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International Journal of General... 2022To determine the prevalence of hypocomplementemia in primary Sjogren's syndrome (pSS) patients and compare the clinical characteristics of patients with and without...
OBJECTIVE
To determine the prevalence of hypocomplementemia in primary Sjogren's syndrome (pSS) patients and compare the clinical characteristics of patients with and without hypocomplementemia.
METHODS
A retrospective study was conducted in 120 treatment-naive Chinese patients that met the 2012 American College of Rheumatology Classification Criteria for pSS and were followed up for 3 to 24 months. Based on the complement results, patients were divided into four groups: only low C3, only low C4, both low C3 and C4 (double low), normal group. The data on patient demographics, clinical manifestations, laboratory results, disease activity and pharmacologic therapy were collected and compared among the four groups.
RESULTS
The prevalence of only low C3, only low C4, both low C3 and C4 in pSS patients was 21.7%, 16.7%, and 10%, respectively. The mean age of the four groups was significantly different. Unlike rampant caries and parotitis, the prevalence of dry eyes and dry mouth differed among the four groups. The proportion of patients with anemia, leukocytopenia, lymphadenopathy, hematological involvement and fatigue was significantly higher in the double low group and lower in the normal complement group. The proportion of patients with increased serum IgG was higher in the only low C4 group than in the other groups. Logistic regression revealed that hypocomplementemia was an independent risk factor for lymphadenopathy and leukopenia. The double low group had a significant history of exposure to glucocorticoids and cyclophosphamide, compared with other groups.
CONCLUSION
Our study found that the clinical characteristics of pSS patients with hypocomplementemia differed from those without hypocomplementemia. Hypocomplementemia in pSS was associated with hematological involvement, hyper-IgG, lymphadenopathy, and fatigue, contributing to more significant exposure to glucocorticoid and cyclophosphamide.
PubMed: 35035231
DOI: 10.2147/IJGM.S346188 -
PLoS Neglected Tropical Diseases Oct 2022Malaria and filariasis are significant vector-borne diseases that are co-endemic in the same human populations. This study aims to collate the evidence, probability, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Malaria and filariasis are significant vector-borne diseases that are co-endemic in the same human populations. This study aims to collate the evidence, probability, and characteristics of malaria and filariasis co-infections in participants among studies reporting the co-occurrence of both diseases.
METHODS
We searched for potentially relevant articles reporting the co-occurrence of malaria and filariasis in five electronic databases (Embase, PubMed, Scopus, Medline, and CENTRAL) from inception to May 22, 2022. We estimated the pooled prevalence and probability of malaria and filariasis co-infections among study participants using random-effects meta-analyses and synthesized the characteristics of patients with co-infections narratively.
RESULTS
We identified 951 articles, 24 of which (96,838 participants) met eligibility criteria and were included in the systematic review. Results of the meta-analysis showed a pooled prevalence of malaria and filariasis co-infections among participants of 11%. The prevalence of co-infections was 2.3% in Africa, 0.2% in Asia, and 1.6% in South America. The pooled prevalences of malaria and Wuchereria bancrofti, malaria and Loa loa, malaria and Mansonella perstans co-infections were 0.7%, 1.2%, and 1.0%, respectively. The meta-analysis results showed that the co-infections between two parasites occurred by probability (P = 0.001). Patients with co-infections were at increased risk of having an enlarged spleen, a lower rate of severe anemia, lower parasite density, and more asymptomatic clinical status. Patients with co-infections had decreased levels of C-X-C motif chemokine 5, tumor necrosis factor-α, interleukin-4, c4 complement, and interleukin-10. In addition, patients with co-infections had a lower interleukin-10/tumor necrosis factor-α ratio and higher interleukin-10/interleukin-6 ratio.
CONCLUSION
The present study showed that the prevalence of malaria and filariasis co-infections was low and varied between geographical areas in the selected articles. Co-infections tended to occur with a low probability. Further studies investigating the outcomes and characteristics of co-infections are needed.
Topics: Animals; Humans; Prevalence; Interleukin-10; Interleukin-4; Coinfection; Tumor Necrosis Factor-alpha; Interleukin-6; Filariasis; Mansonelliasis; Malaria; Probability; Complement C4; Chemokines
PubMed: 36269701
DOI: 10.1371/journal.pntd.0010857 -
International Journal of Molecular... Nov 2022Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis affecting multiple organ systems, including the kidney. Small... (Observational Study)
Observational Study
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis affecting multiple organ systems, including the kidney. Small vessels in the kidney include small-sized arteries, capillaries, and venules. Intrarenal C4 deposits are now increasingly recognized as a potential marker and pathogenic mechanism of autoantibody-mediated tissue damage in ANCA-associated renal vasculitis. We here describe the relevance of complement C4 deposits localized to distinct vascular compartments in a cohort of biopsy-proven ANCA-associated renal vasculitis. A cohort of 43 biopsy-proven cases of ANCA-associated renal vasculitis with myeloperoxidase (MPO) or proteinase 3 (PR3) seropositivity were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with intrarenal C4 deposits in ANCA-associated renal vasculitis. We here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with better short-term survival (p = 0.008), implicating that this subgroup had a superior response to remission induction therapy. Second, C4 deposits in interlobular arteries were associated with eosinophilic infiltrates in renal vasculitis with MPO-ANCA seropositivity (p = 0.021). In renal vasculitis positive for MPO-ANCA, the absence of C4 deposits in the glomerular tuft was associated with sclerotic class ANCA-associated renal vasculitis (p < 0.001), and tubular RBC casts (p = 0.024). Fourth, complement C4 in interlobular arteries is associated with tubular atrophy specifically in renal vasculitis with PR3-ANCA seropositivity (p = 0.006). Finally, complement C4 deposits in peritubular capillaries associated specifically with hyaline casts in cases positive for PR3-ANCA (p = 0.025), implicating a role in tubular injury. Interestingly, C4 deposits were localized to distinct vascular compartments independent of the systemic activation of the complement system, reflected by the consumption of respective serum complement molecules in ANCA-associated renal vasculitis. In summary, we here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with survival and distinct histopathological lesions. Considering recent advances in AAV therapy with the emergence of new therapeutics that inhibit complement activation, we here provide novel insights into complement C4 as a potential marker to identify patients who may benefit most from these drugs. Thus, our results may contribute to a more personalized treatment approach of AAV depending on the relevance of distinct intrarenal complement deposits.
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Complement C4; Retrospective Studies; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Myeloblastin; Kidney; Kidney Diseases; Biomarkers
PubMed: 36430804
DOI: 10.3390/ijms232214325 -
Journal of Immunology (Baltimore, Md. :... May 2022Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways...
Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama () immunization, that bind to human C4b () with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined single-particle cryo-electron microscopy structures in complex with C4b at 3.4-4 Å resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications.
Topics: Animals; Complement Activation; Complement C3-C5 Convertases; Complement C4b; Cryoelectron Microscopy; Humans; Mammals; Single-Domain Antibodies
PubMed: 35428691
DOI: 10.4049/jimmunol.2100647 -
Developmental Neuroscience 2023Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune...
Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.
Topics: Humans; Child; Complement C4b; Complement C4a; Gene Dosage; Genotype; Arthritis
PubMed: 37379808
DOI: 10.1159/000531707 -
Molecular Psychiatry Jul 2021Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a...
Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.
Topics: Animals; Complement C4; Interneurons; Mice; Parvalbumins; Phenotype; Prefrontal Cortex; Schizophrenia
PubMed: 33837272
DOI: 10.1038/s41380-021-01081-6 -
Clinical Medicine Insights. Oncology 2022A cure for the heterogeneous hematological malignancy multiple myeloma (MM) is yet to be developed. To date, the early risk factors associated with poor outcomes in MM...
BACKGROUND
A cure for the heterogeneous hematological malignancy multiple myeloma (MM) is yet to be developed. To date, the early risk factors associated with poor outcomes in MM have not been fully elucidated. Studies have shown an aberrant complement system in patients with MM, but the precise association necessitates elucidation. Therefore, this study scrutinizes the correlation between serum complement level and the disease outcome of patients with MM.
METHODS
A retrospective analysis of 72 patients with MM (new diagnosis) with complement C4 and C3 along with common laboratory indicators was done. The Pearson χ test and the Mann-Whitney -test were done to evaluate categorical or binary variables and intergroup variance, respectively. Kaplan-Meier test and Cox proportional hazards regression were used for quantification of overall survival (OS) and univariate or multivariate analyses, respectively.
RESULTS
The Cox proportional hazard model analysis unveiled the following: platelet ⩽115.5 × 10/L (hazard ratio [HR] = 5.82, 95% confidence interval [CI] = 2.522-13.436, < .001), complement C4 ⩽0.095 g/L(HR = 3.642, 95% CI = 1.486-8.924, = .005), age ⩾67 years (HR = 0.191, 95% CI = 0.078-0.47, < .001), and bone marrow plasma cell percentage ⩾30.75% (HR = 0.171, 95% CI = 0.06-0.482, = .001) can be used as independent predictors of OS. Of these, advanced age, low platelet level, and a high proportion of bone marrow plasma cells have been implicated in poor outcomes in patients with MM. Interestingly, a low complement 4 level can function as a new indicator of poor prognosis in patients with MM.
CONCLUSION
Low levels of C4 are indicative of a poor outcome in newly diagnosed patients with MM.
PubMed: 35250324
DOI: 10.1177/11795549221079171 -
European Archives of Psychiatry and... Oct 2022Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility....
Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (CSMD1) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined C4A and CSMD1 mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; n = 73) and mentally healthy volunteers (n = 48). Imputed C4 locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in CSMD1 expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between C4A and CSMD1 mRNA levels in healthy volunteers but not in FEP cases. In addition, C4 copy number variants previously associated with SZ risk correlated with higher C4A mRNA levels in FEP cases, which confirms the regulatory effect of C4 structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher C4A mRNA levels correlated with more severe general psychopathology symptoms and lower CSMD1 mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of CSMD1 in prefrontal-mediated cognitive functioning.
Topics: Antipsychotic Agents; Cognition; Complement C4a; Humans; Membrane Proteins; Psychotic Disorders; RNA, Messenger; Tumor Suppressor Proteins
PubMed: 35532796
DOI: 10.1007/s00406-022-01409-5 -
European Review For Medical and... Dec 2022Immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) are common types of primary glomerulonephritis (PGD). A lack of specific clinical features makes...
OBJECTIVE
Immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) are common types of primary glomerulonephritis (PGD). A lack of specific clinical features makes diagnosis difficult. Kidney function indicators have been used for their diagnosis. However, the diagnostic performance of these indicators is undetermined. The purpose of this paper is to evaluate their diagnostic potential.
PATIENTS AND METHODS
101 patients with PGD were enrolled, including 50 with MN and 51 with IgAN. The healthy controls included 110 volunteers. The indicators related to kidney function, including TP, ALB, Cre, CysC, eGFR, C1q, Ure, Anti-PLA2R, complement C3, and complement C4 in serum, ACR in urine, and antinuclear antibody profile, IgG staining, IgA staining, IgM staining, C3 staining and C1q staining in tissue samples were evaluated.
RESULTS
Statistical differences were found in TP, ALB, Ure, CysC, eGFR, C1q, Anti-PLA2R, complement C3, complement C4 and ACR among the three groups of subjects. ROC analysis showed that Anti-PLA2R and ACR had the highest specificity for identifying IgAN and/or MN from the healthy controls, ACR had the highest sensitivity. The Sp and Se of IgA and IgG in tissue samples for the identification of IgAN and MN were both high. Both IgAN and MN were predicted by anti-PLA2R, especially MN. In tissue samples, MN patients were more likely to be IgG positive and IgAN patients were more likely to be IgA positive.
CONCLUSIONS
IgAN and MN may be differentiated using serum Anti-PLA2R, tissue IgG, and tissue IgA. Cre is only useful in middle and late stages of GPDs, ACR is an exclusion marker, and CysC and C1q cannot be used to identify MN.
Topics: Humans; Complement C1q; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Immunoglobulin A; Immunoglobulin G
PubMed: 36591820
DOI: 10.26355/eurrev_202212_30657 -
Frontiers in Endocrinology 2021Gestational Diabetes Mellitus (GDM) development is related to underlying metabolic syndrome that is associated with elevated complement C3 and C4. Elevated C3 levels...
INTRODUCTION
Gestational Diabetes Mellitus (GDM) development is related to underlying metabolic syndrome that is associated with elevated complement C3 and C4. Elevated C3 levels have been associated with preeclampsia and the development of macrosomia.
METHODS
This case-control study included 34 pregnant women with GDM and 16 non-diabetic (ND) women in their second trimester. Complement-related proteins were measured and correlated with demographic, biochemical, and pregnancy outcome data.
RESULTS
GDM women were older with a higher BMI (p<0.001); complement C3, C4 and Factor-H were significantly elevated (p=0.001, p=0.05, p=0.01, respectively). When adjusted for age and BMI, Complement C3 (p=0.04) and Factor-H (p=0.04) remained significant. Partial correlation showed significant correlation between C4 with serum alanine aminotransferase (ALT) (p<0.05) and 2 term diastolic blood pressure (p<0.05); Factor-H and C-reactive protein (CRP; p<0.05). Pearson bivariate analysis revealed significant correlations between C3, C4, and Factor-H and CRP; p<0.05; C3 and gestational age at delivery (GA; p<0.05); C4 and ALT and second-trimester systolic blood pressure (STBP) (p=0.008 and p<0.05, respectively); Factor-H and glycated hemoglobin (HbA1c) (p<0.05). Regression analysis showed that the elevation of C3 could be accounted for by age, BMI, GA and CRP, with CRP being the most important predictor (p=0.02). C4 elevation could be accounted for by ALT, CRP and STBP. CRP predicted Factor-H elevation.
CONCLUSION
The increased C3, C4 and Factor-H during the second trimester of pregnancy in GDM are not independently associated with GDM; inflammation and high BMI may be responsible for their elevation. The elevation of second trimester C3 in GDM is associated with earlier delivery and further work is needed to determine if this is predictive.
Topics: Adult; Blood Pressure; Body Mass Index; C-Reactive Protein; Case-Control Studies; Complement C3; Complement C4; Complement Factor H; Diabetes, Gestational; Female; Fetal Macrosomia; Gestational Age; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, Second
PubMed: 33859618
DOI: 10.3389/fendo.2021.641361