Page 820 - Clinical Immunology_ Principles and Practice ( PDFDrive )

792 Part SIX Systemic Immune Diseases

damage. α 1 -antitrypsin, encoded by the gene SERPINA1 (found trigger. Several triggers have been associated with AAV, including
on chromosome 14), is the major inhibitor. Two α 1 -antitrypsin toxins, viral and bacterial infections, and some licit and illicit
alleles, Z and S, are associated with low enzymatic activity. A drugs.
significant correlation with the Z allele (odds ratio [OR] 0.3; p Silica dust exposure has been associated with the development
= 1.25 × 10−5), but not the S allele, is reported in PR3-ANCA– of AAV and other autoimmune diseases, such as SLE, RA, and
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positive patients with GPA. PRTN3 (the gene encoding PR3) scleroderma. Silica is an abundant earth material found in
is associated with GPA, especially among patients who are sand, grain, grass, and wool. Processing these materials may
PR3-ANCA-positive. 17 expose workers to respirable crystalline silica. Silica-induced
The 620WPTPN22 variant of PTPN22 (encoding lymphoid ANCA-positive disease is often associated with p-ANCA, targeting
tyrosine phosphatase) correlates with abnormal regulatory CD4 MPO, and the clinical presentation is usually MPA rather than
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T regulatory cell (Treg) function, increased humoral activity, and GPA. Case-control studies show that a high percentage (22–46%)
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enhanced neutrophil function in patients with GPA. CTLA-4 of patients with AAV were previously exposed to silica. 25,29 A
(encoding cytotoxic T lymphocyte antigen-4) polymorphisms systematic review and meta-analysis of 332 cases and 516 controls
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are associated with GPA, especially the G allele of CT60 (p = found that prior silica exposure was associated with development
0.001) and +49 (p = 0.03). By contrast, only borderline significance of AAV, with a summary odds ratio (OR) of 2.56 (95% CI
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was noted between CT60 SNP and MPA (p = 0.05). CTLA-4 is 1.51–4.36). Pooled ORs were similar for GPA and MPA, 3.56
a negative regulator of T-cell activation, which competes with (95% CI 1.85–6.82) and 3.95 (95% CI 1.89–8.24), respectively.
the costimulatory molecule CD28 for binding of CD80 or CD86 Other confounders, such as other occupational exposures or
on antigen-presenting cells (APCs). Abatacept, a monoclonal tobacco use, were not analyzed, which could have resulted in an
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antibody (mAb), containing the binding domain of CTLA-4 overestimation of the risk attributed to silica. The mechanism
reduces CD28–CD80/CD86 interaction and therefore T-cell by which silica exposure triggers the development of AAV is not
stimulation, which could explain its potential benefit in a fully understood. In vitro, silica can activate monocytes and
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small trial of non–life-threatening GPA. Haplotypes of IL-10 macrophages, releasing cytokines, such as IL-1 and tumor necrosis
(a pleiotropic cytokine with complex and multiple effects in factor-α (TNF-α), as well as releasing oxygen radicals and
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immune modulation) are associated with several immuno- lysosomal enzymes, including proteinase 3 and myeloperoxidase.
logical disorders, including systemic lupus erythematosus Furthermore, silica can inactivate α 1 -antitrypsin. Asbestos, another
(SLE), rheumatoid arthritis (RA), and giant cell arteritis. IL-10 silicon-containing mineral, has been suggested as a trigger for
production is largely (50–70%) determined by genetic factors, and AAV in a small case-control study of 31 patients (22 GPA, 8
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elevated plasma levels are reported in EGPA, but not in GPA. MPA, 1 EGPA) and 30 healthy controls; three patients had prior
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Wieczorek et al. evaluated the impact of functionally relevant exposure to asbestos versus none of the controls. There are few
IL-10 polymorphisms in 403 patients with GPA, 103 with EGPA published studies investigating the potential pathogenic role of
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(compared with 507 controls). There was a significant association asbestos in the development of AAV.
with the 3575/1082/592 TAC haplotype, part of the extended It is estimated that 63% of patients with GPA are chronic
ancient haplotype of IL-10.2, in ANCA-negative EGPA, but not nasal carriers of Staphylococcus aureus, resulting in an increased
in GPA. 26 risk of relapse. Maintenance treatment with trimethoprim-
sulfamethoxazole (cotrimoxazole) has been shown to reduce the
EPIGENETICS incidence of relapse in a double-blind, placebo-controlled study
in patients with GPA, where a maintenance dose of 960 mg two
Genetic factors alone are not enough to explain the range of times daily of trimethoprim-sulfamethoxazole resulted in a 60%
phenotypic presentations in AAV. Epigenetic dysregulation is reduction in relapse. However, this has not been replicated in
increasingly recognized as a contributor to immune-mediated other studies. The mechanism for the pathogenic role of S. aureus
diseases. Epigenetics relates to heritable changes in the function is still unclear. Potential pathways include stimulation of B and/
of genes, without altering the DNA sequence. It includes DNA or T cells by S. aureus superantigens; polyclonal activation of B
methylation, histone, and microRNAs (miRNAs). Epigenetic cells by cell wall components of the bacterium, resulting in
modifications can be stable over time or can respond to devel- persistence of ANCA; and neutrophil priming leading to surface
opmental and environmental triggers, leading to phenotypic expression of PR3. 28
aberrances. Central to the pathogenesis of AAV is a dysregulated Although parvovirus B19 has been proposed as a trigger for
immune response resulting in ANCA production and aberrant AAV in a few case reports, a case-control study failed to dem-
expression of their target autoantigens, MPO and PR3. The onstrate any association because IgG antibodies to parvovirus
expression of MPO and PR3 occurs primarily during early B19 were detected equally in the sera of patients with AAV and
neutrophil development to produce intragranular constituents control subjects, and all 13 patients with AAV and 39 controls
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and is silenced in mature cells. However, in AAV, expression were negative for IgM antibodies and viral DNA. Hepatitis B
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remains active. One epigenetic change that helps explain this is virus (HBV) is implicated in the pathogenesis of PAN, but
the reduced levels of the H3K27me3 histone modification at there is no evidence to support a role for HBV or HCV in AAV.
both the MPO and PR3 gene loci. H3K27me3 histone is associated The presence of circulating c-ANCA and PR3-ANCA has been
with transcriptional silencing in patients with AAV compared reported to be higher in patients with chronic hepatitis B and
with healthy individuals. 27 C compared with controls. In a study of patients with liver disease
(11 patients with primary biliary cirrhosis, 216 with chronic
ENVIRONMENTAL AND INFECTIOUS TRIGGERS hepatitis B, 516 with chronic hepatitis C, and 44 healthy controls),
ANCAs were detected in 55.6% of patients with hepatitis C (all
Genetic and epigenetic modifications may render a patient had a c-ANCA pattern with PR3 specificity and 4.8% had concur-
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susceptible to developing disease in the presence of an appropriate rent MPO specificity). ANCA-positive patients had a higher