transforming-growth-factor-beta and Granulomatosis-with-Polyangiitis

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic small vessel vasculitides associated with ANCA (AAV). Predominant Th1 and Th2 cytokine patterns have been reported for WG and MPA, respectively. Consequently, genotypes suppressing Th1 responses or augmenting Th2 responses may be more frequent in MPA than in WG. Transforming growth beta1 (TGF-beta1) and interleukin-10 (IL-10) genes may modify the course of vasculitis. Therefore, we investigated associations between genotype frequencies of functional polymorphisms of these cytokine genes and clinical manifestations in AAV. One hundred sixty-one AAV patients and 153 healthy blood donors were genotyped for the biallelic polymorphism in codon 25 of the TGF-beta1 gene and the biallelic polymorphism at position -1082 of the IL-10 gene. No difference was found for TGF-beta1 codon 25 polymorphism between control and patient groups. In contrast, a significant shift toward the homozygous AA genotype of the IL-10 (-1082) polymorphism was found in WG (25%, p<0.005) and MPA patients (39%; p<0.00001) compared to controls (10.5%). Furthermore, in MPA the AA homozygous genotype was significantly more frequent in females (62.5%) compared to males (20%, p<0.05). A contribution of the TGF-beta1 codon 25 polymorphism to the susceptibility-defining genetic backgrounds of AAV appears unlikely. In contrast, our findings suggest a role of the enhanced IL-10 (-1082) PM in WG and MPA with a significant gender difference in MPA.

Topics: Alleles; Antibodies, Antineutrophil Cytoplasmic; Cohort Studies; DNA; Female; Genetic Predisposition to Disease; Granulomatosis with Polyangiitis; Humans; Interleukin-10; Male; Middle Aged; Polyarteritis Nodosa; Polymerase Chain Reaction; Polymorphism, Genetic; Sex Factors; Transforming Growth Factor beta

Wegener's granulomatosis is a granulomatous and vasculitic disease of unknown origin. Gene polymorphisms are known to affect phenotypes of numerous diseases. Polymorphisms within the angiotensin-converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), and interleukin-10 (IL-10) genes are suspected to modify the course of granulomatous disorders. We examined whether the genotype frequencies of the named polymorphisms differ in Wegener's granulomatosis from those in healthy controls. Thirty-nine patients with Wegener's granulomatosis were genotyped for the deletion/insertion polymorphism in intron 16 of the ACE gene, a biallelic polymorphism in codon 25 of the TGF-beta1 gene and a biallelic polymorphism at position -1082 of the IL-10 gene and compared with healthy blood donors. For the ACE polymorphism no significant differences were detected neither in the allele frequencies nor in the genotype frequencies. For TGF-beta1 a trend to genotype CG was found. The most interesting result was the observed, significant shift to genotype AA of the IL-10 polymorphism in Wegener's granulomatosis. IL-10 and TGF-beta1, immunoregulatory cytokines capable of down-regulating T helper cell type 1 response, showed a significant shift or a trend, respectively towards genotypes associated with reduced cytokine release, leading to the hypothesis that different immunoregulatory cytokine patterns dependent on gene polymorphisms might be involved in the pathogenesis of Wegener's granulomatosis.

Topics: Adult; Alleles; Case-Control Studies; Codon; Cytokines; Down-Regulation; Female; Gene Deletion; Genotype; Granulomatosis with Polyangiitis; Humans; Interleukin-10; Introns; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1

TGF-beta is a multifunctional cytokine modulating the onset and course of autoimmune diseases as shown in experimental models. The aim of this study was to investigate TGF-beta expression in ANCA-associated vasculitis (AAV), and the possible interactions of this cytokine with lysosomal enzymes identified as ANCA autoantigens (e.g. PR3). This included TGF-beta effects on the translocation of the lysosomal enzymes to the cell surface of polymorphonuclear neutrophils (PMN), and the presumed activation of non-bioactive, latent TGF-beta by these enzymes. Patients with various types of systemic vasculitis (SV) were studied, including three different types of AAV (Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA)). Regardless of the type of assay applied, the TGF-beta 1 isoform was found to be over-expressed in SV, including AAV, and to correlate with disease activity as shown for WG. Mean TGF-beta 1 plasma levels in AAV patients ranged from 8.9 ng/ml (WG) to 13.3 ng/ml (CSS) (control 4.2 ng/ml; P < 0.01), while TGF-beta 2 levels were not elevated. Flow cytometry analysis showed TGF-beta 1 to be a potent translocation factor for PR3 comparable to other neutrophil-activating factors such as IL-8. PR3 membrane expression on primed PMN increased by up to 51% after incubation with TGF-beta 1. PR3 itself was revealed as a potent activator of latent TGF-beta, thus mediating bioeffects of this cytokine. These findings, together with other features of TGF-beta such as induction of angiogenesis and its strong chemotactic capacity, indicate that TGF-beta might serve as a proinflammatory factor in SV, especially in AAV.

Topics: Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Autoantibodies; Base Sequence; Churg-Strauss Syndrome; Cytoplasm; Granulomatosis with Polyangiitis; Humans; Ion Pumps; Leukocytes, Mononuclear; Lysosomes; Molecular Sequence Data; Myeloblastin; Polyarteritis Nodosa; RNA, Messenger; Serine Endopeptidases; Transforming Growth Factor beta

The expression of cytokines that are potentially involved in the pathogenesis of vasculitis was studied in patients with primary systemic vasculitis (PSV). In extension of earlier reports, we detected an overexpression of transforming growth factor beta (TGF beta), interleukin 6 (IL6), and interleukin 8 (IL8), indicating that the whole cytokine cascade is activated to a significant extent in PSV.

Topics: Churg-Strauss Syndrome; Cytokines; Gene Expression; Granulomatosis with Polyangiitis; Humans; Interleukin-6; Interleukin-8; RNA, Messenger; Transforming Growth Factor beta; Vasculitis