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BioRxiv : the Preprint Server For... Apr 2024Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain...
Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain diseases. To understand how immune complement dysregulation - a prevalent locus of brain disease etiology - in PV cells may drive disease pathogenesis, we have developed a transgenic mouse line that permits cell-type specific overexpression of the schizophrenia-associated complement component 4 () gene. We found that overexpression of mouse () in PV cells causes sex-specific behavioral alterations and concomitant deficits in synaptic connectivity and excitability of PV cells of the prefrontal cortex. Using a computational network, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of failed to evoke the same deficits in behavior as PV-specific overexpression, suggesting that perturbations in fast-spiking neurons are more harmful to brain function than pan-neuronal alterations. Together, these results provide a causative link between and the vulnerability of PV cells in brain disease.
PubMed: 38328248
DOI: 10.1101/2024.01.27.575409 -
Frontiers in Medicine 2024The presence of urinary autoantibodies in patients with systemic lupus erythematosus (SLE) has been confirmed by several studies; however, the significance of their...
OBJECTIVE
The presence of urinary autoantibodies in patients with systemic lupus erythematosus (SLE) has been confirmed by several studies; however, the significance of their presence in urine remains unclear. This study aims to further investigate the association between urine autoantibodies and disease activity as well as organ involvement in SLE.
METHODS
This cross-sectional study included 89 SLE patients. Data collected included anti-nuclear antibody (ANA), anti-ENA antibodies, and anti-dsDNA antibody levels in both serum and urine, complement (C) 3, C4 levels in serum, SLE disease activity index-2000 (SLEDAI-2000), renal domains of SLEDAI (RSLEDAI) and non-renal SLEDAI (NRSLEDAI).
RESULTS
The rate of positive urine ANA (uANA) was 33.3% (29/87) among the enrolled patients. Compared to the uANA negative group, the positive group exhibited significantly higher SLEDAI-2000 scores (7.85 ± 5.88 vs. 18.69 ± 6.93, < 0.001), RSLEDAI scores [0 (0, 4.0) vs. 12.0 (8.0, 16.0), < 0.001], and NRSLEDAI [4 (2.0, 8.0) vs. 6.0 (4.0, 9.5), = 0.038]. Patients with positive urine anti-Sm antibody demonstrated significantly elevated SLEDAI-2000 scores compared to those who were negative (25.0 ± 8.80 vs. 10.09 ± 6.63, < 0.001). Similarly, they also had higher RSLEDAI [16.0 (12.0, 16.0) vs. 4.0 (0, 8.0), < 0.001] and NRSLEDAI [9.5 (6.0, 13.5) vs. 4.0 (3.0, 8.0), = 0.012], as well as a greater prevalence of renal involvement compared to their negative counterparts (100% vs. 58.2, = 0.022). There was a positive correlation between uANA titer and both SLEDAI-2000 ( = 0.663, < 0.001) and RSLEDAI ( = 0.662, < 0.001). The serum anti-dsDNA antibody level did not exhibit a significant correlation with RSLEDAI ( = 0.143, = 0.182). Conversely, the urine anti-dsDNA antibody level demonstrated a significant positive correlation with RSLEDAI ( = 0.529, < 0.001).
CONCLUSION
Urine ANA is associated with both global SLEDAI and RSLEDAI scores. Urine anti-Sm antibody is associated with an increased incidence of renal involvement in SLE. The urine anti-dsDNA antibody level, rather than the serum anti-dsDNA antibody level, exhibits a significant association with RSLEDAI in SLE.
PubMed: 38314205
DOI: 10.3389/fmed.2024.1346609 -
Brain, Behavior, and Immunity Mar 2024Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse...
Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications.
Topics: Humans; Schizophrenia; Complement C1q; Psychotic Disorders; Antipsychotic Agents; RNA, Messenger
PubMed: 38301948
DOI: 10.1016/j.bbi.2024.01.219 -
Frontiers in Endocrinology 2023The etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity...
BACKGROUND
The etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity (TAI). This study explores the immunological and metabolic profiles of RSA patients exhibiting positive thyroid antibodies and their connection with the rates of first-trimester miscarriage and live births. The aim is to provide further guidance for clinical interventions.
METHODS
A retrospective analysis included 478 women with RSA. Thyroid profile, thyroid peroxidase antibodies, and anti-thyroglobulin antibodies were measured in all participants. The clinical characteristics and pregnancy outcomes of RSA women were compared between thyroid autoimmunity (TAI)-positive and TAI-negative patients. Significant factors associated with adverse pregnancy outcomes and risk prediction models were explored in TAI-positive patients. Correlation analysis was used to identify specific metabolic or immune biomarkers associated with thyroid autoantibodies.
RESULTS
The prevalence of TAI was 18.6%. Compared with women without TAI, the thyroid-stimulating hormone (TSH) concentration of TAI-positive RSA was significantly higher (2.80 ± 2.98 vs 1.89 ± 1.17, p=0.006). After 28 weeks, the live birth rate of the TAI-positive group was lower than that of the TAI-negative group, with statistical significance (p<0.05). The immune biomarkers that differed between RSA women with live births and those with first-trimester miscarriages were complement C4 and interleukin-6, respectively, in TAI-negative and TAI-positive women. Then, a risk prediction model for first-trimester miscarriage was constructed for TAI-positive women with an AUC of 0.81. Finally, some factors related to thyroid peroxidase antibody (TPO-Ab) levels were explored, and it was found that TPO-Ab levels were positively correlated with free thyroxine and negatively correlated with 25 hydroxyvitamin D, interleukin-4, and fasting blood glucose in RSA patients.
CONCLUSION
TAI-positive RSA patients have higher first-trimester miscarriage rates and a lower live birth rate, which may be related to metabolic immune shifts in TAI-positive RSA patients.
Topics: Pregnancy; Humans; Female; Pregnancy Outcome; Retrospective Studies; Abortion, Habitual; Iodide Peroxidase; Biomarkers
PubMed: 38298186
DOI: 10.3389/fendo.2023.1297902 -
Clinica Chimica Acta; International... Mar 2024In this real-world approach, we examined the serum Anti-Mullerian Hormone (AMH) level and the relationship with serum IgG subclass in the infertile women.
OBJECTIVES
In this real-world approach, we examined the serum Anti-Mullerian Hormone (AMH) level and the relationship with serum IgG subclass in the infertile women.
METHODS
A total of 574 female participants were recruited for this study. The serum AMH, IgG subclass(IgG1, IgG2, IgG3, IgG4) and immunoglobulin (Ig) G、IgM、IgA、IgE as well as complement C, C were analyzed. The difference in serum AMH level was assessed according categorized as above or below the median of the ratio of serum IgG subclass(IgG1, IgG2, IgG3, IgG4) to total IgG (R).
RESULTS
The serum AMH level of the low R group is significantly decreased than that high R group (p < 0.05). The Spearman correlation analysis showed that the serum AMH level was significantly negatively correlated with age and significantly positively correlated with serum IgG1 levels respectively (p < 0.05). GLMMs multivariate model showed that after adjusting the covariate and possible mixed factors including age, serum immunoglobulin, complement C and C, the serum AMH level was significantly positively correlated with IgG1 level (p < 0.01).
CONCLUSIONS
Decreased serum IgG1 may significantly affect the ovarian reserve function of women. Confirmation of this association and elucidation of its underlying mechanisms are needed to place these results in a clinical perspective.
Topics: Female; Humans; Anti-Mullerian Hormone; Immunoglobulin G; Infertility, Female; Retrospective Studies; Serum
PubMed: 38286181
DOI: 10.1016/j.cca.2024.117807 -
PLoS Neglected Tropical Diseases Jan 2024Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and...
BACKGROUND
Extensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and the underlying mechanism remains unclear. This study was designed to investigate the association between C. sinensis infection and HCC and reveal the relationship between C. sinensis infection and cancer stemness.
METHODS
A comprehensive analysis of 839 HCC patients categorized into C. sinensis (-) HCC and C. sinensis (+) HCC groups was conducted. Chi-square and Mann-Whitney U tests were used to assess the association between C. sinensis infection and clinical factors. Kaplan-Meier and Cox regression analyses were used to evaluate survival outcomes. Immunohistochemistry was used to determine CK19 and EpCAM expression in HCC specimens.
RESULTS
Compared to C. sinensis (-) HCC patients, C. sinensis (+) HCC patients exhibited advanced Barcelona Clinic Liver Cancer (BCLC) stage, higher male prevalence and more liver cirrhosis as well as elevated alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), eosinophil, complement 3 (C3), and complement 4 (C4) values. C. sinensis infection correlated with shorter overall survival (OS) (p < 0.05) and recurrence-free survival (RFS) (p < 0.05). Furthermore, Cox multivariate analysis revealed that C. sinensis infection was an independent prognostic factor for OS in HCC patients. Importantly, C. sinensis infection upregulated the expression of HCC cancer stem cell markers CK19 and EpCAM.
CONCLUSION
HCC patients with C. sinensis infection exhibit a poor prognosis following hepatectomy. Moreover, C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC.
AUTHOR SUMMARY
Clonorchis sinensis (C. sinensis) is a prominent food-borne parasite prevalent in regions such as China, particularly in Guangxi. C. sinensis has been associated with various hepatobiliary system injuries, encompassing inflammation, periductal fibrosis, cholangiocarcinoma and even hepatocellular carcinoma (HCC). A substantial body of evidence links C. sinensis to cholangiocarcinoma, However, the connection between C. sinensis and HCC and the intricate mechanisms underlying its contribution to HCC development remain incompletely elucidated. Our study demonstrates clear clinicopathological associations between C. sinensis and HCC, such as gender, BCLC stage, liver cirrhosis, MVI, AFP, CA19-9, circulating eosinophils and complements. Furthermore, we found that the co-occurrence of C. sinensis exhibited a significant association with shorter OS and RFS in patients diagnosed with HCC. A major finding was that C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC. Our results provide a more comprehensive comprehension of the interplay between C. sinensis and HCC, shedding fresh light on the carcinogenic potential of C. sinensis.
Topics: Animals; Humans; Male; Carcinoma, Hepatocellular; Liver Neoplasms; Epithelial Cell Adhesion Molecule; Clonorchiasis; alpha-Fetoproteins; CA-19-9 Antigen; Neoplasm Staging; China; Prognosis; Clonorchis sinensis; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Liver Cirrhosis; Retrospective Studies
PubMed: 38285640
DOI: 10.1371/journal.pntd.0011906 -
Pediatric Health, Medicine and... 2024This study aims to evaluate the immunological features of gastrointestinal (GI) bleeding in children with Henoch-Schönlein purpura (HSP).
BACKGROUND
This study aims to evaluate the immunological features of gastrointestinal (GI) bleeding in children with Henoch-Schönlein purpura (HSP).
STUDY DESIGN
This retrospective study was conducted on children with HSP. Demographic and clinical data were collected, including serum immunoglobulin (Ig) levels, complement C3 and C4 levels, and lymphocyte subtype percentage.
RESULTS
A total of 446 hospitalized children had HSP. Eighty-six children with HSP had GI bleeding, 114 had proteinuria, and 107 had hematuria. Lower arthralgia, prolonged glucocorticoid use, increased white blood cell counts, elevated neutrophils and neutrophil-to-lymphocyte ratio, reduced IgG and C3 levels, elevated CD19 cell percentage, and reduced CD3 cell and natural killer cell percentages were associated with GI bleeding risk in patients with HSP. Multivariate regression analysis revealed that arthralgia, glucocorticoid use, increased neutrophil percentage, reduced IgG and C3 levels, and increased CD19 cell percentage were independent predictors of GI bleeding. Further analysis indicated that the combination of C3 and CD19 cell percentages had a high predictive ability for GI bleeding in children with HSP.
CONCLUSION
This study indicated that reduced C3 and increased CD19 cell percentages contributed to the development of GI bleeding in children with HSP. Specific immunologic profiles may be strongly correlated with GI bleeding risk in children with HSP.
PubMed: 38283766
DOI: 10.2147/PHMT.S429961 -
Infectious Diseases and Therapy Feb 2024Mycoplasma pneumoniae necrotizing pneumonia (MPNP) is an uncommon but increasingly recognized severe complication of pneumonia, and the delayed diagnosis and treatment...
INTRODUCTION
Mycoplasma pneumoniae necrotizing pneumonia (MPNP) is an uncommon but increasingly recognized severe complication of pneumonia, and the delayed diagnosis and treatment are prone to pulmonary sequelae. The aim of this study is to explore independent risk factors for MPNP in children with lung consolidation.
METHODS
A retrospective observational study was conducted on 118 children with MPNP (MPNP group) and 184 children with lung consolidation of Mycoplasma pneumoniae pneumonia (MPP) (control group) admitted to Children's Hospital Affiliated to Zhengzhou University from June 2018 to August 2023. Clinical manifestations and laboratory data were analyzed and the independent risk factors for MPNP in children were analyzed by multivariate logistic regression.
RESULTS
The age of onset, hospitalization days, fever days, proportion of dyspnea, chest pain, complications, and need for fiberoptic bronchoscopic alveolar lavage (FBAL) were higher than those in the control group, and the difference was statistically significant (P < 0.05). The levels of white blood cells (WBC), platelets, neutrophil percentage (N%), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), fibrinogen (Fbg), D-dimer (D-D), erythrocyte sedimentation rate (ESR), alanine transaminase (ALT), γ-glutamyl transpeptidase (γ-GGT), globulin, lactate dehydrogenase (LDH), α-hydroxybutyrate dehydrogenase (α-HBDH), urea, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), complement component 3, antistreptolysin O (ASO), serum ferritin, and interleukin-6 (IL-6) in the MPNP group were higher than those in the control group. Red blood cell (RBC), lymphocyte percentage (L%), activated partial thromboplastin time (APTT), alkaline phosphatase (ALP), total protein, albumin, albumin-to-globulin ratio (AGR), creatine kinase (CK), uric acid, natrium, chlorine, calcium, and complement C4 in the MPNP group were lower than those in the control group, and the difference was statistically significant (P < 0.05). The results of multivariate logistic regression analysis showed that age ≥ 83.50 months, fever days ≥ 10.50, ALT ≥ 15.25 U/l, IgM ≥ 1.46 g/l, complement C3 ≥ 1.47 g/l, Fbg ≥ 3.93 g/l, dyspnea and needing FBAL were independent risk factors for MPNP in children.
CONCLUSIONS
Age, fever days, ALT, IgM, complement C3, Fbg, dyspnea, and needing FBAL were independent risk factors for MPNP in children. For children suspected of MPNP, pediatricians should pay close attention to the above indicators, strive for early diagnosis and treatment, and improve prognosis.
PubMed: 38265626
DOI: 10.1007/s40121-023-00914-x -
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 -
Clinical Kidney Journal Jan 2024Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement...
BACKGROUND
Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement dysregulation is pivotal for the disease to develop. Here, we studied this premise in seven patients with TMA and coexisting MG.
METHODS
Patients with TMA on kidney biopsy and/or peripheral blood were recruited from the prospective COMPETE cohort (NCT04745195) and Limburg Renal Registry. Patients were screened for complement dysregulation, including genetics/factor H autoantibodies (FHAA) and functional testing on microvascular endothelial cells.
RESULTS
Seven (8%) out of 84 patients with TMA presented with a coexisting MG. MG clustered in patients aged over 50 years (= 6/32, 19%). C4 and/or C3 levels were low in three patients, while four patients presented with normal complement levels. None of the patients carried rare variants in complement genes. Massive C5b9 formation on the endothelium was noted in one patient; purified IgG from this patient caused massive C5b9 formation via the alternative pathway of complement activation, pointing to complement dysregulation in the fluid phase. Kidney biopsies from other nephropathies linked to MG rarely exhibited concurrent TMA (N = 1/27, 4%).
CONCLUSIONS
MG clustered in patients with TMA aged over 50 years. TMA and coexisting MG represents a heterogeneous disease spectrum, including a small subset of patients who may present with complement dysregulation.
PubMed: 38250251
DOI: 10.1093/ckj/sfad306