Page 45 - Read Online

Almeida et al. Vessel Plus 2021;5:44 https://dx.doi.org/10.20517/2574-1209.2021.66 Page 9 of 14

EMPs are complex vesicular structures released from activated or apoptotic endothelial cells that play a
singular role in inflammation, coagulation, endothelial function, and angiogenesis. Their dysregulation
disturbs the vascular homeostasis, contributing to the progression of vascular diseases, such as
vasculitis [66,67] . For this reason, research on EMPs identified a positive correlation with disease activity when
compared with patients in remission . These same EMPs may generate excess thrombin and thrombotic
[68]
[69]
[70]
complications, namely in children with systemic vasculitis and cerebral vasculitis of the young .
CECs have also been described as a biomarker of disease activity in vasculitis . These are necrotic, highly
[71]
activated endothelial cells that detach from the vessel wall and positively correlate with vasculitis in adults
and children [67,71] . Upon endothelial lesion, bone marrow-derived endothelial progenitor cells (EPCs)
increase in order to perform endothelial repair. These events have been described to be predictive of early
relapse in adults with AAV, in whom a reduced number of circulating EPCs has been observed .
[72]
Von Willebrand factor (VWF) is yet another biomarker of disease to be confirmed in adult AAV patients.
This plasma protein, synthesized primarily by megakaryocytes and endothelial cells, mediates platelet
aggregation and adhesion. VWF levels increase in response to endothelial injury or activation, and it has
been described as a biomarker of disease activity in childhood CNS vasculitis that was not confirmed in
adults [70,73] .

B cell, T cell, and cytokines
B-cell subset populations have drawn study interest, with data from observational studies suggesting that
incomplete B-cell depletion and B-cell repopulation after rituximab treatment is associated with a
significantly higher relapse rate [74,75] .

[40]
+
B-cell subset populations of interest include regulatory B cells (Bregs), such as CD5 cells . Measurement
of Bregs showed initial promise with a lower CD5 B-cell count correlating with active disease, but a
+
subsequent analysis from the RAVE study found that this count was not predictive of disease relapse,
severity, or treatment failure [76,77] .
In some studies, elevated levels of B-cell activating factor (BAFF) have been found in patients with AAV
active disease, with a corresponding fall after treatment. However, BAFF levels are affected by corticosteroid
treatment, rendering it an inadequate biomarker in AAV .
[78]
T-cell involvement in AAV was previously discussed. CD25 and CD28 T-cell markers were already
correlated with disease activity. CD25 marker on T cells was inversely related to disease activity, however it
+
+
[39]
is not clear if its population reflects a cause or effect of the disease . CD28 T cells are associated with a
high risk of relapse, displaying markers associated with T-cell survival and memory T-cell levels; thus, the
CD8 T-cell profile might be able to identify a group of AAV patients more likely to relapse . Another
[39]
+
subset of T cells, Th17 cells, has been identified as a potential driver of the disease. Th17 cells seem to be
autoantigen-specific and are also spotted in renal lesions of AAV patients . von Borstel et al. analyzed
[79]
[80]
CD19 CD24 CD38 B cells from the peripheral blood of AAV patients in remission and healthy controls.
hi
hi
+
They found a negative correlation between Th17 cells and Breg and concluded that Th17 cells in AAV
patients are at least partially controlled by Breg, highlighting another population that may be responsible for
[80]
the disease and a target for its control . Indeed, targeting B cells by the use of rituximab has shown a
sustained remission at Month 28 when compared with other maintenance options [81,82] . However, as
discussed above, B-cell activity has not been predictive of disease relapse. Other research groups found that
an imbalance of Th17 and regulatory T (Treg) cells may also be of potential use to monitor AVV patients