Brief Report: HLA–DRB1, DQA1, and DQB1 in Juvenile‐Onset Systemic Sclerosis

Stevens, Anne M.; Kanaan, Sami B; Torok, Kathryn S.; Medsger, Thomas A.; Mayes, Maureen D.; Reveille, John D.; Klein-Gitelman, Marisa; Reed, Ann M.; Lee, Tzielan; Li, Suzanne C.; Henstorf, Gretchen; Luu, Christine; Aydelotte, Tessa M.; Nelson, J. Lee

doi:10.1002/art.39765

Cited by 17 publications

(15 citation statements)

References 21 publications

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“…An initial study in the UK examined HLA alleles in 27 patients with jSSc-dermatomyositis overlap, demonstrated an increase of DQA1 * 05 and DRB1 * 03 and a trend toward decreased DRB1 * 15. This finding was confirmed in a larger study of 76 Caucasian patients with a mean onset of SSc onset at 10 years of age in the US (25). Children with SSc did not have an increased frequency of DRB1 * 01, which has been associated with adult limited cutaneous SSc and ACA or HLA-DRB1 * 11 alleles, the group most consistently described in association with SSc in Caucasian adults.…”

Section: Genetic Basis Of Juvenile Systemic Sclerosissupporting

confidence: 64%

“…DRB1 * 01 was under-represented among anti-topoisomerase 1 (ATA) -positive jSSc patients, consistent with a similar observation reported in adult SSc (34). In this study, just as the ATA-associated alleles decreased with age, the prevalence of ATA significantly decreased with increasing age (25).…”

Section: Genetic Basis Of Juvenile Systemic Sclerosismentioning

confidence: 46%

“…Protective HLA alleles in adult-onset SSc (DRB1 * 07, DQB1 * 02:02) were not found to be protective for jSSc. Instead, DQB1 * 06 was protective for jSSc (25).…”

Section: Genetic Basis Of Juvenile Systemic Sclerosismentioning

confidence: 94%

“…Another main difference from adults with SSc is the lack of anti-centromere antibody–positive patients with jSSc ( leq 5% in most cohorts) (6, 9–13, 25), especially with pre-pubertal patients (<10 years at onset) (10). This is true despite ~30% to 50% of patients with jSSc being clinically classified as limited cutaneous SSc (Table 2).…”

Section: Clinical Aspectsmentioning

confidence: 99%

“…The frequency of the adult limited cutaneous SSc-associated allele DRB1 * 01 differed in children with age of disease onset and autoantibody status (25). DRB1 * 01 was less prevalent in patients who were <6 years of age compared to patients 11–16 years at disease onset.…”

Section: Genetic Basis Of Juvenile Systemic Sclerosismentioning

confidence: 99%

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Immunopathogenesis of Juvenile Systemic Sclerosis

Stevens

Torok

et al. 2019

Front. Immunol.

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Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ manifestations of jSSc resemble adult SSc, but with better outcomes and survival. The etiology of jSSc appears to reflect adult-onset SSc, with similar inflammatory mediators and autoantibodies, but with a significant population of children with uncharacterized anti-nuclear antibodies. The genetics of patients with jSSc differ from women with SSc, resembling instead the genes of adult males with SSc, with additional HLA genes uniquely associated with childhood-onset disease. Current treatments are aimed at inhibiting the inflammatory aspect of disease, but important mechanisms of fibrosis regulated by dermal white adipose tissue dendritic cells may provide an avenue for targeting and potentially reversing the fibrotic stage.

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Section: Genetic Basis Of Juvenile Systemic Sclerosissupporting

confidence: 64%

Section: Genetic Basis Of Juvenile Systemic Sclerosismentioning

confidence: 46%

“…Protective HLA alleles in adult-onset SSc (DRB1 * 07, DQB1 * 02:02) were not found to be protective for jSSc. Instead, DQB1 * 06 was protective for jSSc (25).…”

Section: Genetic Basis Of Juvenile Systemic Sclerosismentioning

confidence: 94%

Section: Clinical Aspectsmentioning

confidence: 99%

Section: Genetic Basis Of Juvenile Systemic Sclerosismentioning

confidence: 99%

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Immunopathogenesis of Juvenile Systemic Sclerosis

Stevens

Torok

et al. 2019

Front. Immunol.

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Transcriptomic Evaluation of Juvenile Localized Scleroderma Skin With Histologic and Clinical Correlation

Schutt

Mirizio

Salgado

et al. 2021

Arthritis & Rheumatology

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Objective Juvenile localized scleroderma (LS) is an autoimmune disease of the skin whose pathogenesis is not well understood due to the rarity of the disease. This study was undertaken to determine the skin transcriptome in skin biopsy tissue from children with juvenile LS compared to pediatric healthy controls, with identification of significant molecular targets using RNA sequencing (RNA‐Seq). In this study, differentially expressed genes (DEGs) were assessed for correlations with histopathologic and clinical features in children with juvenile LS, and were used to group the children into distinct genetic clusters based on immunophenotype. Methods RNA‐Seq was performed on sections of paraffin‐embedded skin tissue obtained from 28 children with juvenile LS and 10 pediatric healthy controls. RNA‐Seq was carried out using an Illumina HTS TruSeq RNA Access library prep kit, with data aligned using STAR and data analysis using a DESeq2 platform. A standardized histologic scoring system was used to score skin sections for the severity of inflammation and levels of collagen deposition. Histologic scoring was completed by 2 pathologists who were blinded with regard to the status of each sample. Spearman’s rank correlation coefficients were used to assess significant correlations between DEG expression profiles and skin histologic findings in patients with juvenile LS. Results We identified 589 significant DEGs in children with juvenile LS as compared to healthy controls. Hierarchical clustering was used to demonstrate 3 distinct juvenile LS immunophenotype clusters. The histologic scores of skin inflammation (based on numbers and categories of inflammatory cell infiltrates) were significantly correlated with the expression levels of HLA–DPB1, HLA–DQA2, HLA–DRA, and STAT1 genes (rs > 0.5, P < 0.01). Collagen thickness correlated with the expression levels of collagen organization genes as well as with genes found to be correlated with the severity of inflammation, including genes for major histocompatibility complex (MHC) class I, MHC class II, and interferon‐γ signaling. Conclusion Among children with juvenile LS, 3 distinct genetic signatures, or clusters, were identified. In one cluster, inflammation‐related pathways were up‐regulated, corresponding to the histologic skin inflammation score. In the second cluster, fibrosis‐related pathways were up‐regulated. In the third cluster, gene expression in the skin corresponded to the patterns seen in healthy controls. Up‐regulation of HLA class II genes was observed within the first cluster (characterized by predominant inflammation), a feature that has also been observed in the peripheral blood of patients with morphea and in the skin of patients with systemic sclerosis.

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Wenn die Haut hart wird und verkalkt

Girschick

2023

Klinische Beispiele Pädiatrische Rheumatologie

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Brief Report: HLA–DRB1, DQA1, and DQB1 in Juvenile‐Onset Systemic Sclerosis

Cited by 17 publications

References 21 publications

Immunopathogenesis of Juvenile Systemic Sclerosis

Immunopathogenesis of Juvenile Systemic Sclerosis

Transcriptomic Evaluation of Juvenile Localized Scleroderma Skin With Histologic and Clinical Correlation

Wenn die Haut hart wird und verkalkt

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