Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease
ABSTRACT Objective. Interstitial lung disease (ILD) is a serious complication of SSc. We aimed to identify markers associated with SSc-related ILD. Methods. RNA was prepared from the peripheral blood mononuclear cells of 14 SSc patients, divided into four different RNA pools according to the presence or absence of ILD and to the treatment, and subjected to microarray analysis. Real-time quantitative PCR was used to confirm the microarray results in 43 SSc patients, 42 autoimmune controls and 10 healthy controls. Genomic DNA samples were collected from 149 patients with SSc (70 in Hokkaido and 79 in Tokyo) who underwent a high-resolution CT for the evaluation of ILD and from 230 healthy controls. Genotyping was performed using sequence-specific primers. Results. The microarray analysis revealed HLA-DRB5 to be the only gene commonly up-regulated in patients with ILD compared with those without ILD in both comparison groups. High expression levels of HLA-DRB5 in SSc patients with ILD were confirmed by real-time quantitative PCR. The prevalence of HLA-DRB5 gene carriers increased in the SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLA-DRB5*01:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls. These associations were confirmed in the second cohort. Conclusion. HLA-DRB5 was highly expressed in PBMCs from patients with SSc-related ILD. The HLA-DRB5*01:05 allele is a risk factor for ILD in patients with SSc.
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ABSTRACT: Systemic lupus erythematosus (SLE) is a polygenic, systemic, autoimmune disease. Copy number variants (CNVS) have been discovered to be associated with a number of complex disorders. We undertook the current study to explore the potential associations between genomic CNVS and SLE in Chinese Han population. In the discovery stage, seven SLE patients were examined with the high-density comparative genomic hybridization microarrays in the screening test for SLE associated CNVS. Then, in the validation stage, 135 SLE patients and 219 matched healthy subjects were investigated for the CNVS of gene HLA-DRB5 by AccuCopy™ technology. Quantitative polymerase chain reaction was carried out to determine the copy number (CN) and mRNA level of HLA-DRB5 in SLE patients. Although the mRNA level of HLA-DRB5 between the CN deletion group and the CN normal group in SLE patients was not statistically positive (P = 0.46), our results still showed more CN of HLA-DRB5 in SLE patients than in healthy controls (P = 3.98 × 10(-6)). Odds ratio for CN deletion was 0.38 (95% confidence interval (CI), 0.23-0.61, P = 7.79 × 10(-5)) and for CN duplication was 1.89 (95% CI, 0.56-7.66, P = 0.37), respectively. These findings indicated that CNVS of HLA-DRB5 was associated with the risk of SLE, and CN deletion appeared to be protective for SLE.Acta Biochimica et Biophysica Sinica 12/2013; 46(2). DOI:10.1093/abbs/gmt137 · 1.81 Impact Factor
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ABSTRACT: The purpose of this study is to review recent hypothesis-driven studies that utilize global gene expression data for elucidating the molecular basis of systemic sclerosis (SSc) and its various clinical manifestations. The longitudinal skin gene expression studies indicate that the previously identified molecular subsets are stable over time and might identify inherent subgroups of SSc patients. Skin transcript follow-up studies indicate that the Wnt/β-catenin pathway plays an important role in promotion of fibrogenesis in fibroblasts and preadipocytes. Furthermore, the transcript profile of sclerodermatous graft-versus-host disease (sclGVHD) mice resembles the skin transcriptomes of a subgroup of SSc patientswith IL13/IL4-inducible skin signature wherein the profibrotic chemokine CCL2 plays a key role. The comparison of skin biopsies from SSc patients to skin lesions of patients with cutaneous lupus and dermatomyositis has provided valuable information about the interferon (IFN) signature in these autoimmune diseases. Furthermore, plasma IFN-inducible chemokines correlate with the IFN gene expression score in SSc patients, enabling researchers to examine this molecular signature in large SSc cohorts with serum or plasma collection. Global gene expression profiling in skin and peripheral blood can contribute to a better understanding of SSc pathogenesis and identify novel biomarkers and therapeutic targets.Current opinion in rheumatology 09/2013; DOI:10.1097/01.bor.0000434672.77891.41 · 5.07 Impact Factor
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ABSTRACT: This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies.Seminars in Respiratory and Critical Care Medicine 04/2014; 35(2):181-200. DOI:10.1055/s-0034-1371527 · 2.75 Impact Factor