Emerging concepts in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis

Flint, Shaun; McKinney, Eoín; Smith, Kenneth G. C.

doi:10.1097/bor.0000000000000145

Cited by 23 publications

(12 citation statements)

References 60 publications

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“…The three most clinically prominent vasculitis forms of this type are granulomatosis with polyangitis, and eosinophilic granulomatosis with polyangitis (EGPA) and microscopic polyangitis. Autoantibodies against neutrophils, also known as ANCAs, have also been detected in the perinuclear region staining [ 207 ].…”

Section: Myeloperoxidase Deficiencymentioning

confidence: 99%

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

2018

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Myeloperoxidase (MPO) belongs to the family of heme-containing peroxidases, produced mostly from polymorphonuclear neutrophils. The active enzyme (150 kDa) is the product of the MPO gene located on long arm of chromosome 17. The primary gene product undergoes several modifications, such as the removal of introns and signal peptides, and leads to the formation of enzymatically inactive glycosylated apoproMPO which complexes with chaperons, producing inactive proMPO by the insertion of a heme moiety. The active enzyme is a homodimer of heavy and light chain protomers. This enzyme is released into the extracellular fluid after oxidative stress and different inflammatory responses. Myeloperoxidase is the only type of peroxidase that uses H2O2 to oxidize several halides and pseudohalides to form different hypohalous acids. So, the antibacterial activities of MPO involve the production of reactive oxygen and reactive nitrogen species. Controlled MPO release at the site of infection is of prime importance for its efficient activities. Any uncontrolled degranulation exaggerates the inflammation and can also lead to tissue damage even in absence of inflammation. Several types of tissue injuries and the pathogenesis of several other major chronic diseases such as rheumatoid arthritis, cardiovascular diseases, liver diseases, diabetes, and cancer have been reported to be linked with MPO-derived oxidants. Thus, the enhanced level of MPO activity is one of the best diagnostic tools of inflammatory and oxidative stress biomarkers among these commonly-occurring diseases.

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Section: Myeloperoxidase Deficiencymentioning

confidence: 99%

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

2018

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“…In addition to neutrophil-derived inflammatory mediators contributing to tissue damage in inflammatory conditions as effector molecules, neutrophil proteins such as proteinase-3 and MPO play a key role in the development of autoimmune AAV, acting as targets (i.e., autoantigens) against which the pathogenic immune response has been generated. MPO is a common autoantigen in AAV, a disease characterised by inflammation of small blood vessels including glomerular capillaries in the kidney and commonly associated with the presence of pathogenic neutrophil-activating MPO-ANCA [ 64 ]. Renal biopsies from vasculitis patients show a prominence of glomerular delayed-type hypersensitivity effectors (T cells, macrophages, and fibrin) and neutrophils, suggesting that cellular immunity, together with MPO-ANCA, plays a significant part in the disease process [ 65 ].…”

Section: Mpo As An Autoantigen In Aavmentioning

confidence: 99%

Neutrophil-Mediated Regulation of Innate and Adaptive Immunity: The Role of Myeloperoxidase

Odobasic

Kitching

Holdsworth

2016

Journal of Immunology Research

156

118

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Neutrophils are no longer seen as leukocytes with a sole function of being the essential first responders in the removal of pathogens at sites of infection. Being armed with numerous pro- and anti-inflammatory mediators, these phagocytes can also contribute to the development of various autoimmune diseases and can positively or negatively regulate the generation of adaptive immune responses. In this review, we will discuss how myeloperoxidase, the most abundant neutrophil granule protein, plays a key role in the various functions of neutrophils in innate and adaptive immunity.

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“…NETs are composed of extracellularly spreading chromatin fibers and neutrophil intracellular granule proteins, such as MPO and PR3 (9). Accumulating evidence indicates that excessive NET formation is involved in the pathogenesis of AAV (10–16). …”

Section: Introductionmentioning

confidence: 99%

The Presence of Anti-Lactoferrin Antibodies in a Subgroup of Eosinophilic Granulomatosis with Polyangiitis Patients and Their Possible Contribution to Enhancement of Neutrophil Extracellular Trap Formation

et al. 2016

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Lactoferrin (Lf) is one of the antigens of antineutrophil cytoplasmic antibodies (ANCA) and functions as an endogenous suppressor of neutrophil extracellular trap (NET) formation. However, the prevalence and pathogenicity of anti-lactoferrin antibodies (aLf) in ANCA-associated vasculitis (AAV) remain unrevealed. This study aimed to examine the significance of aLf in AAV, initially. Sixty-five sera from AAV patients, including 41 microscopic polyangiitis, 5 granulomatosis with polyangiitis, and 19 eosinophilic granulomatosis with polyangiitis (EGPA) patients, were subjected to aLf detection using enzyme-linked immunosorbent assay. Clinical characteristics were compared between aLf-positive and aLf-negative patients. Neutrophils from healthy donors were exposed to suboptimal dose (10 nM) of phorbol myristate acetate (PMA) with aLf followed by evaluation of NET formation. Results demonstrated that 4 out of 65 AAV sera (6.2%) were positive for aLf. All of them were EGPA sera (4/19, 21.1%). In EGPA, the frequency of renal involvement, serum CRP levels, and Birmingham Vasculitis Activity Score (BVAS) in the aLf-positive patients was significantly higher than those in the aLf-negative patients, and the aLf titer correlated positively with the serum CRP level and BVAS. The NET formation was particularly enhanced by combined stimulation of 10 nM PMA and 1 µg/mL aLf. IgG isolated from sera of the aLf-positive EGPA patients (250 µg/mL) enhanced NET formation induced by 10 nM of PMA, and the effect was abolished completely by absorption of the aLf. This pilot study suggests that aLf enhance NET formation induced by PMA and are associated with disease activity of EGPA.

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Emerging concepts in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis

Abstract: Our current understanding of the pathogenesis of AAV not only reinforces the central role of neutrophils but also provides a sound rationale for B-cell and complement-directed therapies.

Cited by 23 publications

References 60 publications

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

Neutrophil-Mediated Regulation of Innate and Adaptive Immunity: The Role of Myeloperoxidase

The Presence of Anti-Lactoferrin Antibodies in a Subgroup of Eosinophilic Granulomatosis with Polyangiitis Patients and Their Possible Contribution to Enhancement of Neutrophil Extracellular Trap Formation

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