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

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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Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis

Nature Clinical Practice Nephrology ◽

10.1038/ncpneph0347 ◽

2007 ◽

Vol 3 (1) ◽

pp. 50-58 ◽

Cited By ~ 9

Author(s):

Mohammad Vaseemuddin ◽

Melvin M Schwartz ◽

George Dunea ◽

Mark A Kraus

Keyword(s):

Immune Complex ◽

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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