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Aim Methods Results Conclusion We have previously reported the mid‐term efficacy and safety of tacrolimus (Tac)‐based immunosuppressive therapy in such patients, and herein, we aimed to determine their long‐term outcomes (over 10 years).We retrospectively evaluate the data of 13 consecutive patients with biopsy‐proven long‐standing LN who underwent a long‐term Tac‐based treatment regimen. Tac was administered once daily at a dose of 3 mg as reinduction or maintenance treatment. Treatment outcomes were defined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), urinary protein/creatinine ratio (Up/cr), serum creatinine, estimated glomerular filtration rate (eGFR) and serological lupus markers (complement C3, complement hemolytic activity [CH 50], and anti‐dsDNA antibody titre), and the concomitantly administered prednisolone (PDN) dose. Data on clinical parameters and serological lupus activity were collected annually from each patient throughout the study period.The patients' baseline characteristics at the treatment initiation were as follows: mean age, 18 years; Up/cr, 0.63 ± 0.69; serum C3 level, 57.2 ± 22.4 mg/dL (normal range, 79–152 mg/dL); CH50, 27.9 ± 15.7 U/mL (normal range, 23.0–46.0 U/mL); serum anti‐dsDNA antibody titre, 111.7 ± 123.4 IU/mL (normal range, <12.0 IU/mL); serum creatinine, 0.60 ± 0.19 mg/dL; eGFR, 115.6 ± 21.3 mL/min and SLEDAI, 13 ± 8.1. Despite the gradual tapering of the concomitantly administered PDN dose from 18.7 ± 13.5 mg/day at baseline to 3.5 ± 2.8 mg/day at 10 years (p = .002), a marked improvement in the outcomes, compared with the baseline values, was observed within a year. Additionally, these favourable changes persisted throughout study period in most patients. Compared with the baseline values, the following measures confirmed sustained outcome improvements after a 10‐year treatment: SLEDAI, 1.7 ± 2.0; serum C3 level, 83.8 ± 16.1 mg/dL; CH50, 45.6 ± 10.9 U/mL (all p < .01) and Up/cr, 0.16 ± 0.18 and serum anti‐dsDNA antibody titre, 25.8 ± 28.8 IU/mL (both p < .05). Serum creatinine level and eGFR remained within the normal range in all study participants except for one patient who experienced several flare‐ups. No serious adverse effects were observed.Our results suggest that long‐term Tac‐based immunosuppressive treatment as maintenance therapy is beneficial and has low cytotoxicity. Therefore, it represents an attractive option for the treatment of selected patients with paediatric‐onset LN in a real‐world setting. [ABSTRACT FROM AUTHOR]

Aim: An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis. Method: In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1b (IL-1b), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1b, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis. Results: In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, p value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers. Conclusions: The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease. [ABSTRACT FROM AUTHOR]

In patients with major depressive disorder, various functional areas are impaired, negatively impacting the quality of life. Remission can restore pre-depression functions; however, some patients may still have residual impairments. Distinguishing between near-normal recovery and residual impairment helps identify those at a high risk of relapse risk and helps tailor treatment. Accordingly, we aimed to discover and validate biomarkers that distinguish between near-normal recovery and residual impairment in remission states through serum proteome analysis. Pooled serum and individual serum samples from three groups (depression status, remission status with residual impairment, and remission status with normal recovery) were analyzed using liquid chromatography-tandem mass spectrometry. The combination of four proteins—antithrombin-III, serum amyloid A4 protein, C1q subcomponent subunit B, and serum amyloid P-component—was selected as a candidate biomarker. The trend of protein changes suggests complement C1q subcomponent subunit B and serum amyloid P-component as potential biomarkers for distinguishing remission from residual impairment. Changes in complement C1q subcomponent subunit B and serum amyloid P-component suggest that the complement system and inflammation-related immune mechanisms are associated with residual impairment in remittent major depressive disorder. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions The efficacy and safety of ravulizumab, a terminal complement C5 inhibitor, in adults with anti‐acetylcholine receptor antibody‐positive (AChR Ab+) generalized myasthenia gravis (gMG) were demonstrated in the CHAMPION MG study (NCT03920293). This analysis aimed to characterize the latency to onset of a clinically meaningful therapeutic effect for ravulizumab.Post hoc analysis of data collected for up to 60 weeks from CHAMPION MG was performed to assess the timing of response to ravulizumab. Response was analyzed based on reductions of ≥2 and ≥3 points (minimal clinically important differences [MCIDs]) in Myasthenia Gravis–Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG) total scores, respectively, and on more rigorous reductions of ≥3 and ≥5 points, respectively. Time to first response was assessed using the Kaplan–Meier product‐limit method.The median (95% confidence interval) time to first response was 2.1 (2.1–2.6) and 4.1 (2.3–10.0) weeks for reductions of ≥2 and ≥3 points in MG‐ADL total score, respectively (n = 139), and 4.1 (2.1–10.0) and 18.3 (11.0–33.4) weeks for reductions of ≥3 and ≥5 points in QMG total score, respectively (n = 134). Cumulative response rates at Week 60 (data cut‐off) were 88% and 82% for ≥2‐ and ≥3‐point MG‐ADL score reductions, respectively, and 86% and 59% for ≥3‐ and ≥5‐point QMG score reductions, respectively.The median times to MCID with ravulizumab treatment in patients with AChR Ab+ gMG were ~2 weeks and ~4 weeks based on MCID MG‐ADL and QMG total score reductions, respectively. [ABSTRACT FROM AUTHOR]

Introduction: The complement system plays a key role in the host defense against pathogens. The deficiency of complement components predisposes the system to recurrent infections and autoimmune diseases. In particular, serum C5 deficiency (C5D) may be serious for human health, because this protein plays a key role in controlling infections, mainly with Neisseria spp. Aim: The aim of this article is to present the structure and function of the human C5 gene encoding complement component C5, with particular regard to the molecular characteristics of the mutations causing hereditary complement C5 deficiency. Material and methods: This article is based on the available literature. A total of 35 articles were included in the study. Results and discussion: Based on the literature review, it was shown that C5 mediates inflammatory processes and bacterial cytolysis. The cause of hereditary C5 deficiency in humans is inefficient or reduced serum C5 biosynthesis, due to mutations in the C5 gene. This quantitative and functional C5 deficiency is associated with recurrent Neisseria spp. infections, the lack of bactericidal activity and an impaired ability of serum to induce chemotaxis. The molecular characterization of previously described C5D-related mutations in the human C5 gene has been performed, and the clinical presentation of some molecularly examined C5D probands has also been discussed. Conclusions: The deficiency of C5 protein, which bridges innate and adaptive immunity, is related with 18 different mutations in the C5 gene found in over 30 families of various origins. Screening for complement defects seems particularly important, especially in asymptomatic relatives of probands. [ABSTRACT FROM AUTHOR]

The co-occurrence of Alzheimer's disease (AD) and cardiovascular diseases (CVDs) in older adults highlights the necessity for the exploration of potential shared risk factors. A total of 566 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 111 individuals with AD, 383 with mild cognitive impairment (MCI), and 410 with CVD. The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD with longitudinal changes in 146 plasma proteomic biomarkers (measured at baseline and the 12-month follow-up). The LMM showed that 48 biomarkers were linked to AD and 46 to CVD (p < 0.05). Both AD and CVD were associated with longitudinal changes in 14 biomarkers (α1Micro, ApoH, β2M, BNP, complement C3, cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF), and both MCI and CVD were associated with 12 biomarkers (ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), suggesting intricate connections between cognitive decline and cardiovascular health. Among these, the Tamm Horsfall Protein (THP) was associated with AD, MCI, CVD, and APOE-ε4. This study provides valuable insights into shared and distinct biological markers and mechanisms underlying AD and CVD. [ABSTRACT FROM AUTHOR]

The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK/MAPK, p38/MAPK, JNK/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a complex and multifaceted obstetric syndrome characterized by several distinct molecular subtypes. It complicates up to 5% of pregnancies and significantly contributes to maternal and newborn morbidity, thereby diminishing the long-term quality of life for affected women. Due to the widespread dissatisfaction with the effectiveness of existing approaches for assessing PE risk, there is a pressing need for ongoing research to identify newer, more accurate predictors. This study aimed to investigate early changes in the maternal serum proteome and associated signaling pathways. The levels of 125 maternal serum proteins at 11–13 weeks of gestation were quantified using liquid chromatography–multiple reaction monitoring mass spectrometry (LC-MRM MS) with the BAK-125 kit. Ten serum proteins emerged as potential early markers for PE: Apolipoprotein M (APOM), Complement C1q subcomponent subunit B (C1QB), Lysozyme (LYZ), Prothrombin (F2), Albumin (ALB), Zinc-alpha-2-glycoprotein (AZGP1), Tenascin-X (TNXB), Alpha-1-antitrypsin (SERPINA1), Attractin (ATRN), and Apolipoprotein A-IV (APOA4). Notably, nine of these proteins have previously been associated with PE in prior research, underscoring the consistency and reliability of our findings. These proteins play key roles in critical molecular processes, including complement and coagulation cascades, platelet activation, and insulin-like growth factor pathways. To improve the early prediction of PE, a highly effective Support Vector Machine (SVM) model was developed, analyzing 19 maternal serum proteins from the first trimester. This model achieved an area under the curve (AUC) of 0.91, with 87% sensitivity and 95% specificity, and a hazard ratio (HR) of 13.5 (4.6–40.8) with p < 0.001. These findings demonstrate that serum protein-based SVM models possess significantly higher predictive power compared to the routine first-trimester screening test, highlighting their superior utility in the early detection and risk stratification of PE. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB) remains a significant public health concern, and prediction is an important objective, particularly in the early stages of pregnancy. Many studies have relied on cervical characteristics in the mid-trimester, with limited results. It is therefore crucial to identify novel biomarkers to enhance the ability to identify women at risk. The complement pathway is implicated in the process of placentation, and recent proteomics studies have highlighted the potential roles of some complement proteins in the pathophysiology of PTB. To determine the association between the occurrence of spontaneous preterm birth (sPTB) and the concentration of complement C3, factor B, and factor H in the blood of pregnant women during the first trimester. This prospective cohort study included women with singleton pregnancies, both with and without a history of sPTB, from two health institutions in Bucaramanga, Colombia. The outcome was sPTB before 37 weeks. A blood sample was obtained between 11 + 0 to 13 + 6 weeks. ELISA immunoassay was performed to quantify the levels of C3, factor B, and factor H. A total of 355 patients were analyzed, with a rate of sPTB of 7.6% (27/355). The median plasma concentration for C3, factor B, and factor H were 488.3 μg/mL, 352.6 μg/mL, and 413.2 μg/mL, respectively. The median concentration of factor H was found to be significantly lower in patients who delivered preterm compared to patients who delivered at term (382 μg/mL vs. 415 μg/mL; p = 0.034). This study identified a significant association between low first-trimester levels of factor H and sPTB before 37 weeks. These results provide relevant information about a new possible early biomarker for sPTB. However, the results must be confirmed in different settings, and the predictive value must be examined [ABSTRACT FROM AUTHOR]

C4d is the end degradation product of activated complement component C4b that appears during the early steps of the classical and lectin complement pathways. Within the primary sequence of C4d, there is a reactive thioester group that binds covalently to nearby surfaces, thus labeling the locations of complement activation. This feature makes C4d a target for immunohistochemical staining aimed to aid the diagnosis of, among others, the antibody-mediated rejection of transplanted organs, membranous glomerulonephritis, bullous pemphigoid, or inflammatory myopathies. However, the credibility of C4d immunostaining is debatable, as a high background in surrounding tissues and body fluids and diffused patterns of deposits in target structures are experienced with some of the available anti-C4d antibodies. Herein, we present an improved version of a rabbit anti-C4d antibody, originally raised against the C-terminal linear neoepitope of this complement fragment. Minor cross-reactivity with C4b and native C4 proteins, measured by ELISAs, as well as relatively low concentrations necessary for obtaining a specific signal in immunohistochemical analyses of formalin-fixed paraffin-embedded material, makes the improved antibody superior to commercially available rabbit monoclonal anti-C4d antibody SP91 dedicated to ex vivo diagnostics, as demonstrated by the staining of a panel of kidney transplant biopsies. [ABSTRACT FROM AUTHOR]

The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm‐blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, nonhuman primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. These observations and associations raise questions about how this parasitic infection may alter neural circuits. We previously demonstrated that T. gondii infection triggers the loss of inhibitory perisomatic synapses, a type of synapse whose dysfunction or loss has been linked to neurological and neuropsychiatric disorders. We showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons and not those on cortical interneurons. Moreover, we show that infection induces an increased expression of the complement C3 gene, including by populations of these excitatory neurons. Infecting C3‐deficient mice with T. gondii revealed that C3 is required for the loss of perisomatic inhibitory synapses. Interestingly, loss of C1q did not prevent the loss of perisomatic synapses following infection. Together, these findings provide evidence that T. gondii induces changes in excitatory pyramidal neurons that trigger the selective removal of inhibitory perisomatic synapses and provide a role for a nonclassical complement pathway in the remodeling of inhibitory circuits in the infected brain. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to assess the effect of dietary supplements of either aqueous (AE) or ethanolic (EE) (Juniperus communis) leaf extracts on growth performance, intestinal health, hemato-biochemical indices, antioxidant, inflammation cytokine responses, and resistances against infection in Nile tilapia, Oreochromis niloticus. Fish groups were controlled with no extract (J1) and fed diets (J2, J3, J4, and J5) containing 1.0 and 2.0 g/kg aqueous and ethanolic extract for 60 days. Fish were given an intraperitoneal injection (IP) of Aeromonas hydrophila for 10 days after the feeding trial; then, the fish mortality was recorded. Growth, feed efficiency, and activity of endogenous enzymes (lipase, trypsin, chymotrypsin, and amylase) were significantly improved in all dietary J. communis groups, especially in J5, compared to other groups. Also, J5 showed the highest absorption area, muscularis, goblet cells, villi width, and fewer gut bacterial counts than the other groups. In addition, the J4 and J5 groups of tilapia fish exhibited a significant increase in the levels of total protein, serum albumin, globulin, hemoglobin, white blood cells, and hematocrit (P < 0.05), as well as a significant decrease in the levels of serum alanine, aspartate aminotransferases, glucose, and cholesterol compared to the J1 groups. Moreover, the J4 and J5 fish showed a significant decline in the levels of MDA with improvements in antioxidant (SOD, CAT, and GPX) and immunological (lysozyme, immunoglobulin M, and complement C3) indices compared to the J1 group. Fish in J4 and J5 exhibited downregulated levels of il-8, il-10, il-1β, tnf-α, ifn-γ, and hsp70 genes compared to other groups. In contrast, hepatic catalase (cat), superoxide dismutase (sod), and interleukin (il-10) gene expressions were upregulated. The lowest fish mortality after the bacterial challenge was recorded in the J5 group. These findings suggest that 2.0 g/kg feed ethanolic extract of J. communis-fed Tilapia fish fingerlings improved their growth and intestinal health, boosted their immune systems and antioxidant responses, and increased their resistance to A. hydrophila. [ABSTRACT FROM AUTHOR]

Ectoparasites Dactylogyrus spp. mainly infest fish gills and severely damage the host's gill tissues. Correspondingly, the explanation of the interaction of fish with Dactylogyrus spp. infection is still insufficient. The present study describes the changes in hemato-biochemical, immune, antioxidant, genotoxic, and pathological indices response of Nile tilapia (Oreochromis niloticus) severely (n > 50), mildly infected (n = 1–50), and uninfected with Dactylogyrus spp. Data showed the adverse effect of hemato-biochemical indices in infected fish compared to uninfected, notably in severely infected O. niloticus. Compared to uninfected fish, there is a significantly decreased serum lysozyme and complement C3 and increased IgM and phagocytic activity along with significant upregulation of (COX-2), (IL-1β), (TNF-α), and (IL-10) genes in infected fish partially, in severely infected fish. Concisely, indices of antioxidants in the liver and gills marked an increased level of MDA in the infected fish compared to the uninfected fish. Conversely, levels of SOD, CAT, and GSH were decreased significantly with damaged DNA in the gills and liver of infected groups, particularly in severely infected (P < 0.05). Histopathologically investigating livers and gills in infected Nile tilapia indicated damaging and degenerative alterations, particularly with severe infection. Findings showed that Dactylogyrus spp.–infected Nile tilapia were effective in improving our knowledge of fish-pathogen interactions, which may be essential for fish defense against parasite infection. [ABSTRACT FROM AUTHOR]

Background: Lupus nephritis (LN) is a very severe manifestation of lupus. There is no consensus on which treatment goals should be achieved to protect kidney function in children with LN. Methods: We retrospectively analyzed trends of commonly used laboratory biomarkers of 428 patients (≤ 18 years old) with biopsy-proven LN class ≥ III. We compared data of patients who developed stable kidney remission from 6 to 24 months with those who did not. Results: Twenty-five percent of patients maintained kidney stable remission while 75% did not. More patients with stable kidney remission showed normal hemoglobin and erythrocyte sedimentation rate from 6 to 24 months compared to the group without stable kidney remission. eGFR ≥ 90 ml/min/1.73m2 at onset predicted the development of stable kidney remission (93.8%) compared to 64.7% in those without stable remission (P < 0.00001). At diagnosis, 5.9% and 20.2% of the patients showed no proteinuria in the group with and without stable kidney remission, respectively (P = 0.0001). dsDNA antibodies decreased from onset of treatment mainly during the first 3 months in all groups, but more than 50% of all patients in both groups never normalized after 6 months. Complement C3 and C4 increased mainly in the first 3 months in all patients without any significant difference. Conclusions: Normal eGFR and the absence of proteinuria at onset were predictors of stable kidney remission. Significantly more children showed normal levels of Hb and erythrocyte sedimentation rate (ESR) from 6 to 24 months in the group with stable kidney remission. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a leading cause of cancer mortality globally. This study aims to develop a prognostic model based on disulfidptosis-related genes to assess survival outcomes in CRC, highlighting the tumor microenvironment's role. Methods: The thought of traditional Chinese medicine syndrome differentiation and treatment runs through the whole study. We analyzed CRC tissue data from The Cancer Genome Atlas and the Gene Expression Omnibus using single-sample gene set enrichment and weighted gene correlation network analyses to identify prognostic markers and evaluate immune infiltration. We also investigated predictive drug sensitivities. Results: We identified seven disulfidptosis-related markers -- complement C1q A chain (C1QA), solute carrier family 11 member 1 (SLC11A1), cluster of differentiation 36 (CD36), cluster of differentiation 6 (CD6), interleukin 1 receptor associated kinase 3 (IRAK3), S100 calcium binding protein A8 (S100A8), and CD8 subunit alpha (CD8A) -- that significantly influence prognosis. Patients classified in the low-risk group demonstrated improved overall survival compared to those in the high-risk group across training (P = 0.0026) and validation cohorts (P = 0.032). Differential gene expression was significant in the high-risk group (P < 0.001), and prevalent mutations included APC regulator of WNT signaling pathway (APC), tumor protein P53 (TP53), Titin (TTN), and Kirsten rat sarcoma viral oncogene (KRAS). The risk score correlated linearly with tumor microenvironment attributes. The results of drug analysis showed that some traditional drugs may have anticancer effects through the vertical action of disulfidptosis. Conclusion: Our prognostic model, integrating seven disulfidptosis-related genes, categorizes CRC patients by survival probability and underscores these genes as potential biomarkers linked to the tumor microenvironment. These findings support their use in refining therapeutic strategies for CRC. [ABSTRACT FROM AUTHOR]

Objective: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long‐term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. Methods: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow‐up. Results: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6–37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52–72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. Conclusion: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow‐up, and adverse events, including infection, were observed. [ABSTRACT FROM AUTHOR]

Malignant cells are part of a complex network within the tumor microenvironment, where their interaction with host cells and soluble mediators, including complement components, is pivotal. The complement system, known for its role in immune defense and homeostasis, exhibits a dual effect on cancer progression. This dichotomy arises from its antitumoral opsonophagocytosis and cytotoxicity versus its protumoral chronic inflammation mediated by the C5a/C5aR1 axis, influencing antitumor T‐cell responses. Recent studies have revealed distinct co‐expression patterns of complement genes in various cancer types, correlating with prognosis. Notably, some cancers exhibit co‐regulated overexpression of complement genes associated with poor prognosis, while others show favorable outcomes. However, significant intra‐patient heterogeneity further complicates this classification. Moreover, the involvement of locally produced and intracellular complement proteins adds complexity to the tumor microenvironment dynamics. This review highlights the unique interplay of complement components within different cancers and patient cohorts, showing that "one size does not fit all", for complement in cancer. It summarizes the clinical trials for complement targeting in cancer, emphasizing the need for tailored therapeutic approaches. By elucidating the mechanistic basis of complement's context‐dependent role, this review aims to facilitate the development of personalized cancer therapies, ultimately improving patient care and outcomes. [ABSTRACT FROM AUTHOR]

Background and objectives: Lupus nephritis (LN) is a severe clinical manifestation seen in individuals with systemic lupus erythematous (SLE). It has a poor long-term prognosis in pediatric patients with high morbidity and mortality rates. MicroRNAs (miRNAs) are noncoding small RNAs that act as epigenetic modulators, regulating gene expression, and modulating the understanding of mechanisms and pathogenesis of human diseases. Depending on bioinformatics analysis, we aimed to investigate urinary expression of miR-663a in LN among SLE children and discriminate between proteinuria of LN versus chronic renal disease without SLE. Methods: The urinary miR-663a expression levels were estimated in cellular pellets from 15 SLE patients, 15 SLE and biopsy-proven active LN patients, 15 chronic kidney disease (CKD) patients rather than LN and 15 healthy controls. Results: LN patients had significantly higher urinary miR-663a expression levels compared to other groups (p < 0.0001). Urinary miR-663a at a cutoff of 8.61 had a diagnostic value of 93.3% for LN among pediatric SLE with 100% specificity (p < 0.0001). Moreover, miR-663a was upregulated in advanced grades and LN classes V, IV, and III compared to class II. Furthermore, miR-663a was positively correlated with the duration of SLE, activity index, chronicity index, urinary protein, anti-dsDNA, and SLEDAI score, and negatively correlated with serum complement C3 (p < 0.05). Conclusion: miR-663a could be related to the pathogenesis of kidney damage in LN; that could provide a specific noninvasive diagnostic and follow -up tool for LN patients. [ABSTRACT FROM AUTHOR]

Complement C3 (C3) is usually deposited spontaneously on the surfaces of invading bacteria prior to internalization, but the impact of C3 coating on cellular responses is largely unknown. Staphylococcus aureus (S. aureus) is a facultative intracellular pathogen that subverts autophagy and replicates in both phagocytic and nonphagocytic cells. In the present study, we deposited C3 components on the surface of S. aureus by complement opsonization before cell infection and confirmed that C3-coatings remained on the surface of the bacteria after they have invaded the cells, suggesting S. aureus cannot escape or degrade C3 labeling. We found that the C3 deposition on S. aureus notably enhanced cellular autophagic responses, and distinguished these responses as xenophagy, in contrast to LC3-associated phagocytosis (LAP). Furthermore, this upregulation was due to the recruitment of and direct interaction with autophagy-related 16-like 1 (ATG16L1), thereby resulting in autophagydependent resistance to bacterial growth within cells. Interestingly, this autophagic effect occurred only after C3 activation by enzymatic cleavage because full-length C3 without cleavage of the complement cascade reaction, although capable of binding to ATG16L1, failed to promote autophagy. These findings demonstrate the biological function of intracellular C3 upon bacterial infection in enhancing autophagy against internalized S. aureus. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD. [ABSTRACT FROM AUTHOR]

Equine endometritis is one of the main causes of subfertility in the mare. Unraveling the molecular mechanisms involved in this condition and pinpointing proteins with biomarker potential could be crucial in both diagnosing and treating this condition. This study aimed to identify the endometritis-induced changes in the endometrial proteome in mares and to elucidate potential biological processes in which these proteins may be involved. Secondly, biomarkers related to bacterial endometritis (BE) in mares were identified. Uterine lavage fluid samples were collected from 28 mares (14 healthy: negative cytology and culture, and no clinical signs and 14 mares with endometritis: positive cytology and culture, in addition to clinical signs). Proteomic analysis was performed with a UHPLC-MS/MS system and bioinformatic analysis was carried out using Qlucore Omics Explorer. Gene Ontology enrichment and pathway analysis (PANTHER and KEGG) of the uterine proteome were performed to identify active biological pathways in enriched proteins from each group. Quantitative analysis revealed 38 proteins differentially abundant in endometritis mares when compared to healthy mares (fold changes >4.25, and q-value = 0.002). The proteins upregulated in the secretome of mares with BE were involved in biological processes related to the generation of energy and REDOX regulation and to the defense response to bacterium. A total of 24 biomarkers for BE were identified using the biomarker workbench algorithm. Some of the proteins identified were related to the innate immune system such as isoforms of histones H2A and H2B involvement in neutrophil extracellular trap (NET) formation, complement C3a, or gelsolin and profilin, two actin-binding proteins which are essential for dynamic remodeling of the actin cytoskeleton during cell migration. The other group of biomarkers were three known antimicrobial peptides (lysosome, equine cathelicidin 2 and myeloperoxidase (MPO)) and two uncharacterized proteins with a high homology with cathelicidin families. Findings in this study provide the first evidence that innate immune cells in the equine endometrium undergo reprogramming of metabolic pathways similar to the Warburg effect during activation. In addition, biomarkers of BE in uterine fluid of mares including the new proteins identified, as well as other antimicrobial peptides already known, offer future lines of research for alternative treatments to antibiotics. • Mares with bacterial endometritis exhibited a significantly higher relative abundance of endometrial proteins compared to clinically healthy mares. • The proteins upregulated in the secretome of mares with bacterial endometritis were involved in biological processes related to the generation of energy and REDOX regulation and to the defense response to bacterium (neutrophil extracellular trap (NET) formation pathway). • A total of 24 biomarkers for bacterial endometritis were identified. Some of the proteins identified were related to the innate immune system such as isoforms of histones H2A and H2B, complement C3a, or gelsolin and profilin. The other group of biomarkers were three known antimicrobial peptides (lysosome, equine cathelicidin 2 and MPO) and two uncharacterized proteins with a high homology with cathelicidin families. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions The expressions of complement component C5a and NLRP3 inflammasome and the antiproliferative effect of resveratrol in benign prostatic hyperplasia (BPH) model rat were analyzed to clarify the BPH proliferative mechanism.This study used the pathological stromal‐dominant BPH model rat by urogenital sinus implantation (UGS). Expression of C5a, NLRP3, Caspase‐1, IL‐1β, and IL‐18 using rat BPH tissues at 2, 3, and 8 weeks (n = 6, respectively) after UGS implantation were analyzed by qRT‐PCR, western blotting analysis, and immunohistochemical (IHC) analysis. Serum IL‐1β levels in BPH model and sham rats were measured by enzyme‐linked immunosorbent assay. Furthermore, resveratrol, as the NLRP3 pathway inhibitor, was administered to BPH model rat to assess the antiproliferative effect on the BPH proliferative process. The proliferative effect on prostate was evaluated by Ki‐67 protein expression.The expression levels of C5a, NLRP3, Caspase‐1, IL‐1β, and IL‐18 in qRT‐PCR, western blotting, and IHC were significantly upregulated in BPH tissues compared to control prostate tissues and showed increases with time (all p < 0.05). Serum IL‐1β levels in BPH model rats had significantly increased compared to sham rats. On IHC, deposition of C5a, NLRP3, Caspase‐1, IL‐1β, and IL‐18 was abundant in stromal areas of BPH. The administration of resveratrol significantly decreased prostate weight and expressions of NLRP3, IL‐1β, IL‐18, and Ki‐67 (all p < 0.05).NLRP3 inflammasome activation by complement C5a produces IL‐1β and IL‐18 through Caspase‐1 during the BPH proliferative process. NLRP3 inflammasome have the possibilities to be a therapeutic target for BPH proliferation by inhibiting the NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]

This article discusses a case report of a successful treatment of lichen planus pemphigoides (LPP) with tofacitinib, a JAK inhibitor. LPP is a rare condition characterized by pruritic papules, plaques, and bullae on the skin. Previous treatments have shown limited efficacy, so alternative strategies such as JAK inhibitors have been explored. The patient in this case experienced significant improvement with tofacitinib, allowing for a gradual tapering of prednisolone. The article suggests that JAK inhibitors could be a promising treatment option for LPP by targeting the inflammatory processes and suppressing aberrant cytokine production. [Extracted from the article]

This article discusses the pathogenesis of IgA nephropathy (IgAN), a kidney disease characterized by the presence of immunodeposits containing IgA, IgG, and C3 in the glomeruli. The article highlights the role of abnormal O-glycosylation of IgA1 in the development of IgAN, as well as the genetic factors and cytokines involved in this process. It also explores the formation of pathogenic immune complexes consisting of galactose-deficient IgA1 bound by IgG autoantibodies, which contribute to kidney injury. The article concludes by emphasizing the need for further research in genomics and glycomics to inform the development of new therapeutic approaches for IgAN. [Extracted from the article]

The present study was conducted to evaluate the hormesis and toxicity of shortterm low-dose aflatoxin B1 in grass carp (Ctenopharyngodon idellus). Triplicate isonitrogenous and isocaloric aflatoxin B1 diets—CD (control, 0 ug/kg), D1 (20 ug/kg), and D2 (500 ug/kg)—were prepared and fed to grass carp with an initial mean body weight of (15.2 ± 0.1) g for 56 days. The results showed that the weight gain rate and specific growth rate of grass carp fed diet D2 were significantly higher, and the feed coefficient and crude fat content of the whole body were significantly lower (P < 0.05) compared with those fed diet CD. Serum superoxide dismutase content of grass carp fed D1 diet increased significantly (P < 0.05) with an increasing dose of aflatoxin B1, but when the dose reached 500 ug/kg (D2), serum superoxide dismutase, complement C3, and immunoglobulin M of grass carp decreased significantly (P < 0.05), while malondialdehyde increased significantly (P < 0.05). After short-term feeding of aflatoxin B1-containing diets (D1 and D2), liver body index, visceral body index, serum total cholesterol, triglyceride, and urea nitrogen content of grass carp increased significantly (P < 0.05), total bile acid secretion decreased significantly (P < 0.05), and structural damages such as increase in vacuoles, organizational structure loosening, and nucleus translocation were observed in the liver. Meanwhile, liver function indexes such as serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase increased significantly with the increase of aflatoxin B1 dose (P < 0.05). In addition, the height of intestinal villi, crypt depth, villus–crypt ratio, and tubular cell number, as well as the content of trypsin and lipase activities in the intestine of grass carp in the D2 group, were significantly higher than those in the CD group (P < 0.05). In conclusion, after a short-term intake of low doses of aflatoxin B1 (≤500 ug/kg), the toxicological damage of aflatoxin B1 was pronounced, although it produced a certain degree of hormesis on the growth performance and intestinal structure and function of grass carp. At a dose of 20 ug/kg, the non-specific immune system and liver structure and function of grass carp showed obvious toxic damage. [ABSTRACT FROM AUTHOR]

The given text is a collection of abstracts from the European Journal of Immunology, covering a wide range of topics related to immunology research. The abstracts discuss the role of complement activation in various diseases, such as lupus nephritis and MPGN, and suggest potential therapeutic strategies. They also explore genetic factors influencing disease susceptibility and the development of therapies targeting the complement system. These abstracts provide valuable insights into the current research and understanding of the complement system and its implications in different biological processes and medical conditions. [Extracted from the article]

We aimed to develop a novel method for measuring the complement-binding ability of anti-blood type antibodies (ab-Abs), the flow cytometry method for the complement C1q test (FCM-C1q) for detecting antibody-mediated rejection (AMR) caused by ab-Abs in ABO-incompatible kidney transplantation (ABOI-KTx). FCM-C1q distribution was surveyed in 44 healthy participants and 43 dialysis patients (Cohort A). The relationship between AMR and FCM-C1q levels was examined along with ab-Ab titers by the flow cytometry method for the IgG test (FCM-IgG) in 62 ABOI-KTx patients (Cohort B). FCM-IgG and C1q levels were significantly higher in type O participants than in A/B participants in Cohort A. There were minimal differences in the distribution of FCM-IgG and C1q between dialysis and healthy participants. Sixteen cases were suspected of acute rejections (ARs) in Cohort B, of whom nine had AR clinically. One patient with severe AMR was highly suspected of hyperacute rejection along with another patient with severe AMR. Their postoperative FCM-C1q and FCM-IgG levels were elevated. Another two patients showed high FCM-IgG and C1q levels before KTx, and these levels remained low after KTx with no or mild rejection. In conclusion, our results suggest that a high positivity rate for FCM-C1q may predict moderate to severe AMR caused by ab-Abs and poor prognosis in ABOI-KTx. [ABSTRACT FROM AUTHOR]

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 in vivo 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 (200μg). 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. [ABSTRACT FROM AUTHOR]

Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations. [ABSTRACT FROM AUTHOR]

Introduction: The membrane oxygenator in extracorporeal circulation circuits is coated with acrylate-copolymer (ACP) or immobilized heparin (IHP) to enhance hemocompatibility. To evaluate the relative features of both coatings, we compared blood components circulated in the circuits with ACP-and IHP-coated membranes in vitro using whole human blood. Methods: Whole human blood was heparinized and circulated in two experimental circuits with an ACP-coated reservoir, tubes, and an ACP- or IHP-coated membrane. Platelet (PLT) counts and the amount of total protein (TP), complement component 3 (C3), and complement component 4 (C4) were measured at 0, 8, 16, 24, and 32 h in each experiment (n = 5). Results: The PLT count at 0-h circulation was lower in the IHP-coated than in the ACP-coated circuits (p = 0.034); however, no significant difference was observed at other time points. Reduction in TP at 8-h and 16-h circulation and in C3 at 32-h circulation was lesser in the ACP-coated than in the IHP-coated circuits (p = 0.004, 0.034, and 0.027, respectively); reduction in TP and C3 at other time points and C4 at each time point was not significantly different. There were significant interactions between coating type and circulation duration in the PLT, TP, and C3 transitions (p = 0.008, 0.020, and 0.043, respectively). Conclusions: Our findings suggest that ACP-coated membranes can prevent the initial drop in PLT count and C3 consumption over 32 h, whereas IHP-coated membranes could not prevent this drop in extracorporeal circulation. Therefore, ACP-coated membranes are suitable for short- and long-term extracorporeal life support. [ABSTRACT FROM AUTHOR]

Complement component 3 (C3) deficiency has recently been reported as one of the novel causes of constipation. To identify a unique gene specific to constipation caused by C3 deficiency, the total RNA extracted from the mid colon of C3 knockout (C3 KO) mice was hybridized to oligonucleotide microarrays, and the function of the candidate gene was verified in in vitro and in vivo models. C3 KO mice used for microarrays showed definite phenotypes of constipation. Overall, compared to the wild type (WT), 1237 genes were upregulated, and 1292 genes were downregulated in the C3 KO mice. Of these, the major genes included were lysine (K)-specific demethylase 5D (KDM5D), olfactory receptor 870 (Olfr870), pancreatic lipase (PNLIP), and alkaline phosphatase intestinal (ALPI). Specifically, the ALPI gene was selected as a novel gene candidate based on alterations during loperamide (Lop)-induced constipation and intestinal bowel disease (IBD). The upregulation of ALPI expression treated with acetate recovered the expression level of mucin-related genes in primary epithelial cells of C3 KO mice as well as most phenotypes of constipation in C3 KO mice. These results indicate that ALPI plays an important role as the novel gene associated with C3 deficiency-induced constipation. [ABSTRACT FROM AUTHOR]

Autoantibody production is a hallmark of systemic sclerosis (SSc) and the most extensively studied role of B cells in the pathogenesis of the disease. However, the potential involvement of innate immune molecules in B-cell dysfunction in SSc is less understood. B-cell activation is an early event in the pathogenesis of SSc and is influenced by complement receptors (CRs) and Toll-like receptors (TLRs), shaping antibody responses. CR2 and CR1 modulate B-cell activation, and the roles of CR3 and CR4 are associated with autoimmune conditions. We investigated the expression of CRs in B cells from patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and the effect of TLR CD180 ligation on their expression. We found no significant difference in the basal expression of CD21 and CD11c in B cells between dcSSc and healthy controls (HCs). However, reduced basal CD11b expression in B cells in dcSSc compared to HCs, accompanied by a decrease in CD35 and an increase in CD11c expression following CD180 ligation may promote plasma cell formation and autoantibody production. Additionally, we searched for correlations between dcSSc-associated anti-DNA topoisomerase I (Scl-70) autoantibody, anti-citrate synthase (CS) natural autoantibody and complement component 3 (C3) levels and found a negative correlation between C3 and anti-CS autoantibody in dcSSc but not in HCs, supporting the hypothesis that natural autoantibodies could activate the complement system contributing to tissue injury in SSc. [ABSTRACT FROM AUTHOR]

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

Mycobacterium tuberculosis , the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood–brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis -specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1–4) and the capacity of M. tuberculosis -specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis , characterized by an enrichment of M. tuberculosis -specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis -specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fcγ receptor-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis -specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease. [ABSTRACT FROM AUTHOR]

Background/objectives: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody–positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. Methods: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis–Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. Results: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy. Discussion: Eculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab. [ABSTRACT FROM AUTHOR]

Avacopan is currently approved in several regions of the world as an oral treatment in combination with standard therapy, including glucocorticoids, for adult patients with severe active antineutrophil cytoplasmic autoantibody‐associated vasculitis. In vitro and clinical studies have established that avacopan is primarily eliminated through cytochrome P450 3A4 metabolism. This Phase 1, open‐label, single‐dose study (ClinicalTrials.gov identifier: NCT06004934) was conducted to evaluate the effect of mild (n = 8) or moderate (n = 8) hepatic impairment compared with normal hepatic function (n = 8) on the pharmacokinetics, safety, and tolerability of a single oral dose of 30 mg of avacopan in patients without active antineutrophil cytoplasmic autoantibody‐associated vasculitis. Relative to participants with normal hepatic function, in participants with mild or moderate hepatic impairment, the avacopan area under the plasma concentration‐time curve from time 0 to infinity geometric mean ratios (90% confidence intervals) were 1.3 (0.9‐2.0) and 1.1 (0.6‐2.0), respectively, and the avacopan maximum plasma concentration geometric mean ratios (90% CIs) were 1.0 (0.8‐1.3) and 0.8 (0.6‐1.1), respectively. The geometric mean ratios of metabolite M1 also revealed no pharmacokinetically relevant increase in the peak exposure of M1 in participants with mild or moderate hepatic impairment. Thus, no avacopan dosage adjustment is necessary for patients with mild or moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate disparities in clinical profiles and autoantibody patterns between patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) in a cohort and to identify risk factors associated with NPSLE in the Chinese population. Methods: SLE patients were retrospectively reviewed from two tertiary hospitals. The relationships between NPSLE and immunological biomarkers were explored. Results: Among the 945 SLE patients, 75 (7.94%) were diagnosed with NPSLE. The most prevalent NP manifestations involved cognitive disorder (30.67%), headache (26.67%), seizure disorder (26.67%), and psychosis (26.67%).We observed significant associations between psychosis and anti-β2GPI antibodies (F = 6.092, p = 0.015), polyneuropathy and anti-Scl70 antibodies (F = 20.161, p < 0.001), demyelinating syndrome and anti-cardiolipin antibodies (F = 6.637, p = 0.011), myasthenia gravis and anti-RNP (F = 5.864, p = 0.017), and anti-Smith antibodies (F = 5.096, p = 0.026). Multivariate logistics analysis showed that anti-prothrombin (aPT) IgM antibodies (OR = 10.985, CI 1.279–94.343, p = 0.029), age (OR = 1.169, CI 1.032–1.325, p = 0.014), and serum creatinine (SCr) (OR = 1.014, CI 1.003–1.025, p = 0.009) were independent risk factors of NPSLE, while anti-Sjogren syndrome antigen B (SSB) antibodies (OR 0.023, CI 0.002–0.622, p = 0.023) and high complement C3 (OR = 0.001, CI 0–0.045, p < 0.001) indicated reduced risk of NPSLE. Conclusion: Various neuropsychiatric manifestations in SLE were found to be correlated with specific autoantibodies. Independent risk factors for NPSLE included aPT IgM antibodies, age, and elevated serum creatinine, while the absence of anti-SSB antibodies and low complement C3 levels were associated with increased risk. Key points: •Significant associations were found between specific autoantibodies and neuropsychiatric symptoms, shedding light on potential biomarkers for predicting and understanding NPSLE. •The study identifies independent risk factors for NPSLE in the Chinese population, including the presence of anti-prothrombin IgM antibodies, older age, elevated serum creatinine, and lower complement C3 levels. [ABSTRACT FROM AUTHOR]

Objective: Development of a nomogram model for predicting the magnitude of risk of transferring hospitalized children with influenza to the ICU. Methods: In a single-center retrospective study, 318 children with influenza who were hospitalized in our hospital from January 2018 to August 2023 were collected as study subjects. Children with influenza were randomly assigned to the training set and validation set in a ratio of 4:1. In the training set, risk factors were identified using univariate and multivariate logistic regression analyses, and a nomogram model was created on this basis. The validation set was used to evaluate the predictive power of the model. Results: Multifactorial logistic regression analysis revealed six independent risk factors for transfer to the ICU in hospitalized children with influenza, including elevated peripheral white blood cell counts, elevated large platelet ratios, reduced mean platelet width, reduced complement C3, elevated serum globulin levels, and reduced total immunoglobulin M levels. Using these six metrics as predictors to construct a nomogram graphical model, the C-index was 0.970 (95% Cl: 0.953–0.988). The areas under the curve for the training and validation sets were 0.966 (95%Cl 0.947–0.985) and 0.919 (95%Cl 0.851–0.986), respectively. Conclusion: A nomogram for predicting the risk of transferring to the ICU for children with influenza was developed and validated, which demonstrates good calibration and clinical benefits. [ABSTRACT FROM AUTHOR]

Background and Objective: Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that can be associated with primary immunodeficiency. The pathogenesis of PG has not yet been elucidated, although contributions from dysregulation of the immune system in patients with apparent genetic predispositions have been postulated. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review with the objective of identifying inborn errors of immunity in the presence of PG as well as their clinical characteristics of severity including number of PG lesions and anatomic areas affected, and treatment outcomes. Methods: A literature search was performed using PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science through August 24, 2023, for studies published in English using the search terms: "pyoderma gangrenosum," "inborn error of immunity," "immune defect*," and a list of genetic mutations potentially associated with PG. Results: Seventy-four cases of PG associated with inborn errors of immunity were identified. The results demonstrate an association of PG with a variety of inborn errors of immunity, including genetic mutations not classically associated with the condition. Genetic mutations such as BTK, IL1RN, ITGB2, LPIN2, MEFV, NFkB1, NLRP3, NLRP12, NOD2, PSMB8, PLCG2, PSTPIP1, RAG1, TTC37, and WDR1, as well as complement component 2/complement component 4 (C2/C4) and complement component 7 (C7) deficiencies were identified in the presence of either idiopathic or syndromic PG. Of note, mutations in genes such as PSMB8, NLRP3, and IL1RN were found to be associated with a more severe and atypical course of PG, whereas mutations in RAG1 as well as those causing a C2/C4 deficiency were associated with the mildest clinical presentations of PG. Mutations in NFkB1, ITGB2, and PSTPIP1 were associated with the most heterogeneous clinical presentations. Conclusions: Human inborn errors of immunity may be implicated in the genetic predisposition to PG and may influence the clinical presentation. Due to the rarity of these diseases, further work must be done to describe the association between inborn errors of immunity and PG. Identifying inborn errors of immunity that may contribute to the development of PG may assist in further elucidating the mechanism of PG, guiding targeted treatment, and improving clinical outcomes for these patients. [ABSTRACT FROM AUTHOR]

Context.--Pemphigus is an autoimmune blister disease that causes blisters on the skin and mucosal surfaces. Direct immunofluorescence (DIF) testing is critical for the clinical diagnosis of pemphigus. However, it is limited to fresh tissue specimens and fluorescence microscopy. Objective.--To assess the value of C3d immunohistochemistry (IHC) on paraffin-embedded skin tissue for the diagnosis of pemphigus by comparing C3d-IHC results to DIF and enzyme-linked immunosorbent assay testing in pemphigus and other blister-related skin diseases. Design.--C3d-IHC assays were retrospectively performed on paraffin-embedded skin tissue sections from 115 patients (63 with pemphigus and 52 controls). Both the case group and the control group underwent the same protocol, and cases with C3d position in the peripheral spinous layer were considered as positive samples. Results.--C3d-IHC and DIF testing had similar performance for pemphigus diagnosis, with a sensitivity of 71.0% (95% CI, 51.8%-85.1 %) and 77.4% (95% CI, 58.5%-89.7%), specificity of 96.4% (95% CI, 79.8%-99.8%) and 100% (95% CI, 85.0%-100%), positive predictive value of 95.7% (95% CI, 76.0%-99.8%) and 100% (95% CI, 82.8%-100%), and a negative predictive value of 75.0% (95% CI, 57.5%-87.3%) and 80.0% (95% CI, 62.5%-90.9%), respectively. Conclusions.--Our study indicated that C3d-IHC results for paraffin-fixed tissues were not significantly different from DIF results for the diagnosis of pemphigus. The C3d-IHC assay has the potential for routine diagnosis of pemphigus, especially in the absence of fresh-frozen tissue. [ABSTRACT FROM AUTHOR]

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Kruppel‐like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)‐induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ‐induced seizure in mice. HP‐specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down‐stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4‐KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c‐Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ‐induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ‐induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs. [ABSTRACT FROM AUTHOR]

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

This research aimed to investigate the effects of polysaccharide from Atractylodes macrocephala koidze (PAMK) on growth performance, antioxidant capacity, immune response, and resistance of rainbow trout (Oncorhynchus mykiss) to Aeromonas salmonicida infection. Fish (average weight 58.40 ± 1.10 g) were fed four concentrations (0, 400, 800, and 1600 mg/kg diet) of PAMK in 4 treatments with 3 replicates for 8 weeks. At the end of the feeding trial, the fish were infected with A. salmonicida for 7 days. Results revealed that fish fed diets supplemented with 800 mg/kg PAMK exhibited enhancing growth performance and feed utilization compared to those in the other groups (p < 0.05), whereas differences were not found in body composition among the groups (p > 0.05). The serum superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), lysozyme (LZM), alkaline phosphatase (AKP), acid phosphatase (ACP), total protein (TP), and albumin (ALB) contents were significantly greater in the 800 mg/kg PAMK group than in the control group (p < 0.05). Before and after infection, dietary PAMK upregulated the mRNA expression of anti-inflammatory cytokines (TGF-β, IL-4/13A and IL-10), complement components (C3 and C4) and immunoglobulin M (IgM) but downregulated the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6); these parameters significantly changed in the 800 mg/kg PAMK group (p < 0.05). The highest survival rate was observed in the 800 mg/kg PAMK group. These results collectively suggest that 800 mg/kg PAMK can be used to enhance the growth performance, antioxidant activity, immune response, and disease resistance of rainbow trout. [ABSTRACT FROM AUTHOR]

Background: FOXP3 is a transcription factor that regulates the development and function of Treg, playing an essential role in preventing autoimmune diseases. Variation in FOXP3 can impair the function of Treg cells, thus destroying their inhibitory capacity and leading to autoimmune diseases. This paper investigated whether the three SNPs in the FOXP3 gene (-3279 C/A, -924 A/G and -6054 del/ATT) are associated with systemic lupus erythematosus (SLE) susceptibility in the Han Chinese population. Materials and methods: The study cohort comprised 122 SLE patients and 268 healthy controls. Genotyping was performed by polymerase chain reaction sequence-specific primer (PCR-SSP). Furthermore, we examined the potential clinical manifestations associated with FOXP3 polymorphisms in SLE patients. Results: The results showed that the -3279 (C > A) was significantly associated with the SLE risk in a homozygote (OR = 3.24, 95% CI = 1.23-8.52, p = .013, AA vs. CC), dominant (OR = 1.68, 95% CI = 1.07-2.65, p = .025, AC + AA vs. CC), recessive (OR = 2.90, 95% CI = 1.12-7.55, p = .023, AA vs. AC + CC) and allelic (OR = 1.72, 95% CI = 1.18-2.53, p = .005, A vs. C) models. In addition, -924 (A >G) was positively associated with SLE risk in the heterozygote (OR = 1.66, 95% CI = 1.04-2.66, p = .033, AG vs. AA) and dominant (OR = 1.59, 95% CI = 1.01-2.49, p = .042, AG + GG vs. AA) models, whereas -6054 (del> ATT) was not associated with SLE. Moreover, the immunological index analysis suggested that decreased complement C4 occurred more frequently in SLE patients carrying the minor allele (A) -3279 (C > A) than those not (p = .005). Conclusions: We demonstrated that -3279 (C > A) and -924 (A >G) were associated with an increased risk of SLE and the immunological index, indicating that the FOXP3 variation is potentially related to the occurrence and development of SLE. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a prevalent complication among patients with cancer, contributing significantly to morbidity and mortality. However, the relationship between VTE-related genes (VRGs) and their potential impact on prognosis, immune response, and therapeutic targets in various cancer types remains unclear. Based on the coagulation and complement pathways, we identified hub VRGs that play a role in regulating the immune response in cancer. Specifically, coagulation factor III (F3), plasminogen activator (PLAT) and complement C1s (C1S) were identified as genes that exhibit high expression levels, positively correlating with tumor stemness and copy number variations, while inversely correlating with methylation levels, in particular cancer types. Pan-cancer survival analysis revealed detrimental effects of these VRGs in several cancer types, notably in glioblastoma and lower grade glioma (GMBLGG). Further analysis using receiver operating characteristic (ROC) curves demonstrated a high accuracy of F3, PLAT and C1S in predicting outcomes in GBMLGG, with area under the curve (AUC) values ranging from 0.78 to 0.9. Validation of the prognostic value of these three genes in GMBLGG was conducted using an independent Gene Expression Omnibus (GEO) dataset. Additionally, gene–drug association analysis identified ciclosporin, ouabain and 6- mercaptopurine, which all exhibit immunosuppressive properties, as potential therapeutic options for tumor patients exhibiting high F3, PLAT or C1S expression, respectively. In summary, our findings provide a bioinformatics perspective on VRGs in pan-cancer, highlighting the pivotal roles of F3, PLAT and C1S, which could potentially be therapeutically exploited and targeted in several cancers, especially in GBMLGG. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focuses on how Tasmanian sea-farmed Atlantic salmon respond to a natural infection with a parasite that causes amoebic gill disease (AGD), a major health issue for salmon globally. The research aimed to understand the progression of the disease by examining the salmon's gills at different stages of the outbreak and evaluating their response to freshwater treatment. The study employed both macroscopic and microscopic examinations of gills, as well as molecular tools to measure the abundance of amoebae and the expression of specific genes that indicate inflammation. Key findings showed a strong correlation between different measures of gill health and significant differences between distinct stages of AGD. After treatment, a varied response among the fish was observed, indicating that management strategies need to account for individual genetic, environmental, and health factors. The expression patterns of some inflammation-related genes highlight their potential as biomarkers for early detection of gill damage in salmon aquaculture worldwide. The results of this research are important as they can help develop better ways to detect and manage this disease early, potentially reducing losses in salmon farming and ensuring the sustainability of this vital food resource. Gill health has become a significant global challenge for Atlantic salmon (Salmo salar) aquaculture, particularly during the marine phase of farming. The increasing prevalence of gill pathologies has been linked to rising seawater temperatures, underscoring the need to evaluate existing tools for monitoring gill health and to develop novel approaches for early detection. In this study, we investigated the gill responses of commercially farmed Atlantic salmon to natural infection with Neoparamoeba perurans during an outbreak of amoebic gill disease (AGD) in Tasmania. Our focus spanned the low AGD prevalence, high AGD prevalence, and post-freshwater treatment stages of the outbreak. Evaluations of gill tissue included assessments of the gross AGD score, histopathological score, abundance of N. perurans (measured by 18S rRNA gene expression), and expression levels of inflammation-related transcripts. We demonstrated a strong correlation between different measures of AGD-related gill pathology and significant differences between distinct stages of the N. perurans outbreak. Post-treatment, fish exhibited considerable variability in their responses to the freshwater bath, highlighting the necessity for personalized management strategies that consider genetic, environmental, and health status factors. The expression patterns of angiogenin-1 (ANG1) and complement C1q tumour necrosis factor-related protein 3-like (C1QTNF3) emphasize their potential as biomarkers for early detection of gill damage in salmon aquaculture worldwide. [ABSTRACT FROM AUTHOR]