue homeostasis. Recent discoveries have expanded its role beyond immunity, linking complement dysregulation to numerous diseases and positioning it as a target for pharmacotherapy. Complement-based treatments for precision medicine are emerging, with several pharmaceuticals either already approved or under investigation. In aortic disease, complement activation and dysregulation have unveiled novel mechanisms and clinical implications. Human and experimental studies suggest that all three complement pathways contribute to disease pathophysiology. The complement system induces direct cellular damage via the membrane attack complex, as well as matrix-metalloproteinase (MMP)-associated tissue damage by promoting MMP-2 and MMP-9 expression. The anaphylatoxins C3a and C5a exacerbate disease by recruiting immune cells and triggering proinflammatory responses. Examples include neutrophil extracellular trap formation and cytokine release by polymorphonuclear neutrophils. These findings highlight the complement system as a promising novel diagnostic and therapeutic target in aortic disease with potential for individualized treatment. However, gaps remain, emphasizing the need for standardized multisite preclinical studies to improve reproducibility and translation. Biomarker studies must also be validated across diverse patient cohorts for clinical applicability. This review examines current knowledge regarding complement in aortic disease, aiming to evaluate its potential for innovative diagnostic and personalized treatment strategies.

Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF often requires the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than shock, and survivors are usually left with severe scarring and tissue loss. Despite these challenging features, PF is a pathophysiologically distinct, homogeneous, and highly predictable form of sepsis-associated DIC for which poor outcomes are not a foregone conclusion. The fundamental pathologic lesion in PF is a failure of the anticoagulant protein C pathway, which leads to uncontrolled microvascular clotting and inadequate protein C-mediated cytoprotective effects, which are vital for survival in sepsis. Herein, we review the clinical features and diagnosis of PF. Drawing from existing clinical literature and recent advances in our understanding of the pathophysiology of PF, we describe rationally designed treatment approaches for this disorder, including repletion of natural circulating anticoagulants, use of therapeutic anticoagulation, and ways to optimize transfusion support, and we outline specific interventions that we would recommend avoiding.

The complement system plays an integral role in both innate and adaptive immune responses. Beyond its protective function against infections, complement is also known to influence tumor immunity, where its activation can either promote tumor progression or mediate tumor cell destruction, depending on the context. One such context can be provided by antibodies, with their inherent capacity to activate the classical complement pathway. In recent years, our understanding of the mechanisms governing complement activation by IgG and IgM antibodies has expanded significantly. At the same time, preclinical and clinical studies on antibodies such as rituximab, ofatumumab, and daratumumab have provided evidence for the role of complement in therapeutic success, encouraging strategies to further enhance its activity. In this review we examine the main determinants of antibody-mediated complement activation, highlighting the importance of antibody subclass, affinity, valency, and geometry of antigen engagement. We summarize the evidence for complement involvement in anti-tumor activity and challenges of accurately estimating the extent of its contribution to therapeutic efficacy. Furthermore, we explore several engineering approaches designed to enhance complement activation, including increased Fc oligomerization and C1q affinity, bispecific C1q-recruiting antibodies, IgG subclass chimeras, as well as antibody and paratope combinations. Strategies targeting membrane-bound complement regulatory proteins to overcome tumor-associated complement inhibition are also discussed as a method to boost therapeutic efficacy. Finally, we highlight the potential of complement-dependent cellular cytotoxicity (CDCC) and complement-dependent cellular phagocytosis (CDCP) as effector mechanisms that warrant deeper investigation. By integrating advances in antibody and complement biology with insights from efforts to enhance complement activation in therapeutic antibodies, this review aims to provide a comprehensive framework of antibody design and engineering strategies that optimize complement activity for improved anti-tumor efficacy.

The limitations of traditional blood supply systems, particularly where ideal storage is unfeasible, challenge the efficacy of transfusion medicine, especially in emergencies and battlefield scenarios. This study investigates a novel hemoglobin-based oxygen carrier (HBOC) using a dual-coating approach with metal phenolic networks (MPNs) and polyethylene glycol (PEG). Utilizing zeolitic imidazolate framework-8 (ZIF-8) nanoparticles for their porosity and biocompatibility, the addition of MPN and PEG coatings enhances biocompatibility and stabilizes encapsulated hemoglobin (Hb). This reduces Hb release and minimizes interactions with the coagulation cascade, as evidenced by stable prothrombin and activated partial thromboplastin times. Complement activation studies showed slight increases in C5a levels, indicating low potential for severe immune reactions. In vivo evaluations demonstrated that both MPN-coated and PEGylated Hb-loaded ZIF-8 NPs have enhanced circulation times, with significantly longer half-lives than free Hb. However, PEGylation did not offer additional benefits over MPN coating alone, possibly due to suboptimal PEG density or shielding. Biodistribution studies indicated similar accumulation patterns in the liver and kidneys for both NP types, suggesting common clearance pathways. These findings suggest our PEGylated Hb-loaded ZIF-8 NPs as promising alternatives to traditional transfusions. Future research will assess their efficacy in resuscitation from hemorrhagic shock to validate their clinical application.

Diabetic nephropathy (DN), one of the most common complications of diabetes mellitus (DM), accounts for a major cause of chronic kidney disease (CKD) worldwide, with a complicated pathogenesis and limited effective strategies nowadays. The mineralocorticoid receptor (MR) is a classical ligand-activated nuclear transcription factor. It is expressed in the renal intrinsic and immune cells, especially macrophages. Over-activation of the MR was observed in patients with DN and was associated with DN prognosis. The renoprotective role of a new generation of non-steroidal selective mineralocorticoid receptor antagonist (MRA), finerenone, has been confirmed in DM and CKD patients. However, the mechanism by which finerenone improves renal inflammation in DN has yet to be completely understood. It was found in this research that the oral administration of finerenone attenuated the kidney injuries in established DN in db/db mice, and particularly improved the pathological changes in the renal tubulointerstitia. Specifically, finerenone inhibited the over-activation of the MR in macrophages, thereby reducing the expression of G protein subunit alpha i2 (GNAI2, Gnαi2), a key downstream component of the C5aR1 pathway. Animal experiments demonstrated that C5aR1 knockout alleviated renal injuries, confirming the critical pathogenic role of C5aR1 in DN. Moreover, finerenone mitigated inflammatory and chemotaxis responses by downregulating Gnαi2 in macrophages. These effects were reflected by reduced expressions of the pro-inflammatory chemokines CXCL15 and CCL2, the regulation of macrophage polarization and improvements in apoptosis. This study intends to understand the protective role of finerenone in DN, which is conducive to revealing the pathophysiological mechanism of DN and further optimizing the treatment of DN patients.

Diverse inflammatory pathology is involved in acute respiratory distress syndrome (ARDS). This study aimed to assess the role of complement component fragment 5a (C5a) receptor 2 (C5aR2) in prognosis of patients with ARDS.

A total of 64 adult patients diagnosed with ARDS were prospectively recruited to the study over a period of one year after obtaining the informed consent. The serum C5a and C5aR2were determined using ELISA Kit sandwich method. Area under receiver operating characteristic (AUROC) was used to analyse the prognostic performance of C5a, C5R2, and C5a/C5R2 ratio using MedCalc. The relationship of these biomarkers with the parameters of poor prognosis (non-recovery, hospitalization, ventilation and ICU admission) was analysed through regression using SPSSv20.

The mean age of the included participants was 49.17 (SD:14.81) years. C5a/C5aR2 ratio had better discrimination (AUC: 0.707 vs 0.699 vs 0.511) and higher specificity (78.1 vs 71.9 vs 3.1) than C5R2 and C5a in predicting the poor prognosis among ARDS patients. The increased level of C5aR2 (OR: 0.225; p = 0.009) was significantly associated with better recovery and the high C5a/C5aR2 ratio (OR: 3.281; p = 0.036) was significantly associated with non-recovery in moderate to severe patients. Additionally, steroid treatment significantly associated with better recovery in patients with a high C5a/C5aR2 ratio (OR: 0.104; p = 0.007).

The current evidence indicates that a higher levels of C5aR2 significantly associated with better recovery, whereas high levels of C5a/C5aR2 significantly associated to poor prognosis in moderate to severe ARDS patients. However, adequately powered studies are required to confirm these findings in future.

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.

In the aging retina, persistent activation of microglia is known to play a key role in retinal degenerative diseases like age-related macular degeneration (AMD). Furthermore, dysregulation of the alternative complement pathway is generally accepted as the main driver for AMD disease progression and microglia are important producers of local complement and are equipped with complement receptors themselves. Here, we investigate the involvement of anaphylatoxin signaling, predominantly on Iba1+ cell activity, in light-induced retinal degeneration as a model for dry AMD, using anaphylatoxin receptor knockout (KO) mice.

Bright white light with an intensity of 10,000 lux was applied for 30 minutes to complement component 3a receptor 1 (C3ar1) or complement component 5a receptor 1 (C5ar1) KO and wildtype (WT) mice. Analyses of transcriptome changes and migration activity of Iba1+ cells as well as retinal thickness were performed 4 days after light exposure.

Full body KO mice of either C3aR1 or C5aR1 were tested, but none led to mitigated migration of Iba1+ cells to the subretinal space or decreased expression of complement factors after light damage compared to WT mice. However, a partial rescue of retinal thickness was shown in C3aR1 KO mice, which was mirrored by significant less membrane attack complex (MAC) occurrence in the outer retina.

We conclude that deletion of the anaphylatoxin receptor C3aR1 cannot modulate mononuclear phagocytes but diminishes retinal degeneration through interference with the complement pathway and thus decreased MAC assembling. C3aR1-targeted therapy may be considered for patients with dry AMD.

To investigate the follicle microenvironments of women with premature ovarian insufficiency (POI), with normal ovarian reserve function, and who are older (age >40 years) and to identify potential therapeutic targets.

In total, 9 women who underwent in vitro fertilization(IVF) or intracytoplasmic sperm injection(ICSI) were included in this study. The first punctured follicle of each patient was used. Single-cell RNA sequencing was subsequently performed to explore the characteristics of the follicle microenvironments of women with POI, with a normal ovarian reserve and who were older.

In total, 87,323 cells were isolated and grouped into six clusters: T cells, B cells, neutrophils, basophils, mononuclear phagocytes (MPs), and granulosa cells. The study demonstrated that the POI samples had a smaller component ratio of MPs than did the other samples. The correlation between MPs and granulosa cells may lead to the development of POI. We found that the gene that was simultaneously downregulated in the POI group compared with the normal and older age groups was HLA-DRB5. Moreover, we observed that HLA-DRB5 was expressed mainly in monocytes. The temporal differentiation trajectory revealed that different monocytes play important roles in the beginning and end stages of differentiation. The C5AR1 gene is highly expressed in monocytes.

Our findings revealed that the interaction between monocytes and granulocytes may contribute to the development of POI. We found that POI lacked HLA-DRB5 expression and had impaired antigen processing and presentation activities. To a certain extent, C5AR1 could be used to predict the development of POI.

It has been reported that patients with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) have worse prognosis and outcomes than those whose cancer relapses after prior local therapy (PLT-mCSPC). Our aim was to interrogate and validate underlying differences in tumor gene expression profiles between dn-mCSPC and PLT-mCSPC.

The inclusion criteria were histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data for treatment-naïve primary prostate tissue. RNA sequencing was performed by Tempus or Caris Life Sciences, both of which have Clinical Laboratory Improvement Amendments certification. The Tempus cohort was used for interrogation, while the Caris cohort was used for validation. Differential gene expression analysis between the cohorts was conducted using the DEseq2 pipeline. The resulting gene expression profiles were further analyzed using Gene Set Enrichment software to identify pathways with enrichment in each cohort.

Overall, 128 patients were eligible, of whom 78 were in the Tempus cohort (dn-mCSPC 37, PLT-mCSPC 41) and 50 were in the Caris cohort (dn-mCSPC 30, PLT-mCSPC 20). Tumor tissues from patients with dn-mCSPC had higher expression of genes associated with inflammation pathways, while tissues from patients with PLT-mCSPC had higher expression of genes involved in oxidative phosphorylation, fatty acid metabolism, and androgen response pathways.

Our study revealed upregulation of distinct genomic pathways in dn-mCSPC in comparison to PLT-mCSPC. These hypothesis-generating data could guide personalized therapy for men with prostate cancer and explain different survival outcomes for dn-mCSPC and PLT-mCSPC.

We measured gene expression levels in tumors from patients with metastatic castration-sensitive prostate cancer. In patients with metastatic disease at first diagnosis, inflammatory pathways were upregulated. In patients whose metastasis occurred on relapse after treatment, androgen response pathways were upregulated. These findings could help in personalizing therapy for prostate cancer and explaining differences in survival.

Despite their prevalence and potential severity, non-IgE-mediated drug-induced hypersensitivity reactions (DHRs) are under-researched and poorly defined, particularly in children. Presentations range from mild cutaneous reactions to severe systemic diseases, with pathophysiological mechanisms and reliable diagnostic markers not well established. The lack of validated tests often leads to permanent drug restrictions, reliance on second-line drugs, and increased costs. Focusing on recent advancements and areas needing further research, this review aims to enhance children's recognition, diagnosis, and management of non-IgE-mediated DHRs.

Recent studies have enhanced the understanding of immediate and delayed non-IgE-mediated drug reactions. Key findings include the Mas-related G protein-coupled receptor X2 in mast cells and the identification of HLA alleles linked to severe cutaneous adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Improved diagnostic techniques, including skin testing, show promise in identifying immediate and delayed non-IgE DHRs. Additionally, research highlights the impact of cofactors, drug metabolites, and co-infections on these DHRs and explores potential biomarkers for predicting reaction severity.

Non-IgE-mediated DHRs are a significant cause of morbidity and treatment changes in pediatric patients. Recent research underscores their clinical presentations and mechanisms, paving the way for more precise diagnostic and therapeutic strategies to improve patient outcomes.

Originally discovered in the 1890s, the complement system has traditionally been viewed as a "compliment" to the body's innate and adaptive immune response. However, emerging data have shown that the complement system is a much more complex mechanism within the body involved in regulating inflammation, gene transcription, attraction of macrophages, and many more processes. Sustained complement activation contributes to autoimmunity and chronic inflammation. Pulmonary hypertension is a disease with a poor prognosis and an average life expectancy of 2-3 years that leads to vascular remodeling of the pulmonary arteries; the pulmonary arteries are essential to host homeostasis, as they divert deoxygenated blood from the right ventricle of the heart to the lungs for gas exchange. This review focuses on direct links between the complement system's involvement in pulmonary hypertension, along with autoimmune conditions, and the reliance on the complement system for vascular remodeling processes of the pulmonary artery. Furthermore, circadian rhythmicity is highlighted as the disrupted homeostatic mechanism in the inflammatory consequences in the vascular remodeling within the pulmonary arteries, which could potentially open new therapeutic cues. The current treatment options for pulmonary hypertension are discussed with clinical trials using complement inhibitors and potential therapeutic targets that impact immune cell functions and complement activation, which could alleviate symptoms and block the progression of the disease. Further research on complement's involvement in interstitial lung diseases and pulmonary hypertension could prove beneficial for our understanding of these various diseases and potential treatment options to prevent vascular remodeling of the pulmonary arteries.

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.

Antibodies that trigger the complement system play a pivotal role in the immune defense against pathogenic bacteria and offer potential therapeutic avenues for combating antibiotic-resistant bacterial infections, a rising global concern. To gain a deeper understanding of the key parameters regulating complement activation by monoclonal antibodies, we developed a novel bioassay for quantifying classical complement activation at the monoclonal antibody level, and employed this assay to characterize rare complement-activating antibacterial antibodies on the single-antibody level in postimmunization murine antibody repertoires. We characterized monoclonal antibodies from various antibody isotypes against specific pathogenic bacteria (Bordetella pertussis and Neisseria meningitidis) to broaden the scope of our findings. We demonstrated activation of the classical pathway by individual IgM- and IgG-secreting cells, that is, monoclonal IgM and IgG2a/2b/3 subclasses. Additionally, we could observe different epitope density requirements for efficient C1q binding depending on antibody isotype, which is in agreement with previously proposed molecular mechanisms. In short, we found that antibody density most crucially regulated C1q recruitment by monoclonal IgG isotypes, but not IgM isotypes. This study provides additional insights into important parameters for classical complement initiation by monoclonal antibodies, a knowledge that might inform antibody screening and vaccination efforts.

Discovered in late 2019, the SARS-CoV-2 coronavirus has caused the largest pandemic of the 21st century, claiming more than seven million lives. In most cases, the COVID-19 disease caused by the SARS-CoV-2 virus is relatively mild and affects only the upper respiratory tract; it most often manifests itself with fever, chills, cough, and sore throat, but also has less-common mild symptoms. In most cases, patients do not require hospitalization, and fully recover. However, in some cases, infection with the SARS-CoV-2 virus leads to the development of a severe form of COVID-19, which is characterized by the development of life-threatening complications affecting not only the lungs, but also other organs and systems. In particular, various forms of thrombotic complications are common among patients with a severe form of COVID-19. The mechanisms for the development of thrombotic complications in COVID-19 remain unclear. Accumulated data indicate that the pathogenesis of severe COVID-19 is based on disruptions in the functioning of various innate immune systems. The key role in the primary response to a viral infection is assigned to two systems. These are the pattern recognition receptors, primarily members of the toll-like receptor (TLR) family, and the complement system. Both systems are the first to engage in the fight against the virus and launch a whole range of mechanisms aimed at its rapid elimination. Normally, their joint activity leads to the destruction of the pathogen and recovery. However, disruptions in the functioning of these innate immune systems in COVID-19 can cause the development of an excessive inflammatory response that is dangerous for the body. In turn, excessive inflammation entails activation of and damage to the vascular endothelium, as well as the development of the hypercoagulable state observed in patients seriously ill with COVID-19. Activation of the endothelium and hypercoagulation lead to the development of thrombosis and, as a result, damage to organs and tissues. Immune-mediated thrombotic complications are termed "immunothrombosis". In this review, we discuss in detail the features of immunothrombosis associated with SARS-CoV-2 infection and its potential underlying mechanisms.

Angiogenesis, the process of formation of new capillaries from existing blood vessels, is required for multiple physiological and pathological processes. Complement factor H (CFH) is a plasma protein that inhibits the alternative pathway of the complement system. Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity, including complement 3a, complement 5a, and membrane attack complex. CFH protein contains binding sites for C-reactive protein, malondialdehyde, and endothelial heparan sulfates. Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events. Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization. The Cfh-deficient mice show an increase in angiogenesis, which is decreased by administration of recombinant CFH protein. In this review, we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression. The therapeutic potential of recombinant CFH protein in angiogenesis-related diseases has also been discussed.

Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1-/- mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown.

For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice.

Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2-/- mice.

In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury.

As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.

The complement system is a complex network of proteins that plays a crucial role in the innate immune response. One important component of this system is the C5a-C5aR1 complex, which is critical in the recruitment and activation of immune cells. In-depth investigation of the activation mechanism as well as biased signaling of the C5a-C5aR1 system will facilitate the elucidation of C5a-mediated pathophysiology. In this study, we determined the structure of C5a-C5aR1-Gi complex at a high resolution of 3 Å using cryo-electron microscopy (Cryo-EM). Our results revealed the binding site of C5a, which consists of a polar recognition region on the extracellular side and an amphipathic pocket within the transmembrane domain. Furthermore, we found that C5a binding induces conformational changes of C5aR1, which subsequently leads to the activation of G protein signaling pathways. Notably, a key residue (M265) located on transmembrane helix 6 (TM6) was identified to play a crucial role in regulating the recruitment of β-arrestin driven by C5a. This study provides more information about the structure and function of the human C5a-C5aR1 complex, which is essential for the proper functioning of the complement system. The findings of this study can also provide a foundation for the design of new pharmaceuticals targeting this receptor with bias or specificity.

Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.

The complement system is an evolutionarily ancient component of innate immunity that serves as an important first line of defense against pathogens, including viruses. In response to infection, the complement system can be activated by three distinct yet converging pathways (classical, lectin, and alternative) capable of engaging multiple antiviral host responses to confront acute, chronic, and recurrent viral infections. Complement can exert profound antiviral effects via multiple mechanisms including the induction of inflammation and chemotaxis to sites of infection, neutralization/opsonization of viruses and virally infected cells, and it can even shape adaptive immune responses. With millions of years of co-evolution and the ability to establish life-long infections, herpesviruses have evolved unique mechanisms to counter complement-mediated antiviral defenses, thus enabling their survival and replication within humans. This review aims to comprehensively summarize how human herpesviruses engage with the complement system and highlight our understanding of the role of complement in human cytomegalovirus (HCMV) infection, immunity, and viral replication. Herein we describe the novel and unorthodox roles of complement proteins beyond their roles in innate immunity and discuss gaps in knowledge and future directions of complement and HCMV research.

Stroke is a serious disease that can lead to local neurological dysfunction and cause great harm to the patient's health due to blood cerebral circulation disorder. Synaptic pruning is critical for the normal development of the human brain, which makes the synaptic circuit completer and more efficient by removing redundant synapses. The complement system is considered a key player in synaptic loss and cognitive impairment in neurodegenerative disease. After stroke, the complement system is over-activated and complement proteins can be labeled on synapses. Microglia and astrocytes can recognize and engulf synapses through corresponding complement receptors. Complement-mediated excessive synaptic pruning can cause post-stroke cognitive impairment (PSCI) and secondary brain damage. This review summarizes the latest progress of complement-mediated synaptic pruning after stroke and the potential mechanisms. Targeting complement-mediated synaptic pruning may be essential for exploring therapeutic strategies for secondary brain injury (SBI) and neurological dysfunction after stroke.

Pregnancy is a fascinating immunological phenomenon because it allows allogeneic fetal and placental tissues to survive inside the mother. As a component of innate immunity with high inflammatory potential, the complement system must be tightly regulated during pregnancy. Dysregulation of the complement system plays a role in pregnancy complications including pre-eclampsia and intrauterine growth restriction. Complement components are also used as biomarkers for pregnancy complications. However, the mechanisms of detrimental role of complement in pregnancy is poorly understood. C5a is the most potent anaphylatoxin and generates multiple immune reactions via two transmembrane receptors, C5aR1 and C5aR2. C5aR1 is pro-inflammatory, but the role of C5aR2 remains largely elusive. Interestingly, murine NK cells have been shown to express C5aR2 without the usual co-expression of C5aR1. Furthermore, C5aR2 appears to regulate IFN-γ production by NK cells in vitro. As IFN-γ produced by uterine NK cells is one of the major factors for the successful development of a vital pregnancy, we investigated the role anaphylatoxin C5a and its receptors in the establishment of pregnancy and the regulation of uterine NK cells by examinations of murine C5ar2-/- pregnancies and human placental samples. C5ar2-/- mice have significantly reduced numbers of implantation sites and a maternal C5aR2 deficiency results in increased IL-12, IL-18 and IFN-γ mRNA expression as well as reduced uNK cell infiltration at the maternal-fetal interface. Human decidual leukocytes have similar C5a receptor expression patterns showing clinical relevance. In conclusion, this study identifies C5aR2 as a key contributor to dNK infiltration and pregnancy success.

Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to aortic rupture. The pathophysiology of the disease is not well characterized but is known to be caused by the general breakdown of the extracellular matrix within the aortic wall. In this comprehensive literature review, all current research on proteins that have been investigated for their potential prognostic capabilities in patients with AAA was included. A total of 45 proteins were found to be potential prognostic biomarkers for AAA, predicting incidence of AAA, AAA rupture, AAA growth, endoleak, and post-surgical mortality. The 45 proteins fell into the following seven general categories based on their primary function: (1) cardiovascular health, (2) hemostasis, (3) transport proteins, (4) inflammation and immunity, (5) kidney function, (6) cellular structure, (7) and hormones and growth factors. This is the most up-to-date literature review on current prognostic markers for AAA and their functions. This review outlines the wide pathophysiological processes that are implicated in AAA disease progression.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Glioblastoma is the most common and aggressive type of malignant brain tumor with a poor prognosis due to the lack of effective treatment options. Therefore, new treatment options are required. Sphingolipids are essential components of the cell membrane, while complement components are integral to innate immunity, and both play a critical role in regulating glioblastoma survival signaling. This review focuses on recent studies investigating the functional roles of sphingolipid metabolism and complement activation signaling in glioblastoma. It also discusses how targeting these two systems together may emerge as a novel therapeutic approach.

The complement is an important arm of the innate immune system, once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammation. Recent studies have shown that over-activated complement is the main proinflammatory system of autoimmune diseases (ADs). In addition, activated complements interact with autoantibodies, immune cells exacerbate inflammation, further worsening ADs. With the increasing threat of ADs to human health, complement-based immunotherapy has attracted wide attention. Nevertheless, efficient and targeted delivery of complement inhibitors remains a significant challenge owing to their inherent poor targeting, degradability, and low bioavailability. Nanosystems offer innovative solutions to surmount these obstacles and amplify the potency of complement inhibitors. This prime aim to present the current knowledge of complement in ADs, analyse the function of complement in the pathogenesis and treatment of ADs, we underscore the current situation of nanosystems assisting complement inhibitors in the treatment of ADs. Considering technological, physiological, and clinical validation challenges, we critically appraise the challenges for successfully translating the findings of preclinical studies of these nanosystem assisted-complement inhibitors into the clinic, and future perspectives were also summarised. (The graphical abstract is by BioRender.).

Whole blood transcriptome analysis is a valuable approachin medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a data set that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.

Obesity is associated with insulin resistance, hypertension, and coronary artery diseases which are grouped as metabolic syndrome. Rather than being a storage for energy, the adipocytes could synthesis and secret diverse hormones and molecules, named as adipokines. Under obese status, the adipocytes are dysfunctional with excessively producing the inflammatory related cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α). Concerning on the vital role of adipokines, it is proposed that one of the critical pathological factors of obesity is the dysfunctional adipocytic pathways. Among these adipokines, acylation stimulating protein, as an adipokine synthesized by adipocytes during the process of cell differentiation, is shown to activate the metabolism of triglyceride (TG) by regulating the catabolism of glucose and free fatty acid (FFA). Recent attention has paid to explore the underlying mechanism whereby acylation stimulating protein influences the biological function of adipocyte and the pathological development of obesity. In the present review, we summarized the progression of acylation stimulating protein in modulating the physiological and hormonal catabolism which affects fat distribution. Furthermore, the potential mechanisms which acylation stimulating protein regulates the metabolism of adipose tissue and the process of metabolic syndrome were also summarized.