The complement system, a critical component of innate immunity in fish, plays a pivotal role in the defense against Grass Carp Reovirus (GCRV) infection in grass carp. This study explores the structural characteristics of C1S, a crucial molecule in the classical pathway of the complement system, and its involvement in the response to GCRV infection. We found that the grass carp C1S gene comprises six domains similar to those in mammals: two CUB (Complement C1r/C1s, Uegf, Bmp1) domains, two CCP (Complement control protein) domains, one EGFCA (Calcium-binding epidermal growth factor) domain, and one Tryp_SPc (Trypsin-like serine protease) domain, albeit without chromosomal collinearity to humans. Comparative analysis revealed that the identity and similarity of this gene with those in other species range from 30.6 to 89.4 % and 30.7-89.7 %, respectively. Phylogenetic analysis positioned C1S in close relation with R. klamathensis and D. rerio. Tissue expression profiles in both healthy and GCRV-infected grass carp indicated primary expression of C1S in the liver, with expression peaks at day 7 post-infection in the liver and spleen, and at day 5 in the kidney. Functional assays demonstrated that C1S activates the complement system via cleavage of complement component 3 (C3) into C3b, further inhibiting GCRV replication and upregulating antiviral genes IFN1, IRF3, and IRF7. These findings elucidate the mechanism by which the complement system mediates resistance to GCRV infection in grass carp, offering a substantial theoretical foundation for further research.

Complement factor H (CFH), mainly produced in the liver, is a key alternative complement pathway regulator. Recent studies unveiled some novel functions of CFH independent of complement activation. The kidney, as a vulnerable organ to complement-induced damage, produced several complement proteins. Here, we examined the functions of CFH in glomerular mesangial cells. Using single-cell sequencing data of the kidney, we identified glomerular mesangial cells as the kidney intrinsic cells expressing the highest amount of CFH. We then confirmed the expression of CFH in primary human glomerular mesangial cells (pHGMCs). Our findings revealed that exposure IgA1-containing immune complexes from IgA nephropathy patients led to a reduction in the relative mRNA expression of CFH in pHGMCs. Silencing CFH in pHGMCs led to increased deposition of C3c and C5b-9, especially after exposure to IgAN-IgA1-ICs, while overexpression of CFH reduced the deposition. Furthermore, pHGMCs-derived CFH was more efficient in regulating complement activation than exogenously supplemented CFH. In addition to its canonical function, we also discovered that pHGMCs-derived CFH downregulated KLF4 and p21 and up-regulated CDK 2/4/6, cyclin D1/E2, thereby promoting cell proliferation. Moreover, altering CFH expression in pHGMCs affected the expression of Cdc42, as well as actin cytoskeleton and cell motility. However, exogenously supplemented CFH did not influence cell proliferation and the cytoskeleton of pHGMCs. Our results indicate that CFH derived from glomerular mesangial cells not only plays a canonical regulatory role in complement activation but also has non-canonical functions, such as affecting cell proliferation and maintaining the actin cytoskeleton.

Systemic complement is a major contributor to the onset and progression of kidney graft injury. However, the kidney itself is an important site of complement production. Renal-derived complement plays a key role in graft dysfunction, unlike in some other solid organ transplants. Complement factors are generated by multiple renal cell types under both physiological and pathological conditions. Renal complement production mediates ischemia/reperfusion injury and acute cellular and humoral rejection but protective effects of the complement cascade have been reported as well. More recently, intracellular complement production and activation (complosome) has also been shown to be an important regulator of key metabolic and cellular functions in renal cells and in immune kidney infiltrates, adding complexity to the field. Herein, we review current knowledge on the role of renal-derived complement in the pathophysiology of kidney graft damage and the current landscape of complement targeted therapeutics in kidney transplantation.

The complement cascade and Neutrophil Extracellular Traps (NETs) represent fundamental tools in protecting the host from foreign pathogens. Complement components and relative fragments, classically assigned to the innate immunity, represent a key link with the humoral immune response. NETs are a crucial component of the innate immune response, consisting of chromatin release from activated neutrophils. These web-like structures facilitate pathogen entrapment and elimination through proteolytic degradation and antimicrobial effectors. Previous findings suggested complement components and NETs have a significant role in the pathogenesis of several diseases characterized by inflammation, such as autoimmune and infectious diseases. However, the crosstalk between NETs and the complement cascade has only recently been investigated, and several aspects still need to be fully clarified. Recent evidence seems to suggest a bidirectional link between the complement cascade and NETosis. We here present the interaction between complement components and NETs in specific autoimmune diseases that mostly affect the kidney, such as systemic lupus erythematosus, Antineutrophilic Cytoplasmic Antibody (ANCA)-associated vasculitis and antiphospholipid syndrome. The mechanisms reported here may represent specific targets for the development of possible therapeutic strategies.

Ground-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its "double-edged sword" role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies. In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors.

Cancer remains a formidable global health challenge requiring the continued exploration of innovative therapeutic approaches. While traditional treatment strategies including surgery, chemotherapy, and radiation therapy have had some success, primarily in early-stage disease, the quest for more targeted, personalized, safer, and effective therapies remains an ongoing pursuit. Over the past decade, significant advances in the field of tumor immunology have dramatically shifted a focus towards immunotherapy, although the ability to harness and coopt the immune system to treat cancer is still just beginning to be realized. One important area that has yet to be fully explored is the complement system, an integral part of innate immunity that has gathered attention recently as a source of potential targets for anti-cancer therapy. The complement system has a complex and context dependent role in cancer biology in that it not only contributes to immune surveillance but also may promote tumor progression. Complement regulators, including CD46, CD55, CD59, and complement factor H, exercise defined control over complement activation, and have also been acknowledged for their role in the tumor microenvironment. This review explores the intricate role of complement regulators in cancer development and progression, examining their potential as therapeutic targets, current strategies, challenges, and the evolving landscape of clinical research.

Maintenance of the retina, part of the central nervous system, and other structures in the eye is critical for vision preservation. Aging increases the prevalence of vision impairment, including glaucoma, macular degeneration, and diabetic retinopathy. The retina is primarily maintained by glial cells; however, recent literature suggests that lymphocytes may play a role in the homeostasis of central nervous system tissues. Natural antibodies are produced by B cells without infection or immunization and maintain tissue homeostasis. Here, we explored the potential role of natural immunoglobulin M (IgM) produced by B lymphocytes in maintaining retinal health during aging in mice.

Our results indicate that the vitreous humor of both mice and humans contains IgM and IgG, suggesting that these immunoglobulins may play a role in ocular function. Furthermore, we observed that aged mice lacking secreted IgM (µs-/-) exhibited pronounced retinal degeneration, accompanied by reactive gliosis, and a proinflammatory cytokine environment. This contrasts with the aged wild-type counterparts, which retain their ability to secrete IgM and maintain a better retinal structure and anti-inflammatory environment. In addition to these findings, the absence of secreted IgM was associated with significant alterations in the retinal pigment epithelium, including disruptions to its morphology and signs of increased stress. This was further observed in changes to the blood-retinal-barrier, which is critical for regulation of retinal homeostasis.

These data suggest a previously unrecognized association between a lack of secreted IgM and alterations in the retinal microenvironment, leading to enhanced retinal degeneration during aging. Although the precise mechanism remains unclear, these findings highlight the potential importance of secreted IgM in processes that support retinal health over time. By increasing our understanding of ocular aging, these results show that there is a broader role for the immune system in retinal function and integrity in advanced age, opening new areas for the exploration of immune-related interventions in age-associated retinal conditions.

Kidney transplantation is the most optimal treatment for patients with end-stage renal disease, offering significant improvements in patient outcomes over dialysis. However, the potential for immune rejection, where the recipient's immune system attacks the transplanted kidney, can compromise transplant success. The complement system, a key component of the immune response, plays a crucial role in both acute and chronic rejection, including T-cell- and antibody-mediated rejection. Understanding and controlling the complement system is essential for managing rejection and enhancing graft survival and overall success of kidney transplantation. In allogeneic transplantation, complement activation through various pathways contributes to graft damage and failure. Recent advancements in genetic engineering enable the development of transgenic pigs expressing human complement regulatory proteins, which display potential for reducing rejection in xenotransplantation. Despite these advances, the complex mechanisms of complement activation and regulation are not fully understood, necessitating further research. This review examines the role of the complement system in kidney transplantation, explores the latest developments in complement regulatory strategies, and discusses potential therapeutic approaches to improve transplant outcomes.

Complement is a critical component of innate immunity, evolved to defend against pathogens and clear toxic debris ranging from dead and dying cells to immune complexes. These roles make complement a key player in homeostasis; however, complement has a dark side. When the rigid control mechanisms fail, complement becomes dysregulated, acting as a driver of inflammation and resultant pathology in numerous diseases. Roles of complement in Alzheimer's disease (AD) and other dementias have emerged in recent years, supported by genetic, biomarker and pathological evidence and animal model studies. Numerous questions remain regarding the precise roles of complement in the brain in health and disease, including where and when complement is expressed, how it contributes to immune defence and garbage disposal in the healthy brain, and exactly how complement contributes to pathology in dementias. In this brief review, we will summarise current knowledge on complement roles in brain, present the evidence implicating complement in AD and explore whether complement represents an attractive therapeutic target for AD.

Major Human Histocompatibility complex (MHC or HLA in humans) has been associated to autoimmune diseases. However, only statistical phenomenological and no pathogenetic description has been reached after decades. This shows that MHC single locus association studies are probably useless for HLA/diseases association. Extended HLA (class I and class II genes) haplotypes should also be studied conjointly with class III or complement alleles (complotypes). Complotypes in humans are defined as alleles belonging to C2, C4 and Bf (Factor B) genes/proteins (class III). Also, the placing of MHC class I and class II genes close together with complement genes from at least birds to humans shows existence of a strong selection to gather conjointly these loci that fight microbes, help self-maintenance and avoid autoimmunity. In this paper we aim to study Bf alleles in primates in order to rise again interest to study the role of Bf alleles together with other MHC genes in their physiopathology and evolution.

Orangutan (Pongo pygmaeus, Popy) cell lines RNA from 6 different individuals were retrotranscribed, PCR amplified, cloned and DNA sequenced in order to study Bf alleles.

A Bf allele identical to that found in chimpanzee (Patr-Bf*A01) and human (rs641153) was found in two of the six studied orangutans: Popy-Bf*A01 and Popy-Bf*A02. This polymorphism is placed in Factor B codon 32 that defines BF*S and Bf*F proteins in man and produce Leu instead of Arg (Bf*S) or Gln (Bf*F). In addition, each new orangutan allele present synonymous differences with each other at codon 25: Popy-Bf*A01 shows ACG while Popy-Bf*A02 bears ACA, both codifying for Thr.

The selection for about 15 million years (time gap of evolutionary appearance between orangutan and hominids) shows the importance of this particular allele conservation in immune and self defense in primates. The complotypes (Bf,C2 and C4 loci) alleles together with other MHC class I and Cass II loci alleles are often transmitted in block to the germinal line: this indicates that all specific alleles from the MHC different loci may work together to accomplish MHC functions. All MHC loci alleles should be studied together to unveil their physiopathology and also maintenance of specific alleles (like the one described in this paper) for so long time in evolution should be further studied in Bf and the other neighbouring complement loci (C2 and C4).

Aggregatibacter actinomycetemcomitans ApiA is a trimeric autotransporter outer membrane protein (Omp) that participates in multiple functions, enabling A. actinomycetemcomitans to adapt to a variety of environments. The goal of this study is to identify regions in the apiA gene responsible for three of these functions: auto-aggregation, buccal epithelial cell binding, and complement resistance. Initially, apiA was expressed in Escherichia coli. Finally, wild-type A. actinomycetemcomitans and an apiA-deleted version were tested for their expression in the presence and absence of serum and genes related to stress adaptation, such as oxygen regulation, catalase activity, and Omp proteins. Sequential deletions in specific regions in the apiA gene as expressed in E. coli were examined for membrane proteins, which were confirmed by microscopy. The functional activity of epithelial cell binding, auto-aggregation, and complement resistance were then assessed, and regions in the apiA gene responsible for these functions were identified. A region spanning amino acids 186-217, when deleted, abrogated complement resistance and Factor H (FH) binding, while a region spanning amino acids 28-33 was related to epithelial cell binding. A 13-amino-acid peptide responsible for FH binding was shown to promote serum resistance. An apiA deletion in a clinical isolate (IDH781) was created and tested in the presence and/or absence of active and inactive serum and genes deemed responsible for prominent functional activity related to A. actinomycetemcomitans survival using qRT-PCR. These experiments suggested that apiA expression in IDH781 is involved in global regulatory mechanisms that are serum-dependent and show complement resistance. This is the first study to identify specific apiA regions in A. actinomycetemcomitans responsible for FH binding, complement resistance, and other stress-related functions. Moreover, the role of apiA in overall gene regulation was observed.

Aquafeed kept at elevated temperatures and humidity can result in malondialdehyde (MDA) formation, adversely affecting aquafeed quality and triggering negative reactions in fish. To investigate the detrimental effects of dietary MDA on fish, six experimental diets with varying MDA levels (ranging from 0.03 to 17.72 mg/kg, on dietary crude lipid basis) were administered to three replicates of hybrid grouper for 8 weeks. Dietary inclusion of 4.43 mg/kg MDA significantly decreased serum complement 4 content and lysozyme activity, along with intestinal complement 3, complement 4, and immunoglobulin M contents. Furthermore, dietary inclusion of 8.86 mg/kg MDA significantly increased the activities of interleukin-1 receptor-associated kinase, ubiquitin-protein ligase, p38 mitogen-activated protein kinase, and tumor necrosis factor-α, downregulated the relative expression of Occludin but upregulated the relative expression of HSP70 in the hindgut. Additionally, the highest inclusion of MDA (17.72 mg/kg) significantly upregulated the relative levels of pro-inflammatory cytokines (IL-1β and TNF-α), caused intestinal inflammation, and damaged the intestinal microbial structure and fish fillet texture. This study demonstrated a dose-dependent response of MDA on hybrid grouper. A low dietary dose of MDA (<2.21 mg/kg) exhibited minimal impact on immune response and fillet quality. However, higher inclusion levels (≥4.43 mg/kg) impaired the intestinal health and fillet quality. Consequently, the safety limit for MDA content in the diet for hybrid grouper has been established at 4.43 mg/kg based on dietary crude lipid basis.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). In most patients, the disease starts with an acute onset followed by a remission phase, subsequent relapses and a later transition to steady chronic progression. In a minority of patients, this progressive phase develops from the beginning. MS relapses are characterized predominantly by the de novo formation of an inflammatory CNS lesion and the infiltration of immune cells, whereas the pathological features of MS progression include slowly expanding lesions, global brain atrophy and an inflammatory response predominantly mediated by macrophages/microglia. Importantly, this CNS-intrinsic pathophysiology appears to initiate early during the relapsing-remitting disease phase, while it turns into the key clinical MS feature in later stages. Currently approved disease-modifying treatments for MS are effective in modulating peripheral immunity by dampening immune cell activity or preventing the migration of immune cells into the CNS, resulting in the prevention of relapses; however, they show limited success in halting MS progression. In this manuscript, we first describe the pathological mechanisms of MS and summarize the approved therapeutics for MS progression. We also review the treatment options for progressive MS (PMS) that are currently under investigation. Finally, we discuss potential targets for novel treatment strategies in PMS.

The Complement System is composed of more than 40 proteins that act in innate and adaptive immunity. C3 is the most abundant one and C3-deficient patients are more susceptible to recurrent and severe infections. Several studies have demonstrated the importance of C3 in controlling infections. However, its role in leukocyte biology is still poorly understood. This study aimed to evaluate several cellular parameters in macrophages from C3-deficient mice and compare them to similar cells from wild-type counterparts. We observed that in the absence of C3, the population of F4/80low macrophages in the peritoneal cavity of thioglycolate-treated mice is diminished, probably due to the lack of chemotactic factors like C3a and low levels of C5a. Using fluorescence microscopy analysis, we observed that macrophages from C3-deficient mice exhibited morphological alterations when compared to similar cells from wild-type mice. We observed a significant increase in the expression of CD11c, which is part of CR4 (CD11c/CD18), in macrophages from C3-deficient compared to cells from wild-type mice. Treatment with 12-o-tetradecanoylphorbol-13-acetate, stimulated ROS production and MAPK activation by macrophages. However, these parameters were lower in macrophages from C3-deficient mice when compared to wild-type counterparts. In addition, the phagocytosis of iC3b-opsonized Zymosan particles was diminished in macrophages from C3-deficient mice. Our results suggest that C3 deficiency in C57Black/6 mice may influence specific morphological and functional parameters of macrophages, cells of fundamental importance for both the innate and acquired immune responses.

The complement system is a set of over 50 proteins that constitutes an essential part of the innate immune system. Complement system activation involves an organized proteolytic cascade. Overactivation of complement system activation is the main pathogenic mechanism of several diseases and contributes to the manifestations of many other conditions. This review describes the normal complement system and the role for complement dysregulation in critical illnesses, notably sepsis and acute respiratory distress syndrome. Complement activation is involved in the immune system response to pathogens but, when excessive, can contribute to tissue damage, runaway inflammation, and capillary leakage syndrome. Complement overactivation may play a key role in severe forms of coronavirus disease 2019 (COVID-19). Two diseases whose manifestations are mainly caused by complement overactivation, namely, atypical hemolytic and uremic syndrome (aHUS) and myasthenia gravis, are discussed. A diagnostic algorithm for aHUS is provided. Early complement-inhibiting therapy has been proven effective. When renal transplantation is required, complement-inhibiting drugs can be used prophylactically to prevent aHUS recurrence. Similarly, acetylcholine-receptor autoantibody-positive generalized myasthenia gravis involves complement system overactivation and responds to complement inhibition. The two main complement inhibitors used in to date routine are eculizumab and ravulizumab. The main adverse event is Neisseria infection, which is rare and preventable, but can be fatal. The complement system is crucial to health but, when overactivated, can cause or contribute to disease. Effective complement inhibitors are now available, although additional data are required to determine optimal regimens. Further research is also needed to better understand the complement system, develop advanced diagnostic tools, and identify markers that allow the personalization of treatment strategies.

The precise molecular processes underlying the complement's activation, which follows exposure to physical stress still remain to be fully elucidated. However, some possible mechanisms could play a role in initiating changes in the complement's activity, which are observed post-exposure to physical stress stimuli. These are mainly based on metabolic shifts that occur in the microenvironment of muscle tissue while performing its function with increased intensity, as well as the adipose tissue's role in sterile inflammation and adipokine secretion. This review aims to discuss the current opinions on the possible link between the complement activation and diet, age, sex, and health disorders with a particular emphasis on endocrinopathies and, furthermore, the type of physical activity and overall physical fitness. It has been indicated that regular physical activity incorporated into therapeutic strategies potentially improves the management of particular diseases, such as, e.g., autoimmune conditions. Moreover, it represents a favorable influence on immunoaging processes. A better understanding of the complement system's interaction with physical activity will support established clinical therapies targeting complement components.

The grass carp (Ctenopharyngodon idella) constitutes a significant economic resource within the aquaculture sector of our nation, yet it has been chronically afflicted by the Grass Carp Reovirus (GCRV) disease. The complement system, a vital component of fish's innate immunity, plays a crucial role in combating viral infections. This research investigates the potential role of MASP1, a key molecule in the lectin pathway of the complement system, in the GCRV infection in grass carp. An analysis of the molecular characteristics of MASP1 in grass carp revealed that its identity and similarity percentages range from 35.10 to 91.00 % and 35.30-91.00 %, respectively, in comparison to other species. Phylogenetically, MASP1 in C. idella aligns closely with species such as Danio rerio, Cyprinus carpio, and Carassius carassius, exhibiting chromosomal collinearity with the zebrafish. Subsequent tissue analysis in both healthy and GCRV-infected grass carp indicated that MASP1's basal expression was predominantly in the liver. Post-GCRV infection, MASP1 expression in various tissues exhibited temporal variations: peaking in the liver on day 5, spleen on day 7, and kidney on day 14. Furthermore, employing Complement Component 3 (C3) as a benchmark for complement system activation, it was observed that MASP1 could activate and cleave C3 to C3b. MASP1 also demonstrated an inhibitory effect on GCRV replication (compared with the control group, VP2 and VP7 decreased by 6.82-fold and 4.37-fold) and enhanced the expression of antiviral genes, namely IRF3, IRF7 and IFN1 (compared with the control group, increased 2.25-fold, 45.38-fold and 22.37-fold, respectively). In vivo protein injection experiments substantiated MASP1's influence on the relative mRNA expression levels of C3 in various tissues and its protein expression in serum. This study also verified that C3 could modulate the expression of antiviral genes such as IFN1 and IRF3.

BF/C2 is a crucial molecule in the coagulation complement cascade pathway and plays a significant role in the immune response of grass carp through the classical, alternative, and lectin pathways during GCRV infection. In vivo experiments demonstrated that the mRNA expression levels of BF/C2 (A, B) in grass carp positively correlated with GCRV viral replication at various stages of infection. Excessive inflammation leading to death coincided with peak levels of BF/C2 (A, B) mRNA expression and GCRV viral replication. Correspondingly, BF/C2 (A, B) recombinant protein, CIK cells and GCRV co-incubation experiments yielded similar findings. Therefore, 3 h (incubation period) and 9 h (death period) were selected as critical points for this study. Transcriptome sequencing analysis revealed significant differences in the expression of BF/C2A and BF/C2B during different stages of CIK infection with GCRV and compared to the blank control group (PBS). Specifically, the BF/C2A_3 and BF/C2A_9 groups exhibited 2729 and 2228 differentially expressed genes (DEGs), respectively, with 1436 upregulated and 1293 downregulated in the former, and 1324 upregulated and 904 downregulated in the latter. The BF/C2B_3 and BF/C2B_9 groups showed 2303 and 1547 DEGs, respectively, with 1368 upregulated and 935 downregulated in the former, and 818 upregulated and 729 downregulated in the latter. KEGG functional enrichment analysis of these DEGs identified shared pathways between BF/C2A and PBS groups at 3 and 9 h, including the C-type lectin receptor signaling pathway, protein processing in the endoplasmic reticulum, Toll-like receptor signaling pathway, Salmonella infection, apoptosis, tight junction, and adipocytokine signaling pathway. Additionally, the BF/C2B groups at 3 and 9 h shared pathways related to protein processing in the endoplasmic reticulum, glycolysis/gluconeogenesis, and biosynthesis of amino acids. The mRNA levels of these DEGs were validated in cellular models, confirming consistency with the sequencing results. In addition, the mRNA expression levels of these candidate genes (mapk1, il1b, rela, nfkbiab, akt3a, hyou1, hsp90b1, dnajc3a et al.) in the head kidney, kidney, liver and spleen of grass carp immune tissue were significantly different from those of the control group by BF/C2 (A, B) protein injection in vivo. These candidate genes play an important role in the response of BF/C2 (A, B) to GCRV infection and it also further confirmed that BF/C2 (A, B) of grass carp plays an important role in coping with GCRV infection.

The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS).

Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up).

In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025).

Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.

Lanbuzheng (LBZ) is the traditional seedling medicine in Guizhou, which has the effect of tonifying blood. It has been found that the main active ingredient is tannin, however, the blood-replenishing effect of tannin and its mechanism are still unclear. The study was to explore the mechanisms underlying the therapeutic effects of the total Tannins of Lanbuzheng (LBZT) against anemia in mice. Anemia mice was induced by cyclophosphamide, the effect of LBZT against anemia was determined by analyzing peripheral blood and evaluating organs indexes. Tandem mass tag (TMT)-based quantitative proteomics technology coupled with bioinformatics analysis was then used to identify differentially expressed proteins (DEPs) in spleen. Compared to the model, number of RBCs, PLTs and WBCs, HCT ratio and HGB content were increased, the indexes of thymus, spleen and liver were also increased, after LBZT intervention. A total of 377 DEPs were identified in LBZT group, of which 206 DEPs were significantly up-regulated and 171 DEPs were significantly down-regulated. Bioinformatics analysis showed that hematopoietic function has been restored by activating the complement and coagulation cascade signaling pathways. Results suggest that LBZT exerts it therapeutic effects against anemia by regulating complement and coagulation cascade signaling pathways and provides scientific basis for further mechanistic studies for LBZT.

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.

Endometriosis (EM) is defined as the engraftment and proliferation of functional endometrial-like tissue outside the uterine cavity, leading to a chronic inflammatory condition. While the precise etiology of EM remains elusive, recent studies have highlighted the crucial involvement of a dysregulated immune system. The complement system is one of the predominantly altered immune pathways in EM. Owing to its involvement in the process of angiogenesis, here, we have examined the possible role of the first recognition molecule of the complement classical pathway, C1q. C1q plays seminal roles in several physiological and pathological processes independent of complement activation, including tumor growth, placentation, wound healing, and angiogenesis. Gene expression analysis using the publicly available data revealed that C1q is expressed at higher levels in EM lesions compared to their healthy counterparts. Immunohistochemical analysis confirmed the presence of C1q protein, being localized around the blood vessels in the EM lesions. CD68+ macrophages are the likely producer of C1q in the EM lesions since cultured EM cells did not produce C1q in vitro. To explore the underlying reasons for increased C1q expression in EM, we focused on its established pro-angiogenic role. Employing various angiogenesis assays on primary endothelial endometriotic cells, such as migration, proliferation, and tube formation assays, we observed a robust proangiogenic effect induced by C1q on endothelial cells in the context of EM. C1q promoted angiogenesis in endothelial cells isolated from EM lesions (as well as healthy ovary that is also rich in C1q). Interestingly, endothelial cells from EM lesions seem to overexpress the receptor for the globular heads of C1q (gC1qR), a putative C1q receptor. Experiments with siRNA to silence gC1qR resulted in diminished capacity of C1q to perform its angiogenic functions, suggesting that C1q is likely to engage gC1qR in the pathophysiology of EM. gC1qR can be a potential therapeutic target in EM patients that will disrupt C1q-mediated proangiogenic activities in EM.

South Africa is the epicentre of the global HIV pandemic, with 13.9% of its population infected. Preeclampsia (PE), a hypertensive disorder of pregnancy, is often comorbid with HIV infection, leading to multi-organ dysfunction and convulsions. The exact pathophysiology of preeclampsia is triggered by an altered maternal immune response or defective development of maternal tolerance to the semi-allogenic foetus via the complement system. The complement system plays a vital role in the innate immune system, generating inflammation, mediating the clearance of microbes and injured tissue materials, and a mediator of adaptive immunity. Moreover, the complement system has a dual effect, of protecting the host against HIV infection and enhancing HIV infectivity. An upregulation of regulatory proteins has been implicated as an adaptive phenomenon in response to elevated complement-mediated cell lysis in HIV infection, further aggravated by preeclamptic complement activation. In light of the high prevalence of HIV infection and preeclampsia in South Africa, this review discusses the association of complement proteins and their role in the synergy of HIV infection and preeclampsia in South Africa. It aims to identify women at elevated risk, leading to early diagnosis and better management with targeted drug therapy, thereby improving the understanding of immunological dysregulation.

The complement component C5a contributes to the recruitment of immune cells to inflamed tissues and local inflammation. The proinflammatory cytokine interleukin (IL)-1β is also related to inflammatory disorders through inflammasome activation. However, the association between inflammasome activation and C5a is unclear. Human peripheral blood mononuclear cells (PBMCs) were stimulated with C5a and measured for IL-1β secretion by enzyme-linked immunosorbent assay (ELISA). The pro-IL-1β expression in cell lysates was also examined by Western blot analysis. Similarly, magnetic bead-isolated CD14+ monocyte-depleted and lymphocyte-depleted PBMCs were stimulated with C5a, and immunoblot analysis was performed using an anti-cleaved-IL-1β (p17) antibody. FACS was performed to detect caspase-1-activated cells. C5a-stimulated PBMCs produced IL-1β in C5a concentration-dependent manner. The protein levels of pro-IL-1β in the cell lysates were significantly increased. Furthermore, the cleaved-IL-1β (p17) was faintly detected in the same lysates. Active caspase-1 was demonstrated in C5a-simulated CD14+ monocytes by FACS. Cleaved-IL-1β (p17) was demonstrated in the supernatant of C5a-stimulated PBMCs. Lymphocyte-depleted PBMCs stimulated with C5a but monocyte-depleted PBMCs produced cleaved-IL-1β (p17). C5a induced the production of mature IL-1β in PBMCs. The IL-1β production is mediated mainly by caspase-1 activation in CD14+ monocytes. These results suggest that C5a alone potentiates mature IL-1β production mainly in monocytes.

The complement system serves as the first line of defense against invading pathogens by promoting opsonophagocytosis and bacteriolysis. Antibody-dependent activation of complement occurs through the classical pathway and relies on the activity of initiating complement proteases of the C1 complex, C1r and C1s. The causative agent of Lyme disease, Borrelia burgdorferi, expresses two paralogous outer surface lipoproteins of the OspEF-related protein family, ElpB and ElpQ, that act as specific inhibitors of classical pathway activation. We have previously shown that ElpB and ElpQ bind directly to C1r and C1s with high affinity and specifically inhibit C2 and C4 cleavage by C1s. To further understand how these novel protease inhibitors function, we carried out a series of hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments using ElpQ and full-length activated C1s as a model of Elp-protease interaction. Comparison of HDX-MS profiles between unbound ElpQ and the ElpQ/C1s complex revealed a putative C1s-binding site on ElpQ. HDX-MS-guided, site-directed ElpQ mutants were generated and tested for direct binding to C1r and C1s using surface plasmon resonance. Several residues within the C-terminal region of ElpQ were identified as important for protease binding, including a single conserved tyrosine residue that was required for ElpQ- and ElpB-mediated complement inhibition. Collectively, our study identifies key molecular determinants for classical pathway protease recognition by Elp proteins. This investigation improves our understanding of the unique complement inhibitory mechanism employed by Elp proteins which serve as part of a sophisticated complement evasion system present in Lyme disease spirochetes.

The binding and molecular recognition between α-chain of human complement C3b (α-chain of C3b) and human plasminogen Kringle 5 (Kringle 5) were studied and explored by frontal chromatography and dynamics simulation in the combination of bio-specific technologies. The specific interaction between the α-chain of C3b and Kringle 5 was initially confirmed by ligand blot and ELISA (Kd = 4.243×10-6 L/mol). Furthermore, the binding determination conducted via frontal chromatography showed that the presence of a single binding site between them, with the binding constant of 2.98 × 105 L/mol. Then the molecular recognition by dynamics simulation and molecular docking showed that there were 9 and 13 amino acid residues respective in the Kringle 5 and α-chain of C3b directly implicated in the binding and the main stabilizing forces were electrostatic force (-55.99 ± 11.82 kcal/mol) and Van der Waals forces (-42.70 ± 3.45 kcal/mol). Additionally, a loop structure (65-71) in Kringle 5 underwent a conformational change from a random structure to an α-helix and a loop structure (417-425) in α-chain of C3b was closer to the molecular center, both of them were more conducive to the binding between them. Meanwhile, the involvement of the lysine binding site of Kringle 5 played an important role in the binding process. In addition, the erythrocyte-antibody complement rosette assay substantiated that the presence of Kringle 5 hindered the transportation of α-chain of C3b to antigen-antibody complex in a dose-dependent manner. These findings collectively indicated that the α-chain of C3b is very likely a receptor protein for Kringle 5, which provides a methodology for other similar investigations and valuable insights into expansion of the pharmacological effects and potential application of Kringle 5 in immune-related diseases.

Despite their use as substitutes for perfluorooctanoic acid, the potential toxicities of hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name: GenX) and its analogs (PFDMOHxA, PFDMO2HpA, and PFDMO2OA) remain poorly understood. To assess the hepatotoxicity of these chemicals on females, each chemical was orally administered to female C57BL/6 mice at the dosage of 0.5 mg/kg/d for 28 d. The contribution of peroxisome proliferator-activated receptors (PPARα and γ) and other nuclear receptors involving in these toxic effects of GenX and its analogs were identified by employing two PPAR knockout mice (PPARα-/- and PPARγΔHep) in this study. Results showed that the hepatotoxicity of these chemicals increased in the order of GenX < PFDMOHxA < PFDMO2HpA < PFDMO2OA. The increases of relative liver weight and liver injury markers were significantly much lower in PPARα-/- mice than in PPARα+/+ mice after GenX analog exposure, while no significant differences were observed between PPARγΔHep and its corresponding wildtype groups (PPARγF/F mice), indicating that GenX analog induce hepatotoxicity mainly via PPARα instead of PPARγ. The PPARα-dependent complement pathways were inhibited in PFDMO2HpA and PFDMO2OA exposed PPARα+/+ mice, which might be responsible for the observed liver inflammation. In PPARα-/- mice, hepatomegaly and increased liver lipid content were observed in PFDMO2HpA and PFDMO2OA treated groups. The activated pregnane X receptor (PXR) and constitutive activated receptor (CAR) pathways in the liver of PPARα-/- mice, which were highlighted by bioinformatics analysis, provided a reasonable explanation for hepatomegaly in the absence of PPARα. Our results indicate that GenX analogs could induce more serious hepatotoxicity than GenX whether there is a PPARα receptor or not. These chemicals, especially PFDMO2HpA and PFDMO2OA, may not be appropriate PFOA alternatives.

The complement system, a key component of innate immunity, provides the first line of defense against bacterial infection; however, the COVID-19 pandemic has revealed that it may also engender severe complications in the context of viral respiratory disease. Here, we review the mechanisms of complement activation and regulation and explore their roles in both protecting against infection and exacerbating disease. We discuss emerging evidence related to complement-targeted therapeutics in COVID-19 and compare the role of the complement in other respiratory viral diseases like influenza and respiratory syncytial virus. We review recent mechanistic studies and animal models that can be used for further investigation. Novel knockout studies are proposed to better understand the nuances of the activation of the complement system in respiratory viral diseases.

Complement constitutes a major part of the innate immune system. The study of complement in human health has historically focused on infection risks associated with complement protein deficiencies; however, recent interest in the field has focused on overactivation of complement as a cause of immune injury and the development of anticomplement therapies to treat human diseases. The kidneys are particularly sensitive to complement injury, and anticomplement therapies for several kidney diseases have been investigated. Overactivation of complement can result from loss-of-function mutations in complement regulators; gain-of-function mutations in key complement proteins such as C3 and factor B; or autoantibody production, infection, or tissue stresses, such as ischemia and reperfusion, that perturb the balance of complement activation and regulation. Here, we provide a high-level review of the status of anticomplement therapies, with an emphasis on the transition from rare diseases to more common kidney diseases.

Although regular physical activity improves immune competency and reduces the prevalence of inflammatory diseases, strenuous training in elite athletes is associated with an increased susceptibility to infectious complications. Therefore, the objective of our study was to assess the routinely examined parameters of the complement system in elite athletes. The study was carried out in a cohort of elite athletes (n = 134) and healthy control subjects (n = 110). In all subjects, besides a routine laboratory check-up, serum concentrations of the C3 and C4 complement components, mannose-binding lectin (MBL), as well as activation of all three complement pathways were determined.

Compared to healthy controls, lower C3 and C4 complement component concentrations were observed in elite athletes (0.96 ± 0.1 vs. 1.08 ± 0.2 mg/L, and 0.18 ± 0.1 vs. 0.25 ± 0.1 mg/L, respectively, p < 0.05); with much higher frequency rates of C3 and C4 deficiencies in athletes (31.3 vs. 14.5%, and 6 vs. 0%, p < 0.05). Simultaneously, athletes had much higher frequency rates of deficiencies of activation of classical and alternative complement pathways; while, deficiency of activation of the lectin pathway was similar in both cohorts.

We confirmed a high frequency of defects in the complement system in elite athletes. Lower concentrations of C3 and C4 complement components, with high frequencies of deficiencies of the classical and alternative complement activation pathways were the most prevalent disorder of the complement system in elite athletes. Further studies are needed to uncover the functional impacts of these observations upon the susceptibility to infectious diseases.

As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group characterized by muscle weakness and skin symptoms and are categorized into six subtypes: dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (ASS), immune-mediated myopathy (IMNM), inclusion body myopathy (IBM), and overlap myositis. Myositis-specific autoantibodies were detected for the diagnosis and classification of IIM. This review highlights the pathogenic contributions of the complement system, microangiopathy, and inflammation in IIM.

Deposition of complement around capillaries and/or the sarcolemma was observed in muscle biopsy specimens from patients with DM, ASS, and IMNM, suggesting the pathomechanism of complement-dependent muscle and endothelial cell injury. A recent study using human muscle microvascular endothelial cells showed that Jo-1 antibodies from ASS induce complement-dependent cellular cytotoxicity in vitro. Based on both clinical and pathological observations, antibody- and complement-mediated microangiopathy may contribute to the development of DM and anti-Jo-1 ASS. Juvenile DM is characterized by the loss of capillaries, perivascular inflammation, and small-vessel angiopathies, which may be related to microinfarction and perifascicular atrophy. Several serum biomarkers that reflect the IFN1 signature and microangiopathy are elevated in patients with DM. The pathological observation of myxovirus resistance protein A (MxA), which suggests a type 1 interferon (IFN1) signature in DM, supports the diagnosis and further understanding of the pathomechanism of IIM. A recent report showed that an increase in triggering receptor expressed on myeloid cells (TREM-1) around perimysial blood vessels and muscles in patients with IIM plays a role in triggering inflammation and promoting the migration of inflammatory cells by secreting proinflammatory cytokines, such as tumor necrosis factor α.

The deposition of complement in muscles and capillaries is a characteristic feature of DM, ASS, and IMNM. Microangiopathy plays a pathogenic role in DM, possibly resulting in perifascicular atrophy. Further understanding of the detailed pathomechanism regarding complement, microangiopathy, and inflammation may lead to novel therapeutic approaches for IIM.

Enlarged facial pores are a common cosmetic concern of the skin, rather than a disease, and have not received much attention from dermatologists in recent years. Consequently, progress in understanding their pathogenesis has been limited, and current cosmetic solutions have limitations. Given that the complement system has regained interest as a key player in chronic inflammatory skin conditions, various mechanisms involving this system are being investigated.

We aimed to shed light on the mechanism underlying enlarged facial pores by examining the role of the complement system in skin.

We conducted a comprehensive literature search utilizing various academic databases including PubMed, Web of Science, and Google Scholar. Employing keywords such as "complement system," "inflammation," "facial pores," "enlarged," and "mechanisms," we compiled a selection of relevant studies. These studies provided a comprehensive understanding of the intricate mechanisms underlying the relationship between the "complement system" and "inflammation" within the context of facial pore enlargement.

Our findings suggest that inflammaging mediated by complement activation may be a critical player in the formation of enlarged facial pores. Specifically, overactivation of the complement system leading to the accumulation of complement fragments could be a major contributor to this process. Notably, the complement system in skin may be involved in a range of skin issues, including aging.

Modulating the complement system presents a promising avenue for future research in improving skin health. Further basic and clinical research is necessary to validate these findings, but we hope that this study can serve as a theoretical foundation for the development of targeted cosmetics.

The human complement system is an important part of the innate immune response in the fight against invasive bacteria. Complement responses can be activated independently by the classical pathway, the lectin pathway, or the alternative pathway, each resulting in the formation of a C3 convertase that produces the anaphylatoxin C3a and the opsonin C3b by specifically cutting C3. Other important features of complement are the production of the chemotactic C5a peptide and the generation of the membrane attack complex to lyse intruding pathogens. Invasive pathogens like Staphylococcus aureus and several species of the genus Streptococcus have developed a variety of complement evasion strategies to resist complement activity thereby increasing their virulence and potential to cause disease. In this review, we focus on secreted complement evasion factors that assist the bacteria to avoid opsonization and terminal pathway lysis. We also briefly discuss the potential role of complement evasion factors for the development of vaccines and therapeutic interventions.

The crosstalk among the complement system, immune cells, and mediators of inflammation provides an efficient mechanism to protect the organism against infections and support the repair of damaged tissues. Alterations in this complex machinery play a role in the pathogenesis of different diseases. Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been shown to be active intracellularly as the complosome. The kidney is particularly vulnerable to complement-induced damage, and emerging findings have revealed the role of complement system dysregulation in a wide range of kidney disorders, including glomerulopathies and ischemia-reperfusion injury during kidney transplantation. Different studies have shown that activation of the complement system is an important component of tumorigenesis and its elements have been proved to be present in the TME of various human malignancies. The role of the complement system in renal cell carcinoma (RCC) has been recently explored. Clear cell and papillary RCC upregulate most of the complement genes relative to normal kidney tissue. The aim of this narrative review is to provide novel insights into the role of complement in kidney disorders.

Ulcerative colitis (UC) is an inflammatory bowel disorder (IBD) characterized by relapsing chronic inflammation of the colon that causes continuous mucosal inflammation. The global incidence of UC is steadily increasing. Immune mechanisms are involved in the pathogenesis of UC, of which complement is shown to play a critical role by inducing local chronic inflammatory responses that promote tissue damage. However, the function of various complement components in the development of UC is complex and even paradoxical. Some components (e.g. C1q, CD46, CD55, CD59, and C6) are shown to safeguard the intestinal barrier and reduce intestinal inflammation, while others (e.g. C3, C5, C5a) can exacerbate intestinal damage and accelerate the development of UC. The complement system was originally thought to function primarily in an extracellular mode; however, recent evidence indicates that it can also act intracellularly as the complosome. The current study provides an overview of current studies on complement and its role in the development of UC. While there are few studies that describe how intracellular complement contributes to UC, we discuss potential future directions based on related publications. We also highlight novel methods that target complement for IBD treatment.

The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings.

Complement factor I (FI) is the nexus for classical, lectin and alternative pathway complement regulation. FI is an 88 kDa plasma protein that circulates in an inactive configuration until it forms a trimolecular complex with its cofactor and substrate whereupon a structural reorganization allows the catalytic triad to cleave its substrates, C3b and C4b. In keeping with its role as the master complement regulatory enzyme, deficiency has been linked to immunopathology. In the setting of complete FI deficiency, a consumptive C3 deficiency results in recurrent infections with encapsulated microorganisms. Aseptic cerebral inflammation and vasculitic presentations are also less commonly observed. Heterozygous mutations in the factor I gene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemic syndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also been associated with decreased retinal thickness and is a strong risk factor for the development of age-related macular degeneration. Supplementation of FI using plasma purified or recombinant protein has long been postulated, however, technical difficulties prevented progression into clinical trials. It is only using gene therapy that CFI supplementation has reached the clinic with GT005 in phase I/II clinical trials for geographic atrophy.