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Biomedical subjects

M Gencik

Publications and source records attributed to M Gencik.

26 records · Page 2Linked to original sources
PubMed2001

Novel SNPs in the CD18 gene validate the association with 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.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

The association of CD18 alleles with anti-myeloperoxidase subtypes of ANCA-associated systemic vasculitides.

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.

Alleles↗
PubMed2000

Proteinase 3 gene polymorphisms and Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis (WG) is a rare systemic autoimmune disease characterized by small-vessel vasculitis leading to organ damage and the presence of antineutrophil cytoplasmic autoantibodies (ANCAs). ANCAs were shown to be involved in the pathogenesis of the disease by increasing adhesion of polymorphonuclear cells (PMNs) to endothelial cells and through activation of primed PMN. The main autoantigen of ANCA in WG is proteinase 3 (PR3), a neutrophil- and monocyte-derived neutral serine protease. The association of WG with individuals continuously expressing a high level of PR3 on the surface of PMNs suggests that PR3 variants or altered regulation of PR3 expression might be directly involved in the pathogenesis of the disease. METHODS: We screened the entire coding and promoter sequences of the PR3 gene for polymorphisms by means of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). Allelic, genotypic, and haplotype frequencies were compared between 79 WG patients and a cohort of 129 healthy controls. RESULTS: Seven single-nucleotide polymorphisms (SNPs), one amino acid change (Val119Ile), one 84 bp insertion/deletion, and a microsatellite were identified. An association with WG could be demonstrated for the A-564G polymorphism in the PR3 promoter affecting a putative transcription factor-binding site. CONCLUSIONS: This study excludes certain PR3 epitope variants as autoantigenic stimuli in WG, since the Val119Ile polymorphism showed no differences between patients and controls. Overexpression of PR3, however, might predispose the patient to the development of autoimmune ANCA-associated vasculitis.

Alleles↗
PubMed1999

Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

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.

Adolescent↗
PubMed1993

Multistep transformation in low-grade lymphoproliferative diseases.

BACKGROUND: Carcinogenesis, the formation of solid tumors, is now widely accepted to represent a multistep process. Several genetic events, activation of proto-oncogenes and inactivation of tumor suppressor genes, are involved. DESIGN: Review of the literature for evidence that the concept of multistep transformation has relevance also for the formation of low-grade lymphoproliferative diseases. RESULTS AND CONCLUSION: The common translocations in low-grade lymphoid tumors are probably early events, predominantly involved in the activation of oncogenes, leading to growth stimulation or prolonged cell survival. As a result 'monoclonal lymphoproliferative disorders of undetermined significance (MLDUS)' occur, undetermined, because some translocations may not always led to tumor formation. For progression to full malignancy, additional genetic events are required besides sequential selection of variant subpopulations within the neoplastic clone. Recent data indicate that mutations and deletions of putative tumor suppressor genes, including the P53 and retinoblastoma genes, are also involved in the progression of lymphoproliferative disorders. A list of lymphoproliferative diseases stressing this concept of multistep transformation is presented in this article.

Animals↗