Complement Cascade Research Articles

Proteomics profiling and machine learning in nusinersen-treated patients with spinal muscular atrophy

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

Multi-Omics Exploration of the Mechanism of Curcumol to Reduce Invasion and Metastasis of Nasopharyngeal Carcinoma by Inhibiting NCL/EBNA1-Mediated UBE2C Upregulation.

Nasopharyngeal carcinoma (NPC) is closely linked to Epstein-Barr virus (EBV) infection. Curcumae Rhizoma, a traditional Chinese herb, has shown antitumor effects, primarily through its component curcumol (Cur), which has been shown to reduce NPC cell invasion and migration by targeting nucleolin (NCL) and Epstein-Barr Virus Nuclear Antigen 1 (EBNA1). We constructed an EBV-positive NPC cell model using C666-1 cells and performed transcriptomics studies after treatment with curcumol, which revealed a significant enrichment of ubiquitin-mediated proteolysis, the PI3K-AKT and mTOR signaling pathways, cell cycle and apoptosis involved in tumor invasion and migration. To investigate the importance of NCL and EBNA1 in curcumol-resistant EBV-positive NPC, we performed a multi-omics study using short hairpin NCL (shNCL) and shEBNA1 EBV-positive NPC cells, and the proteomics results showed enrichment in complement and coagulation cascades and ubiquitin-mediated proteolysis signaling pathways. Here, we focused on ubiquitin-conjugating enzyme E2C (UBE2C), which plays an important role in the ubiquitin-mediated proteolysis signaling pathway. In addition, metabolomics revealed that UBE2C is highly associated with 4-Aminobutanoic acid (GABA). In vitro studies further validated the function of the key targets, suggesting that UBE2C plays an important role in NCL and EBNA1-mediated curcumol resistance to nasopharyngeal carcinoma invasion and metastasis.

Testing AI predictions that hyperglycemia-induced non-enzymatic glycation of immune system proteins impairs diabetic immunity

People with type 1, type 2 and gestational diabetes, and newborns of diabetic mothers, have increased risks of contracting microbial infections such as SARS-CoV-2, amplifying comorbidity and mortality risks. Hyperglycemia and its associated hyperinflammation mediate these risks but by unknown mechanisms. We hypothesize that hyperglycemia results in glycation (non-enzymatic addition of sugars to free amino groups such as lysines) of antimicrobial and anti-inflammatory proteins and peptides that mediate innate and adaptive immunity. While glycation of hemoglobin A1c is used as a benchmark for glycemic control, studies of the effects of the glycation of immune system molecules are almost non-existent. Three AI protein-glycation prediction models demonstrate that immune system proteins and peptides such as serotransferrin, lactotransferrin, lysozyme, complement proteins, immunoglobulins, Toll-like receptors, etc., probably glycate at multiple sites affecting function. However, the AI-predicted glycation sites differed significantly among the three models employed. Therefore, three tests of these predictions were carried out. Predicted glycation sites were first evaluated in terms of clinically or experimentally identified glycation sites of homologous proteins and known effects of lysine substitutions at predicted glycation sites. Second, mass spectrometry was used to identify glycation sites on lactoferrin and human lysozyme. Third, the effects on the antimicrobial activity of lactotransferrin and lysozyme glycation were tested using a Candida albicans assay. Results of tests demonstrate that protein glycation occurs and interferes with immune function but that AI glycation prediction models are very inaccurate. Suggestions for improving AI accuracy are provided.

Biologics in Systemic Lupus Erythematosus: Recent Evolutions and Benefits.

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients' quality of life.

Sex-dependent regulation of retinal pigment epithelium and retinal function by Pgc-1α.

Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging is the prominent factor in AMD, studies have reported a higher prevalence of AMD in women compared to age-matched men. Higher levels of the innate immune response's effector proteins complement factor B and factor I were also found in females compared to males in intermediate AMD. However, the mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolic pathways. Previously, we showed that Pgc-1α repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that Pgc-1α repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition in vitro results in lipid droplet accumulation in human RPE. Whether sex is a contributing factor in these phenotypes remains to be elucidated. Using electroretinography, we demonstrate that sex could influence RPE function during aging independent of Pgc-1α in wild-type (WT) mice. We further show that Pgc-1α repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that Pgc-1α differentially regulates genes related to antioxidant enzymes and mitochondrial dynamics in males and females. RPE flat mounts immunolabeled with TOMM20 and DRP1 indicated a sex-dependent role for Pgc-1α in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of Pgc-1α repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of Pgc-1α induces a sex-dependent decline in RPE and retinal function in mice. These observations on the sex-dependent regulation of RPE and retinal function could offer novel insights into targeted therapeutic approaches for age-related RPE and retinal degeneration.

Guanxinning Tablet Alleviates Post-Ischemic Stroke Injury Via Regulating Complement and Coagulation Cascades Pathway and Inflammatory Network Mobilization.

Currently, ischemic stroke (IS) continues to significantly contribute to functional deterioration and reduced life quality. Regrettably, the choice of neuro-rehabilitation interventions to enhance post-IS outcomes is limited. Guanxinning tablet (GXNT), a multi-component medicine composed of Danshen and Chuanxiong, has demonstrated neuroprotective potential against ischemic brain injury and diabetic encephalopathy. However, the therapeutic impact of GXNT on post-IS functional outcomes and pathological injury, as well as the underlying molecular mechanisms and anti-IS active substances, remain unclear. To answer the above questions, neurological and behavioral assessment, cerebral lesions, and blood-brain barrier (BBB) integrity were combined to comprehensively investigate GXNT's pharmacodynamic effects against post-IS injury. The possible molecular mechanisms were revealed through transcriptome sequencing coupled with experimental verification. Furthermore, the brain tissue distribution of main components in GXNT, behavioral changes of IS zebrafish, and molecular docking were integrated to identify the anti-IS active compounds. Treatment with GXNT significantly mitigated the functional deficits, cerebral cortex lesions, and BBB disruption following IS. Transcriptome sequencing and bioinformatics analysis suggested that complement and coagulation cascades as well as inflammation might play crucial roles in the GXNT's therapeutic effects. Molecular biology experiments indicated that GXNT administration effectively normalized the abnormal expression of mRNA and protein levels of key targets related to complement and coagulation cascades (eg C3 and F7) and inflammation (eg MMP3 and MMP9) in the impaired cortical samples of IS mice. The locomotor promotion in IS zebrafish as well as favorable affinity with key proteins (C3, F7, and MMP9) highlighted anti-IS activities of brain-permeating constituents (senkyunolide I and protocatechuic acid) of GXNT. Taken together, these intriguing findings indicate that GXNT intervention exerts a beneficial effect against post-IS injury via regulating the complement and coagulation cascades pathway and mobilizing inflammatory network. Senkyunolide I and protocatechuic acid show promise as anti-IS active compounds.

Immunodeficiency: Complement disorders.

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

Gene expression analysis identifies hub genes and pathways distinguishing fatal from survivor outcomes of Ebola virus disease.

The Ebola virus poses a severe public health threat, yet understanding factors influencing disease outcomes remains incomplete. Our study aimed to identify critical pathways and hub genes associated with fatal and survivor Ebola disease outcomes. We analyzed differentially expressed hub genes (DEGs) between groups with fatal and survival outcomes, as well as a healthy control group. We conducted additional analysis to determine the functions and pathways associated with these DEGs. We found 13,198 DEGs in the fatal and 12,039 DEGs in the survival group compared to healthy controls, and 1873 DEGs in the acute fatal and survivor groups comparison. Upregulated DEGs in the comparison between the acute fatal and survivor groups were linked to ECM receptor interaction, complement and coagulation cascades, and PI3K-Akt signaling. Upregulated hub genes identified from the acute fatal and survivor comparison (FGB, C1QA, SERPINF2, PLAT, C9, SERPINE1, F3, VWF) were enriched in complement and coagulation cascades; the downregulated hub genes (IL1B, 1L17RE, XCL1, CXCL6, CCL4, CD8A, CD8B, CD3D) were associated with immune cell processes. Hub genes CCL2 and F2 were unique to fatal outcomes, while CXCL1, HIST1H4F, and IL1A were upregulated hub genes unique to survival outcomes compared to healthy controls. Our results demonstrate for the first time the association of EVD outcomes to specific hub genes and their associated pathways and biological processes. The identified hub genes and pathways could help better elucidate Ebola disease pathogenesis and contribute to the development of targeted interventions and personalized treatment for distinct EVD outcomes.

Bioinformatics screening and verification of ischemic stroke-related key genes and drug prediction.

Stroke is one of the major causes of disability and death worldwide. The lack of effective medical treatment for stroke heightens the need for new therapeutic targets. In this study, we obtained two microarray data sets from the Gene Expression Omnibus (GEO) database and identified differential genes (DEGs) between MCAO and control groups. Then, enrichment analysis of the DEGs was performed using DAVID and Metascape. The results show 27 DEGs shared between the two datasets. The functional enrichment analysis showed that these genes are mainly enriched in immune response, complement and coagulation cascades, apoptotic processes. The four hub genes (C1qc, Fcgr2b, C1qb, and Cd14) were screened out using the Cytoscape. Next, real-time PCR and Western blot analysis showed that expression of C1q and CD14 increased at 14 days after tMCAO. Furthermore, we took eight small molecule compounds with the lowest score using Cmap and studied their background characteristics. These results are built on a meta-analysis of data, which are generally accessible from the online space. Finally, we evaluated the protective effect of the rolipram through behavior tests after tMCAO, and results showed that the rolipram significantly attenuated neurobehavioral dysfunction at 14 days after brain ischemia. The present results provide novel insights into the biological process and potential therapeutic drugs involved in stroke.

Fufang E’jiao Jiang’s effect on immunity, hematopoiesis, and angiogenesis via a systematic “compound-effect-target” analysis

Fufang E’jiao Jiang (FEJ) as a healthy food consisting of medicine food homology materials approved by China’s Ministry of Health has been extensively applied to replenish qi and nourish blood, and it has a positive impact on women’s health. To find out the material basis and mechanism of FEJ, a systematic “compound-effect-target” analysis including chemical composition resolution, zebrafish, network pharmacology, molecular docking, transcriptome, and bibliometric analysis was adopted. 124 chemical components including ginsenosides, and phenylethanoid glycosides in FEJ were discovered, and effects of FEJ on promoting the generation of immune cells, erythropoiesis and angiogenesis in zebrafish were exhibited. Based on network pharmacology, molecular docking and in vivo activity assay, 6 compounds including jionoside A1, isoacteoside, echinacoside, acteoside, lobetyolin, and rehmannioside D were identified as active components of FEJ. Transcriptome data showed that several pathways such as complement and coagulation cascades, ECM-receptor interaction, and PI3K-Akt signaling pathway were associated with proangiogenic effect of FEJ. 19 common targets were obtained through combined analysis of network pharmacology and transcriptomics, and 5 targets of them were verified by PCR. The bibliometric analysis of these common targets revealed that FEJ was related to energy metabolism, pathway in cancer, etc., which was consistent with the results of network pharmacology and transcriptome. The studies suggested that FEJ could replenish qi and nourish blood through multi-compound and multi-targets.

Effects of Photobiomodulation Associated with Platelet-Rich Plasma in Acute Rheumatoid Arthritis Induced in Female Wistar Rats' Knee.

Objective: Rheumatoid arthritis causes inflammation, pain, and joint degradation, necessitating treatment with anti-inflammatory drugs and corticosteroids, posing various challenges. We aimed to evaluate the effects of photobiomodulation (PBM) at two different doses associated to platelet-rich plasma (PRP) in an invivo model of induced acute arthritis in Wistar rats' knee. Methods: Eighty-four Wistar rats were assigned into seven groups, including animals treated with PBM and/or PRP. On day 0, arthritis was induced in sham and treated groups through the intra-articular injection of zymosan (200 μg). Twenty-four hours after induction, the PBM groups were treated with an AsGaAl laser, whereas the PRP-treated groups received intra-articular injections with a concentration of 8 × 105 platelets obtained from another four animals. After 3 days, the animals were euthanized, and the interleukin (IL)-6 and complement C3 gene and protein expression levels were analyzed. Statistical analysis was performed using the mean ± SD with analysis of variance and Tukey's posttest, with a significance level set at 5% (p < 0.05). Results: Synovial inflammation decreased in PBM-treated groups; however, PRP alone showed no significant difference. Gene expression analysis revealed a significant difference in IL-6 and C3 levels in the PBM and PBM+PRP-treated groups. Meanwhile, the PRP alone group exhibited significance for IL-6. Moreover, the PBM and PBM+PRP-treated groups showed a significant difference in C3 protein expression levels, whereas the PRP alone group showed no difference. Conclusion: The increase in cellular activity in the synovial membrane and the decrease protein expression levels are owing to the reduction in proinflammatory mediators following PBM therapy.

Sugar transporters PpSWEET9a and PpSWEET14 synergistically mediate peach sucrose allocation from source leaves to fruit

Sugar content is a critical indicator of fruit quality and is mainly controlled by sugar transporters. Sugars will eventually be exported transporters (SWEET) proteins play an indispensable role in sugar allocation between and within plant organs. Sucrose is the major sugar in many fruits and the predominant form of sugar translocated in peach (Prunus persica). However, the role of the multiple peach SWEET genes in sucrose allocation to fruit remains elusive. In this study, a total of 19 SWEET candidates have been identified in the peach genome, and two Clade III SWEET genes, PpSWEET9a and PpSWEET14, are found to be highly expressed in mature source leaves and branches. Complementation assays, transgene manipulations, and protein interaction studies reveal that PpSWEET9a and PpSWEET14 serve as sucrose efflux proteins and form a heterooligomer that synergistically directs sucrose allocation from source leaves to fruits. Our findings provide insights into the effect of SWEETs on sugar accumulation in peach fruit and identify genetic candidates for improving fruit quality.

Research Note: Comprehensive proteomic, phosphoproteomic, and N-glycoproteomic analysis of chicken egg yolk plasma

Chicken egg yolk plasma (EYP), the supernatant fraction of egg yolk obtained by water dilution and centrifugation, is a rich source of various bioactive substances and a significant bearer of yolk-emulsifying properties. This study utilized proteomics to conduct a comprehensive and in-depth analysis of both common and modified EYP proteins (phosphorylated proteins and N-glycosylated proteins). Total of 208 proteins were identified in EYP, including 42 phosphorylated proteins with 137 phosphorylation sites and 150 N-glycoproteins with 332 N-glycosylation sites. Among the phosphorylation sites, tyrosine accounted for 80.6%, while the N-glycosylation sites predominantly featured "N-X-T" motifs, accounting for 58.7%. Functional enrichment analysis revealed that most proteins were involved in regulating enzyme activity and inhibition with a particular focus on modulating peptidase activity. Notably, vitellogenins-2 (30 phosphorylation sites, 9 N-glycosylation sites) and apolipoprotein B (10 phosphorylation sites, 56 N-glycosylation sites) were the 2 proteins with the most modification sites. Additionally, EYP was found to contain the highly N-glycosylated complement proteins C3 and C4. These findings provide new insights into the protein composition of EYP and its roles in chicken embryo development and immune defense, offering a theoretical foundation for the application of EYP in various fields.

Single-cell RNA sequencing identifies inherent abnormalities of adipose-derived stem cells from nonlesional sites of patients with localized scleroderma

BackgroundLocalized scleroderma (LoS) is an autoimmune disorder that primarily affects the skin, and is often treated with autologous fat grafting (AFG). Nevertheless, the retention rate of AFG in patients with LoS is typically low. We hypothesize that the low retention rate may be partially attributed to the inherent abnormalities of adipose-derived stem cells (ASCs) from nonlesional sites of patients with LoS.MethodsWe performed a comparative analysis of the single-cell transcriptome of the SVF from nonlesional sites of patients with LoS and healthy donors, including cellular compositional analysis, differential expression analysis, and high-dimensional weighted gene coexpression network analysis. Experimental validation with fluorescence-activated cell sorting and bleomycin-induced skin fibrosis mice models were conducted.ResultsWe found a significant reduction in the relative proportion of CD55high interstitial progenitors in ASCs under the condition of LoS. Differential expression analysis revealed inherent abnormalities of ASCs from patients with LoS, including enhanced fibrogenesis, reduced anti-inflammatory properties, and increased oxidative stress. Compared with CD55low ASCs, CD55high ASCs expressed significantly higher levels of secreted protein genes that had functions related to anti-inflammation and tissue regeneration (such as CD55, MFAP5, and METRNL). Meanwhile, CD55high ASCs expressed significantly lower levels of secreted protein genes that promote inflammation, such as chemokine and complement protein genes. Furthermore, we provided in vivo experimental evidence that CD55high ASCs had superior treatment efficacy compared with CD55low ASCs in bleomycin-induced skin fibrosis mice models.ConclusionsWe found that the low retention rate of AFG may be partially ascribed to the reduced pool of interstitial progenitor cells (CD55high) present within the ASC population in patients with LoS. We demonstrated the potential for improving the efficacy of AFG in the treatment of LoS by restoring the pool of interstitial progenitors within ASCs. Our study has significant implications for the field of translational regenerative medicine.

Pork cuts, hams, and sausages have digestible indispensable amino acid scores (DIAAS) close to or over 100

AbstractBackgroundThe “Digestible Indispensable Amino Acid Score” (DIAAS) method measures protein quality in human foods. Animal‐based products generally have high protein quality, but DIAAS values for some pork products are not available. Therefore, the objective of this experiment was to determine standardized ileal digestibility (SID) of amino acids (AA) and DIAAS values for pork products, including three types of pork cuts, Italian hams, and sausages, and to test the hypothesis that all pork products have DIAAS equal to or greater than 100.ResultsThe mean SID of the indispensable AA in all pork products was above 90% and indicated excellent digestibility. For children from 6 months to 3 years old and individuals older than 3 years, prosciutto had greater (p &lt; 0.05) DIAAS than all other pork products. Tenderloin and Coppa had greater (p &lt; 0.05) DIAAS than back ribs, shoulder butt, chorizo, and bratwurst. There were no limiting AA in any of the pork products (DIAAS &gt;100) with the exception that sulfur AA (SAA: methionine + cysteine) were limiting in chorizo for children from 6 months to 3 years old (DIAAS = 99).ConclusionWith the exception of chorizo for children less than 3 years old, all pork products have “excellent” protein quality for individuals older than 6 months of age, with DIAAS greater than 100. Pork proteins can, therefore, complement proteins with low quality to produce a meal that is adequate in all AA.

Transcriptomic analysis reveals bovine herpesvirus 1 infection regulates innate immune response resulted in restricted viral replication in neuronal cells

BackgroundBovine herpesvirus 1 (BoHV-1) is a major pathogen that affects the global bovine population, primarily inducing respiratory and reproductive disorders. Its ability to establish latent infections in neuronal cells and to reactivate under certain conditions poses a continual threat to uninfected hosts. In this study, we aimed to analyze the replication characteristics of BoHV-1 in neuronal cells, as well as the effects of viral replication on host cell immunity and physiology. MethodsUsing the Neuro-2a neuronal-origin cell line as a model, we explored the dynamics of BoHV-1 replication and analyzed differential gene expression profiles post-BoHV-1 infection using high-throughput RNA sequencing. ResultsBoHV-1 demonstrated restricted replication in Neuro-2a cells. BoHV-1 induced apoptotic pathways and enhanced the transcription of interferon-stimulated genes and interferon regulatory factors while suppressing the complement cascade in Neuro-2a cells. ConclusionsDifferent from BoHV-1 infection in other non-highly differentiated somatic cells result in viral dominance, BoHV-1 regulated the innate immune response in neuronal cells formed a “virus-nerve cell” relative equilibrium state, which may account for the restricted replication of BoHV-1 in neuronal cells, leading to a latent infection. These findings provide a foundation for further research into the mechanism underlying BoHV-1-induced latent infection in nerve cells.

Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

The complement system: A key player in the host response to infections.

Infections are one of the most significant healthcare and economic burdens across the world as underscored by the recent coronavirus pandemic. Moreover, with the increasing incidence of antimicrobial resistance, there is an urgent need to better understand host-pathogen interactions to design effective treatment strategies. The complement system is a key arsenal of the host defense response to pathogens and bridges both innate and adaptive immunity. However, in the contest between pathogens and host defense mechanisms, the host is not always victorious. Pathogens have evolved several approaches, including co-opting the host complement regulators to evade complement-mediated killing. Furthermore, deficiencies in the complement proteins, both genetic and therapeutic, can lead to an inefficient complement-mediated pathogen eradication, rendering the host more susceptible to certain infections. On the other hand, overwhelming infection can provoke fulminant complement activation with uncontrolled inflammation and potentially fatal tissue and organ damage. This review presents an overview of critical aspects of the complement-pathogen interactions during infection and discusses perspectives on designing therapies to mitigate complement dysfunction and limit tissue injury.

Disentangling the riddle of systemic lupus erythematosus with antiphospholipid syndrome: blood transcriptome analysis reveals a less-pronounced IFN-signature and distinct molecular profiles in venous versus arterial events

IntroductionSystemic lupus erythematosus with antiphospholipid syndrome (SLE-APS) represents a challenging SLE endotype whose molecular basis remains unknown.MethodsWe analysed whole-blood RNA-sequencing data from 299 patients with SLE (108 SLE-antiphospholipid antibodies (aPL)-positive,...

Proteomics Analysis of Human Chorionic Villi Reveals Dysregulated Pathways That Contribute to Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) represents a common disorder with consequences on family and society. As more than half of the RPL cases do not have a clearly identified cause, uncovering the mechanisms behind the idiopathic RPL is urgently needed. Using label-free data-independent LC-MS/MS acquisition coupled with ion mobility, we compared the proteome of chorionic villi from 13 RPL cases with 10 age and gestational week-matched elective pregnancies. Transcriptional levels of selected candidate biomarkers were determined in chorionic villi of 35 RPL cases and 25 controls using quantitative polymerase chain reaction (qPCR). Statistically significant difference in abundance (Benjamini-Hochberg [B-H] p≤0.05) and fold change ≥1.5 showed 128 proteins. Bioinformatics analysis identified complement and coagulation cascades, platelet activation, tricarboxylic acid cycle (TCA) cycle, and ferroptosis as pathways with the highest significance. Correlation with transcriptome datasets revealed a weak statistically significant positive correlation with 45% of the co-differentially expressed proteins/genes displaying the same regulation trend. The transcription levels of neurofilament light polypeptide (NEFL), dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex_mitochondrial (DLST), nitric oxide synthase3 (NOS3), and ceruloplasmin (CP) were significantly increased in the RPL, consistent with the proteomics findings. Our data suggests alteration of several pathways as potential causes of idiopathic RPL from the fetal side and opens the way for investigations concerning clinical management.