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Background: The activation of neutrophils and monocytes by ANCA, resulting in the release of reactive oxygen species and proteases like myeloperoxidase (MPO), is essential to the pathogenesis of ANCA-associated vasculitis. As the A allele of the G-463A MPO gene polymorphism is associated with diminished activity of MPO, it is conceivable that the presence of this allele protects against MPO-ANCA-associated vasculitis., Methods: Allelic frequencies of the G-463A polymorphism were studied in 119 ANCA-associated vasculitis patients, 48 with MPO-ANCA and 71 with proteinase 3 (PR3)-ANCA., Results: Allelic frequencies of MPO G-463A promoter polymorphism did not differ between MPO-ANCA- and PR3-ANCA-associated vasculitis patients. Moreover, allelic distribution was similar to that of the normal population., Conclusions: The data suggest that G-463A polymorphism does not seem to contribute to either MPO-ANCA- or PR3-ANCA-associated vasculitis formation.

Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and the Churg-Strauss syndrome (CSS) are small vessel vasculitides associated with anti-neutrophil cytoplasmic antibodies (ANCA). Cytoplasmic (c)-ANCA mainly target proteinase 3 (PR3) and are often observed in WG patients, while perinuclear (p)-ANCA predominantly bind to myeloperoxidase (MPO) and are common in patients with MPA and CSS. It is suspected that a genetic background contributes to disease formation since the diseases are more prevalent in Caucasian populations. This article provides a detailed review of the genetic impact of the pathogenesis and prognosis of ANCA-associated vasculitides. Alpha-1 anti-trypsin is the physiological inhibitor of PR3 and carriage of the defective allele PI*Z was observed as the first genetic risk factor for the development of PR3-ANCA-associated vasculitis. Expression analyses have revealed that PR3 surface expression is genetically determined. Elevated levels of PR3 expression have been observed in WG patients and high levels of PR3 expression corresponded to increased risk of disease relapses. Furthermore, the non-carriage of CTLA-4 allele 86 was associated with WG formation, while homocygotic carriage of the CCR5 allele delta 32 seemed to prevent ANCA-negative WG. MPO-ANCA vasculitides were associated with certain alleles of CD18 polymorphisms. Lack of or only weak allelic associations of ANCA-vasculitides with polymorphic cytokine, HLA, and Fcgamma receptor genes have been shown. Although, in practice, it is sometimes difficult to differentiate between WG and MPA, the diseases appear to be based on different genetic backgrounds.

In patients with PR3-ANCA associated vasculitides the carrier frequency of alpha1-antitrypsin (AAT) deficiency allele PI*Z is increased and linkage disequilibrium between polymorphic markers within a cluster of serine protease inhibitor (serpin) genes, including AAT gene, at chromosome 14q32.1 has been described. A1-antichymotrypsin (AACT), part of an extended serpin gene cluster, was discussed to contribute to PR3-ANCA associated vasculitis formation. To analyse, if an AACT gene polymorphism within the signal peptide sequence is associatedwith antineutrophil cytoplasm autoantibodies (ANCA) vasculitis allelic frequencies of AACT polymorphism were analysed in 128 control persons, 79 PR3-ANCA, and 30 MPO-ANCA patients. In MPO-ANCA patients also phenotyping of AAT was performed as well as frequency and linkage analysis of simple tandem repeat polymorphisms in the genes of cortisol-binding globulin, AAT, protein C inhibitor, and three extragenic markers (S48, S55, S51) of the gene cluster. Allelic frequencies of the AACT polymorphism did not differ between controls and vasculitis patients. In the MPO-ANCA group no patient expressed the Pi*Z defective allele of AAT and the allelic frequencies of polymorphic markers within the serpin gene cluster did not differ from those of the controls. Strong linkage disequilibrium was detected in MPO-ANCA patients neither. Therefore, we can not support the hypothesis that AACT polymorphism contributes to the pathogenesis of PR3-ANCA vasculitis. Nor is it probable that any factor, coded by the serpin gene cluster, contributes to MPO-ANCA vasculitis.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg-Strauss syndrome (CSS) are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Anti-myeloperoxidase (MPO)-ANCA are a typical feature of MP and CSS, while anti-proteinase 3 (PRTN3)-ANCA are highly specific for WG. Several reports indicate that ANCA may directly contribute to pathological processes, ie, through an increase of adhesivity between polymorphonuclear (PMN) and endothelial cells (EC). PMN interact and endothelium interact via the adhesion cascade (AC). CD18 is a key molecule of the AC, as CD18 defects abrogate the adhesion of PMN and cause leukocyte adhesion deficiency, an immunodeficient trait. We have screened the entire coding and regulatory regions of the CD18 gene. Ten single nucleotide polymorphisms (SNP) were identified, four of them showing significant associations with MPO-ANCA(+) vasculitis. One of these SNP's was localized in an alternate transcription initiation site. This polymorphism may influence CD18 gene expression, resulting in dose-dependent increase in adhesion and consecutively facilitated degranulation and respiratory burst. In this manner the pro-adherent genotype may predispose to MPO-ANCA(+) vasculitis.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg Strauss syndrome (CSS) are rare systemic autoimmune disorders. Common features are anti-neutrophil cytoplasmic antibodies (ANCA) in patient sera. Whereas WG patients show mainly anti-proteinase 3 ANCA, MP and CSS patients typically present anti-myeloperoxidase (MPO) ANCA. ANCA play an important role in the pathogenesis in the vessel wall by activating polymorphonuclear cells (PMN) and increased adhesivity between PMN and endothelial cells via adhesion molecules. Here we investigated major adhesion molecules as predisposition factors via common polymorphisms in or in the vicinity of the candidate genes ICAM-1, e-selectin, PLAUR, CD11b, and CD18. A restriction fragment-length polymorphism in exon 11 of the CD18 gene was associated with MPO-ANCA(+) systemic vasculitis. Our data indicate that a common variant of the CD18 gene confers increased risk for CSS and MP, supporting that genetic factors are involved in the etiology and pathogenesis of ANCA-associated systemic vasculitides., (Copyright 2000 Academic Press.)

Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA-DRB1*13 and HLA-DQB1*0603 individuals was observed in our cohort of ANCA-associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA-DRB1*04 individuals were over-represented in a subgroup of patients with WG in end-stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)alpha, IL-2, IL-5 receptor alpha (IL-5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFalpha as well as in the coding region of the FcgammaIIRA genes. Polymorphisms of the TNFalpha promotor (TNF-308) as well as in the FcgammaIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL-2 and IL-5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)-ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.