Page 819 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 791

KEY CONCEPtS
Pathogenic Mechanisms in ANCA-Associated Vasculitides

• The recognition of an association between some forms of vasculitis • Environmental factors
and the presence of antibodies to neutrophil cytoplasm (ANCA) has • Silica exposure
transformed understanding of the group of diseases considered to be • Specific strains of Staphylococcus aureus
associated with ANCA and in which ANCAs are suspected to have a • Inflammatory processes
pathogenic role. • Ineffective T-cell regulation
• Granulomatosis with polyangiitis (GPA) • Neutrophil generation of extracellular traps (NETs) containing proteinase
• Microscopic polyangiitis (MPA) 3 and myeloperoxidase
• Eosinophilic granulomatosis with polyangiitis (EGPA) • Activation of alternative complement pathway by ANCA-activated
• A genome-wide association study (GWAS) has demonstrated strong neutrophils
associations with specific alleles.
• Anti-proteinase 3 ANCA with specific HLA-DP alleles and alleles
encoded by genes for α 1 -antitrypsin and proteinase 3
• Anti-myeloperoxidase ANCA with specific HLA-DQ alleles

effect but resulted in high levels of circulating c-ANCA; transfer GENETICS
of splenocytes from these immunized animals into mice with
severe combined immunodeficiency (SCID) resulted in vasculitis There has been significant progress in the understanding of AAV
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and severe segmental and necrotizing glomerulonephritis. genetics following the publication of two genome-wide association
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Transfer of splenocytes from the CFA-alone-immunized mice studies (GWAS). The strongest human leukocyte antigen (HLA)
(controls) resulted in no disease, further suggesting that disease association is with the HLA-DPB1 haplotype, initially described
development depends on PR3-specific immune responses. In a in German cohorts and confirmed in both GWAS, especially
second model of PR3ANCA vasculitis, based on animals with a for the PR3-ANCA–positive subgroup, regardless of the clinical
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human–mouse chimeric immune system, >70% of mice treated diagnosis. Further analysis has revealed an association between
with IgG from patients with antiPR3 AAV (as compared with MPO-ANCA and a single nucleotide polymorphism (SNP) in
IgG from patients with nonvasculitic renal disease; or healthy the HLA-DQ region, which had probably been masked previ-
controls) developed mild kidney disease with glomerular hyper- ously as a result of the small number of MPO-ANCA–positive
cellularity and focal pulmonary hemorrhage. Fifteen (83%) mice patients included in initial analyses. Other HLA associations are
treated with antiPR3 IgG later showed mild kidney disease with reported, such as HLA-DRB1*09:01 and HLA-DQB1*03:03 in
glomerular hypercellularity, and three (17%) had severe glo- Japanese patients with MPA. Less robust findings, not replicated
merular injury. In the lungs, 13 (72%) showed areas of focal in other studies, include a protective effect of HLA-DR13(6)
pulmonary hemorrhage, whereas lungs of the control group (n and HLA-DR1, but an increased proportion of HLA-DR4 in
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= 8) appeared normal (p < 0.01). There were no granulomatous Dutch patients with GPA compared with controls ; HLA-DRB1
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lesions, but because granulomatous lesions are dependent on a in PR3-ANCA-positive (but not MPO-ANCA) patients ;
robust T cell–mediated response, the authors argued that a HLA-B50, HLA-DR1, HLA-DR9, HLA-DQw7, and HLA-DR3
refinement of the model to include greater levels of chimerism in GPA. 19-21 In EGPA, the most robust association is with
and administration of interleukin-7 (IL-7)–Fc protein to augment HLA-DRB4. Overall, there is evidence for genetic susceptibility
T-cell development would be required to study this. 15 to AAV, related to specific SNPs in the HLA region. Other genetic
Even though these studies strongly support a pathogenic role associations with GPA include PRTN3, SERPINA 1, PTPN22, and
for ANCA, conventional serological assays fail to detect ANCA CTLA4.
in some patients with classic clinical and pathological features PR3 is either stored in neutrophil azurophilic granules or
of AAV, and titers do not correlate well with disease activity. exposed on the cell membrane (where it can interact directly
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Roth et al. examined MPO epitopes specificities, reporting 25 with ANCA). Although the proportion of neutrophils displaying
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different epitopes bound by anti-MPO antibodies; although some membrane PR3 (mPR3 ) is stable over time, surface expression
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epitopes were associated with active disease, others were either of PR3 may be enhanced. The percentage of mPR3 neutrophils
not specific to active disease or not associated with disease at is genetically determined. Schreiber et al. showed that among
all. Igs purified from patients with ANCA-negative vasculitis 125 healthy controls, 35 patients with GPA, 15 patients with
could bind to a specific MPO epitope. Furthermore, the absence other inflammatory diseases, and 27 pairs of monozygotic (MZ)
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of ANCA in some patients could be explained by competitive and dizygotic (DZ) twins, the percentage of mPR3 neutrophils
binding to a fragment of ceruloplasmin (CP), the natural inhibi- correlated significantly in MZ twins (but not in DZ twins) and
tor of MPO. This CP fragment decreased anti-MPO 447–459 the heritability percentage was estimated as 99%. Furthermore,
autoantibody reactivity by 30–50%, whereas full-length CP did the absolute number of PR3 molecules expressed on the cell
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not have any effect. ANCAs are reported in small numbers membrane was correlated among MZ (but not DZ) twins, with
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of healthy individuals. How the pathogenic transformation of a heritability estimate of 96.7%. Patients with GPA have a higher
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ANCA occurs is still unclear, but it is probably a multifactorial percentage of mPR3 neutrophils compared with healthy controls
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process requiring a complex interaction among genetics, the or patients with other inflammatory diseases (mPR3 percentage
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environment, and the immune system facilitating a break in of 76.8% vs 56.1% vs 59.4%, respectively). Following neutrophil
immune tolerance. activation and enzyme release, PR3 can mediate direct tissue