Page 823 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 795

Cocaine-induced midline destructive lesions (CIMDLs) in the stimulator (BLyS) levels are significantly increased, thereby
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upper respiratory tract mimic limited forms of GPA. Patients promoting B-cell differentiation, proliferation, and survival.
with CIMDLs may present with or without ANCA, and when B cells may play a number of roles in AAV: as precursors to
ANCA-positive, the pattern often varies. Some patients are positive antibody-producing plasma cells; as APCs; producing proinflam-
for c-ANCA with PR3 specificity, but more often, patients with matory mediators; or in costimulation of T cells.
CIMDLs present p-ANCA with specificity for atypical ANCA,
such as HNE. Wiesner et al. reported that 76% of the patients ROLE OF NEUTROPHILS
with CIMDLs were ANCA-positive (mostly p-ANCA): 57% had
PR3-ANCA and 86% had HNE-ANCA; this compares with the In addition to containing the antigens for ANCA, activated
absence of HNE-ANCA in GPA and MPA, suggesting that the neutrophils release many mediators that modulate the inflam-
presence of HNE-ANCAs may be helpful in distinguishing CIMDL matory response and can directly contribute to tissue inflam-
from GPA. 41 mation, vascular injury, and damage in AAV via phagocytosis,
Table 58.2 provides a summary of the most significant associa- degranulation, and cytokine production. Neutrophils release B
tions between drugs and ANCA or AAV. The management of cell–activating factors (BAFFs) that enhance B-cell proliferation
all forms of drug-induced AAV is withdrawal of the offending and retard apoptosis. Neutrophils from patients with AAV are
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agent, supportive measures, and, in severe cases, immunosup- more prone to spontaneous release of NETs. In the normal
pression, dialysis, and plasma exchange. immune system, NETs consist of chromatin fibers released from
dying neutrophils and are designed to trap and kill extracellular
LOSS OF B- AND T-CELL TOLERANCE IN pathogens. NETs not only contain proinflammatory proteins
ANCA-ASSOCIATED VASCULITIS that directly cause endothelial cell damage and complement
activation but also form a link between innate and adaptive
The imbalance of effector and Tregs underpins the autoimmune immunity via providing access to MPO and PR3.
dysregulation seen in AAV with multiple alterations in the circulat-
ing T-cell population. Patients with AVV have a reduced number ROLE OF COMPLEMENT
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of circulating Tregs, which are functionally impaired, and an
expanded population of CD4 effector memory T cells with an Despite the apparent paucity of immune complexes in AAV,
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increased number of activated T cells. Persistence of CD4 T-cell complement (and in particular activation of the alternative
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activation in peripheral blood correlates with disease severity. complement pathway) plays a crucial role in the pathogenesis
Aberrant T helper (Th) polarization, with an increase in proin- of AAV. When primed neutrophils are activated by ANCA, they
flammatory Th17 responses, further contributes to vascular produce C5a, which, in addition to recruitment, primes addi-
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injury. It has been suggested that these alterations to the tional neutrophils for further activation by ANCA. C3a, C5a,
peripheral T-cell compartment could be influenced by environ- and soluble C5b-9 levels are elevated in active disease; plasma
mental factors, such as infection. levels of complement factor H, a regulator of the alternative
The discovery of B cells in the inflammatory lesions in AAV complement pathway, are significantly lower in patients with
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together with the success of B-cell depletion therapies suggests that active AAV. Low serum levels of C3 at diagnosis are associated
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B cells play a significant role in the pathogenesis of AAV; however, with a worse prognosis. There is also a suggestion that C5a
the exact mechanism of this involvement is still not known. may play a role in the hypercoagulability associated with active
Regulatory B cells are reduced in AAV, whereas B-lymphocyte AAV.
TABLE 58.2 Drug-Induced Vasculitis associated With aNCa Positivity—Implicated Drugs,
Proposed Mechanisms of action and Laboratory Findings

Other aNCa
Drug/Class Proposed Mechanism of action IF Pattern aNCa Serotype autoantigens Other antibodies ref.
allopurinol Limited data p-ANCA MPO-ANCA - ANA 50
anti–tNF-α TNF-α may induce the formation of p-ANCA MPO-ANCA - ANA 51
(aDa, EtN, immune complexes, activation of c-ANCA PR3-ANCA
IFX) complement and mediate
inflammation by switching from a
cytokine response of T-helper type 1
to type 2, upregulating antibody
production
Benzylthiouracil Limited data p-ANCA MPO-ANCA HNE - 52
Lactoferrin
Carbimazole Limited data p-ANCA MPO-ANCA - -
c-ANCA PR3-ANCA

Cocaine Enhanced formation of NETs enriched c-ANCA PR3-ANCA HNE 40, 41
in neutrophil elastase and p-ANCA
inflammatory mitochondrial DNA with
enhanced release of B cell–activating
factor belonging to the TNF family (B
cell–activating factor [BAFF])
Continued