-
Frontiers in Immunology 2022A proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients.
BACKGROUND
A proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients.
METHODS
We analyzed the demographic and clinical data and complement levels of 85 patients with IgG4-RD. We defined hypocomplementemia as serum C3 and/or C4 levels below the lower limit of normal at diagnosis. We also compared the characteristics of patients with and without IgG4-RD.
RESULTS
Thirty-two (38%) patients had hypocomplementemia at diagnosis. Patients with hypocomplementemia had more lymph node (p < 0.01), lung (p < 0.01), and kidney (p = 0.02) involvement and a higher IgG4-RD responder index than those without (p = 0.05). Additionally, patients with hypocomplementemia had significantly higher IgG (p < 0.01), IgG4 (p < 0.01), and soluble interleukin 2-receptor (sIL-2R) (p < 0.01) levels and total IgG minus IgG4 (p < 0.01). C3 and C4 levels negatively correlated with IgG, IgG4, and sIL-2R levels, total IgG minus IgG4, and number of IgG4-RD responder index: a measure of the disease activity in IgG4-RD. Patients with hypocomplementemia at diagnosis had a significantly higher frequency of relapse (p = 0.024), as determined using the log-rank test. A multivariate logistic regression analysis showed the presence of hypocomplementemia was independently associated with relapse (OR, 6.842; 95% confidence interval [95%CI], 1.684-27.79; p = 0.007).
CONCLUSIONS
Patients with IgG4-RD with hypocomplementemia have a more active clinical phenotype, suggesting contributions of the complement system in the pathophysiology of IgG4-RD.
Topics: Complement System Proteins; Hematologic Diseases; Humans; Immune System Diseases; Immunoglobulin G; Immunoglobulin G4-Related Disease; Receptors, Interleukin-2; Recurrence
PubMed: 35296071
DOI: 10.3389/fimmu.2022.828122 -
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 -
Frontiers in Immunology 2022The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement...
BACKGROUND
The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement activation in active (aABMR). We quantified complement activation markers, C3, C3d, and C5b-9 in plasma of aABMR, and acute T-cell mediated rejection (aTCMR), and non-rejection kidney transplant recipients. Intra-renal complement markers were analyzed as C4d, C3d, C5b-9, and CD59 deposition. We examined complement activation and CD59 expression on renal endothelial cells upon incubation with human leukocyte antigen antibodies.
METHODS
We included 50 kidney transplant recipients, who we histopathologically classified as aABMR (n=17), aTCMR (n=18), and non-rejection patients (n=15).
RESULTS
Complement activation in plasma did not differ across groups. C3d and C4d deposition were discriminative for aABMR diagnosis. Particularly, C3d deposition was stronger in glomerular (P<0,01), and peritubular capillaries (P<0,05) comparing aABMR to aTCMR rejection and non-rejection biopsies. In contrast to C3d, C5b-9 was only mildly expressed across all groups. For C5b-9, no significant difference between aABMR and non-rejection biopsies regarding peritubular and glomerular C5b-9 deposition was evident. We replicated these findings using renal endothelial cells and found complement pathway activation with C4d and C3d, but without terminal C5b-9 deposition. Complement regulator CD59 was variably present in biopsies and constitutively expressed on renal endothelial cells .
CONCLUSION
Our results indicate that terminal complement might only play a minor role in late aABMR, possibly indicating the need to re-evaluate the applicability of terminal complement inhibitors as treatment for aABMR.
Topics: Antibodies; Complement C4b; Complement Membrane Attack Complex; Complement System Proteins; Endothelial Cells; Female; Graft Rejection; Humans; Kidney; Kidney Diseases; Male
PubMed: 35493506
DOI: 10.3389/fimmu.2022.845301 -
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 -
Frontiers in Immunology 2020To investigate complement(C) factors(F) and their activation fragments expression in OA joint tissues. (Clinical Trial)
Clinical Trial
OBJECTIVE
To investigate complement(C) factors(F) and their activation fragments expression in OA joint tissues.
DESIGN
Immunohistochemistry and quantitative imaging were performed to analyze C3, C4, and CF (factor) B expression on osteochondral biopsies (43 patients) collected during arthroplasty. Isolated chondrocytes and synoviocytes, cartilage and synovial tissues obtained from surgical specimens of OA patients (15 patients) were cultured with or without IL-1β. Real time PCR for CFB, C3, and C4 was performed. Culture supernatants were analyzed for C3a, C5a, CFBa, and terminal complement complex (TCC) production.
RESULTS
In osteochondral biopsies, C factor expression was located in bone marrow, in a few subchondral bone cells and chondrocytes. C3 was the most expressed while factor C4 was the least expressed factor. Gene expression showed that all C factors analyzed were expressed both in chondrocytes and synoviocytes. In chondrocyte cultures and cartilage explants, CFB expression was significantly higher than C3 and C4. Furthermore, CFB, but not C3 and C4 expression was significantly induced by IL-1β. As to C activation factors, C3a was the most produced and CFBa was induced by IL-1β in synovial tissue. TCC production was undetectable in isolated chondrocytes and synoviocytes cell culture supernatants, whereas it was significantly augmented in cartilage explants.
CONCLUSION
C factors were locally produced and activated in OA joint with the contribution of all tissues (cartilage, bone, and synovium). Our results support the involvement of innate immunity in OA and suggest an association between some C alternative pathway component and joint inflammation.
Topics: Adult; Aged; Aged, 80 and over; Cartilage, Articular; Complement Pathway, Alternative; Complement System Proteins; Female; Humans; Interleukin-1beta; Male; Middle Aged; Osteoarthritis; Synovial Membrane
PubMed: 33193305
DOI: 10.3389/fimmu.2020.535010 -
RMD Open Jul 2023To assess the sensitivity and specificity of the 2019 EULAR/American College of Rheumatology (ACR) classification criteria for systemic lupus erythematosus (SLE) in... (Observational Study)
Observational Study
OBJECTIVES
To assess the sensitivity and specificity of the 2019 EULAR/American College of Rheumatology (ACR) classification criteria for systemic lupus erythematosus (SLE) in outpatients at an academic tertiary care centre and to compare them to the 1997 ACR and the 2012 Systemic Lupus International Collaborating Clinics criteria.
METHODS
Prospective and retrospective observational cohort study.
RESULTS
3377 patients were included: 606 with SLE, 1015 with non-SLE autoimmune-mediated rheumatic diseases (ARD) and 1756 with non-ARD diseases (hepatocellular carcinoma, primary biliary cirrhosis, autoimmune hepatitis). The 2019 criteria were more sensitive than the 1997 criteria (87.0% vs 81.8%), but less specific (98.1% vs 99.5% in the entire cohort and 96.5% vs 98.8% in patients with non-SLE ARD), resulting in Youden Indexes for patients with SLE/non-SLE ARD of 0.835 and 0.806, respectively. The most sensitive items were history of antinuclear antibody (ANA) positivity and detection of anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies. These were also the least specific items. The most specific items were class III/IV lupus nephritis and the combination of low C3 and low C4 complement levels, followed by class II/V lupus nephritis, either low C3 or low C4 complement levels, delirium and psychosis, when these were not attributable to non-SLE causes.
CONCLUSIONS
In this cohort from an independent academic medical centre, the sensitivity and specificity of the 2019 lupus classification criteria were confirmed. Overall agreement of the 1997 and the 2019 criteria was very good.
Topics: Humans; United States; Rheumatology; Retrospective Studies; Prospective Studies; Lupus Nephritis; Tertiary Care Centers; Lupus Erythematosus, Systemic; Rheumatic Diseases; Complement C4
PubMed: 37419524
DOI: 10.1136/rmdopen-2023-003037 -
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 -
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 -
Schizophrenia Research Aug 2021Schizophrenia is a complex brain disorder with genetic and environmental factors contributing to its etiology. Complement C4 genes are schizophrenia susceptibility loci...
Schizophrenia is a complex brain disorder with genetic and environmental factors contributing to its etiology. Complement C4 genes are schizophrenia susceptibility loci and are activated in response to infections and gut microbiome imbalances. We hypothesize that C4 genetic susceptibility predisposes individuals to neuropathological effects from pathogen exposures or a microbiome in dysbiosis. In 214 individuals with schizophrenia and 123 non-psychiatric controls, we examined C4 gene copy number and haplotype groups for associations with schizophrenia and microbial plasma biomarkers. C4A copy number and haplotypes containing HERV-K insertions (C4A-long; C4AL-C4AL) conferred elevated odds ratios for schizophrenia diagnoses (OR 1.58-2.56, p < 0.0001), while C4B-short (C4BS) haplogroups conferred decreased odds (OR 0.43, p < 0.0001). Haplogroup-microbe combinations showed extensive associations with schizophrenia including C4AL with Candida albicans IgG (OR 2.16, p < 0.0005), C4AL-C4BL with cytomegalovirus (CMV) IgG (OR 1.79, p < 0.008), C4BS with lipopolysaccharide-binding protein (LBP) (OR 1.18, p < 0.0001), and C4AL-C4AL with Toxoplasma gondii IgG (OR = 17.67, p < 0.0001). In controls, only one haplogroup-microbe combination was significant: C4BS with CMV IgG (OR 0.52, p < 0.02). In schizophrenia only, LBP and CMV IgG levels were inversely correlated with C4A and C4S copy numbers, respectively (R = 0.13-0.16, p < 0.0001). C4 haplogroups were associated with altered scores of cognitive functioning in both cases and controls and with psychiatric symptom scores in schizophrenia. Our findings link complement C4 genes with a susceptibility to infections and a dysbiotic microbiome in schizophrenia. These results support immune system mechanisms by which gene-environmental interactions may be operative in schizophrenia.
Topics: Biomarkers; Complement C4; Complement C4a; Gene-Environment Interaction; Humans; Schizophrenia
PubMed: 33632634
DOI: 10.1016/j.schres.2021.02.001 -
Immunobiology Nov 2019Alex Law and Paul Levine recall their work to establish the covalent bond between C3 and target surfaces. It started with a naive experiment by analyzing the membrane... (Review)
Review
Alex Law and Paul Levine recall their work to establish the covalent bond between C3 and target surfaces. It started with a naive experiment by analyzing the membrane polypeptides of sheep erythrocytes bound with I-labelled C3. They found complexes with molecular weight higher than the individual C3 polypeptides. These complexes survived all conditions designed to disrupt non-covalent interactions. They then showed that the bond was an ester, with an active acyl group on C3 which reacted with a hydroxyl group on the acceptor molecule. With the discovery of an internal thioester by Jim Prahl, Jamila Janatova, Brian Tack and their colleagues, it became clear that the reaction was by an acyl transfer from the thioester of C3 to the target hydroxyl group. Later on they showed that C4 also bound covalently to target molecules. By establishing a fluid phase system to study the kinetics of the binding reactions of C3 and C4, Alex was able to continue the work in the MRC Immunochemistry Unit in Oxford from 1981, to eventually determine the chemical mechanism of the binding reaction. In order to give some sense of reality, this article is written as a narrative from Alex, who did the experiments. Both Alex and Paul are retired. Pauls lives on Martha's Vineyard where he writes occasional articles on science for one of the Island's newspapers. Alex lives in Hong Kong and tries to make some sense of the local politics.
Topics: Animals; Complement C3; Complement C4; History, 20th Century; Humans; Protein Binding
PubMed: 31445811
DOI: 10.1016/j.imbio.2019.08.003