The effect of immune complex composition on complement activation and complement dependent complex release

Abstract We compared the performance of six complement tests: electrophoresis, immunofixation, immunoelectrophoresis, and nephelometric quantifications of C3, C4, and C3d. We used 123 blood samples from 60 control subjects and 63 patients with immune complex diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, rheumatoid arthritis, acquired immunodeficiency syndrome, renal diseases, vasculitis, cryoglobulinemia, Gram-negative bacteremia, Hashimoto's thyroiditis, rheumatic heart disease, malaria, and chronic active hepatitis. Immunofixation and quantification of C3d were better for detecting complement activation, their sensitivity rates (90.5% and 89.3%, respectively) being higher than those of the other tests studied. Immunofixation is a relatively simple and inexpensive test, provides good resolution of protein bands, and yields results that are easily quantified with a densitometer. Nephelometry of C3d provides more rapid and accurate quantitative results than immunofixation, but commercial reagents are not yet available. The causes of false-positive results in complement tests and the mechanisms of complement activation in AIDS are also discussed.

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Immune Complex-Mediated Complement Activation in a Patient with IgG4-Related Tubulointerstitial Nephritis

Case Reports in Nephrology and Urology ◽

10.1159/000330664 ◽

2011 ◽

Vol 1 (1) ◽

pp. 7-14 ◽

Cited By ~ 6

Author(s):

Seiji Nagamachi ◽

Isao Ohsawa ◽

Nobuyuki Sato ◽

Masaya Ishii ◽

Gaku Kusaba ◽

...

Keyword(s):

Immune Complex ◽

Complement Activation ◽

Tubulointerstitial Nephritis

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Immune complex bound C1q enhances complement activation on glomerular endothelial cells

Molecular Immunology ◽

10.1016/j.molimm.2009.05.212 ◽

2009 ◽

Vol 46 (14) ◽

pp. 2827

Author(s):

Roelof Flierman ◽

Ria M.C. Faber-Krol ◽

Simon C. Satchell ◽

Peter W. Mathieson ◽

Cees van Kooten ◽

...

Keyword(s):

Endothelial Cells ◽

Immune Complex ◽

Complement Activation ◽

Glomerular Endothelial Cells

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Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena

European Respiratory Journal ◽

10.1183/13993003.00117-2020 ◽

2020 ◽

Vol 56 (4) ◽

pp. 2000117 ◽

Cited By ~ 7

Author(s):

Manali Mukherjee ◽

David Felipe Forero ◽

Stephanie Tran ◽

Marie-Eve Boulay ◽

Mylène Bertrand ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Immune Complex ◽

Complement Activation ◽

Late Onset ◽

Real Life ◽

Blood Eosinophil ◽

Eosinophilic Asthma ◽

Asthma Control Questionnaire ◽

Number Of Patients ◽

Autoimmune Phenomena

BackgroundIn clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50–60%.ObjectiveTo observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response.MethodsIn four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.ResultsSuboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.ConclusionA significant number of patients who meet currently approved indications for anti-IL5 mAbs show suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.

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The role of Fc:Fc interactions in insoluble immune complex formation and complement activation

Molecular Immunology ◽

10.1016/0161-5890(88)90048-x ◽

1988 ◽

Vol 25 (12) ◽

pp. 1331-1337 ◽

Cited By ~ 20

Author(s):

Simon B. Easterbrook-Smith ◽

Robert J. Vandenberg ◽

John R. Alden

Keyword(s):

Complex Formation ◽

Immune Complex ◽

Complement Activation ◽

Immune Complex Formation

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Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb

Journal of Biological Chemistry ◽

10.1074/jbc.m116.719443 ◽

2016 ◽

Vol 291 (33) ◽

pp. 17122-17132 ◽

Cited By ~ 6

Author(s):

Xueqin Li ◽

Peng Liu ◽

Shuzhen Gan ◽

Chunmao Zhang ◽

Yuling Zheng ◽

...

Keyword(s):

Immune Complex ◽

Complement Activation ◽

Hydrophobic Interactions ◽

Cell Envelope ◽

Alternative Pathway ◽

Streptococcus Suis ◽

Factor H ◽

Immune Recognition ◽

Bacterial Surface ◽

Pathogen Protein

Streptococcus suis serotype 2 (S. suis 2)-induced sepsis and meningitis are often accompanied by bacteremia. The evasion of polymorphonuclear leukocyte-mediated phagocytic clearance is central to the establishment of bacteremia caused by S. suis 2 and is facilitated by the ability of factor H (FH)-binding protein (Fhb) to bind FH on the bacterial surface, thereby impeding alternative pathway complement activation and phagocytic clearance. Here, C3b/C3d was found to bind to Fhb, along with FH, forming a large immune complex. The formation of this immune complex was mediated by domain II of Fhb via electrostatic and hydrophobic interactions, which, to our knowledge, is a new type of interaction. Interestingly, Fhb was found to be associated with the cell envelope and also present in the culture supernatant, where secreted Fhb inhibited complement activation via interactions with domain II, thereby enhancing antiphagocytic clearance by polymorphonuclear leukocytes. Thus, Fhb is a multifunctional bacterial protein, which binds host complement component C3 as well as FH and interferes with innate immune recognition in a secret protein manner. S. suis 2 therefore appears to have developed a new strategy to combat host innate immunity and enhance survival in host blood.

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Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN

Journal of the American Society of Nephrology ◽

10.1681/asn.2017030258 ◽

2017 ◽

Vol 29 (1) ◽

pp. 283-294 ◽

Cited By ~ 27

Author(s):

Paraskevas Iatropoulos ◽

Erica Daina ◽

Manuela Curreri ◽

Rossella Piras ◽

Elisabetta Valoti ◽

...

Keyword(s):

Immune Complex ◽

Complement Activation ◽

Solid Phase ◽

Alternative Pathway ◽

Disease Onset ◽

Simple Algorithm ◽

Fluid Phase ◽

Disease Etiology ◽

High Prevalence ◽

Distinct Disease

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement–mediated C3 glomerulopathy (C3G) and immune complex–mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1–3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.

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