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Biomedicines Apr 2024Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia....
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia. Complement system disturbance is implicated in the pathogenesis of SLE. In this work, we aim to study how a full assessment of the complement system, which includes the evaluation of its three pathways, relates to blood cell counts in a population of patients with SLE. New-generation functional assays of the classical, alternative, and lectin pathways of the complement system were conducted in 284 patients with SLE. Additionally, serum levels of inactive molecules (C1q, C2, C3, C4, factor D) and activated molecules (C3a), as well as regulators (C1-inhibitor and factor H), were evaluated. Complete blood cell counts were analyzed. Multivariable linear regression analysis was performed to study the relationship of hematological profiles with this full characterization of the complement system. After multivariable adjustments that included age, sex, SLICC-DI (damage), and SLEDAI (activity) scores, as well as the use of aspirin, prednisone, methotrexate, azathioprine, and mycophenolate mofetil, several relationships were observed between the C pathways and the individual products and blood cells profile. Lower values of C1q and C2 were associated with lower hemoglobin levels. Lower leukocyte counts showed significantly lower values of C4, C1 inhibitor, C3, factor D, and alternative pathway functional levels. Neutrophil counts showed significant negative relationships only with the alternative pathway and C1-inh. In the case of lymphocytes, associations were found, especially with functional tests of the classical and alternative pathways, as well as with C2, C4, C3, and C3a. On the contrary, for platelets, significance was only observed, after multivariable adjustment, with lower C2 concentrations. In conclusion, the serum complement system and hematological profile in SLE are independently linked, after adjustment for disease activity and damage. These relationships are basically negative and are predominantly found in lymphocytes.
PubMed: 38790929
DOI: 10.3390/biomedicines12050967 -
Diseases (Basel, Switzerland) Apr 2024Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered....
Role of B Cells beyond Antibodies in HBV-Induced Oncogenesis: Fulminant Cancer in Common Variable Immunodeficiency-Clinical and Immunotransplant Implications with a Review of the Literature.
Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host-virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 10 copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111-220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.
PubMed: 38785735
DOI: 10.3390/diseases12050080 -
Current Issues in Molecular Biology May 2024Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as... (Review)
Review
Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, , , , , , , , , , and are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include , and . Finally, specific mutations have been associated with the onset of CRS (, ) and ICANS (, , , ). More research is essential in this field to achieve better outcomes for our patients.
PubMed: 38785556
DOI: 10.3390/cimb46050288 -
Journal of Traditional Chinese Medicine... Jun 2024To investigate the underlying protein molecular mechanisms of " stagnation and blood stasis syndrome" (QS) and " deficiency and blood stasis syndrome" (QD), as two...
Proteomics analysis of coronary atherosclerotic heart disease with different Traditional Chinese Medicine syndrome types before and after percutaneous coronary intervention.
OBJECTIVE
To investigate the underlying protein molecular mechanisms of " stagnation and blood stasis syndrome" (QS) and " deficiency and blood stasis syndrome" (QD), as two subtypes of coronary artery disease (CAD) in Traditional Chinese Medicine (TCM), following percutaneous coronary intervention (PCI).
METHODS
In this study, a total of 227 CAD patients with QS and 211 CAD patients with QD were enrolled; all participants underwent PCI. Label-free quantification proteomics were employed to analyze the changes in serum in two subtypes of CAD patients before and 6 months after PCI, aiming to elucidate the intervention mechanism of PCI in treating CAD characterized by two different TCM syndromes.
RESULTS
Biochemical analysis revealed significant changes in tumor necrosis factor-α, high density lipoprotein cholesterol, blood stasis clinical symptoms observation, and Gensini levels in both patient groups post-PCI; Proteomic analysis identified 79 and 95 differentially expressed proteins in the QS and QD patient groups, respectively, compared to their control groups. complement C8 alpha chain, complement factor H, apolipoprotein H, apolipoprotein B, plasminogen, carbonic anhydrase 2, and complement factor I were altered in both comparison groups. Furthermore, enrichment analysis demonstrated that cell adhesion and connectivity-related processes underwent changes in QS patients post-PCI, whereas lipid metabolism-related pathways, including the peroxisome proliferator-activated receptor signaling pathway and extracellular matrix receptor interaction, underwent changes in the QD group. The protein-protein interaction network analysis further enriched 52 node proteins, including apolipoprotein B, lipoprotein (a), complement C5, apolipoprotein A4, complement C8 alpha chain, complement C8 beta chain, complement C8 gamma chain, apolipoprotein H, apolipoprotein A-Ⅱ, albumin, complement C4-B, apolipoprotein C3, among others. The functional network of these proteins is posited to contribute to the pathophysiology of CAD characterized by TCM syndromes.
CONCLUSION
The current quantitative proteomic study has preliminarily identified biomarkers of CAD in different TCM subtypes treated with PCI, potentially laying the groundwork for understanding the protein profiles associated with the treatment of various TCM subtypes of CAD.
Topics: Humans; Proteomics; Male; Female; Middle Aged; Percutaneous Coronary Intervention; Coronary Artery Disease; Aged; Medicine, Chinese Traditional
PubMed: 38767640
DOI: 10.19852/j.cnki.jtcm.20240408.001 -
Psychiatry and Clinical... Jun 2023There are increasing investigations about the potential role of the complement system in disorders affecting the central nervous system, including schizophrenia....
BACKGROUND
There are increasing investigations about the potential role of the complement system in disorders affecting the central nervous system, including schizophrenia. Therefore, we aim to evaluate the levels of complement 3 and complement 4 and the factors affecting treatment resistance in schizophrenia patients.
METHODS
This cross-sectional study was conducted between January 2020 and January 2021 and included schizophrenia patients resistant to treatment or in remission and healthy controls. The Structured Clinical Interview for Diagnostic and Statistical Manual-5 was used to confirm the diagnosis according to Diagnostic and Statistical Manual -5 criteria. We evaluated the patients with some scales and forms. The complement 3 and complement 4 levels were measured from blood samples.
RESULTS
In the treatment-resistant schizophrenia group, complement 3 ( = .001) and complement 4 (001) levels were significantly higher compared to schizophrenia patients in remission and healthy controls. While the Brief Psychiatric Rating Scale (001), the Positive and Negative Syndrome Scale-positive (001), the Positive and Negative Syndrome Scale-negative (001), the Positive and Negative Syndrome Scale-psychopathology (001), the Positive and Negative Syndrome Scale-total (001), and the Clinical Global Impression Scale-Severity (001) scores were significantly higher in treatment-resistant schizophrenia patients, the General Assessment of Functioning (001), and Beck Cognitive Insight Scale (001) scores were significantly lower compared to the other groups. In schizophrenia patients, complement 3 levels were positively correlated with the Positive and Negative Syndrome Scale-negative (046), the Positive and Negative Syndrome Scale-psychopathology (001), the Positive and Negative Syndrome Scale -total (025), and Clinical Global Impression Scale-Severity of Disease (004). Also, complement 4 levels were positively correlated with Brief Psychiatric Rating Scale (004), the Positive and Negative Syndrome Scale-positive (003), the Positive and Negative Syndrome Scale -negative (014), the Positive and Negative Syndrome Scale-psychopathology (001), the Positive and Negative Syndrome Scale-total (002), and Clinical Global Impression Scale-Severity of Disease (001) in patients with schizophrenia. It was determined that a higher C4 level increased the risk of treatment resistance (odds ratio: 1.133, 95% CI: 1.012-1.268; 030), while a higher Beck Cognitive Insight Scale score decreased the risk of treatment resistance (odds ratio: 0.317, 95% CI: 0.191-0.526; 001).
CONCLUSION
In light of the analyses, it can be said that complement concentration increases in certain stages of schizophrenia, and its imbalance may be associated with symptom severity and treatment resistance.
PubMed: 38765923
DOI: 10.5152/pcp.2023.22580 -
Frontiers in Immunology 2024Kidney transplant recipients often experience significant alterations in their immune system, which can lead to increased susceptibility to infections. This study aimed...
INTRODUCTION
Kidney transplant recipients often experience significant alterations in their immune system, which can lead to increased susceptibility to infections. This study aimed to analyze time-dependent changes in serum immunoglobulin and complement levels and determine the risk factors associated with infection.
METHODS
A retrospective analysis of serum samples from 192 kidney transplant recipients who received transplantations between August 2016 and December 2019 was conducted. The serum samples were obtained at preoperative baseline (T0), postoperative 2 weeks (T1), 3 months (T2), and 1 year (T3). The levels of serum C3, C4, IgG, IgA, and IgM were measured to evaluate immune status over time.
RESULTS
The analysis revealed significant decreases in IgG and IgA levels at T1. This period was associated with the highest occurrence of hypogammaglobulinemia (HGG) and hypocomplementemia (HCC), as well as an increased incidence of severe infection requiring hospitalization and graft-related viral infections. Using a time-dependent Cox proportional hazards model adjusted for time-varying confounders, HGG was significantly associated with an increased risk of infection requiring hospitalization (HR, 1.895; 95% CI: 1.871-1.920, P-value<0.001) and graft-related viral infection (HR, 1.152; 95% CI: 1.144-1.160, P-value<0.001).
DISCUSSION
The findings suggest that monitoring serum immunoglobulin levels post-transplant provides valuable insights into the degree of immunosuppression. Hypogammaglobulinemia during the early post-transplant period emerges as a critical risk factor for infection, indicating that serum immunoglobulins could serve as feasible biomarkers for assessing infection risk in kidney transplant recipients.
Topics: Humans; Kidney Transplantation; Male; Female; Middle Aged; Retrospective Studies; Adult; Time Factors; Immunoglobulins; Risk Factors; Agammaglobulinemia; Biomarkers; Infections
PubMed: 38707898
DOI: 10.3389/fimmu.2024.1374535 -
Kidney International Reports May 2024Complement system overactivation is pivotal in lupus nephritis (LN) pathophysiology. Considering that anti-C3 autoantibodies play a significant role in LN...
INTRODUCTION
Complement system overactivation is pivotal in lupus nephritis (LN) pathophysiology. Considering that anti-C3 autoantibodies play a significant role in LN pathophysiology, we explored them as disease activity biomarkers and compared them to the ones against the homologous protein, C4.
METHODS
We investigated the presence of anti-C3 and anti-C4 IgG autoantibodies in a LN cohort ( = 85 patients) and monitored their changes over time. We correlated autoantibody presence with clinical parameters. We conducted cross-sectional and longitudinal analyses ( = 295 samples, 8 years follow-up) to explore associations between autoantibodies and disease progression. Antigen-specific anti-C3 or anti-C4 IgG were purified from plasma by affinity chromatography and their reactivity was tested for cross-reactivity against purified C3 or C4 by enzyme-linked immunosorbent assay (ELISA).
RESULTS
The reactivity against C3 was independent of C4. Our study revealed distinct roles for anti-C3 and anti-C4 in LN. Anti-C3 IgG exhibited stronger clinical correlations than anti-C4, showing associations with hypocomplementemia, anti-dsDNA, class IV LN, and active disease according to British Isles Lupus Assessment Group (BILAG) renal score. In a longitudinal analysis, anti-C3 positivity at initial sampling predicted present and future disease exacerbation alone and even better when combined with anti-dsDNA, as indicated by a transition to BILAG category A.
CONCLUSION
Our research provides insights into anti-C3/C3b and anti-C4 autoantibodies in LN, revealing that they are often not cross-reactive. Anti-C3 utility as disease activity biomarkers is underscored by its stronger clinical associations and predictive value for future flares. Combining anti-C3 and anti-dsDNA out-performs the 2 factors alone, suggesting that the incorporation of anti-C3/C3b quantification into routine clinical practice could improve LN management.
PubMed: 38707805
DOI: 10.1016/j.ekir.2024.01.052 -
Journal of the American Chemical Society May 2024The classical complement pathway is activated by antigen-bound IgG antibodies. Monomeric IgG must oligomerize to activate complement via the hexameric C1q complex, and...
The classical complement pathway is activated by antigen-bound IgG antibodies. Monomeric IgG must oligomerize to activate complement via the hexameric C1q complex, and hexamerizing mutants of IgG appear as promising therapeutic candidates. However, structural data have shown that it is not necessary to bind all six C1q arms to initiate complement, revealing a symmetry mismatch between C1 and the hexameric IgG complex that has not been adequately explained. Here, we use DNA nanotechnology to produce specific nanostructures to template antigens and thereby spatially control IgG valency. These DNA-nanotemplated IgG complexes can activate complement on cell-mimetic lipid membranes, which enabled us to determine the effect of IgG valency on complement activation without the requirement to mutate antibodies. We investigated this using biophysical assays together with 3D cryo-electron tomography. Our data revealed the importance of interantigen distance on antibody-mediated complement activation, and that the cleavage of complement component C4 by the C1 complex is proportional to the number of ideally spaced antigens. Increased IgG valency also translated to better terminal pathway activation and membrane attack complex formation. Together, these data provide insights into how nanopatterning antigen-antibody complexes influence the activation of the C1 complex and suggest routes to modulate complement activation by antibody engineering. Furthermore, to our knowledge, this is the first time DNA nanotechnology has been used to study the activation of the complement system.
Topics: Nanostructures; Humans; DNA; Complement Activation; Immunoglobulin G; Antigen-Antibody Complex
PubMed: 38703132
DOI: 10.1021/jacs.4c02772 -
Journal of Clinical Medicine Apr 2024: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating...
: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. : We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. : The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-β, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. : The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed.
PubMed: 38673624
DOI: 10.3390/jcm13082353 -
The Journal of International Medical... Apr 2024To investigate the role of albumin-to-globulin ratio (AGR) in systemic lupus erythematosus (SLE) and its relationship with disease activity.
OBJECTIVE
To investigate the role of albumin-to-globulin ratio (AGR) in systemic lupus erythematosus (SLE) and its relationship with disease activity.
METHODS
This retrospective study consecutively selected patients with SLE and healthy controls. Patients were divided into three groups according to the SLE Disease Activity Index 2000 (SLEDAI-2K): group 1 (mild disease activity, SLEDAI-2K ≤ 6), group 2 (moderate disease activity, SLEDAI-2K 7-12) and group 3 (severe disease activity, SLEDAI-2K > 12). Predictors of SLE disease activity were analysed by ordinal logistical regression.
RESULTS
A total of 101 Chinese patients with SLE and 75 healthy Chinese controls were included. Patients with SLE had lower AGR values than healthy individuals, and group 3 patients with SLE displayed lower AGR values than those in group 1, but similar values to group 2. AGR was inversely correlated with SLEDAI-2K (r = -0.543). Ordinal logistic regression analysis showed that lower AGR (β = -1.319) and lower complement C4 (β = -1.073) were independent risk factors for SLE disease activity.
CONCLUSIONS
AGR was decreased in patients with SLE and may be utilized as a useful inflammatory biomarker for monitoring SLE disease activity.
Topics: Adult; Female; Humans; Male; Middle Aged; Biomarkers; Case-Control Studies; Complement C4; Logistic Models; Lupus Erythematosus, Systemic; Retrospective Studies; Risk Factors; Serum Albumin; Serum Globulins; Severity of Illness Index
PubMed: 38661083
DOI: 10.1177/03000605241244761