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Journal of Autoimmunity May 2023Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the... (Review)
Review
Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.
Topics: Humans; Complement C1q; Autoimmune Diseases; Complement System Proteins; Lupus Erythematosus, Systemic; Hereditary Complement Deficiency Diseases; Complement C4; Complement C4a
PubMed: 36535812
DOI: 10.1016/j.jaut.2022.102979 -
Frontiers in Immunology 2021Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading... (Review)
Review
Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Communicable Diseases; Complement Activation; Complement C4; Host-Pathogen Interactions; Humans; Signal Transduction
PubMed: 34335607
DOI: 10.3389/fimmu.2021.694928 -
Nature Neuroscience Feb 2021The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an...
The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
Topics: Animals; Behavior, Animal; Complement C4; Dendritic Spines; Depression; Female; Gene Dosage; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia; Nerve Net; Psychomotor Performance; Schizophrenia; Schizophrenic Psychology; Synapses; Synaptosomes
PubMed: 33353966
DOI: 10.1038/s41593-020-00763-8 -
Developmental Neuroscience 2023Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment....
Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p < 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01-0.77, R2 = 0.18, p < 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p < 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.
Topics: Humans; Complement C4; Schizophrenia; Inflammation; Biomarkers; Immunoglobulin G
PubMed: 37734326
DOI: 10.1159/000534185 -
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 -
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 -
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 -
Pediatric Research Jan 2020Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3...
BACKGROUND
Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3 and C4 on cardiometabolic risk in healthy non-Hispanic white adolescents.
METHODS
Body mass index (BMI), BMI percentile, waist circumference, and percent body fat were assessed in 75 adolescents. Arterial stiffness was assessed using arterial tomography and endothelial function using reactive hyperemia. Fasting lipids, inflammatory markers, and complement levels were measured and oral glucose tolerance test was performed. A single C3 polymorphism and C4 gene copy number variations were assessed.
RESULTS
C3 plasma levels increased with measures of obesity. Endothelial function worsened with increased C3 and C4 levels. Triglycerides and low-density lipoprotein increased and high-density lipoprotein (HDL) and insulin sensitivity decreased with increasing C3 levels, but the relationships were lost when body habitus was included in the model. C4 negatively related to HDL and positively to inflammatory markers. Subjects with at least one C3F allele had increased BMI and fat mass index. HDL was significantly related to C4L, C4S, C4A, and C4B gene copy number variation.
CONCLUSIONS
C3 levels increase with increasing body mass and increased C4 levels and copy number are associated with increased cardiometabolic risk in healthy adolescents.
Topics: Adiposity; Adolescent; Age Factors; Body Mass Index; Cardiometabolic Risk Factors; Child; Complement C3; Complement C4; Complement C4a; Complement C4b; Cross-Sectional Studies; DNA Copy Number Variations; Female; Gene Dosage; Humans; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Assessment; Vascular Stiffness; Waist Circumference; White People
PubMed: 31404919
DOI: 10.1038/s41390-019-0534-1 -
Viruses Jan 2021Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One...
Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating.
Topics: Adenoviridae; Antibodies, Neutralizing; Antibodies, Viral; Binding Sites; Capsid; Capsid Proteins; Complement C4; Humans; Immunoglobulin G; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 33467558
DOI: 10.3390/v13010111 -
Journal of Clinical Laboratory Analysis May 2020The prognostic role of complement C3 and C4 in peripheral blood in early stage of acute pancreatitis (AP) is unknown. In this study, we aimed to evaluate the prognostic...
OBJECTIVE
The prognostic role of complement C3 and C4 in peripheral blood in early stage of acute pancreatitis (AP) is unknown. In this study, we aimed to evaluate the prognostic value of C3 and C4 in early stage of AP.
METHODS
A total of 164 patients were enrolled in this study. The blood samples were collected within 24 hours after AP onset. We compared C3 and C4 levels in patients with different AP severity. The optimal cutoff value for them to predict severe AP (SAP) was determined by receiver operating characteristic (ROC) curve analysis.
RESULTS
The reduction of C3 and C4 levels was observed. For prediction of MSAP and SAP, the AUC of C3 and C4 levels was 0.695 (95% CI: 0.612-0.779) and 0.739 (95% CI: 0.657-0.821). The cutoff value of C3 and C4 levels was 0.705 and 0.145 g/L, with the sensitivity of 0.612 and 0.735, and the specificity of 0.735 and 0.710. For prediction of SAP, the AUC of C3 and C4 levels was 0.749 (95% CI: 0.607-0.891) and 0.766 (95% CI: 0.596-0.936). The cutoff value of C3 and C4 levels was 0.400 and 0.125 g/L, with the sensitivity of 0.859 and 0.767, and the specificity of 0.600 and 0.786.
CONCLUSIONS
A marked change of complement C3 and C4 was observed in peripheral blood of patients with AP, suggesting the participation of complement system in the early phase of AP. C3 and C4 levels were sensitive and accurate in judging the severity of AP.
Topics: Adult; Aged; Biomarkers; Complement C3; Complement C4; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; ROC Curve
PubMed: 32187754
DOI: 10.1002/jcla.23205