complement receptors
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2021 ◽  
Vol 137 ◽  
pp. 75-83
Author(s):  
Arya Ghate ◽  
Samriddhi Sharma ◽  
Palak Agrawal ◽  
Arvind Sahu

Author(s):  
LK Metthew Lam ◽  
John Patrick Reilly ◽  
Ann H Rux ◽  
Sophia Murphy ◽  
Leticia Kuri-Cervantes ◽  
...  

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multi-system organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and pre-clinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in COVID-19 patients using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.


2021 ◽  
Vol 12 ◽  
Author(s):  
Vicente Escamilla-Rivera ◽  
Manjula Santhanakrishnan ◽  
Jingchun Liu ◽  
David R. Gibb ◽  
James E. Forsmo ◽  
...  

Complement impacts innate and adaptive immunity. Using a model in which the human KEL glycoprotein is expressed on murine red blood cells (RBCs), we have shown that polyclonal immunoprophylaxis (KELIg) prevents alloimmunization to transfused RBCs when a recipient is in their baseline state of heath but with immunoprophylaxis failure occurring in the presence of a viral-like stimulus. As complement can be detected on antibody coated KEL RBCs following transfusion, we hypothesized that recipient complement synergizes with viral-like inflammation to reduce immunoprophylaxis efficacy. Indeed, we found recipient C3 and C1q were critical to immunoprophylaxis failure in the setting of a viral-like stimulus, with no anti-KEL IgG alloantibodies generated in C3-/- or C1q-/- mice following KELIg treatment and KEL RBC transfusion. Differences in RBC uptake were noted in mice lacking C3, with lower consumption by splenic and peripheral blood inflammatory monocytes. Finally, no alloantibodies were detected in the setting of a viral-like stimulus following KELIg treatment and KEL RBC transfusion in mice lacking complement receptors (CR1/2-/-), narrowing key cells for immunoprophylaxis failure to those expressing these complement receptors. In-vitro studies showed complement fixed opsonized RBCs were significantly less likely to bind to B-cells from CR1/2-/- than wild type mice, potentially implicating lowered B-cell activation threshold in the presence of complement as being responsible for these findings. We thus propose a two-hit model for inflammation-induced immunoprophylaxis failure, where the first “hit” is recipient inflammation and the second “hit” is complement production/sensing. These results may have translational relevance to antigen-antibody interactions in humans.


Author(s):  
Anna Erdei ◽  
Kristóf G. Kovács ◽  
Zsuzsa Nagy-Baló ◽  
Szilvia Lukácsi ◽  
Bernadett Mácsik-Valent ◽  
...  

2021 ◽  
Vol 29 (1) ◽  
pp. 44-51
Author(s):  
Irina Momcheva ◽  
I. Kazmin ◽  
S. Hristova ◽  
V. Madjova

Abstract         Low-grade inflammation is part of the pathogenesis of osteoarthritis (OA) from its earliest stages and contributes to the acceleration of the degenerative process. Innate immunity has a leading role in it.        Activation of the innate immune response is initiated by stimulation of the receptors on the cell membrane to recognize the secreted PAMPs (pathogen-associated molecular patterns). However, PAMPs can also be activated by endogenous damage-related molecular patterns (DAMPs). The group of DAMPs also includes toll-like receptors (TLRs).The disruption of matrix homeostasis in the course of OA is an example of activation of these receptors in chronic damage.      The complement system is a key element of the innate immune system. It is one of the serum enzyme systems whose function is to opsonize antigens. The complement receptors on the surface of the cell membranes adhere to the targets for phagocytosis. The C3R fraction activates the complement cascade itself, as well as the oxygen metabolism of the cell, which is essential for the phagocytosis. The cartilage damage products released during joint damage are a separate class of potent complement modulators.     Complement fractions bind to complement receptors on the surface of the chondrocyte and the synoviocyte cell membranes by TLR. The complement system is involved in many processes in the course of osteoarthritis: chondrocyte degeneration, ECM degradation, low-grade inflammation in the osteoarthritis, cell lysis, unbalanced bone remodeling, osteophyte formation, and neoangiogenesis. Whether drug control of complement activation may be a future therapeutic strategy in the treatment of OA and prevent its progression is a subject of future studies.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 149.1-150
Author(s):  
K. Sterner ◽  
C. J. K. Fouodo ◽  
I. König ◽  
A. Künstner ◽  
H. Busch ◽  
...  

Background:The morbidity and mortality of systemic sclerosis (SSc) are largely determined by vascular and fibrotic pathologies. Levels of autoantibodies (ab) against G protein-coupled receptors (GPCR), growth factors (GF) and growth factor receptors (GFR) are altered in SSc compared to healthy controls (HC) 1. Thus, higher angiotensin II receptor type 1 - (AT1R) and endothelin receptor type A - (ETAR) ab levels are associated with severe disease and SSc-related mortality 2. CXC motiv chemokine receptor 3 - (CXCR3) and 4 - (CXCR4) ab have predictive value for deterioration of pulmonary fibrosis (PF) 3.Objectives:We used statistical methods to identify associations between disease manifestations and 28 new ab directed against GPCR, GF and GFR in SSc.Methods:Ab against the following targets were measured in sera from SSc patients (n = 177) and HC (n = 88): Adrenoceptors alpha-1 (ADRA1), alpha-2 (ADRA2), beta-1 (ADRB1), beta-2 (ADRB2); muscarinoceptors 1-5 (M1R - M5R); AT1R, ETAR, endothelin B receptor (ETBR); CXCR3, CXCR4; complement receptors 3a (C3aR) and 5a (C5aR); protease-activated receptors 1 (PAR1) and 2 (PAR2); vascular endothelial growth factor A (VEGFA) and its receptors 1 (VEGFR1) and 2 (VEGFR2), epithelial growth factor (EGF)/ - receptor (EGFR); hepatocyte growth factor (HGF)/ - receptor (HGFR), platelet-derived growth factor-AA (PDGFAA), placental growth factor (PlGF).The organ involvement (PF, cardiac involvement, PAH, gastrointestinal tract) and quantitative markers (modified Rodnan skin score, SSc activity score, pulmonary function, cardiac enzymes and echocardiography, routine laboratory, autoimmune diagnostics) as well as demographic data were recorded retrospectively at the time of sample collection. Statistical analysis was performed using the Mann-Whitney U test (MWU), Pearson correlations, ROC analysis, and age-adjusted logistic regression models.Results:In SSc 20 of 28 measured ab levels are significantly altered compared to HC. According to the Pearson correlation matrix, the ab-levels are highly correlated and build a network that differs between HC and SSc. Furthermore, altered network signatures are formed in the differentiated analysis of several disease manifestations of SSc such as SSc-subtype or PF. Based on ROC analysis, FGF-ab, ADRB1-ab and PlGF-ab are well suited to predict SSc (Figure 1).In addition, limited cutaneous SSc (lSSc) patients displayed lower levels of most ab than diffuse cutaneous SSc patients, whereas cardiac and pulmonary involvement are associated with higher ab levels. In the logistic regression lSSc is associated with lower levels of ab against M1R, M2R, C5aR, ETAR, AT1R, PAR1, EGFR. Higher levels for ab against M1R, M2R, ETBR, C5aR are associated with PF, higher levels of ab against complement receptors, adrenoreceptors and EGF with NT-proBNP elevation.Conclusion:The newly described antibodies against GPCR, GF and GFR are highly correlated. Associations with morbidity- and mortality-determining organ involvement indicate their possible functional relevance and novel pathophysiological mechanisms. As new biomarkers, some of the ab have prognostic value for SSc; for other manifestations, their value should be evaluated in further studies.References:[1]Cabral-Marques, O., Marques, A., Giil, L.M. et al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat Commun9, 5224 (2018). https://doi.org/10.1038/s41467-018-07598-9[2]Riemekasten G, Philippe A, Näther M, et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis Annals of the Rheumatic Diseases 2011;70:530-536.[3]Weigold, F., Günther, J., Pfeiffenberger, M. et al. Antibodies against chemokine receptors CXCR3 and CXCR4 predict progressive deterioration of lung function in patients with systemic sclerosis. Arthritis Res Ther 20, 52 (2018). https://doi.org/10.1186/s13075-018-1545-8Disclosure of Interests:Kristina Sterner: None declared, Césaire J. K. Fouodo: None declared, Inke König: None declared, Axel Künstner: None declared, Hauke Busch: None declared, Harald Heidecke Shareholder of: Owner of CellTrend, Anja Schumann: None declared, Antje Müller: None declared, Gabriela Riemekasten: None declared, Susanne Schinke Grant/research support from: UCB sponsors EULAR registration fees


2021 ◽  
Vol 12 ◽  
Author(s):  
Jessica C. Anania ◽  
Annika Westin ◽  
Jeremy Adler ◽  
Birgitta Heyman

Follicular dendritic cells (FDCs) are rare and enigmatic cells that mainly reside in germinal centers (GCs). They are capable of capturing immune complexes, via their Fc (FcRs) and complement receptors (CRs) and storing them for long periods in non-degradative vesicles. Presentation of ICs on FDCs to B cells is believed to drive affinity maturation. CR1 and CR2 are expressed on B cells and FDCs. Cr2 knock out (KO) mice, lacking both receptors, have impaired antibody and GC responses. Utilizing a novel ImageJ macro to analyze confocal fluorescence microscopy images of spleen sections, we here investigate how FDCs in wild type (WT) and Cr2 KO mice behave during the first two weeks after immunization with sheep red blood cells (SRBC). Mice were immunized with SRBC i.v. and spleen and serum samples harvested at various time points. As expected, antibody and GC responses in Cr2 KO mice were impaired in comparison to WT mice. Fewer FDCs were identified in Cr2 KO mice, and these exhibited differential localization and organization in comparison to WT mice. WT FDCs were primarily located within GCs at the light zone/dark zone border. FDCs from WT but not Cr2 KO mice were actively dispersed in GCs, i.e. tended to move away from each other, presumably to increase their surface area for B cell interaction. FDCs from Cr2 KO mice were more often found on follicles outside of the GCs and those within the GCs were closer to the periphery in comparison to WT FDCs. Expression of CR1 and CR2, FcγRIIB, and FcµR increased in FDCs from WT mice during the course of immunization. The results suggest that decreased ability to capture ICs by FDCs lacking CR1 and CR2 may not be the only explanation for the impaired GC and antibody responses in Cr2 KO mice. Poor FDC organization in GCs and failure to increase receptor expression after immunization may further contribute to the inefficient immune responses observed.


2021 ◽  
pp. 1-11
Author(s):  
Sinan Muldur ◽  
Felix Ellett ◽  
Anika L. Marand ◽  
Charles Marvil ◽  
John A. Branda ◽  
...  

Human neutrophils are highly sensitive to the presence of Borrelia burgdorferi (Bb), the agent of Lyme disease (LD), in tissues. Although Bb is also found in the blood of LD patients, far less is known about how neutrophils respond to Bb in the presence of blood. In this study, we employed microfluidic tools to probe the interaction between human neutrophils and Bb and measured the activation of human neutrophils in blood samples from patients. We found that neutrophils migrate vigorously toward Bb in the presence of serum, and this process was complement-dependent. Preventing complement factor 5 cleavage or blocking complement receptors decreased neutrophil’s ability to interact with Bb. We also found that spiking Bb directly into the blood from healthy donors induced spontaneous neutrophil motility. This response to Bb was also complement-dependent. Preventing complement factor 5 cleavage decreased spontaneous neutrophil motility in Bb-spiked blood. Moreover, we found that neutrophils in blood samples from acute LD patients displayed spontaneous motility patterns similar to those observed in Bb-spiked samples. Neutrophil motility was more robust in blood samples from LD patients than that measured in healthy and ill controls, validating the utility of the microfluidic assay for the study of neutrophil-Bb interactions in the presence of blood.


2021 ◽  
Vol 2 (3) ◽  
pp. 216-217
Author(s):  
Cassio Marinho Campelo

The complement system is one of the host’s primary defence mechanisms against pathogens. Its activation involves proteolytic cascades of enzymatic reactions that result in products with effector functions and recognition of molecules on the surface of microorganisms [1,2].


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