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Molecular Immunology Oct 2018Properdin, the widely known positive regulator of the alternative pathway (AP), has undergone significant investigation over the last decade to define its function in... (Review)
Review
Properdin, the widely known positive regulator of the alternative pathway (AP), has undergone significant investigation over the last decade to define its function in inflammation and disease, including its role in arthritis, asthma, and kidney and cardiovascular diseases. Properdin is a glycoprotein found in plasma that is mainly produced by leukocytes and can positively regulate AP activity by stabilizing C3 and C5 convertases and initiating the AP. Promotion of complement activity by properdin results in changes in the cellular microenvironment that contribute to innate and adaptive immune responses, including pro-inflammatory cytokine production, immune cell infiltration, antigen presenting cell maturation, and tissue damage. The use of properdin-deficient mouse models and neutralizing antibodies has contributed to the understanding of the mechanisms by which properdin contributes to promoting or preventing disease pathology. This review mainly focusses on the multifaceted roles of properdin in inflammation and diseases, and how understanding these roles is contributing to the development of new disease therapies.
Topics: Animals; Complement Activation; Complement Pathway, Alternative; Humans; Inflammation; Mice; Properdin
PubMed: 29954621
DOI: 10.1016/j.molimm.2018.05.018 -
Frontiers in Immunology 2018The complement is the first line of immune defense system involved in elimination of invading pathogens and dying host cells. Its activation is mainly triggered by... (Review)
Review
The complement is the first line of immune defense system involved in elimination of invading pathogens and dying host cells. Its activation is mainly triggered by immune complexes or pattern recognition molecules (PRMs) upon recognition against non-self or altered self-cells, such as C1q, collectins, ficolins, and properdin. Recent findings have interestingly shown that the pentraxins (C-reactive protein, CRP; serum-amyloid P component, SAP; long pentraxin 3, PTX3) are involved in complement activation and amplification via communication with complement initiation PRMs, but also complement regulation via recruitment of complement regulators, for instance C4b binding protein (C4BP) and factor H (fH). This review addresses the potential roles of the pentraxins in the complement system during infection and inflammation, and emphasizes the underlining implications of the pentraxins in the context of complement activation and regulation both under physiological and pathological conditions.
Topics: Animals; C-Reactive Protein; Complement Activation; Complement C4b-Binding Protein; Complement Factor H; Disease Models, Animal; Humans; Infections; Inflammation; Receptors, Pattern Recognition; Serum Amyloid P-Component
PubMed: 30619374
DOI: 10.3389/fimmu.2018.03046 -
Immunological Reviews Nov 2016The complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of... (Review)
Review
The complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate and positively regulate alternative pathway activity. Properdin is produced by many different leukocyte subsets and circulates as cyclic oligomers of monomeric subunits. While the formation of non-physiological aggregates in purified properdin preparations and the presence of potential properdin inhibitors in serum have complicated studies of its function, properdin has, regardless, emerged as a key player in various inflammatory disease models. Here, we review basic properdin biology, emphasizing the major hurdles that have complicated the interpretation of results from properdin-centered studies. In addition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potential utility of properdin inhibitors as long-term therapeutic options to treat diseases marked by increased formation of platelet/granulocyte aggregates. Finally, we describe the interplay between properdin and the alternative pathway negative regulator, Factor H, and how aiming to understand these interactions can provide scientists with the most effective ways to manipulate alternative pathway activation in complex systems.
Topics: Animals; Complement Factor H; Complement Pathway, Alternative; Humans; Immunomodulation; Inflammation; Molecular Targeted Therapy; Platelet Aggregation; Properdin; Thrombosis
PubMed: 27782331
DOI: 10.1111/imr.12466 -
International Journal of Molecular... Sep 2021Thalassemia, a chronic disease with chronic anemia, is caused by mutations in the β-globin gene, leading to reduced levels or complete deficiency of β-globin chain... (Review)
Review
Thalassemia, a chronic disease with chronic anemia, is caused by mutations in the β-globin gene, leading to reduced levels or complete deficiency of β-globin chain synthesis. Patients with β-thalassemia display variable clinical severity which ranges from asymptomatic features to severe transfusion-dependent anemia and complications in multiple organs. They not only are at increased risk of blood-borne infections resulting from multiple transfusions, but they also show enhanced susceptibility to infections as a consequence of coexistent immune deficiency. Enhanced susceptibility to infections in β-thalassemia patients is associated with the interplay of several complex biological processes. β-thalassemia-related abnormalities of the innate immune system include decreased levels of complement, properdin, and lysozyme, reduced absorption and phagocytic ability of polymorphonuclear neutrophils, disturbed chemotaxis, and altered intracellular metabolism processes. According to available literature data, immunological abnormalities observed in patients with thalassemia can be caused by both the disease itself as well as therapies. The most important factors promoting such alterations involve iron overload, phenotypical and functional abnormalities of immune system cells resulting from chronic inflammation oxidative stress, multiple blood transfusion, iron chelation therapy, and splenectomy. Unravelling the mechanisms underlying immune deficiency in β-thalassemia patients may enable the designing of appropriate therapies for this group of patients.
Topics: Adaptive Immunity; Biomarkers; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Immune System; Immunity, Innate; beta-Thalassemia
PubMed: 34575839
DOI: 10.3390/ijms22189677 -
Cells Aug 2023Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than...
INTRODUCTION
Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than inherently due to PCOS. We directly compared complement factors from an obese, insulin-resistant PCOS population to a nonobese, non-insulin-resistant PCOS population in a proteomic analysis to investigate this.
METHODS
Plasma was collected from 234 women (137 with PCOS and 97 controls) from a biobank cohort and compared to a nonobese, non-insulin-resistant population (24 with PCOS and 24 controls). Slow off-rate modified aptamer (SOMA) scan plasma protein measurement was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, Mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5).
RESULTS
The alternative pathway of the complement system was overexpressed in both obese and nonobese PCOS, with increased C3 ( < 0.05) and properdin ( < 0.01); additionally, factor B increased in obese PCOS ( < 0.01). For inhibitors of this pathway, factor I was increased ( < 0.01) in both slim and obese PCOS, with an increase in CFHR5 and factor H in obese PCOS ( < 0.01). Complement factors iC3b, C3d and C5a, associated with an enhanced B cell response and inflammatory cytokine release, were increased in both slim and obese PCOS ( < 0.05). C3a and its product, C3adesArg, were both significantly elevated in nonobese PCOS (<0.01) but not altered in obese PCOS. Hyperandrogenemia correlated positively with properdin and iC3b in obese PCOS ( < 0.05) but not in nonobese PCOS. There was no association with insulin resistance. BMI correlated positively in both groups with factor B, factor H and C5a. Additionally, in obese PCOS, BMI correlated with C3d, factor D, factor I, CFHR5 and C5a ( < 0.05), and in nonobese PCOS, BMI correlated with properdin, iC3b, C3, C3adesArg, C3a, C4, C5, C5a and C1q. In obese controls, BMI correlated with C3, C3desArg, C3a, C3d, C4, factor I, factor B, C5a and C5, whilst in nonobese controls, BMI only correlated negatively with C1q. Comparison of nonobese and obese PCOS showed that properdin, C3b, iC3b, C4A, factor D, factor H and MBL differed.
CONCLUSION
The upregulation of the alternative complement pathway was seen in nonobese PCOS and was further exacerbated in obese PCOS, indicating that this is an inherent feature of the pathophysiology of PCOS that is worsened by obesity and is reflected in the differences between the nonobese and obese PCOS phenotypes. However, the increase in the complement proteins associated with activation was counterbalanced by upregulation of complement inhibitors; this was evident in both PCOS groups, suggesting that insults, such as a cardiovascular event or infection, that cause activation of complement pathways may be amplified in PCOS.
PubMed: 37566081
DOI: 10.3390/cells12152002 -
Molecular Immunology Dec 2013The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement... (Review)
Review
The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement activation at the time of its discovery more than a half century ago, the role and mechanism of action of properdin in the complement cascade has undergone significant conceptual evolution since then. Despite the long history of research on properdin, however, new insight and unexpected findings on the role of properdin in complement activation, pathogen infection and host tissue injury are still being revealed by ongoing investigations. In this article, we provide a brief review on recent studies that shed new light on properdin biology, focusing on the following three topics: (1) its role as a pattern recognition molecule to direct and trigger complement activation, (2) its context-dependent requirement in complement activation on foreign and host cell surfaces, and (3) its involvement in alternative pathway complement-mediated immune disorders and considerations of properdin as a potential therapeutic target in human diseases.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Complement Activation; Complement Pathway, Alternative; Complement System Proteins; Humans; Properdin
PubMed: 23816404
DOI: 10.1016/j.molimm.2013.06.002 -
Research and Practice in Thrombosis and... May 2022Evidence of crosstalk between the complement and coagulation cascades exists, and dysregulation of either pathway can lead to serious thromboinflammatory events. Both...
BACKGROUND
Evidence of crosstalk between the complement and coagulation cascades exists, and dysregulation of either pathway can lead to serious thromboinflammatory events. Both the intrinsic pathway of coagulation and the alternative pathway of complement interact with anionic surfaces, such as glycosaminoglycans. Hitherto, there is no evidence for a direct interaction of properdin (factor P [FP]), the only known positive regulator of complement, with coagulation factor XI (FXI) or activated FXI (FXIa).
OBJECTIVES
The aim was to investigate crosstalk between FP and the intrinsic pathway and the potential downstream consequences.
METHODS
Chromogenic assays were established to characterize autoactivation of FXI in the presence of dextran sulfate (DXS), enzyme kinetics of FXIa, and the downstream effects of FP on intrinsic pathway activity. Substrate specificity changes were investigated using SDS-PAGE and liquid chromatography-mass spectrometry (LC-MS). Surface plasmon resonance (SPR) was used to determine direct binding between FP and FXIa.
RESULTS/CONCLUSIONS
We identified a novel interaction of FP with FXIa resulting in functional consequences. FP reduces activity of autoactivated FXIa toward S-2288. FXIa can cleave FP in the presence of DXS, demonstrated using SDS-PAGE, and confirmed by LC-MS. FXIa can cleave factor IX (FIX) and FP in the presence of DXS, determined by SDS-PAGE. DXS alone modulates FXIa activity, and this effect is further modulated by FP. We demonstrate that FXI and FXIa bind to FP with high affinity. Furthermore, FX activation downstream of FXIa cleavage of FIX is modulated by FP. These findings suggest a novel intercommunication between complement and coagulation pathways.
PubMed: 35647477
DOI: 10.1002/rth2.12715 -
Frontiers in Immunology 2019Ocular inflammation is a defining feature of sight threating diseases and its dysregulation can catalyze and or propagate ocular neurodegenerative maladies such as... (Review)
Review
Ocular inflammation is a defining feature of sight threating diseases and its dysregulation can catalyze and or propagate ocular neurodegenerative maladies such as age-related macular degeneration (AMD). The complement system, an intrinsic component of the innate immunity, has an integral role in maintaining immune-surveillance and homeostasis in the ocular microenvironment; however, overstimulation can drive ocular inflammatory diseases. The mechanism for complement disease propagation in AMD is not fully understood, although there is accumulating evidence showing that targeted modulation of complement-specific proteins has the potential to become a viable therapeutic approach. To date, a major focus of complement therapeutics has been on targeting the alternative complement system in AMD. Recent studies have outlined potential complement cascade inhibitors that might mitigate AMD disease progression. First-in-class complement inhibitors target the modulation of complement proteins C3, C5, factor B, factor D, and properdin. Herein, we will summarize ocular inflammation in the context of AMD disease progression, current clinical outcomes and complications of complement-mediated therapeutics. Given the need for additional therapeutic approaches for ocular inflammatory diseases, targeted complement modulation has emerged as a leading candidate for eliminating inflammation-driven ocular maladies.
Topics: Animals; CD59 Antigens; Complement Activation; Complement C3; Complement C5; Complement Factor D; Humans; Immunity, Innate; Inflammation; Macular Degeneration; Molecular Targeted Therapy; Properdin
PubMed: 31156618
DOI: 10.3389/fimmu.2019.01007 -
Seminars in Immunology Apr 2016The innate immune system comprises both a cellular and a humoral arm. Neutrophils are key effector cells of the immune and inflammatory responses and have emerged as a... (Review)
Review
The innate immune system comprises both a cellular and a humoral arm. Neutrophils are key effector cells of the immune and inflammatory responses and have emerged as a major source of humoral pattern recognition molecules (PRMs). These molecules, which include collectins, ficolins, and pentraxins, are specialised in the discrimination of self versus non-self and modified-self and share basic multifunctional properties including recognition and opsonisation of pathogens and apoptotic cells, activation and regulation of the complement cascade and tuning of inflammation. Neutrophils act as a reservoir of ready-made soluble PRMs, such as the long pentraxin PTX3, the peptidoglycan recognition protein PGRP-S, properdin and M-ficolin, which are stored in neutrophil granules and are involved in neutrophil effector functions. In addition, other soluble PRMs, such as members of the collectin family, are not expressed in neutrophils but can modulate neutrophil-dependent immune responses. Therefore, soluble PRMs are an essential part of the innate immune response and retain antibody-like effector functions. Here, we will review the expression and general function of soluble PRMs, focusing our attention on molecules involved in neutrophil effector functions.
Topics: Animals; Biomarkers; Gene Expression Regulation; Humans; Immunity, Humoral; Immunity, Innate; Ligands; Neutrophil Activation; Neutrophils; Protein Binding; Receptors, Pattern Recognition; Signal Transduction
PubMed: 27021644
DOI: 10.1016/j.smim.2016.03.005