Page 46 - Read Online

Page 10 of 14 Almeida et al. Vessel Plus 2021;5:44 https://dx.doi.org/10.20517/2574-1209.2021.66

[83]
with renal involvement . An increase of Th17 cells and a decrease of Treg cells, along with a downward
trend for IL-2 and IL-4 and an upward one for IL-6, IL-10, TNF-α, IFN-γ, and IL-17A, were observed in
[83]
AVV patients .

T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells balance is critical for humoral immune
responses and relevant in autoimmune diseases . AVV patients present increased circulating Tfh cells
[84]
+
+
+
+
(CD4 CXCR5 CD25 CD127 interm-hi ), decreased Tfr cells (CD4 CXCR5 CD25 CD127 lo-interm ), and elevated
−
+
Tfh/Tfr ratios compared with healthy control . Moreover, this study observed a Tfh2/Tfh1 shift and
[84]
[84]
increased plasma IL-21 level associated with AAV and disease activity . This suggests Tfh phenotype as a
promising biomarker for AVV disease activity.
Complement
Alternative complement pathway activation is a fundamental way of developing disease. Gou et al. found
[85]
that urinary levels of Bb, C3a, C5a, and soluble C5b-9 were significantly higher in active disease.
Recently, the role of C5a in ANCA-induced neutrophil activation was shown, relating the generation of C5a
by supernatants from ANCA-stimulated neutrophils with the role of C5a mediated effects via its specific
receptor, allowing neutrophils to generate ROS in response to ANCA . It was demonstrated that the lack
[31]
of C5a receptor induces resistance to ANCA-induced disease, namely experimental anti-MPO vasculitis
with the significant attenuation of the neutrophil glomerular influx and lower albuminuria, showing a
potential therapeutic target in AAV .
[86]
[87]
In the first AAV human study of C5a, Yuan et al. demonstrated higher levels of C5a in patients with
active AAV compared with AAV in remission. Similarly, plasma levels of fragment Bb were significantly
higher in active AAV than in patients in remission or healthy controls. Those levels positively correlated
with the number of crescents on renal histology, vasculitis activity score, and serum inflammatory
markers . More recently, the ADVOCATE study group investigated an C5 receptor inhibitor in patients
[88]
with ANCA-associated vasculitis-avacopan, which proved noninferior but not superior to prednisone taper
with respect to remission at Week 26 and was superior to prednisone taper with respect to sustained
remission at Week 52 . This result represents a role for C5 as a possible biomarker, as described above in
[89]
the pathogenesis of the disease.

Finally, Manenti et al. reported that low serum C3 levels at diagnosis is associated with poorer patient and
[90]
renal outcomes in AAV patients; however, there were no significant association between serological and
pathohistological phenotypes and serum C3 levels.

CONCLUSION
In this review, we discuss an updated understanding of the pathogenesis and novel biomarkers of AAV. The
knowledge gap in the pathophysiology and follow-up of AAV diseases has raised research interest.
Innovations in methodology, such as modern “omics”, and new discoveries from other fields have
incremented the AAV pathogenesis perception. Genetic, epigenetic, and environmental factors
identification, along with the role of neutrophils, other immune cells, and humoral factor contributions,
have now contributed to another milestone in AAV research. However, disease activity monitoring,
treatment, and relapse prediction are not yet effective. Our most recent knowledge on the pathogenesis is
identifying pivotal players in this disease and engendering new biomarkers soon to be studied in clinical
settings. However, the demonstration of either the very high sensitivity or the very high specificity of new
biomarkers has not yet reached clinically relevant outcomes.