Page 206 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

182 Constantina Yiannakis, Lorna Ward and Matthew David Morgan

Etiopathogenesis

There is increasing evidence for a pathogenic role of ANCA in the etiopathogenesis of
inflammation and organ damage mediated by immune mechanisms. With regards to the
innate immune system, neutrophils play a pivotal role in the effector phase causing organ and
tissue damage. Complement activation, particularly the alternative pathway, seems to be
important in glomerulonephritis. The adaptive immune system is important in the
development of autoimmunity with the production of autoantibodies against proteinase 3 or
myeloperoxidase by B-cells and increasing evidence for a pathogenic role for T-cells. Genetic
susceptibility factors encoded by certain human leukocyte antigen (HLA) haplotypes [38],
notably HLA-DPB1*0401 alleles are associated with an increased risk for development of
GPA [39], and HLA-DRB1*0901 is associated with MPA [40]. The DRB1*15 haplotypes was
associated with anti-PR3 AAV in African Americans [41]. There are polymorphisms of genes
encoding the CD226 antigen (CD226), the protein tyrosine phosphatase, nonreceptor-type, 22
protein (PTPN22P), cytotoxic T lymphocyte-associated 4 (CTLA-4) and interleukin 10 (IL-
10), involved in the control of the immune system that lead to an increased risk of developing
vasculitis [42-46], although none have been specific for AAV. Copy number variation of the
Fc fragment of IgG receptor, low affinity IIIb (FCGR3B) and human ß-defensin (DEFB4)
may be important mechanisms in the susceptibility AAV [42, 47].

Genes expressed by memory T-cells as well as a CD8+ T-cell transcription signature,
have been described in systemic lupus erythematosus and AAV with associated poorer
outcome. This signature is thought to comprise of enriching genes involved in the IL-7
receptor and T-cell receptor signaling pathway [48].

Carriage of the dysfunctional z allele of the ?-1-antitrypsin (A1AT) gene is associated
with an increased risk of developing AAV and predicts more severe outcomes [49-54].
Patients carrying the z allele not only have an increased risk of AAV but also have increased
concentrations of circulating A1AT polymers capable of priming circulating neutrophils for
ANCA-induced activation [55].

Environmental factors may also have a role in disease development. Provocation of an
immune response and inflammation is thought to occur after exposure to silica dust with 22-
46% of patients with AAV having documented exposure to silica prior to disease
development. It is proposed that exposure results in accelerated apoptosis of macrophages and
polymorphonuclear leukocytes, thereby triggering disease development [56, 57]. Infectious
triggers have also been implicated in the etiopathogenesis of AAV. A contributory role of
low-grade Staphylococcus aureus infection in the etiopathogenesis of AVV has been based on
the observation that 63% of patients with GPA had chronic nasal carriage of it when
compared with 20% of control individuals, moreover nasal carriage was also related to
disease relapse [58] and the further observation that patients who received maintenance
treatment with co-trimoxazole had fewer relapses [59]. A study of bronchioalveolar lavage
fluid (BALF) in GPA patients identified increased levels of infection compared to controls
and demonstrated that BALF was permissive for bacterial growth [60]. Molecular mimicry
may also underlie the development of necrotizing and crescentic glomerulonephritis (NCGN)
through infection with fimbriated bacteria, such as Escherichia coli and Klebsiella pneumonia
[61]. The bacterial adhesion protein FimH was found to be homologous to a major epitope of

Complimentary Contributor Copy