complex genetics of wegener granulomatosis

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  • ePeter Jagielloa,*, Wolfgang L. Grossb, Jfrg T. Epplena


    Wegener granulomatosis (WG) are characterized by a

    primary process of inflammation and damage of blood

    on the variety of clinical symptoms and the similar-

    ities in histology. So far, SV are differentiated by size

    of affected vessels, i.e. large vessels (e.g. Takayasu

    Wegener granulomatosis (WG) belongs to a heterogeneous group of systemic anti-neutrophil cytoplasmatic antibody

    (ANCA) associated vasculitides (AASV). WG is characterized by necrotizing granulomatous inflammation of the upper and

    lower respiratory tract, glomerulonephritis and vasculitis. As a multifactorial model disease, WG is hallmarked by the

    presence of specific ANCA-subtypes directed against a defined antigen. WG is more predominant among Caucasians and

    the genetic predisposition appears quite complex. Here, we provide a brief overview concerning genetic factors in the

    pathogenesis of WG and discuss intricacies of molecular genetic approaches.

    D 2004 Elsevier B.V. All rights reserved.

    Keywords: Wegener granulomatosis; Multifactorial disease; Predisposing genetic factor

    Autoimmunity Reviews 4 (2001. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

    Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

    References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

    Systemic vasculitides (SV) such as giant cell

    arteritis, Takayasu arteritis, Kawasaki disease and

    vessel walls [1]. Differentiation of defined entities in

    this enigmatic group of SV is often problematic, basedAbstractaDepartment of Human Genetics, Ruhr-University Bochum, Universitaetsstrasse 150, 44801 Bochum, GermanybRheumatology, Medizinische Universitatsklinik Lubeck and Rheumaklinik Bad Bramstedt, Germany

    Received 1 June 2004; accepted 23 June 2004

    Available online 26 July 2004Complex genetics of W1568-9972/$ - see front matter D 2004 Elsevier B.V. All rights reserved.


    * Correspon


    E-mail address: (P. Jagiello).gener granulomatosis

    5) 4247 Kawasaki disease)arteritis), intermediate vesselsding author. Tel.: +49 234 3223831; fax: +49 234and small vessels (e.g. WG, microscopic polyangiitis

    [MPA] or ChurgStrauss syndrome [CSS]). A feature

  • unityof the last-mentioned group concerns the presence of

    anti-neutrophil cytoplasmatic antibody (ANCA) that

    act as diagnostic markers positively correlating with

    disease activity [2]. Whereas ANCA against myelo-

    peroxidase (MPO-ANCA) occur in MPA and CSS,

    proteinase 3 (PRTN3-)ANCA are observed in patients

    suffering from WG [2].

    Several findings suggest genetic predisposition

    factors for WG [3]. Therefore, ANCA target genes

    were already extensively investigated. The membrane

    expression of the main ANCA target antigen PRTN3

    (previously designated as PR-3) is genetically deter-

    mined [4]. In addition, association of a promoter

    polymorphism in the PRTN3 gene with WG has been

    demonstrated affecting a putative SP1-transcription

    factor-binding site [5]. This polymorphism leads

    potentially to increased PRTN3 expression. PRTN3

    belongs to the serine proteinase family, which is

    inhibited by the serin protease inhibitors (serpins),

    their genes clustering (in addition to further loci) at

    chromosome 14q32.1. Interestingly, linkage disequi-

    librium in this gene cluster points to associated

    haplotypes with WG [6]. Moreover, association

    studies concerning the PRTN3 inhibitor alpha1-

    antitrypsin (a1-AT) gene showed that the frequencythe a1-AT deficiency allele PI*Z is increased in WGpatients. Yet, the carriers of this allele did not suffer

    from any vasculitis symptoms in a larger population

    of PI*Z+ individuals [7].

    Whenever ANCA are demonstrable, infectious

    aetiologies may be discussed and, therefore, a relation

    between (polymorphonuclear neutrophil [PMN]-medi-

    ated) host defence and ANCA induction appears

    conceivable. For example, PMN-derived antibiotic

    proteins represent a source of innate immune defence

    playing a role in recognition and neutralization of the

    proinflammatory surface components (e.g. endotoxins)

    of bacteria [8]. Interestingly, most of these molecules

    are target antigens for ANCA [9]. Yet, in 6% of ANCA

    associated vasculitides (AASV), bactericidal/perme-

    ability-increasing protein (BPI)-ANCA is detected.

    Therefore, in a further association study, the function-

    ally relevant Glu216Lys polymorphism of theBPI gene

    has been genotyped (Jagiello et al., unpublished data).

    Comparison of allele frequencies and genotypes did not

    reveal differences between WG patients and healthy

    P. Jagiello et al. / Autoimmcontrols. In addition, alleles of an ad hoc designed in-

    tragenic microsatellite marker were not linked to WG.Binding of ANCA to antigens on the surface of

    PMN results in cellular activation as mediated by Fcgreceptors (FcgR) [10]. Most analyses of these highlypolymorphic genes did not show significant differences

    in genotype distributions or allele frequencies between

    patients and controls. Yet, a trend for increased

    homozygosity of the FcgRIIIb-NA1 allele was evidentwhich may have implications for disease susceptibility

    being significant in MPO-ANCA+ patients [11]. In

    addition, WG patients were more prone to disease

    relapse if they were homozygous for, both, the R131

    isoform of FcgRIIa and the F158 isoform ofFcggRIIIa. This fact might be related to chronic nasalcarriage of Staphylococcus aureus and the inability of

    the immune system to eliminate this bacterium,

    respectively [12]. Furthermore, adhesiveness of leuko-

    cytes to the endothelium is an important pathophysio-

    logical element of WG. Adhesion is augmented by

    expression of molecules like CD11, CD18, ICAM-1

    and E-selectin. Whereas studies did not reveal specific

    associations in the aforementioned genes as risk factors

    for WG, linkage was evidenced between given CD18

    alleles and MPO-ANCA vasculitides [13].

    Many autoimmune disorders are characterized by

    predominance of T helper 1 (Th1) cells, the cytokine

    pattern of which has also been observed in granulo-

    mata of WG patients [14]. As the cytotoxic T cell

    antigen 4 (CTLA4) has a role in inducing a Th1

    response also by suppressing Th2 cytokines, poly-

    morphisms in the CTLA4 gene were investigated. In a

    small WG cohort, an association of a simple AT repeat

    polymorphism in the 3V-untranslated region wasidentified [15]. In T cells from patients with myas-

    thenia gravis longer AT dinucleotide blocks cause

    reduced expression of CTLA-4 due to decreased

    mRNA stability [16]. A second single nucleotide

    polymorphism (SNP) in the promoter region revealed

    association with WG [17], but relevance for WG

    pathogenesis has still to be demonstrated, as this SNP

    is not comprised in any known consensus sequence,

    e.g. for transcription factor binding sites or other

    regulatory elements. Another SNP results in amino

    acid exchange (Y to A, position 49) without any

    association. Interestingly, linkage disequilibrium was

    demonstrated between the Y residue and the shortest

    allele of the AT microsatellite in controls but not in

    Reviews 4 (2005) 4247 43patients [17]. The functional significance of the

    genotypes for protection against WG remains elusive.

  • unityStudies on gene polymorphism in cytokines,

    chemokines and their receptors have also been carried

    out. In this context, SNPs in the tumor necrosis factor

    (TNF) genes were investigated whereby a TNFapromotor polymorphism at position 308 and anintronic SNP in the TNFh gene did not revealstatistically significant differences between patients

    and controls [18]. Yet concerning the clinical course

    of the disease, WG patients with a defined TNF 1/1

    phenotype were found to have a higher mean disease

    extension index than TNF 1/2 individuals [18]. In part

    these results were confirmed in a later study that, on

    the other hand, excluded certain interleukin 2 (IL2)

    and IL5 receptor (IL5R)a alleles as predisposinggenetic factors [19]. Furthermore, polymorphisms in

    the genes for IL1h and IL1Ra were examinedconcerning the clinical manifestation and outcome

    of AASV [20]. A distinct combination of these

    polymorphisms leads to a pro-inflammatory genotype

    increased in PRTN3-ANCA+ patients with end-stage-

    renal disease [20]. In a Swedish WG population

    variations in the IL4 and IL10 genes were investigated

    [21]. Both IL4 and IL10 belong to Th2 cytokine

    pattern and reduced levels of these anti-inflammatory

    cytokines might be related to WG manifestation.

    While IL4 variations did not reveal an association

    with WG, a so-called microsatellite polymorphism

    located in the promotor region of IL10 showed a

    significantly higher percentage of patients heterozy-

    gous for two specific alleles [21]. In addition, in

    another study on Caucasians, a significant shift

    toward the homozygous AA genotype of an IL10

    polymorphism was observed in WG patients. Fur-

    thermore, the latter study excluded the polymorphism


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