The Role of Complement and Its Receptor in the Elimination of Immune Complexes

Epstein, Franklin H.; Schifferli, Jürg A.; Ng, Y C; Peters, D. K.

doi:10.1056/nejm198608213150805

Cited by 334 publications

(32 citation statements)

References 43 publications

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“…The classic pathway contributes to its protective role in the clearance of apoptotic material and circulating IC [22,62]. In theory, chronic systemic complement inhibition may increase circulating IC and exacerbate disease [34].…”

Section: Studies Of Complement In Experimental Lupus Modelsmentioning

confidence: 99%

Complement in Lupus Nephritis: New Perspectives

2015

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Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder caused by loss of tolerance to self-antigens, the production of autoantibodies and deposition of complement-fixing immune complexes (ICs) in injured tissues. SLE is characterized by a wide range of clinical manifestations and targeted organs, with lupus nephritis being one of the most serious complications. The complement system consists of three pathways and is tightly controlled by a set of regulatory proteins to prevent injudicious complement activation on host tissue. The involvement of the complement system in the pathogenesis of SLE is well accepted; yet, its exact role is still not clear. Summary: Complement plays dual roles in the pathogenesis of SLE. On the one hand, the complement system appears to have protective features in that hereditary homozygous deficiencies of classical pathway components, such as C1q and C4, are associated with an increased risk for SLE. On the other hand, IC-mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathological features that are logical consequences of complement activation. Studies in genetically altered mice have shown that lack of complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF) accelerates the development of experimental lupus nephritis, while treatment with recombinant protein inhibitors, such as Crry-Ig, CR2-Crry, CR2-DAF and CR2-CFH, ameliorates the disease development. Complement-targeted drugs, including soluble complement receptor 1 (TP10), C1 esterase inhibitor and a monoclonal anti-C5 antibody (eculizumab), have been shown to inhibit complement safely, and are now being investigated in a variety of clinical conditions. Key Messages: SLE is an autoimmune disorder which targets multiple systems. Complement is centrally involved and plays dual roles in the pathogenesis of SLE. Studies from experimental lupus models and clinical trials support the use of complement-targeted therapy in the treatment of SLE.

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Section: Studies Of Complement In Experimental Lupus Modelsmentioning

confidence: 99%

Complement in Lupus Nephritis: New Perspectives

2015

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“…These complexes become coated with C3b and subsequently bind to CR1 receptors on erythrocytes. Erythrocytes then carry the immune complexes to the liver and spleen where they are destroyed 72 . The failure to clear immune complexes results in their tissue deposition and complement activation, leading to inflammation and tissue injury.…”

Section: Functions Of the Complement Systemmentioning

confidence: 99%

Complement

Varela

Tomlinson

2015

Hematology/Oncology Clinics of North America

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“…To maintain homeostasis, one important function of RBCs is to trap potentially harmful immune complexes (ICs) in the circulation. Complement receptor type 1 (CR1) on RBCs binds to complement fragment-opsonized ICs and transfers them to mononuclear phagocytes in the liver and spleen (31,32). Circulating ICs have been detected in DHF patient serum during the acute phase (33,34).…”

Section: Mps Demonstrated That Cd235mentioning

confidence: 99%

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Punyadee

Mairiang

Thiemmeca

et al. 2015

J Virol

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Shedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces. Ex vivo analysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1-anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP shedding in vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever. IMPORTANCEDengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care. E ach year, up to 390 million people are infected by dengue virus (DENV), the most significant mosquito-borne virus of the Flaviviridae family, posing serious socioeconomic and health burdens globally (1). Four serotypes of viruses (DENV serotype 1 [DENV-1], DENV-2, DENV-3, and DENV-4) are transmitted to humans by Aedes mosquitoes to establish both endemic and epidemic transmission cycles primarily in tropical and subtropical countries (1). Although the majority of DENV infections in humans are subclinical, a small fraction of infected individuals develops clinical symptoms ranging from a self-...

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The Role of Complement and Its Receptor in the Elimination of Immune Complexes

Cited by 334 publications

References 43 publications

Complement in Lupus Nephritis: New Perspectives

Complement in Lupus Nephritis: New Perspectives

Complement

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

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