China
Africa
Explore chapters and articles related to this topic
The Acute Phase Complement Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Complement proteins of the classical and alternative pathways and C5 are synthesized in several cell types. Thus, activation of the cascade through C5 can be accomplished by proteins synthesized at the extrahepatic sites without a requirement for liver-derived proteins. The widespread synthesis of the prominent acute phase complement proteins, C3 and factor B, which have been identified in virtually every cell type studied, suggests that this extrahepatic synthesis provides a source of alternative complement proteins for local host defense before the influx of serum proteins. The synthesis of two other alternative complement proteins, factor D and properdin, at extrahepatic sites is consistent with this conept and because of their distribution with novel potential functions unrelated to host defenses. Mononuclear phagocytes provide the single richest extrahepatic source of complement proteins, with synthesis of all the activator and inhibitor proteins in both activation pathways, with the exception of factor H. Fibroblasts are also a source of complement proteins, synthesizing at least seven effectors and inhibitors of the system. The functional importance of this extrahepatic complement production is supported by the elaborate tissue-specific and developmentally regulated controls of complement gene expression now recognized in several species.
Psychometric Testing in Functional GI Disorders
Published in Kevin W. Olden, Handbook of Functional Gastrointestinal Disorders, 2020
Interpretation of the POMS calls for evaluating each of the six mood-state categories. Factor T (tension-anxiety) includes somatic tension, panic, nervousness, and anxiety, and comprises nine items of the POMS. Factor D (depression-dejection) consists of 15 items of the POMS and represents a mood of depression accompanied by a sense of personal inadequacy, worthlessness, futility, emotional isolation, sadness, and guilt. Factor A (anger-hostility) consists of 12 items and indicates a mood of anger and antipathy toward others. It includes both intense overt anger and mild feelings of hostility. Factor V (vigor-activity), consisting of eight items, depicts a mood of vigorousness, ebullience, and high energy. Factor F (fatigue-inertia) represents a mood of weariness, inertia, and low energy. It consists of seven adjectives: worn out, listless, fatigued, exhausted, sluggish, weary, and bushed. Factor C (confusion-bewilderment) consists of seven items: confused, unable to concentrate, muddled, bewildered, inefficient, forgetful, uncertain about things. It is not clear from studies whether this represents a mood or a trait of cognitive inefficiency related to anxiety or other such states that might impair cognitive abilities.
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
Defects in the early classical pathway (C1q, C2, and C4) result in SLE-like symptoms and increased susceptibility to infection with encapsulated bacteria. Deficiencies in late components of the membrane attack complex (C5, C6, C7, C8, and C9) place patients at risk for disseminated Neisseria infections, as does Properdin and factor D deficiencies in the alternative pathway. Deficiencies in the mannose binding lectin pathway include mannose binding lectin serine protease 2 (MASP2) deficiency and Ficolin 3 deficiency. Both result in varying degrees of increased susceptibility to recurrent pyogenic infections. Abnormalities of factor H and factor I result in recurrent atypical hemolytic uremic syndrome. Deficiency in factor H and I results in a secondary fourfold increase in the catabolic rate of C3 complement component. Patients are prone to recurrent pyogenic infections, particularly with encapsulated bacteria such as S. pneumoniae and N. meningitidis. They are also prone to the development of immune complex disease. “Anaphylactoid” reactions secondary to the spontaneous generation of C3a are also frequently observed in these patients.
Investigational drugs in clinical trials for macular degeneration
Published in Expert Opinion on Investigational Drugs, 2022
Michael J Tolentino, Andrew J Tolentino
The complement pathway is a complex interplay of serine proteases that requires activation, amplification and lysis. This pathway involves multiple enzymatic processes. The most critical process is the formation of c3 convertase C3bBb. The alternative pathway is regulated by complement factor H which binds to c3b in order to displace Bb and degrade c3 convertase. This critical step is the ideal target for complement pathway inhibition. Complement factor D is important in producing the Bb portion of C3 convertase. While critical and rate limiting, inhibiting mature factor D may not be enough to reduce factor D adequately. Factor D is produced as a pro-enzyme and requires cleavage of 6-amino acid peptide for maturation. This cleavage is under the control of mannose-binding lectin–associated serine protease-3 which is involved in the lectin complement pathway. To inhibit factor D effectively in the majority of patients, inhibition of both factor D and its proenzyme may be necessary. The other possibility is that Factor D may not play such a critical role in the alternative pathway as thought, and may be more critical for the lectin pathway [91].
Ravulizumab in the treatment of paroxysmal nocturnal hemoglobinuria
Published in Expert Opinion on Orphan Drugs, 2020
Factor B (FB), a trypsin-like serine protease, plays an important role in central amplification of C3b production and circulates as a latent zymogen [38]. During alternative pathway activation, FB first binds to C3b [39]. C3b-FB is then cleaved by Factor D (FD), to C3bBb, a C3 convertase with active catalytic Bb subunit of FB. C3bBb amplifies C3b production, positively feeding into the complement cascade. Another unit of C3b binding to C3 convertase generates C3bBbC3b, a C5 convertase complex, which further generates MAC and C5a anaphylatoxin. Factor B and Factor D inhibitors are promising therapies for complement-mediated conditions. A recent publication by Schubart et al. has demonstrated efficacy in vivo with animal studies and ex vivo with human samples, as indicated by the prevention of hemolysis of PNH erythrocytes [38].
Complement inhibition as a therapeutic strategy in retinal disorders
Published in Expert Opinion on Biological Therapy, 2019
Enoch Kassa, Thomas A. Ciulla, Rehan M. Hussain, Pravin U. Dugel
AMD is a polygenic disease with complex etiology and multiple implicated pathways including abnormalities in inflammation, lipid metabolism, autophagy, angiogenesis, and apoptosis. Within the inflammatory pathway, both the complement system and inflammasomes have been implicated. Furthermore, even if the complement system were the main culprit in the pathogenesis of AMD, it may only play a key role early, prior to apoptosis of retinal cellular elements, and thus the timing of intervention would be crucial. Any of these aforementioned factors may partially account for the failed clinical trials of complement factor D inhibition, and C5 inhibition in GA. Although the phase 2 trial of C3 inhibition for GA is promising, the associated increased rate of choroidal neovascularization is concerning. However, results from the DERBY and OAKS phase 3 clinical trials will not be available for several years.