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Sports Medicine - Open Jan 2024Although regular physical activity improves immune competency and reduces the prevalence of inflammatory diseases, strenuous training in elite athletes is associated...
BACKGROUND
Although regular physical activity improves immune competency and reduces the prevalence of inflammatory diseases, strenuous training in elite athletes is associated with an increased susceptibility to infectious complications. Therefore, the objective of our study was to assess the routinely examined parameters of the complement system in elite athletes. The study was carried out in a cohort of elite athletes (n = 134) and healthy control subjects (n = 110). In all subjects, besides a routine laboratory check-up, serum concentrations of the C3 and C4 complement components, mannose-binding lectin (MBL), as well as activation of all three complement pathways were determined.
RESULTS
Compared to healthy controls, lower C3 and C4 complement component concentrations were observed in elite athletes (0.96 ± 0.1 vs. 1.08 ± 0.2 mg/L, and 0.18 ± 0.1 vs. 0.25 ± 0.1 mg/L, respectively, p < 0.05); with much higher frequency rates of C3 and C4 deficiencies in athletes (31.3 vs. 14.5%, and 6 vs. 0%, p < 0.05). Simultaneously, athletes had much higher frequency rates of deficiencies of activation of classical and alternative complement pathways; while, deficiency of activation of the lectin pathway was similar in both cohorts.
CONCLUSIONS
We confirmed a high frequency of defects in the complement system in elite athletes. Lower concentrations of C3 and C4 complement components, with high frequencies of deficiencies of the classical and alternative complement activation pathways were the most prevalent disorder of the complement system in elite athletes. Further studies are needed to uncover the functional impacts of these observations upon the susceptibility to infectious diseases.
PubMed: 38252367
DOI: 10.1186/s40798-024-00681-0 -
Journal of Clinical Medicine Aug 2023Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular...
Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular events. Systemic lupus erythematosus (SLE) is characterized by the consumption of complement (C) proteins and has been associated with an increased risk of cardiovascular disease. CEC is reduced in SLE patients compared to controls. In the present work, our objective was to analyze whether the disruption of C influences CEC in patients with SLE. New-generation functional assays of the three pathways of the C system were performed in 207 patients with SLE. Additionally, serum levels of inactive (C1q, C2, C3, C4, and factor D) and activated (C3a) molecules, and regulators (C1-inhibitor and factor H) of C system were measured. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed. Multivariable linear regression analysis was performed to assess the relationship between C system and CEC. After full multivariable analysis, the alternative C cascade functional test showed a significant and negative relationship with CEC. This was also the case for C2 and C3, in which the associations were found to be positive and statistically significant, after adjustment for covariates. In conclusion, C system and CEC are interconnected in patients with SLE.
PubMed: 37629447
DOI: 10.3390/jcm12165405 -
Free Radical Biology & Medicine Feb 2024Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response....
BACKGROUND
Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response. Complement C4 and C3 are considered the central components of the classical activation pathway and often participate in the response process in the early stages of virus infection.
METHODS
In our study, we constructed a mouse model of CVB3-related viral myocarditis via intraperitoneal injection of Fer-1 and detected myocarditis and ferroptosis markers in the mouse myocardium. Then, we performed co-IP and protein mass spectrometry analyses to explore which components interact with the ferroptosis gene transferrin receptor (TFRC). Finally, functional experiments were conducted to verify the role of complement components in regulating ferroptosis in CVB3 infection.
RESULTS
It showed that the ferroptosis inhibitor Fer-1 could alleviate the inflammation in viral myocarditis as well as ferroptosis. Mechanistically, during CVB3 infection, the key factor TFRC was activated and inhibited by Fer-1. Fer-1 effectively prevented the consumption of complement C3 and overload of the complement product C4b. Interestingly, we found that TFRC directly interacts with complement C4, leading to an increase in the product of C4b and a decrease in the downstream complement C3. Functional experiments have also confirmed that regulating the complement C4/C3 pathway can effectively rescue cell ferroptosis caused by CVB3 infection.
CONCLUSIONS
In this study, we found that ferroptosis occurs through crosstalk with complement C4 in viral myocarditis through interaction with TFRC and that regulating the complement C4/C3 pathway may rescue ferroptosis in CVB3-infected cardiomyocytes.
Topics: Animals; Mice; Myocarditis; Complement C3; Ferroptosis; Coxsackievirus Infections; Enterovirus B, Human; Myocardium; Immunologic Factors; Virus Diseases; Complement C4; Receptors, Transferrin
PubMed: 38169212
DOI: 10.1016/j.freeradbiomed.2023.12.038 -
Kidney International Jan 2024Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV),...
Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and ΔCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP-specific therapeutic target in AAV.
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Disease Susceptibility; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Immunologic Factors; Properdin
PubMed: 37923132
DOI: 10.1016/j.kint.2023.10.013 -
Frontiers in Endocrinology 2023We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients.
OBJECTIVE
We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients.
METHODS
This is a retrospective study involving 2,441 participants. DKD was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Participants were classified as stages G1-G5 by KDIGO glomerular filtration rate (GFR) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI).
RESULTS
After balancing age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1C), serum triglyceride (TG), and urinary albumin-to-creatinine ratio (UACR) between the G2-G5 and control groups, per 0.1 g/L increment in serum complement C3 was significantly associated with a 27.8% reduced risk of DKD at G5 stage (OR, 95% CI, P: 0.722, 0.616-0.847, <0.001) relative to the G1 stage. Conversely, per 0.1 g/L increment in serum complement C4 was associated with an 83.0-177.6% increased risk of G2-G5 stage (P<0.001). Serum complement C1q was not statistically significant compared to controls at all stages prior to or after propensity score matching.
CONCLUSIONS
Our results indicate that high concentrations of serum C4 were associated with the significantly elevated risk of kidney function deterioration across all stages, and reduced serum C3 levels with an increased risk of DKD stage G5.
Topics: Humans; Diabetic Nephropathies; Retrospective Studies; Kidney; Kidney Function Tests; Glomerular Filtration Rate; Diabetes Mellitus
PubMed: 38047115
DOI: 10.3389/fendo.2023.1195966 -
Current Pain and Headache Reports Apr 2024Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide... (Review)
Review
PURPOSE OF REVIEW
Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies.
RECENT FINDINGS
An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle-Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). The most important proteins identified involved transferrin, α-, β-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response.
PubMed: 38652420
DOI: 10.1007/s11916-024-01244-4 -
BioRxiv : the Preprint Server For... Jul 2023The complement component 4 gene locus, composed of the and genes and located on chromosome 6, encodes for C4 protein, a key intermediate in the classical and lectin...
The complement component 4 gene locus, composed of the and genes and located on chromosome 6, encodes for C4 protein, a key intermediate in the classical and lectin pathways of the complement system. The complement system is an important modulator of immune system activity and is also involved in the clearance of immune complexes and cellular debris. The gene locus exhibits copy number variation, with each composite gene varying between 0-5 copies per haplotype, genes also vary in size depending on the presence of the HERV retrovirus in intron 9, denoted by for long-form and for short-form, which modulates expression and is found in both and . Additionally, human blood group antigens Rodgers and Chido are located on the C4 protein, with the Rodger epitope generally found on C4A protein, and the Chido epitope generally found on C4B protein. copy number variation has been implicated in numerous autoimmune and pathogenic diseases. Despite the central role of C4 in immune function and regulation, high-throughput genomic sequence analysis of variants has been impeded by the high degree of sequence similarity and complex genetic variation exhibited by these genes. To investigate C4 variation using genomic sequencing data, we have developed a novel bioinformatic pipeline for comprehensive, high-throughput characterization of human sequence from short-read sequencing data, named C4Investigator. Using paired-end targeted or whole genome sequence data as input, C4Investigator determines gene copy number for overall and , additionally, C4Ivestigator reports the full overall aligned sequence, enabling nucleotide level analysis of . To demonstrate the utility of this workflow we have analyzed variation in the 1000 Genomes Project Dataset, showing that the genes are highly poly-allelic with many variants that have the potential to impact C4 protein function.
PubMed: 37503256
DOI: 10.1101/2023.07.18.549551 -
BMC Psychiatry Oct 2023Anxiety and depression are psychosomatic disorders that are frequently observed in chronic conditions such as systemic lupus erythematosus (SLE). Anxiety and depression...
BACKGROUND
Anxiety and depression are psychosomatic disorders that are frequently observed in chronic conditions such as systemic lupus erythematosus (SLE). Anxiety and depression can be induced by immunological and neurotransmitter dysregulation, which is characterized by hypothalamic-pituitary-adrenal (HPA) axis dysfunction, production of proinflammatory cytokines, and activation of complement in the blood, such as C3 and C4. The causes of anxiety and depression in SLE are complex, ranging from neuropsychiatric involvement to drug adverse effects. Detecting anxiety and depression symptoms in SLE patients is critical to preventing disability from impacting quality of life.
OBJECTIVE
To assess the relationship between anxiety and depression symptomatology, SLE disease activity with levels of C3 and C4 in Cipto Mangunkusumo National Hospital.
METHODS
This study used a cross-sectional design. The study included 120 SLE patients from Cipto Mangunkusumo National Hospital, aged 18 to 60 years. All patients were requested to complete a Hospital Anxiety and Depression Scale (HADS) questionnaire to assess their anxiety and depression symptoms. Subjects with anxiety and depression were assessed for disease activity using the Mexican Systemic Lupus Erythematosus Systemic Disease Activity (Mex-SLEDAI), and blood samples were collected to test complement C3 and C4 levels. Spearman's correlation test was used to examine the relationship between HADS scores, Mex-SLEDAI, and C3 and C4 levels.
RESULTS
The results of the study showed a very weak statistically significant negative correlation between anxiety symptoms based on HADS and C3 levels (r = -0.189; p = 0.038) and a weak correlation between anxiety symptoms and C4 levels (r = -204; p = 0.026). Depressive symptoms based on HADS revealed a very poor connection and no statistical significance with levels of C3 (r = -0.056; p = 0.546) and C4 (r = -0.068; p = 0.461). Anxiety (r = 0.06; p = 0.173) and depression (r = 0.031; p = 0.753) symptoms have a weak and insignificant positive connection with SLE activity.
CONCLUSION
C3 and C4 serum levels appeared to decrease when the presence of anxious symptoms increased. There was no significant correlation in SLE disease activity between anxious and depressed patients.
Topics: Humans; Complement C3; Quality of Life; Depression; Cross-Sectional Studies; Lupus Erythematosus, Systemic; Anxiety
PubMed: 37884917
DOI: 10.1186/s12888-023-05285-8 -
Acta Neurologica Belgica Aug 2023Neuromyelitis Optica Spectrum Disorders (NMOSD) is an antibody-mediated disorder of the Central Nervous System where a leading role of the complement system has been...
BACKGROUND
Neuromyelitis Optica Spectrum Disorders (NMOSD) is an antibody-mediated disorder of the Central Nervous System where a leading role of the complement system has been demonstrated.
OBJECTIVE
To measure the levels of complement factors C3, C4 and C5a in serum and plasma of clinical remission patients with AQP4-IgG + NMOSD.
METHODS
Twelve patients with NMOSD AQP4 + according to 2015 criteria from a General Hospital in Buenos Aires, Argentina, were included in the study, and 19 age- and sex-matched healthy volunteers as a control group (HC). AQP4 antibodies were measured in serum by CBA analysis. Fresh blood samples were centrifuged to obtain serum and plasma. C3, C4, and AQP4 antibodies were measured in the serum, whereas C5a was measured in the plasma, which was obtained using Futhan (BD FUT-175®, BD Biosciences, San Jose, CA, USA).
RESULTS
The complement factors, C3, C4, and C5a were measured in all samples. The mean concentration of C3 was 130.7 mg/dl (SD 16.1 mg/dl), and the mean concentration of C4 was 21.6 mg/dl (SD 4.8 mg/dl); both values were within the normal reference range (C3: 84-193 mg/dl; C4: 20-40 mg/dl) and were not significantly different (p > 0.05) from the mean levels in healthy controls (C3: 116.9 mg/dl; C4: 21.9 mg/dl). When analyzing the mean plasma level of C5a, we found a statistically significant difference (p = 0.0444) between the mean concentration of C5a in NMOSD patients (43.1 ng/ml; SD 48.7 ng/ml) and the HC group (17.7 ng/ml; SD 16.7 ng/ ml).
CONCLUSIONS
In conclusion, the present study demonstrates that plasma C5a may be interesting to investigate as a potential biomarker of disease activity in NMOSD, in a larger and prospective cohort.
Topics: Humans; Aquaporin 4; Complement C5a; Prospective Studies; Autoantibodies; Neuromyelitis Optica; Immunoglobulin G
PubMed: 37024715
DOI: 10.1007/s13760-023-02261-7 -
Schizophrenia (Heidelberg, Germany) Feb 2024Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide....
Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an immune gene involved in the innate immune system and located in the major histocompatibility complex (MHC) region, has been identified to be strongly associated with schizophrenia risk. In addition, recent findings have also suggested that the MHC region has been associated with suicide risk across disorders, making C4 a potential candidate of interest for studying suicidality in schizophrenia patients. Despite growing interest in investigating the association between the C4 gene and schizophrenia, to our knowledge, no work has been done to examine the potential of C4 variants as suicide risk factors in patients with schizophrenia. In this study, we investigated the association between different C4 copy number variants and predicted C4 brain expression with suicidal outcomes (suicide attempts/suicidal ideation). We directly genotyped 434 schizophrenia patients to determine their C4A and C4B copy number variants. We found the C4AS copy number to be marginally and negatively associated with suicide risk, potentially being protective against suicide attempts (OR = 0.49; p = 0.05) and suicidal ideation (OR = 0.65; p = 0.07). Furthermore, sex-stratified analyses revealed that there are no significant differences between males and females. Our preliminary findings encourage additional studies of C4 and potential immune dysregulation in suicide.
PubMed: 38341430
DOI: 10.1038/s41537-024-00440-w