Prevalence of Anti-Neutrophil Cytoplasmic Antibodies and Associated Vasculitis in COPD Associated With Alpha-1 Antitrypsin Deficiency

Deshayes, Samuel; Silva, Nicolas Martin; Khoy, Kathy; Mariotte, D.; Mornex, Jean‐François; Pison, Christophe; Cuvelier, A.; Balduyck, Malika; Pujazon, M.-C.; Fournier, Michel; Ilalne, Brahim Ait; Thabut, Gabriel; Mal, Hervé; Aouba, A.

doi:10.1016/j.chest.2020.04.054

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…(25,26) However, the mere presence of AAT deficiency did not increase the prevalence of PR3-ANCA and PR3-AAV as observed in patients with AAT deficiency-related chronic obstructive lung disease supporting the importance of the HLA context. (44) Our data might seem paradoxical at first sight, as plasma AAT levels were found to be increased in the vast majority of active PR3-and MPO-AAV patients with only one remission PR3-AAV patient having low AAT plasma levels. AAT is mainly produced by the liver and levels increase with the acute-phase inflammatory response.…”

Section: Discussioncontrasting

confidence: 68%

“…PR3-AAV associations with SNPs in the SERPINA1 gene that were in linkage disequilibrium with the z allele were found in GWAS, suggesting a link between AAT levels and disease risk ( 25 , 26 ). However, the mere presence of AAT deficiency did not increase the prevalence of PR3-ANCA and PR3-AAV as observed in patients with AAT deficiency–related chronic obstructive lung disease supporting the importance of the HLA context ( 44 ). Our data might seem paradoxical at first, as plasma AAT levels were found to be increased in the vast majority of patients with active PR3- and MPO-AAV, with only 1 patient with remission PR3-AAV with low AAT plasma levels.…”

Section: Discussionmentioning

confidence: 72%

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Protective α1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation

Ebert¹,

Jerke²,

Eulenberg-Gustavus³

et al. 2022

Journal of Clinical Investigation

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Background. Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCA directed against proteinase 3 (PR3) or myeloperoxidase (MPO) bind their cell surfacepresented antigen, activate neutrophils and cause vasculitis. An imbalance between PR3 and its major inhibitor 1-antitrypsin (AAT) was proposed to underlie PR3-but not MPO-AAV. We measured AAT and PR3 in healthies and AAV patients and studied protective AAT effects pertaining to PR3-and MPO-ANCA. Methods.Plasma and blood neutrophils were assessed for PR3 and AAT. Wild-type, mutant, and oxidation-resistant AAT species were produced to characterize AAT-PR3 interactions by flow cytometry, immunoblotting, FRET assays, and surface plasmon resonance measurements. Neutrophil activation was measured using the ferricytochrome C assay and AAT methionine-oxidation by Parallel Reaction Monitoring.Results. We found significantly increased PR3 and AAT pools in both PR3-and MPO-AAV patients, however, only in PR3-AAV did the PR3 pool correlate with ANCA titer, inflammatory response and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, thereby reducing neutrophil surface antigen for ligation by PR3-ANCA. Active PR3-AAV patients showed critical methionine-oxidation in plasma AAT that was recapitulated by ANCA-activated neutrophils. The protective PR3-related AAT effects were compromised by methionine-oxidation in the AAT reactive center loop but preserved when two critical methionines were substituted by valine and leucine. Conclusion.Pathogenic differences between PR3-and MPO-AAV are related to AAT regulation of membrane-PR3, attenuating neutrophil activation by PR3-rather than MPO-ANCA. Oxidation-resistant AAT could serve as adjunctive therapy in PR3-AAV.

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Section: Discussioncontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 72%

Protective α1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation

Ebert¹,

Jerke²,

Eulenberg-Gustavus³

et al. 2022

Journal of Clinical Investigation

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“…Case reports of adults with AATD have indicated a possible relationship with cutaneous or systemic vasculitis and neutrophilic panniculitis (107,108). The estimated prevalence of neutrophilic panniculitis is 0.1-0.9% in patients with AATD; these are most commonly white individuals with a Pi*ZZ genotype.…”

Section: Alpha-1 Antitrypsin Deficiencymentioning

confidence: 99%

Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease

Chalmers,

Kettritz,

Korkmaz

2023

Front. Immunol.

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Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil serine proteases (NSPs), primarily neutrophil elastase, proteinase 3, cathepsin G, and NSP4, which have essential functions in immune modulation and tissue repair following injury. Normally, NSP activity is controlled and modulated by endogenous antiproteases. However, disruption of this homeostatic relationship can cause diseases in which neutrophilic inflammation is central to the pathology, such as chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, bronchiectasis, and cystic fibrosis, as well as many non-pulmonary pathologies. Although the pathobiology of these diseases varies, evidence indicates that excessive NSP activity is common and a principal mediator of tissue damage and clinical decline. NSPs are synthesized as inactive zymogens and activated primarily by the ubiquitous enzyme dipeptidyl peptidase 1, also known as cathepsin C. Preclinical data confirm that inactivation of this protease reduces activation of NSPs. Thus, pharmacological inhibition of dipeptidyl peptidase 1 potentially reduces the contribution of aberrant NSP activity to the severity and/or progression of multiple inflammatory diseases. Initial clinical data support this view. Ongoing research continues to explore the role of NSP activation by dipeptidyl peptidase 1 in different disease states and the potential clinical benefits of dipeptidyl peptidase 1 inhibition.

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“… 43 The clinical significance of AAV in AATD is difficult to determine due to the low prevalence of AAV in patients with severe AATD genotypes; at least in one small study, the presence of AATD does not seem to expose patients to an increased risk of AAV. 44 Further research is required to assess the need for augmentation therapy in individuals with AAV associated with AATD.…”

Section: Other Disease Manifestations In Aatdmentioning

confidence: 99%

The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency

Tejwani

Stoller

2021

Therapeutic Advances in Chronic Disease

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Alpha-1 antitrypsin (AAT) deficiency (AATD) is an autosomal co-dominant condition that predisposes to the development of lung disease, primarily emphysema. Emphysema results from the breakdown of lung matrix elastin by proteases, including neutrophil elastase, a protease normally inhibited by AAT. AATD also predisposes to liver (cirrhosis) and skin (panniculitis) disease, and to vasculitis. The prevalence of AATD is estimated to be approximately 1 in 3,500 individuals in the United States. However, lack of awareness of AATD among some physicians, misperceptions regarding the absence of effective therapy, and the close overlap in symptoms with asthma and non-AATD chronic obstructive pulmonary disease are thought to contribute to under-recognition of the disease. In patients with AATD, treatment with intravenous AAT augmentation therapy is the only currently available treatment known to slow the progression of emphysema. Moreover, smoking cessation and other lifestyle interventions also help improve outcomes. Early diagnosis and intervention are of key importance due to the irreversible nature of the resultant emphysema. Liver disease is the second leading cause of death among patients with AATD and a minority of patients present with panniculitis or antineutrophil cytoplasmic antibody-associated vasculitis, thought to be directly related to AATD. Though no randomized trial has assessed the effectiveness of augmentation therapy for AATD-associated panniculitis, clinical experience and case series suggest there is a benefit. Other diseases putatively linked to AATD include aneurysmal disease and multiple neurological conditions, although these associations remain speculative in nature.

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Prevalence of Anti-Neutrophil Cytoplasmic Antibodies and Associated Vasculitis in COPD Associated With Alpha-1 Antitrypsin Deficiency

Cited by 6 publications

References 10 publications

Protective α1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation

Protective α1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation

Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease

The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency

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