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European Journal of Pediatrics Jun 2024The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This...
UNLABELLED
The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This single-center, retrospective cohort study used clinical data of children with newly active lupus nephritis hospitalized in the Department of Nephrology between December 2004 and February 2023. Patients were divided into a belimumab or traditional treatment group according to whether or not they received belimumab. Renal remission and recurrence rates and glucocorticoid dose were compared between groups. Forty-seven children (median age 11 years) were enrolled, including 30 and 17 children in the traditional treatment and belimumab groups, respectively. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2000) score of children in the belimumab group (23.59 ± 7.78) was higher than that in the traditional treatment group (19.13 ± 6.10) (P = 0.035). The two groups showed no significant difference in the frequency of pyuria, gross hematuria, and the levels of 24-h proteinuria and estimated glomerular filtration rate. The complement C3/C4 in the belimumab group recovered faster than that in the traditional treatment group (P < 0.05). There were no between-group differences in the complete renal remission rate at 6 or 12 months (P = 0.442, P = 0.759). There were no between-group differences in 1-year recurrence rate (P = 0.303). Furthermore, 6 and 12 months after treatment, glucocorticoid doses were lower in the belimumab than the traditional treatment group (17.87 ± 6.96 mg/d vs. 27.33 ± 8.40 mg/d, P = 0.000; 10.00 (5.3) mg/d vs. 13.75 (10.0) mg/d, P = 0.007), respectively.
CONCLUSION
With an equivalent renal remission rate, belimumab combined with the standard traditional regimen might promote the tapering of glucocorticoids, and the incidence of adverse events is low.
WHAT IS KNOWN
• Belimumab is documented as an adjunctive treatment with systemic lupus erythematosus (c-SLE) LN with efficacy. • Due to the paucity of studies, its effects and side effects in children with LN remain unclear.
WHAT IS NEW
• This single-center, retrospective cohort study evaluated the efficacy and safety of belimumab combined with the standard regimen in treating children with proliferative LN. • Belimumab combined with the standard traditional treatment might promote the tapering of glucocorticoids, while exhibiting a low occurrence of adverse events.
PubMed: 38940925
DOI: 10.1007/s00431-024-05662-9 -
Immunology and Allergy Clinics of North... Aug 2024The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor... (Review)
Review
The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.
Topics: Humans; Bradykinin; Biomarkers; Complement C1 Inhibitor Protein; Angioedema; Angioedemas, Hereditary; Mutation
PubMed: 38937015
DOI: 10.1016/j.iac.2024.03.011 -
Archives of Rheumatology Jun 2024This study aimed to evaluate the early effectiveness and safety of belimumab in addition to standard therapy in patients with systemic lupus erythematosus (SLE) for 24...
OBJECTIVES
This study aimed to evaluate the early effectiveness and safety of belimumab in addition to standard therapy in patients with systemic lupus erythematosus (SLE) for 24 weeks.
PATIENTS AND METHODS
This retrospective study was conducted with 60 adult patients with active SLE between June 2020 and August 2022. The patients either received intravenous belimumab in addition to standard therapy (n=31; 24 females, 7 males; mean age: 33.7±14.1 years; range, 18 to 52 years) or only standard therapy (n=29; 22 females, 7 males; mean age: 34.1±13.4 years; range, 19 to 66 years) for 24 weeks. Outcome measures, including safety and effectiveness (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI]), changes in biomarkers (double-stranded DNA [deoxyribonucleic acid]), serum complement levels, and immunoglobin G (IgG) were recorded. Adverse events were recorded.
RESULTS
Baseline demographic and clinical characteristics were similar between the two groups. More patients in the belimumab group achieved a reduction of ≥4 points in SELENA-SLEDAI at weeks 12 and 24 (week 12, 77.4% 41.4%, p=0.008; week 24, 87.1% 48.3%, p=0.002). The mean score of SELENA-SLEDAI was significantly lower in the belimumab group compared to the standard therapy group at week 12. However, a significant difference was not reached at week 24. Moreover, mean levels of serum C3 and C4 in the belimumab group were significantly higher than those in the standard therapy group at weeks 12 and 24. A higher proportion of patients in the belimumab group had a normal C3 level than in the standard therapy group. In addition, belimumab treatment resulted in a significant decrease in IgG levels at both weeks 12 and 24. At week 24, the belimumab group had a higher reduction in prednisone dose than the standard therapy group. Furthermore, the percentages of patients with more than 50% reduction in prednisone over baseline were significantly greater for belimumab versus standard therapy at week 12 (p=0.002). The occurrence of adverse events was similar between the two groups (standard therapy group, 44.8%; belimumab group, 51.6%).
CONCLUSION
Intravenous belimumab was well tolerated and significantly improved disease activity in Chinese patients with SLE at the early stage of treatment. More importantly, belimumab treatment could result in a rapid reduction in prednisone dose as early as week 12.
PubMed: 38933729
DOI: 10.46497/ArchRheumatol.2024.9977 -
Frontiers in Immunology 2024The classical pathway of the complement system is activated by the binding of C1q in the C1 complex to the target activator, including immune complexes. Factor H is...
The classical pathway of the complement system is activated by the binding of C1q in the C1 complex to the target activator, including immune complexes. Factor H is regarded as the key downregulatory protein of the complement alternative pathway. However, both C1q and factor H bind to target surfaces via charge distribution patterns. For a few targets, C1q and factor H compete for binding to common or overlapping sites. Factor H, therefore, can effectively regulate the classical pathway activation through such targets, in addition to its previously characterized role in the alternative pathway. Both C1q and factor H are known to recognize foreign or altered-self materials, e.g., bacteria, viruses, and apoptotic/necrotic cells. Clots, formed by the coagulation system, are an example of altered self. Factor H is present abundantly in platelets and is a well-known substrate for FXIIIa. Here, we investigated whether clots activate the complement classical pathway and whether this is regulated by factor H. We show here that both C1q and factor H bind to the fibrin formed in microtiter plates and the fibrin clots formed under physiological conditions. Both C1q and factor H become covalently bound to fibrin clots, and this is mediated via FXIIIa. We also show that fibrin clots activate the classical pathway of complement, as demonstrated by C4 consumption and membrane attack complex detection assays. Thus, factor H downregulates the activation of the classical pathway induced by fibrin clots. These results elucidate the intricate molecular mechanisms through which the complement and coagulation pathways intersect and have regulatory consequences.
Topics: Humans; Complement Factor H; Fibrin; Blood Coagulation; Complement C1q; Complement Pathway, Classical; Protein Binding; Complement Activation; Blood Platelets
PubMed: 38933264
DOI: 10.3389/fimmu.2024.1368852 -
Antioxidants (Basel, Switzerland) May 2024This study was conducted to investigate the effects of dietary phosphatidylserine (PS) supplementation on the growth performance, stress response, non-specific immunity...
This study was conducted to investigate the effects of dietary phosphatidylserine (PS) supplementation on the growth performance, stress response, non-specific immunity and antioxidant capacity of juvenile blunt snout bream () cultured under a high stocking density. A 2 × 2 two-factorial design was adopted, including two stocking densities (10 and 20 fish/m) and two dietary PS levels (0 and 50 mg/kg). After the 12-week feeding trial, the high stocking density significantly decreased the final weight; weight gain rate; specific growth rate; feed intake; nitrogen retention efficiency; plasma complement 3 (C3) level; albumin/globulin (ALB/GLB, A/G) ratio; activity of myeloperoxidase, lysozyme (LZM) and glutathione peroxidase (GPX); transcription; and abundance of sirtuin3 (Sirt3) and nuclear factor erythroid-2-related factor 2 (Nrf2). However, it significantly increased the plasma levels of cortisol, glucose (GLU), lactic acid (LD), total protein and GLB; hepatic malondialdehyde (MDA) content; and transcription. PS supplementation significantly increased the plasma ALB and C4 levels; the A/G ratio; the activity of LZM, CAT and GPX; the transcription of , , manganese-containing superoxide dismutase and catalase; and the Nrf2 abundance. However, it significantly decreased the plasma levels of cortisol, GLU and GLB, as well as the hepatic MDA content. In addition, there was a significant interaction between the stocking density and PS supplementation regarding the effects on the plasma LD, ALB, GLB and C3 levels; A/G ratio; hepatic CAT activity; and protein abundance of Sod2. In conclusion, PS supplementation can counteract the high stocking density-induced stress response, redox imbalance and immunosuppression in blunt snout bream.
PubMed: 38929083
DOI: 10.3390/antiox13060644 -
Medicina 2024Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults (20-30%). Light microscopy shows thickening of glomerular basement membrane...
INTRODUCTION
Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults (20-30%). Light microscopy shows thickening of glomerular basement membrane with appearance of spikes. These histological findings are not evident in early forms, in which case the granular deposition pattern of IgG and/or C3 in the basement membrane by immunofluorescence (IF) constitutes the diagnostic tool that allows to differentiate it from minimal change disease (MCD). Complement system plays a key role in the pathophysiology of MN. C4d is a degradation product and a marker of the complement system activation. C4d labelling by immunohistochemical (HI) technique can help in the differential diagnosis between both glomerulopathies NM and MCD when the material for IF is insufficient and light microscopy is normal. Our objective was to explore the discrimination power of C4d to differentiate between MN and MCD in renal biopsy material.
METHODS
Paraffin-embedded samples were recovered from renal biopsies with a diagnosis of MN and MCD performed between 1/1/2008 and 4/1/2019. IH staining was performed by immunoperoxidase technique using a rabbit anti-human C4d polyclonal antibody.
RESULTS
In all cases with MN (n = 27, 15 males) with a median age of 63 (range: 18-87) years, C4d deposits were detected. In 21 cases with MCD (12 males) with a median age of 51 (range: 18-87) years, the C4d marking was negative in every samples.
CONCLUSION
The results indicate that the marking of the renal biopsy with C4d is a useful tool for the differential diagnosis between NM and MCD.
Topics: Glomerulonephritis, Membranous; Humans; Male; Adult; Middle Aged; Female; Aged; Complement C4b; Young Adult; Diagnosis, Differential; Aged, 80 and over; Adolescent; Biopsy; Biomarkers; Nephrosis, Lipoid; Peptide Fragments; Retrospective Studies
PubMed: 38907960
DOI: No ID Found -
Chinese Medicine Jun 2024Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic...
BACKGROUND
Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction.
METHODS
Indicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin-eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD and CD proteins in the thymus and spleen tissues.
RESULTS
The findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD content, decreased CD content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood.
CONCLUSIONS
LJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions.
PubMed: 38867320
DOI: 10.1186/s13020-024-00939-5 -
Annals of Medicine Dec 2024FOXP3 is a transcription factor that regulates the development and function of Treg, playing an essential role in preventing autoimmune diseases. Variation in can...
BACKGROUND
FOXP3 is a transcription factor that regulates the development and function of Treg, playing an essential role in preventing autoimmune diseases. Variation in 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 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 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, = .013, AA vs. CC), dominant (OR = 1.68, 95% CI = 1.07-2.65, = .025, AC + AA vs. CC), recessive (OR = 2.90, 95% CI = 1.12-7.55, = .023, AA vs. AC + CC) and allelic (OR = 1.72, 95% CI = 1.18-2.53, = .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, = .033, AG vs. AA) and dominant (OR = 1.59, 95% CI = 1.01-2.49, = .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 ( = .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 variation is potentially related to the occurrence and development of SLE.
Topics: Humans; Lupus Erythematosus, Systemic; Female; Forkhead Transcription Factors; Male; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adult; Asian People; China; Case-Control Studies; Middle Aged; Genotype; Gene Frequency; Young Adult; Risk Factors; Alleles; East Asian People
PubMed: 38848045
DOI: 10.1080/07853890.2024.2363937 -
The Journal of Biological Chemistry Jun 2024Complement receptor 1 (CR1) is a membrane glycoprotein with a highly duplicated domain structure able to bind multiple ligands such as C3b and C4b, the activated...
Complement receptor 1 (CR1) is a membrane glycoprotein with a highly duplicated domain structure able to bind multiple ligands such as C3b and C4b, the activated fragments of complement components C3 and C4, respectively. We have previously used our knowledge of this domain structure to identify CSL040, a soluble extracellular fragment of CR1 containing the long homologous repeat (LHR) domains A, B, and C. CSL040 retains the ability to bind both C3b and C4b but is also a more potent complement inhibitor than other recombinant CR1-based therapeutics. To generate soluble CR1 variants with increased inhibitory potential across all three complement pathways, or variants with activity skewed to specific pathways, we exploited the domain structure of CR1 further by generating LHR domain duplications. We identified LHR-ABCC, a soluble CR1 variant containing a duplicated C3b binding C-terminal LHR-C domain that exhibited significantly enhanced alternative pathway inhibitory activity in vitro compared to CSL040. Another variant, LHR-BBCC, containing duplications of both LHR-B and LHR-C with four C3b binding sites, was shown to have reduced classical/lectin pathway inhibitory activity compared to CSL040, but comparable alternative pathway activity. Interestingly, multiplication of the C4b-binding LHR-A domain resulted in only minor increases in classical/lectin pathway inhibitory activity. The CR1 duplication variants characterized in these in vitro potency assays, as well as in affinity in solution C3b and C4b binding assays, not only provides an opportunity to identify new therapeutic molecules, but also additional mechanistic insights to the multiple interactions between CR1 and C3b/C4b.
PubMed: 38844131
DOI: 10.1016/j.jbc.2024.107451 -
Arthritis Care & Research Jun 2024Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine...
OBJECTIVE
Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine (HCQ) whole blood levels with changes in complement.
METHODS
We performed two analyses on data prospectively collected from an SLE cohort. In the first (a "new starts on HCQ" analysis), we compared changes in complement between those starting hydroxychloroquine and those who did not. The second analysis evaluated the association between hydroxychloroquine whole blood levels and low complement in all cohort visits using conditional logistic regression.
RESULTS
In the "new starts on HCQ" analysis, a higher percentage of patients starting hydroxychloroquine (as reflected in HCQ blood levels>50) experienced a normalization of C4 compared to those who did not (23/57 (40%) vs. 9/56 (13%), p=0.011), as well as a significantly greater increase in both C3 and C4 (p=0.048 and p=0.017 respectively). In the "all cohort visits" analysis, there was a statistically significant higher probability of having normal C4 levels in visits with higher hydroxychloroquine whole blood levels (OR 1.8 to 2.6 depending on the levels). This relationship was most pronounced for whole blood hydroxychloroquine levels of 200ng/ml or more.
CONCLUSION
We observed significant improvement in complement levels when hydroxychloroquine was started and among those with higher whole blood levels of hydroxychloroquine, particularly with respect to C4. Modulating the pathogenic mechanisms that lead to complement consumption may be one mode by which hydroxychloroquine prevents poor outcomes in SLE.
PubMed: 38831658
DOI: 10.1002/acr.25381