Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.
ABSTRACT Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.
Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain.
The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants.
We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.
Article: T cells, B cells, and polarized immune response in the pathogenesis of fibrosis and systemic sclerosis.[show abstract] [hide abstract]
ABSTRACT: A better comprehension of the interactions between cells of the adaptive immune system with fibroblasts and endothelial cells is required to understand abnormal extracellular matrix deposition, development of pathologic fibrosis, and vasculopathy. Skin T cells with high IL-4 production potential and peripheral blood T cells preferentially expressing chemokine receptors associated with Th2 functions are found in individuals with active systemic sclerosis. Animal models indicate that Th2 cells and IL-13 can induce muscular hypertrophy in pulmonary arterial vasculature. In bleomycin-induced fibrosis, B cells produce fibrogenic cytokines upon interaction of an endogenous ligand (hyaluronan) with toll-like receptor-4. In the sclerodermatous graft versus host model, the lack of tumor necrosis factor-production by CD4+ T cells is permissive for fibrosis development. Dermal fibrosis and capillary loss typical of systemic sclerosis can be reversible after high-dose immunosuppression and hematopoietic stem cell transplantation. Although immunosuppressive strategies to treat patients with systemic sclerosis and allied conditions are largely disappointing, thus indicating a permissive rather than causative role of immunoinflammatory events characteristic of the disease, new findings stress that cells of the adaptive immune system play important roles in assisting fibrogenesis and vascular abnormalities. This may help in identifying efficacious strategies aimed at their control.Current opinion in rheumatology 12/2008; 20(6):707-12. · 4.60 Impact Factor
Article: Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis.[show abstract] [hide abstract]
ABSTRACT: Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis. There is a close association between specific autoantibodies and clinical features in patients with SSc. A number of studies have demonstrated that various cytokines, such as transforming growth factor-beta, modulate the synthesis of extracellular matrix by fibroblasts. However, it is not clear as to how autoimmunity and tissue fibrosis interact with each other. Recent studies have revealed that B cells play a critical role in various systemic autoimmune disorders. CD19 is a central regulator of B cell signaling threshold, and B cells from SSc patients exhibit an increased expression of CD19 that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by decreased but activated memory B cells, which is possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic B cell activation. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Therefore, augmented cytokine production by B cells is a potential candidate for the induction of skin sclerosis. Alternatively, B cells may influence tissue fibrosis by regulating T cell activation and cytokine production through their antigen-presenting and co-stimulatory abilities. Thus, altered B cell function may result in tissue fibrosis, as well as autoimmunity, in SSc.Journal of Dermatological Science 08/2005; 39(1):1-7. · 3.72 Impact Factor
Article: Identification of a nuclear protein (Scl-70) as a unique target of human antinuclear antibodies in scleroderma.Journal of Biological Chemistry 11/1979; 254(20):10514-22. · 4.77 Impact Factor