Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: Two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis

doi:10.1016/0272-6386(95)90489-1

American Journal of Kidney Diseases

Volume 26, Issue 3, September 1995, Pages 439-445

https://doi.org/10.1016/0272-6386(95)90489-1 Get rights and content

Abstract

Circulating autoantibodies against the Goodpasture antigen (α3 chain of type IV collagen) in the glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasm antibodies (ANCA) are each associated clinically with the development of a rapidly progressive glomerulonephritis. Antibodies with both these specificities coexist in a subset of patients, raising the possibility that they might be a result of cross-reactivity. In this study we have shown that 21% of patients with anti-GBM antibodies also had ANCA, and by using cross-inhibition assays, antigen-specific enzyme-linked immunosorbent assays, and Western blot analysis, these were shown to be two distinct populations of autoantibodies. In patients with both specificities, a greater proportion of the ANCA had specificity for myeloperoxidase (73.5%) than in patients with ANCA alone (36.6%). The presence of ANCA should be ascertained in all patients with anti-GBM disease as the prognosis for these double-positive patients may be dependent on both populations of antibodies.

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Cited by (95)

Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis
2024, Autoimmunity Reviews
Anti-glomerular basement membrane (GBM) disease is a small-vessel vasculitis that represents the most aggressive form of autoimmune glomerulonephritis. The study aimed to investigate the prevalence, clinical characteristics, risk factors, and outcomes of anti-GBM disease through a systematic review and meta-analysis involving 47 studies with 2830 patients. The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per million population per annum. In rapidly progressive glomerulonephritis and crescentic glomerulonephritis, the pooled incidence rates were 8.0% and 12.8%, respectively. The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively. Patients with combined ANCA positivity demonstrated a prognosis comparable to those patients with only anti-GBM antibodies, though with differing clinical features. The pooled one-year patient and kidney survival rates were 76.2% and 30.2%, respectively. Kidney function on diagnosis and normal glomeruli percentage were identified as strong prognostic factors. This study represents the first comprehensive meta-analysis on anti-GBM disease, providing insights into its management. However, caution is warranted in interpreting some results due to the observational nature of the included studies and high heterogeneity.
ANCA and anti-glomerular basement membrane double-positive patients: A systematic review of the literature
2021, Autoimmunity Reviews
Double-positive patients (DPP) exhibiting anti-glomerular basement membrane (GBM) and anti-neutrophil cytoplasmic antibodies (ANCAs) belong to an entity that is newly and poorly described, mainly in short series. We aimed to better characterize the epidemiological features, clinical presentation and therapeutic outcomes of these patients through a systematic review.
We performed a systematic review of English-, German-, Spanish- and French-written publications from February 1987 to March 2020 reporting cases of DPP using the following databases: PubMed, Scielo, ScienceDirect, Google Scholar, The Cochrane Library, Open Grey, The Grey Literature Report, Clinicaltrials.gov and International Clinical Trial Registry Platform of the World Health Organization.
In total, 538 DPP were identified from 90 articles. Their clinical presentations were often severe, and the majority exhibited acute kidney failure (91.8%) with a median initial serum creatinine level of 873 μmol/L; 50.7% had alveolar haemorrhage. Other manifestations were present in 30.3% of DPP, mainly ear, nose, throat and articular manifestations. ANCAs were predominantly directed against MPO (n = 377/523; 72.1%) compared to PR3 (n = 107/523; 20.5%), with rare cases of triple positivity (n = 15/538; 2.9%). Although most patients received initial immunosuppressive therapy (n = 285/317; 89.9%), the one-year overall, renal and relapse-free survival rates were 64.8%, 38.7% and 71.1%, respectively.
DPP are associated with the characteristics of two eponymous vasculitis types, responsible for a poor overall and renal prognosis. Thus, simultaneous testing of both antibodies and systematic renal biopsy should be recommended in every patient with rapidly progressive glomerulonephritis to recognize this difficult-to-treat and rare disease.
The biology, pathogenetic role, clinical implications, and open issues of serum anti-neutrophil cytoplasmic antibodies
2021, Autoimmunity Reviews
Citation Excerpt :
During an immune response against a target pathogen, antibodies may be produced against different epitopes of the same antigen and even against more than one antigen [37,38]. Of note, epitope spreading may also underlie the frequent association of ANCA with anti-Glomerular Basement Membrane autoantibodies (anti-GBM) [39,40]. Intramolecular (i.e. shift from linear to conformational epitopes recognition of the same molecule) and intermolecular epitope spreading (i.e. recognition of epitopes on autoantigens different from the original one) were hypothesized to allow the development of ANCA and anti-GBM from a common unknown origin [41].
Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.
ANCA and anti-MBG double-positive vasculitis: An update on the clinical and therapeutic specificities and comparison with the two eponymous vasculitis
2020, Revue de Medecine Interne
La vascularite dite double-positive anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA) et anti-membrane basale glomérulaire (anti-MBG) est une entité rare de vascularites systémiques cumulant la présence d’ANCA et d’anticorps anti-MBG. L’agrégation progressive des données cliniques et thérapeutiques montre l’intérêt de rechercher et différencier cette entité des deux vascularites respectivement associées à la présence isolée de chacun de ces deux anticorps. En effet, la vascularite double-positive ANCA et anti-MBG semble associer les caractéristiques, d’une part de la démographie et de l’extension clinique extra-rénale et pulmonaire des vascularites à ANCA, et d’autre part de l’histologie et du pronostic rénal sévère des vascularites anti-MBG, cette dernière atteinte étant la seule constamment observée. Cette mise au point a pour objectif de décrire les caractéristiques épidémiologiques, clinico-biologiques, histologiques et pronostiques de cette entité, et ce à la lumière de la littérature récente et des changements thérapeutiques en cours dans les deux vascularites éponymes.
Double-positive vasculitis with anti-polynuclear cytoplasm (ANCA) and anti-glomerular basement membrane (GBM) antibodies is a rare entity of systemic vasculitis defined by the presence of ANCA and anti-GBM antibodies. The gradual accumulation of clinical and therapeutic data shows the usefulness of identifying and differentiating this entity from the two vasculitis respectively associated with the isolated presence of each of these two antibodies. Indeed, the double-positive ANCA and anti-GBM vasculitis appears to associate the characteristics of the demography and the extra-renal and pulmonary involvement of the ANCA-associated vasculitis on the one hand, and of the histological type and severe renal prognosis of the anti-MBG vasculitis on the other hand, with the renal involvement which is the only involvement consistently observed in double-positive vasculitis. The aim of this focus is to describe the epidemiological, clinico-biological, histological and prognostic characteristics of this entity, in light of recent literature and ongoing therapeutic changes in the two eponymous vasculitis.
Anti–Glomerular Basement Membrane Disease
2018, Rheumatic Disease Clinics of North America
Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients
2017, Kidney International
Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such ‘double-positive’ cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies.

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^☆: Dr Short is supported by an MRC Training Fellowship; Dr Lockwood is funded by the Wellcome Trust.

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Original investigationAnti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: Two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis☆

Abstract

Lancet

Kidney Int

Lancet

Kidney Int

Lancet

Kidney Int

Methods Enzymol

J Immunol Methods

Kidney Int

The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis

J Exp Med

Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis

N Engl J Med

Antibodies to neutrophil granulocyte myeloperoxidase and elastase: Autoimmune responses in glomerulonephritis due to hydralazine treatment

J Intern Med

Identification of apparent dual ANCA specificities in a subset of patients with systemic vasculitis and crescentic glomerulonephritis

Adv Exp Med Biol

Presence of anticardiolipin antibodies (ACA) discriminates between Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA)

Adv Exp Med Biol

Original investigation
Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: Two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis☆