Elucidating allergic reaction mechanisms in response to SARS-CoV-2 mRNA vaccination in adults.

Background: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined.

Methods: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors.

A Monoclonal Antibody That Provides a Model for C3 Nephritic Factors.

Complement is a major innate defense system that protects the intravascular space from microbial invasion. Complement activation results in the assembly of C3 convertases, serine proteases that cleave complement protein C3, generating bioactive fragments C3a and C3b. The complement response is rapid and robust, largely due to a positive feedback regulatory loop mediated by alternative pathway (AP) C3 convertase.

Complement activation on neutrophils initiates endothelial adhesion and extravasation.

Neutrophils are essential to the pathogenesis of many inflammatory diseases. In the autoantibody-mediated K/BxN model of inflammatory arthritis, the alternative pathway (AP) of complement and Fc gamma receptors (FcγRs) are required for disease development while the classical pathway is dispensable. The reason for this differential requirement is unknown.

Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse.

Problem: Crry is a widely expressed type 1 transmembrane complement regulatory protein in rodents which protects self-tissue by downregulating C3 activation. Crry concepti produced by Crry  × Crry matings are attacked by maternal complement system leading to loss before day 10. The membrane attack complex is not the mediator of this death.

Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy.

Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue.

Anti-complement activity of the Ixodes scapularis salivary protein Salp20.

Complement, a major component of innate immunity, presents a rapid and robust defense of the intravascular space. While regulatory proteins protect host cells from complement attack, when these measures fail, unrestrained complement activation may trigger self-tissue injury, leading to pathologic conditions. Of the three complement activation pathways, the alternative pathway (AP) in particular has been implicated in numerous disease and injury states.

Role of complement receptor 1 (CR1; CD35) on epithelial cells: A model for understanding complement-mediated damage in the kidney.

The regulators of complement activation gene cluster encodes a group of proteins that have evolved to control the amplification of complement at the critical step of C3 activation. Complement receptor 1 (CR1) is the most versatile of these inhibitors with both receptor and regulatory functions. While expressed on most peripheral blood cells, the only epithelial site of expression in the kidney is by the podocyte.

Anti-mouse properdin TSR 5/6 monoclonal antibodies block complement alternative pathway-dependent pathogenesis.

The complement alternative pathway (AP) is a major contributor to a broad and growing spectrum of diseases that includes age-related macular degeneration, atypical hemolytic uremic syndrome, and preeclampsia. As a result, there is much interest in the therapeutic disruption of AP activity. Properdin, the only positive regulator of the AP, is a particularly promising AP target.

Synergy between surface and core entrapped metals in a mixed manganese-gadolinium nanocolloid affords safer MR imaging of sparse biomarkers.

High-relaxivity T1-weighted (T1w) MR molecular imaging nanoparticles typically present high surface gadolinium payloads that can elicit significant acute complement activation (CA). The objective of this research was to develop a high T1w contrast nanoparticle with improved safety. We report the development, optimization, and characterization of a gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC; 138±10 (Dav)/nm; PDI: 0.

Physicochemical signatures of nanoparticle-dependent complement activation.

Nanoparticles are potentially powerful therapeutic tools that have the capacity to target drug payloads and imaging agents. However, some nanoparticles can activate complement, a branch of the innate immune system, and cause adverse side-effects. Recently, we employed an tro hemolysis assay to measure the serum complement activity of perfluorocarbon nanoparticles that differed by size, surface charge, and surface chemistry, quantifying the nanoparticle-dependent complement activity using a metric called Residual Hemolytic Activity (RHA).

Using mutagenesis and structural biology to map the binding site for the Plasmodium falciparum merozoite protein PfRh4 on the human immune adherence receptor.

To survive and replicate within the human host, malaria parasites must invade erythrocytes. Invasion can be mediated by the P. falciparum reticulocyte-binding homologue protein 4 (PfRh4) on the merozoite surface interacting with complement receptor type 1 (CR1, CD35) on the erythrocyte membrane.

Application of a hemolysis assay for analysis of complement activation by perfluorocarbon nanoparticles.

Unlabelled: Nanoparticles offer new options for medical diagnosis and therapeutics with their capacity to specifically target cells and tissues with imaging agents and/or drug payloads. The unique physical aspects of nanoparticles present new challenges for this promising technology. Studies indicate that nanoparticles often elicit moderate to severe complement activation.

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation.

Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression.

Detection of complement activation using monoclonal antibodies against C3d.

During complement activation the C3 protein is cleaved, and C3 activation fragments are covalently fixed to tissues. Tissue-bound C3 fragments are a durable biomarker of tissue inflammation, and these fragments have been exploited as addressable binding ligands for targeted therapeutics and diagnostic agents. We have generated cross-reactive murine monoclonal antibodies against human and mouse C3d, the final C3 degradation fragment generated during complement activation.

Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a complex inflammatory vascular disease. There are currently limited treatment options for AAA when surgery is inapplicable. Therefore, insights into molecular mechanisms underlying AAA pathogenesis may reveal therapeutic targets that could be manipulated pharmacologically or biologically to halt disease progression.

Access to the complement factor B scissile bond is facilitated by association of factor B with C3b protein.

Factor B is a zymogen that carries the catalytic site of the complement alternative pathway C3 convertase. During convertase assembly, factor B associates with C3b and Mg(2+) forming a pro-convertase C3bB(Mg(2+)) that is cleaved at a single factor B site by factor D. In free factor B, a pair of salt bridges binds the Arg(234) side chain to Glu(446) and to Glu(207), forming a double latch structure that sequesters the scissile bond (between Arg(234) and Lys(235)) and minimizes its unproductive cleavage.

Variable antibody-dependent activation of complement by functionalized phospholipid nanoparticle surfaces.

A wide variety of nanomaterials are currently being developed for use in the detection and treatment of human diseases. However, there is no systematic way to measure and predict the action of such materials in biological contexts. Lipid-encapsulated nanoparticles (NPs) are a class of nanomaterials that includes the liposomes, the most widely used and clinically proven type of NPs.

Oversulfated heparin by-products induce thrombin generation in human plasmas through contact system activation.

Thrombin generation is thought to be mediated predominantly by the tissue factor or ''extrinsic'' coagulation pathway. An alternate pathway to thrombin generation (the ''intrinsic'' pathway or contact system) has been observed when blood or plasma comes in contact with artificial surfaces. Here we present evidence for a new route to thrombin formation that begins with the activation of the contact system protein prekallikrein by oversulfated heparin (OS-HB).

Properdin: emerging roles of a pattern-recognition molecule.

Complement is an innate immune system that is a first line of defense against pathogens and facilitates elimination of apoptotic and injured cells. During complement activation, the complement convertases are assembled on target surfaces and initiate their proteolytic activities, a process that marks targets for phagocytosis and/or lysis. The complement alternative activation pathway has been implicated in a number of autoimmune conditions including arthritis and age-related macular degeneration.

Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.

Background: We previously established that neutrophils play a critical role in the development of experimental abdominal aortic aneurysm (AAA). The signal that initiates the influx of neutrophils to the aortic wall, however, remains unknown. In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall.

Properdin: New roles in pattern recognition and target clearance.

Properdin was first described over 50 years ago by Louis Pillemer and his collaborators as a vital component of an antibody-independent complement activation pathway. In the 1970s properdin was shown to be a stabilizing component of the alternative pathway convertases, the central enzymes of the complement cascade. Recently we have reported that properdin can also bind to target cells and microbes, provide a platform for convertase assembly and function, and promote target phagocytosis.

The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis.

Apoptotic cells must be rapidly eliminated to avoid harmful inflammatory and autoimmune reactions. Innate immunity is designed/poised to identify dying cells by their unique surface-associated molecular patterns. Here we demonstrate for the first time, to our knowledge, that the human complement protein properdin binds to early apoptotic T cells and initiates complement activation, leading to C3b opsonization and ingestion by phagocytic cells.

Evidence for non-traditional activation of complement factor C3 during murine liver regeneration.

Unlabelled: Complement signaling has been implicated as important for normal hepatic regeneration. However, the specific mechanism by which complement is activated during liver regeneration remains undefined. To address this question, we investigated the hepatic regenerative response to partial hepatectomy in wildtype mice, C3-, C4-, and factor B-null mice, and C4-null mice treated with a factor B neutralizing antibody (mAb 1379).

Properdin and complement activation: a fresh perspective.

The C3 convertases are the major proteases of the complement cascade and are assembled at the site of complement activation via several different pathways. Properdin's functional role in stabilizing the alternative pathway convertase has been long established; however, new evidence demonstrates that properdin can also bind to certain microbial surfaces, and provide a platform for de novo convertase assembly. Therefore, properdin participates in two distinct mechanisms for complement activation: the alternative pathway and a properdin-directed pathway.