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Autoantibodies Against C3b-Functional Consequences and Disease Relevance.

ABSTRACT: The complement component C3 is at the heart of the complement cascade. It is a complex protein, which generates different functional activated fragments (C3a, C3b, iC3b, C3c, C3d). C3b is a constituent of the alternative pathway C3 convertase (C3bBb), binds multiple regulators, and receptors, affecting thus the functioning of the immune system. The activated forms of C3 are a target for autoantibodies. This review focuses on the discovery, disease relevance, and functional consequences of the anti-C3b autoantibodies. They were discovered about 70 years ago and named immunoconglutinins. They were found after infections and considered convalescent factors. At the end of the twentieth century IgG against C3b were found in systemic lupus erythematosus and recently in lupus nephritis, correlating with the disease severity and flare. Cases of C3 glomerulopathy and immune complex glomerulonephritis were also reported. These antibodies recognize epitopes, shared between C3(H2O)/C3b/iC3b/C3c and have overt functional activity. They correlate with low plasmatic C3 levels in patients. In vitro, they increase the activity of the alternative pathway C3 convertase, without being C3 nephritic factors. They perturb the binding of the negative regulators Complement Receptor 1 and Factor H. The clear functional consequences and association with disease severity warrant further studies to establish the link between the anti-C3b autoantibodies and tissue injury. Comparative studies with such antibodies, found in patients with infections, may help to uncover their origin and epitopes specificity. Patients with complement overactivation due to presence of anti-C3b antibodies may benefit from therapeutic targeting of C3.

SUBMITTER: Vasilev VV

PROVIDER: S-EPMC6361862 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Autoantibodies Against C3b-Functional Consequences and Disease Relevance.

Vasilev Vasil V VV Radanova Maria M Lazarov Valentin J VJ Dragon-Durey Marie-Agnes MA Fremeaux-Bacchi Veronique V Roumenina Lubka T LT

Frontiers in immunology 20190129

The complement component C3 is at the heart of the complement cascade. It is a complex protein, which generates different functional activated fragments (C3a, C3b, iC3b, C3c, C3d). C3b is a constituent of the alternative pathway C3 convertase (C3bBb), binds multiple regulators, and receptors, affecting thus the functioning of the immune system. The activated forms of C3 are a target for autoantibodies. This review focuses on the discovery, disease relevance, and functional consequences of the an ...[more]

PMID: 30761135

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Project description:PURPOSE OF REVIEW:Humoral autoimmunity has gained highest interest in neurology and psychiatry. Despite numerous recent articles on this hot topic, however, the biological significance of natural autoantibodies (AB) and the normal autoimmune repertoire of mammals remained quite obscure. AB may contribute to disorder-relevant phenotypes and are even believed to induce diseases themselves, but the circumstances under which AB become pathogenic are not fully understood. This review will focus on the highly frequent AB against the N-methyl-d-aspartate receptor 1 (NMDAR1-AB) as an illustrating example and provide a critical overview of current work (please note that the new nomenclature, GluN1, is disregarded here for consistency with the AB literature). In particular, it will demonstrate how little is known at this point and how many conclusions are drawn based on small numbers of individuals, fragmentary experimental approaches or missing controls. RECENT FINDINGS:NMDAR1-AB were investigated by clinicians world-wide with numerous small studies and case reports appearing yearly. Many publications were on 'anti-NMDAR encephalitis' cases or tried to separate those from other NMDAR1-AB associated conditions. Original exclusivity claims (e.g. electroencephalogram, EEG or functional magnetic resonance imaging, fMRI findings) turned out not to be exclusive for 'anti-NMDAR encephalitis'. Systematic analyses of representative NMDAR1-AB positive sera of all immunoglobulin (Ig) classes showed comparable distribution of different epitopes, often polyspecific/polyclonal, across health and disease. Sophisticated imaging tools provided findings on synapse trafficking changes induced by NMDAR1-AB from psychotic subjects but still lack epitope data to support any claimed disorder link. Persistently high titers of NMDAR1-AB (IgG) in immunized mice with open blood-brain barrier (BBB)-induced psychosis-like symptoms but failed to induce inflammation in the brain. Knowledge on peripheral NMDAR, for example in the immune system, and on potential inducers of NMDAR1-AB is only slowly increasing. SUMMARY:The present knowledge on the (patho) physiological role of NMDAR1-AB is very limited and still characterized by adamant rumors. Much more experimental work and more solid and informative clinical reports, including large numbers of subjects and adequate control groups, follow-up investigations and interdisciplinary approaches will be necessary to obtain a better understanding of the significance of humoral autoimmunity in general (in focus here: NMDAR1-AB) and its disease-relevance in particular.

Project description:Background and objectivesApproximately 20%-30% of patients with anti-glomerular basement membrane disease present coexisting anti-myeloperoxidase (MPO) autoantibodies. We previously showed the recognition of a linear fragment of the MPO heavy chain N-terminus ((1)H, MPO279-409) in plasma from most double-positive patients. Herein, we investigated the frequency of autoantibodies against overlapping (1)H-derived linear peptides in plasma from patients with anti-glomerular basement membrane disease.Design, setting, participants, & measurementsWe synthesized 13 overlapping linear peptides ((1)H-1 to (1)H-13) covering MPO279-409. We retrospectively collected plasma samples from 67 patients with anti-glomerular basement membrane disease from 1996 to 2012, and we screened them for IgG autoantibodies by ELISA using intact human MPO and the overlapping peptides as antigens, and we further investigated the clinical significance. Autoantibody binding to the linear MPO structure was confirmed by Western blotting.ResultsWe followed up the 67 patients until 2015, with a median follow-up time of 10.0 (2.3-36.0) months, and 56 ESRD events occurred among the 67 patients with follow-up data. Plasma from 23.9% (16) of the patients recognized intact human MPO, whereas 62.7% (42) plasma samples recognized MPO279-409 linear peptides. Of the 13 linear peptides, (1)H-4 (44.8%, 30 patients) and (1)H-12 (40.3%, 27 patients) exhibited the highest recognition frequencies. Patients with autoantibodies against (1)H-11 or (1)H-12 (MPO371-400) were older (46.1±18.8 versus 34.1±16.6 years; P<0.01), had higher serum creatinine upon diagnosis (median 7.8 mg/dl, interquartile range 4.9-12.6 mg/dl versus median 5.4 mg/dl, interquartile range 2.4-7.3 mg/dl; P=0.02), and had a higher probability of progressing to ESRD; however, multivariate Cox regression analysis showed that (1)H-11 or 12 reaction was not an independent risk factor for renal failure (hazard ratio, 1.2; 95% confidence interval, 0.8 to 2.8; P=0.19).ConclusionsAutoantibodies against linear peptides of MPO can be detected in the majority of patients with anti-glomerular basement membrane disease, and several are associated with disease severity. The potential common pathogenic mechanism between anti-glomerular basement membrane antibodies and anti-MPO autoantibodies in anti-glomerular basement membrane disease requires further investigation.

Dataset Information

Autoantibodies Against C3b-Functional Consequences and Disease Relevance.

Publications

Autoantibodies Against C3b-Functional Consequences and Disease Relevance.

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