Immunopathogenesis of ANCA-Associated Vasculitis

Kronbichler, Andreas; Lee, Keum Hwa; Denicolò, Sara; Choi, Daeun; Lee, Hyojeong; Ahn, Dong-Hyun; Kim, Kang Hyun; Lee, Ji Han; Kim, Hyung-Tae; Hwang, M.; Jung, Sun Wook; Lee, Changjun; Lee, Ho‐June; Sung, Haejune; Lee, Dongkyu; Hwang, Jae-Hyuk; Kim, Sohee; Hwang, Injae; Kim, Do Young; Kim, Hyung Jun; Cho, Geonjae; Cho, Yunryoung; Kim, Dong-Il; Choi, Minje; Park, Junhye; Park, Junseong; Tizaoui, Kalthoum; Li, Han; Smith, Lee; Koyanagi, Ai; Jacob, Louis; Gauckler, Philipp; Smıth, Lee

doi:10.3390/ijms21197319

Cited by 82 publications

(74 citation statements)

References 172 publications

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“…To our knowledge, this is the largest study to date on AAV that reports the systematic histological scoring of tubulointerstitial lesions in MPO-ANCA and PR3-ANCA GN compared to clinical and laboratory findings. Differences between AAV subtypes have been previously described: PR3-AAV is characterized by predominant involvement of the upper respiratory tract, whereas MPO-AAV less frequently affects the lower respiratory tract and the kidneys [ 24 , 25 ]. Both entities present with a similar renal histomorphology, while a reduced number of normal glomeruli and more interstitial fibrosis reflecting chronic damage have been observed in MPO-ANCA GN.…”

Section: Discussionmentioning

confidence: 99%

Systematic Histological Scoring Reveals More Prominent Interstitial Inflammation in Myeloperoxidase-ANCA Compared to Proteinase 3-ANCA Glomerulonephritis

Hakroush

Kluge

Ströbel

et al. 2021

JCM

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Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Kidney involvement is a common and severe complication of ANCA AAV which is observed in a considerable subset of patients, mainly affecting glomeruli. However, tubulointerstitial lesions have also been described in ANCA glomerulonephritis (GN). Therefore, we aim to describe active and chronic tubulointerstitial lesions in ANCA GN subtypes by systematic scoring analogous to the Banff scoring system while also utilizing clinical and laboratory findings. Methods: A total of 49 kidney biopsies with ANCA GN were retrospectively included in a single-center cohort study between 2015–2020. Results: We report that MPO-ANCA GN is associated with more severe deterioration of kidney function independent of systemic markers of AAV disease activity, and is also associated with increased proteinuria in MPO-ANCA GN and a decreased fraction of normal glomeruli. Finally, MPO-ANCA GN showed distinct, active, and chronic tubulointerstitial lesions. Conclusion: New insights into the pathophysiology of both entities, as well as differences in the clinical presentation of MPO- versus PR3-ANCA GN, could potentially pave the way for more precise treatment regimens. Therefore, it is important to understand the differences in histopathological presentation, especially in yet underestimated active tubulointerstitial lesions of ANCA GN subtypes. This research could further improve our understanding of distinct pathophysiological mechanisms.

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Section: Discussionmentioning

confidence: 99%

Systematic Histological Scoring Reveals More Prominent Interstitial Inflammation in Myeloperoxidase-ANCA Compared to Proteinase 3-ANCA Glomerulonephritis

Hakroush

Kluge

Ströbel

et al. 2021

JCM

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“…Although the dysregulation of both the innate and adaptive immune systems is broadly observed and is thought to play a crucial role in AAV pathogenesis, neutrophils are traditionally regarded as major effector cells at the initial stage of AAV development (21,22). Upon inflammatory stimuli, neutrophils are primed and in vivo 35: 1761-1768 (2021) activated by ANCAs, which are responsible for the induction and maintenance of vascular inflammation (23). Interestingly, ANCAs also induce the release of neutrophil extracellular traps (NETs), which are now increasingly recognized to play an essential pathogenic role in AAV (21).…”

Section: Discussionmentioning

confidence: 99%

Association Between Serum Alarmin Levels and Disease-specific Indices in Patients With Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis

Ahn¹,

Yoon²,

Song³

et al. 2021

In Vivo

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Background/Aim: We evaluated the relationship between serum alarmin levels and disease-specific indices in patients with anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitis (AAV). Patients and Methods: Sera and data from 79 patients were utilized. For AAV-specific indices, Birmingham vasculitis activity score (BVAS), five-factor score (FFS), and vasculitis damage index (VDI) were collected and serum levels of four alarmins (hepatoma-derived growth factor, high mobility group box protein 1, S100A9, and S100A12) were measured using enzyme-linked immunosorbent assay. Associations between alarmin levels, AAV-specific indices, and inflammatory laboratory markers were assessed. Results: S100A9 levels were significantly correlated with Creactive protein levels (r=0.316, p=0.005) and S100A12 levels correlated with VDI (r=0.232, p=0.040), which was consistent in a subgroup of patients with myeloperoxidase (perinuclear)-ANCA positivity. No other associations were found between alarmin levels and BVAS, FFS, and VDI. Conclusion: The serum S100A12 level was associated with organ damage in AAV, especially in myeloperoxidase (perinuclear)-ANCApositive patients.Alarmins, often used interchangeably with the term 'damageassociated molecular patterns' are defined as an endogenous group of molecules that are released due to cellular injury or damage (1). First described as damage-associated molecular patterns in 2004 by Seong et al., alarmins are expressed constitutively in various cells and are thought to play a critical role in cellular regeneration and remodeling (2). Alarmins may also act as potent mediators of inflammation by promoting chemotaxis and inducing the expression of proteins implicated in immune activation when they are secreted extracellularly (3). Mechanistically, secreted alarmins bind to pattern recognition receptors, i.e. Toll-like receptors and receptors for advanced glycation end-products, to elicit their physiological effects. Dysregulation of this signaling can trigger aberrant immune responses (4, 5). Previous studies have indicated that among the alarmins, hepatoma-derived growth factor (HDGF), high mobility group box protein 1 (HMGB1), and S100 proteins can play important roles in autoimmunity (6-8).Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune condition that belongs to a group of primary systemic vasculitides. A typical pathological feature of AAV is the presence of necrotizing inflammation in small-sized vessels, such as intraparenchymal arteries, arterioles, capillaries, and venules, and various organ involvement may be present in AAV (9). AAV comprises three distinct diseases: Microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. These diseases can be differentiated according to their clinicopathological and laboratory findings of ANCA serology. As mentioned above, based on the crucial role of alarmins in the immune system, several previous studies have demonstrated that the...

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“…Antibodies to self-antigens produced in autoimmune diseases can be used as biomarkers. For example, in vasculitis, the number of antibodies to myeloperoxidase and proteinase 3 in neutrophils was clinically tested [ 95 , 96 ]. In SLE, the number of antibodies to double-stranded DNA and small nuclear ribonucleoprotein in the nucleus has also been clinically tested [ 97 , 98 ].…”

Section: Target Discovery Using Phage Display Technologymentioning

confidence: 99%

Phage Display Technology as a Powerful Platform for Antibody Drug Discovery

Nagano

Tsutsumi

2021

Viruses

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Antibody drugs with a high affinity and specificity are effective and safe for intractable diseases, such as cancers and autoimmune diseases. Furthermore, they have played a central role in drug discovery, currently accounting for eight of the top 20 pharmaceutical products worldwide by sales. Forty years ago, clinical trials on antibody drugs that were thought to be a magic bullet failed, partly due to the immunogenicity of monoclonal antibodies produced in mice. The recent breakthrough in antibody drugs is largely because of the contribution of phage display technology. Here, we reviewed the importance of phage display technology as a powerful platform for antibody drug discovery from various perspectives, such as the development of human monoclonal antibodies, affinity enhancement of monoclonal antibodies, and the identification of therapeutic targets for antibody drugs.

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Immunopathogenesis of ANCA-Associated Vasculitis

Cited by 82 publications

References 172 publications

Systematic Histological Scoring Reveals More Prominent Interstitial Inflammation in Myeloperoxidase-ANCA Compared to Proteinase 3-ANCA Glomerulonephritis

Systematic Histological Scoring Reveals More Prominent Interstitial Inflammation in Myeloperoxidase-ANCA Compared to Proteinase 3-ANCA Glomerulonephritis

Association Between Serum Alarmin Levels and Disease-specific Indices in Patients With Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis

Phage Display Technology as a Powerful Platform for Antibody Drug Discovery

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