Clinical complementology: recent progress and future trends

Morgan, B. Paul

doi:10.1111/j.1365-2362.1994.tb01078.x

Cited by 53 publications

(21 citation statements)

References 89 publications

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“…The complement system has been associated with shock syndromes (15). In addition, activation of complement may induce clotting and hence may be implicated in intravascular coagulation, both complications seen in DHF and DSS.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Dengue Virus-Specific Serum Immunoglobulin Classes and Subclasses Correlate with Clinical Outcome of Infection

et al. 2001

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The kinetics of dengue virus (DEN)-specific serum immunoglobulin classes (immunoglobulin M [IgM] andIgA) and subclasses (IgG1 to IgG4) were studied in patients suffering from dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Serum samples from non-DEN febrile patients were included as controls. IgM, IgG1, and IgG3 serum antibodies were the predominant immunoglobulins throughout the course of illness in all three patient groups. In contrast, IgA antibodies were significantly higher in the acute phase in DSS patients compared to those in DF patients (P < 0.05). The levels of IgG1 differed significantly between patients with DF and those with DHF and DSS (P < 0.05). A significant difference was also found in IgG3 levels between DF patients and DHF patients (P < 0.05) but not between DF patients and DSS patients. Finally, levels of IgG4 antibodies differed significantly between DF patients and DSS patients (P < 0.05). Collectively, these data show that increased levels of DEN-specific IgA, IgG1, and IgG4 serum antibodies are risk markers for the development of DHF and DSS and that their measurement may provide valuable guidance for early therapeutic intervention.Dengue virus (DEN) is a mosquito-borne virus belonging to the family Flaviviridae. The four serotypes (DEN 1 to 4) are transmitted to humans through the bite of infected mosquitoes, which mainly belong to the Aedes aegypti and Aedes albopictus species. An estimated 50 million people annually are infected with DEN, and more than 2 billion people are at risk of acquiring DEN infection in tropical and subtropical regions (27). Infection with DEN may either be asymptomatic or be characterized by a variety of clinical manifestations. The majority of dengue patients develop an illness characterized by fever, chills, frontal headache, myalgia, arthralgia, and a rash, symptoms which together form the clinical syndrome of dengue fever (DF). More severe manifestations of the disease are associated with the development of hemorrhagic phenomena with plasma leakage (dengue hemorrhagic fever [DHF]) and shock (dengue shock syndrome [DSS]) (26). DHF and DSS mainly affect young children, accounting for approximately 250,000 deaths annually (18, 26). The above-mentioned features of DEN infection, as well as the fact that the mosquito vectors have a wide distribution in tropical and subtropical areas, have led to the emergence of DEN as one of the most important public health problems worldwide (11).Despite decades of research, the pathogenesis of DEN infection remains poorly understood. Several hypotheses have been formulated to explain the development of DHF and DSS, with antibody-dependent enhancement (ADE) of infection (13, 21) being the most widely accepted. It has also been speculated that viremia plays an important role in the pathogenesis of severe DEN infections; however, it was recently demonstrated that the magnitude and duration of viremia were not significantly different among patients with primary versus secondary DEN infections ...

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Section: Discussionmentioning

confidence: 99%

Kinetics of Dengue Virus-Specific Serum Immunoglobulin Classes and Subclasses Correlate with Clinical Outcome of Infection

et al. 2001

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“…Third, C activation leads to release of anaphylatoxins, which stimulate the release of a large number of inflammatory products. Fourth, the MAC has direct cytolytic properties (6). Last, recent evidence shows that early activation of the C plays a role in shaping the subsequent, adaptive immune response; therefore, it may lead to a more powerful neuroantigen-specific immune response in EAE (33).…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: C3, a Key Component of Complement Activation, Is Not Required for the Development of Myelin Oligodendrocyte Glycoprotein Peptide-Induced Experimental Autoimmune Encephalomyelitis in Mice

Calida¹,

Constantinescu

Purev³

et al. 2001

The Journal of Immunology

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Experimental autoimmune encephalomyelitis (EAE), an inflammatory demyelinating disease of the CNS, is regarded as an experimental model for multiple sclerosis. The complement has been implicated in the pathogenesis of multiple sclerosis. To clarify the role of C in mouse EAE, we immunized mice deficient in C3 (C3−/−) and their wild-type (C3+/+) littermates with myelin oligodendrocyte glycoprotein peptide 35–55. C3−/− mice were susceptible to EAE as much as the C3+/+ mice were. No differences were found for the production of IL-2, IL-4, IL-12, TNF-α, and IFN-γ between C3+/+ and C3−/− mice. This finding shows that C3, a key component in C activation, is not essential in myelin oligodendrocyte glycoprotein peptide-induced EAE in mice.

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“…These proteins inhibit the C3 and C5 convertases (multisubunit proteases) by promoting dissociation of the multisubunit complexes and/or by inactivating the complexes through proteolysis (catalyzed by factor I). Several pharmacological agents that regulate or modulate complement activity have been identified by in vitro assay, but most have been shown to be of low activity or toxic (Johnson, 1977;Reynard, 1980;Kalli et al, 1994;Morgan, 1994).…”

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confidence: 99%

Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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The third component of complement, C3, plays a central role in activation of the classical, alternative, and lectin pathways of complement activation. Recently, we have identified a 13-residue cyclic peptide (named Compstatin) that specifically binds to C3 and inhibits complement activation. To investigate the topology and the contribution of each critical residue to the binding of Compstatin to C3, we have now determined the solution structure using 2D NMR techniques; we have also synthesized substitution analogues and used these to study the structure-function relationships involved. Finally, we have generated an ensemble of a family of solution structures of the peptide with a hybrid distance geometry-restrained simulated-annealing methodology, using distance, dihedral angle, and 3JNH.H,-~o~pling constant restraints. The Compstatin structure contained a type I p-turn comprising the segment GlnS-Asp6-Trp7-Glys. Preference for packing of the hydrophobic side chains of Val3, Val4, and Trp' was observed. The generated structure was also analyzed for consistency using NMR parameters such as NOE connectivity patterns, 3JNH.H,-~o~pling constants, and chemical shifts. Analysis of Ala substitution analogues suggested that Val3, G l d , Asp6, Trp7, and Glys contribute significantly to the inhibitory activity of the peptide. Substitution of Gly' caused a 100-fold decrease in inhibitory potency. In contrast, substitution of Val4, His', His", and Arg" resulted in minimal change in the activity. These findings indicate that specific side-chain interactions and the &turn are critical for preservation of the conformational stability of Compstatin and they might be significant for maintaining the functional activity of Compstatin.The complement system is the first line of immunological defense against foreign pathogens (Muller-Eberhard, 1992). Its activation through the classical, alternative, or lectin pathways leads to the generation of anaphylatoxic peptides C3a and C5a and formation of the C5b-9 membrane attack complex. Complement component C3 plays a central role in activation of all three pathways. Activation of C3 by complement pathway C3 convertases and its subsequent attachment to target surface leads to assembly of the membrane attack complex and ultimately to damage or lysis of the target cells (Frank & Fries, 1991). C3 is unique in that it possesses Reprint requests to:

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Clinical complementology: recent progress and future trends

Cited by 53 publications

References 89 publications

Kinetics of Dengue Virus-Specific Serum Immunoglobulin Classes and Subclasses Correlate with Clinical Outcome of Infection

Kinetics of Dengue Virus-Specific Serum Immunoglobulin Classes and Subclasses Correlate with Clinical Outcome of Infection

Cutting Edge: C3, a Key Component of Complement Activation, Is Not Required for the Development of Myelin Oligodendrocyte Glycoprotein Peptide-Induced Experimental Autoimmune Encephalomyelitis in Mice

Solution structure of Compstatin, a potent complement inhibitor

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