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Nature Communications Nov 2022Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination....
Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
Topics: Humans; Complement C4a; Schizophrenia; Psychotic Disorders; Risk Factors
PubMed: 36329007
DOI: 10.1038/s41467-022-33797-6 -
Medicine Jun 2022Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the...
Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the long-term outcome of patients treated with TCZ who developed hypocomplementemia regarding serious bacterial infections or autoimmune diseases (AID).The charts of patients treated with TCZ at two rheumatology centers were reviewed retrospectively. Data regarding patients' age, gender, disease duration, autoantibodies status, previous or concomitant treatments, blood counts, liver enzymes, C3 and C4 levels at baseline and during TCZ treatment, episodes of infections, allergic reactions, and AID were analyzed. Univariate analysis was used to compare patients with low C3, C4 levels versus patients with normal C3, C4 levels. Variables that were statistically significant associated or tended to be associated with low C3 or C4 were included in multiple variable logistic regression.Of 132 patients treated with TCZ, 108 had serial measurements of serum complement concentration. Thirty-three (30%) patients developed low C4 levels and 23 (21%) had also low C3. Mean TCZ treatment period was 4.9 years (range, 1-14 years). All patients had normal complement levels at baseline. Leukopenia occurred in 18 (16.7%) patients, 14 of whom (77%) had low complement. Persistent leukopenia was observed in 8% and 5.3% of patients with normal C3 and C4 levels, respectively, as opposed to 47% and 42% of patients with low C3 or low C4, respectively. Low C3, C4 levels correlated with prolonged TCZ treatment retention time and effectiveness. There were no serious bacterial infections or new onset AID.Hypocomplementemia during TCZ treatment was accompanied by leukopenia that correlated with treatment duration. Hypocomplementemia was not associated with serious bacterial infections or new onset AID. Decreased complement levels were associated with treatment longevity. The role of monitoring complement level in predicting treatment response or assessing disease activity deserves further investigation.
Topics: Antibodies, Monoclonal, Humanized; Complement C3; Follow-Up Studies; Hematologic Diseases; Humans; Leukopenia; Retrospective Studies; Treatment Outcome
PubMed: 35713462
DOI: 10.1097/MD.0000000000029528 -
Frontiers in Endocrinology 2021Early diagnosis and therapy of papillary thyroid carcinoma (PTC) is essential for reducing recurrence and improving the long-term survival. In this study, we aimed to...
BACKGROUND
Early diagnosis and therapy of papillary thyroid carcinoma (PTC) is essential for reducing recurrence and improving the long-term survival. In this study, we aimed to investigate the proteome profile of plasma and screen unique proteins which could be used as a biomarker for predicting PTC.
METHODS
Serum samples were collected from 29 PTC patients and 29 nodular goiter (NG) patients. Five PTC serum samples and five NG serum samples were selected for proteome profiles by proteomics. Eight proteins in PTC and NG serum samples were selected for confirmation by enzyme-linked immunosorbent assay analysis. Receiver operating characteristic curves was used to evaluate the diagnostic value of potential biomarkers.
RESULTS
Complement C4-A (C4A) and plasminogen (PLG) were significantly lower in serum samples of PTC patients compared with NG patients. C4A was observed to have excellent diagnostic accuracy for PTC, with a sensitivity of 91.67% and specificity of 83.33%. The diagnostic value of PLG for PTC was demonstrated by a sensitivity at 87.50% and specificity at 75.00%. The AUC for C4A and PLG was 0.97 ± 0.02 and 0.89 ± 0.05.
CONCLUSION
C4A and PLG appeared to be excellent potential biomarkers for the prediction of PTC.
Topics: Adult; Biomarkers, Tumor; Complement C4a; Female; Humans; Male; Middle Aged; Plasminogen; Proteomics; Sensitivity and Specificity; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 34803909
DOI: 10.3389/fendo.2021.737638 -
Frontiers in Immunology 2019C3 Glomerulopathy (C3G) is a renal disease mediated primarily by dysregulation of the alternative pathway of complement. Complement is the cornerstone of innate... (Review)
Review
C3 Glomerulopathy (C3G) is a renal disease mediated primarily by dysregulation of the alternative pathway of complement. Complement is the cornerstone of innate immunity. It targets infectious microbes for destruction, clears immune complexes, and apoptotic cells from the circulation, and augments the humoral response. In C3G, this process becomes dysregulated, which leads to the deposition of complement proteins-including complement component C3-in the glomerular basement membrane of the kidney. Events that trigger complement are typically environmental insults like infections. Once triggered, in patients who develop C3G, complement activity is sustained by a variety of factors, including rare or novel genetic variants in complement genes and autoantibodies that alter normal complement protein function and/or regulation. Herein, we review two such autoantibodies, one to Factor B and the other to C4b2a, the C3 convertase of the classical, and lectin pathways. These two types of autoantibodies are identified in a small fraction of C3G patients and contribute marginally to the C3G phenotype.
Topics: Autoantibodies; Complement C4b; Complement Factor B; Glomerulonephritis, Membranoproliferative; Humans
PubMed: 31024533
DOI: 10.3389/fimmu.2019.00668 -
American Journal of Transplantation :... Mar 2024The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of...
The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.
Topics: Humans; Kidney Transplantation; Complement C4b; Canada; Kidney; Inflammation; Isoantibodies; Biopsy
PubMed: 38032300
DOI: 10.1016/j.ajt.2023.10.016 -
Annals of the Rheumatic Diseases Feb 2023Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles...
BACKGROUND
Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement in IIM pathology was unknown.
METHODS
We elucidated the gene copy number (GCN) variations of total , and and in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.
RESULTS
The large study populations helped establish the distribution patterns of various GCN groups. Low GCNs of (=2+3) and deficiency (=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10 for , and 2.82 (2.48-3.21), p=7.0×10 for deficiency. Contingency and regression analyses showed that among patients with deficiency, the presence of became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies.
CONCLUSIONS
deficiency is relevant in dermatomyositis, is important in IBM and both deficiency and contribute interactively to risk of polymyositis.
Topics: Adult; Humans; Child; Complement C4; DNA Copy Number Variations; HLA-DRB1 Chains; Dermatomyositis; Autoantibodies; HLA-DR3 Antigen; Genetic Predisposition to Disease; Risk Factors; Complement C4a; Myositis
PubMed: 36171069
DOI: 10.1136/ard-2022-222935 -
Frontiers in Endocrinology 2021Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the... (Review)
Review
Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the molecular basis of a wide spectrum of disease. Multiallelic CNVs represent a considerable fraction of large CNVs and are strictly related to segmental duplications according to their prevalent duplicate alleles. RCCX CNV is a complex, multiallelic and tandem CNV located in the major histocompatibility complex (MHC) class III region. RCCX structure is typically defined by the copy number of a DNA segment containing a series of genes - the serine/threonine kinase 19 (), the complement 4 (), the steroid 21-hydroxylase (), and the tenascin-X () - lie close to each other. In the Caucasian population, the most common RCCX haplotype (69%) consists of two segments containing the genes , with a telomere-to-centromere orientation. Nonallelic homologous recombination (NAHR) plays a key role into the RCCX genetic diversity: unequal crossover facilitates large structural rearrangements and copy number changes, whereas gene conversion mediates relatively short sequence transfers. The results of these events increased the RCCX genetic diversity and are responsible of specific human diseases. This review provides an overview on RCCX complexity pointing out the molecular bases of Congenital Adrenal Hyperplasia (CAH) due to CYP21A2 deficiency, CAH-X Syndrome and disorders related to CNV of complement component C4.
Topics: Adrenal Hyperplasia, Congenital; Complement C4; DNA Copy Number Variations; Genetic Variation; Humans; Nuclear Proteins; Protein Serine-Threonine Kinases; Pseudogenes; Steroid 21-Hydroxylase; Tenascin
PubMed: 34394006
DOI: 10.3389/fendo.2021.709758 -
Complement component C4 levels in the cerebrospinal fluid and plasma of patients with schizophrenia.Neuropsychopharmacology : Official... May 2021Abnormalities in the complement system have been described in patients with schizophrenia, with those individuals having greater frequency of complement component 4A...
Abnormalities in the complement system have been described in patients with schizophrenia, with those individuals having greater frequency of complement component 4A (C4A) alleles and higher C4A transcript levels in postmortem brain tissue. Importantly, abnormalities in C4A and other complement molecules have been associated with synaptic pruning abnormalities that occur during neurodevelopment. A few studies have investigated C4 levels in living patients with schizophrenia, but all of them did so using peripheral blood samples. No studies have examined C4 levels in cerebrospinal fluid (CSF), presumably a better biofluid choice given its intimate contact with the brain. Therefore, we report for the first time on C4 levels in CSF and plasma of patients with schizophrenia. In this study, we obtained CSF in 32 patients with schizophrenia spectrum disorders and 32 healthy volunteers and peripheral blood samples in 33 SSD and 31 healthy volunteers. C4 levels were measured using Abcam ELISA assays. Univariate analysis did not show a statistically significant difference in CSF C4 values between groups. However, a multivariable analysis showed a statistically significant increase in CSF C4 levels between groups after adjusting for sex and age. We also observed a high correlation between CSF C4 levels and age. By contrast, plasma C4 levels were not significantly different between groups. CSF and plasma C4 levels were not significantly correlated. Therefore, the use of CSF samples is critical and should be complementary to the use of peripheral blood samples to allow for a comprehensive understanding of complement C4 abnormalities in schizophrenia.
Topics: Alleles; Complement C4; Humans; Schizophrenia
PubMed: 32961544
DOI: 10.1038/s41386-020-00867-6 -
Clinical and Experimental Immunology Aug 2022The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to... (Review)
Review
The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to cleave C3 and initiate the assembly of the terminal components. While deficiencies of classical pathway components have been recognized since 1966, only recently have gain-of-function variants been described for some of these proteins. Loss-of-function variants in C1, C4, and C2 are most often associated with lupus and systemic infections with encapsulated bacteria. C3 deficiency varies slightly from this phenotypic class with membranoproliferative glomerulonephritis and infection as the dominant phenotypes. The gain-of-function variants recently described for C1r and C1s lead to periodontal Ehlers Danlos syndrome, a surprisingly structural phenotype. Gain-of-function in C3 and C2 are associated with endothelial manifestations including hemolytic uremic syndrome and vasculitis with C2 gain-of-function variants thus far having been reported in patients with a C3 glomerulopathy. This review will discuss the loss-of-function and gain-of-function phenotypes and place them within the larger context of complement deficiencies.
Topics: Complement Activation; Complement C4; Complement Pathway, Classical; Complement System Proteins
PubMed: 35648651
DOI: 10.1093/cei/uxac056 -
The Journal of Trauma and Acute Care... Nov 2022Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
BACKGROUND
Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators remain unclear. Recently, the anaphylatoxin C4a has been shown to bind to thrombin receptors. While plasma-based resuscitation has been shown to modify the endotheliopathy of trauma, it may provide complement zymogens that fuel ongoing inflammatory cascades. We sought to characterize the activation of complement after injury and the effect of fresh frozen plasma (FFP) on this inflammatory response. We hypothesized that trauma induces C4 activation, which is associated with worse outcomes and influenced by FFP resuscitation.
METHODS
Blood was collected from injured patients at a single level I trauma center enrolled in the Control of Major Bleeding after Trauma (COMBAT) randomized clinical trial. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry. For the present observational study, concentrations of complement proteins were analyzed at multiple time points, compared between treatment groups, and correlated with outcomes.
RESULTS
C4 activation occurred over the first 6 hours postinjury with peak activation 6 to 24 hours. Tissue hypoperfusion, defined as base deficit >10 mEq/L, and requirement for massive transfusion were associated with greater C4 activation. C4 activation was associated with mortality, multiple organ failure, and longer ventilator requirement. In addition, temporal trends of C1q, factor B, and C3 by outcome groups support the prevailing theory of primary classical pathway activation with alternative pathway amplification. Resuscitation with FFP over the first 6 hours was associated with increased C4 activation at 12 and 24 hours.
CONCLUSION
C4 activation has an important inflammatory role postinjury, and FFP has the potential to augment this complement activation during resuscitation.
LEVEL OF EVIDENCE
Prognostic/epidemiological, level III.
Topics: Humans; Complement C4; Proteomics; Resuscitation; Plasma; Hemorrhage; Complement Activation
PubMed: 35610738
DOI: 10.1097/TA.0000000000003713