Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses

Hudson, Lori L.; Rocca, Keith M.; Kuwana, Masataka; Pandey, Janardan P.

doi:10.1038/sj.gene.6364180

Cited by 23 publications

(4 citation statements)

References 19 publications

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“…This probably reflects the complex relationship between the antibody profile and clinical phenotype, but also raises the possibility that SSc genetic subtypes may be better characterized by serologic than clinical features. Finally, because of the rarity of SSc, the number of patients in each autoantibody subgroup is relatively small although comparable with the number in larger published studies on SSc subgroup associations (3, 44, 47, 48). This raises the possibility of both Type I (false negative) and Type II (false positive) errors.…”

Section: Discussionmentioning

confidence: 76%

“…Recently, Sato et al reported a strong association between ACA positivity in SSc patients and a specific tumor necrosis factor (TNF) haplotype, including the TNF‐1031C and TNF‐863A alleles (47), which could explain the previous weak links between ACA production and class II major histocompatibility complex alleles. Hudson et al (48) observed differences in the distribution of interleukin‐10 polymorphisms in patients with anti‐RNAP antibodies and anti–U1 RNP antibodies compared with SSc patients without these antibodies. Interestingly, we did not observe an association between the EDNRA SNPs and renal crisis, despite the possible association between anti‐RNAP antibodies and the presence of scleroderma renal involvement (35, 49).…”

Section: Discussionmentioning

confidence: 99%

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Endothelin axis polymorphisms in patients with scleroderma

Fonseca¹,

Renzoni²,

Sestini³

et al. 2006

Arthritis & Rheumatism

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Objective. To evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets.Methods. Two hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence-specific primer-polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, ؊1370 (T-1370G) of the promoter, ؉138 of exon 1 (؉138 A/؊), ؉85 of exon 3 (E106E), and ؉23 of exon 5 (K198N); for EDNRA, ؊231 of exon 1 (G-231A), and ؉69(H323H) and ؉105 (E335E) of exon 6; for EDNRB, ؉2841 of exon 2 (EDNRB-3), ؊2547 of exon 3 (EDNRB-2), and ؊2446 of exon 3 (EDNRB-1).Results. No significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB-1A (76.8% versus 54.4%; P ‫؍‬ 0.002), EDNRB-2A (79.7% versus 60.2%; P ‫؍‬ 0.006), and EDNRB-3G (79.7% versus 56.6%; P ‫؍‬ 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti-RNA polymerase (anti-RNAP) antibodies, compared with both anti-RNAP-negative SSc patients (P < 0.05) and control subjects (P < 0.005).Conclusion. The finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Endothelin axis polymorphisms in patients with scleroderma

Fonseca¹,

Renzoni²,

Sestini³

et al. 2006

Arthritis & Rheumatism

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“…IL-10 inhibits both proliferation and CI synthesis by fibroblasts ( 379 ). Certain IL-10 genotypes have been associated with development of SSc in Caucasian and Japanese subjects ( 380 ). TNF α inhibits CI, stimulates MMP-1 synthesis by fibroblasts, and is a potent chemoattractant for these cells ( 381 ).…”

Section: Fibrosis In Sscmentioning

confidence: 99%

Pathogenesis of Systemic Sclerosis

et al. 2015

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Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

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“…Genetic association of IL10 polymorphism with SSc was also reported. Crilly et al suggested that a haplotype with lower IL-10 production may be associated with dcSSc [14], while other groups reported that a haplotype with high IL-10 production was associated with susceptibility and severity of dcSSc [15,16]. Thus, the role of IL10 polymorphisms in SSc remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Association of IL-10 receptor 2 (IL10RB) SNP with systemic sclerosis

Hikami

Ehara

Hasegawa

et al. 2008

Biochemical and Biophysical Research Communications

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Interleukin-10 (IL-10) signaling has been suggested to play a role in systemic sclerosis (SSc). IL10RB codes for IL-10 receptor 2 (IL-10R2), a component shared in receptor complexes for IL-10, IL-22, IL-26 and interferon (IFN)-lambda. In this study, we examined association of IL10RB polymorphism with susceptibility to SSc. Genotype A/A at rs2834167 (47K/K) was significantly increased in diffuse cutaneous SSc (dcSSc) (41.3% in dcSSc, 20.9% in controls, P=0.0018, odds ratio=2.67). A SNP in the 5' flanking region of IL10RB, rs999788, also showed association with dcSSc; however, this association was shown to be secondarily caused by linkage disequilibrium with rs2834167. Significant association was not observed in limited cutaneous SSc (lcSSc). Presence of anti-topoisomerase I antibody was also associated with rs2834167A/A genotype (P=0.0019). Serum IL-10 level was significantly associated with the number of rs2834167A allele (P=0.007). These findings suggested that signaling through IL-10R2 may play a causative role in dcSSc.

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Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses

Cited by 23 publications

References 19 publications

Endothelin axis polymorphisms in patients with scleroderma

Endothelin axis polymorphisms in patients with scleroderma

Pathogenesis of Systemic Sclerosis

Association of IL-10 receptor 2 (IL10RB) SNP with systemic sclerosis

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