Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Microarray of blood samples of APS-1 patients and matched healthy controls

ABSTRACT: Autoimmune polyendocrine syndrome type I (APS-1) is a rare and devastating organ-specific autoimmune disease characterised by mutations in the Autoimmune Regulator (AIRE) gene. As AIRE is crucial for negative selection in the thymus, increased numbers of undesirable autoreactive T cells are released into the blood with the potential to cause tissue injury, including endocrine organ failure, chronic mucocutaneous candidiasis and hepatitis. B cells are also affected and produce high amounts of neutralising autoantibodies against both cytokines and organ-specific targets. The Aire-deficient mouse model has informed to some extent about immunological aspects of APS-1, but the rarity of APS-1 and inaccessibility of thymic tissue have severely limited immunological studies in patients. Sampling of APS-I patients and controls was performed in standardized manners in PAXgene blood RNA tubes (PreAnalytix, Qiagen, Hombrectikon, Switzerland) and stored at 80ºC until use. Purification of RNA was achieved by the PAXgene blood RNA kit following the instructions from the manufacturer. Samples were quality assessed by Agilent Bioanalyzer, using the Agilent 6000 Nano kit (Agilent, Santa Clara, CA, USA), providing RNA with RNA integrity numbers (RIN) above 6.0. The samples were randomly distributed into 4 batches for RNA extraction, each with 4 patients and 4 sex- and age matched controls and was extracted by the same person on the same day. Following the procedures from Illumina, RNA was subsequently transformed to cRNA, and these constructs were labeled, amplified and quality-checked again by the Agilent Bioanalyzer. The cRNAs were then hybridized to 4 Illumina HumanRef-8 BeadChip microarrays, followed by washing and scanning according to the protocol. Quality control of the arrays was done by BeadStudio.

ORGANISM(S): Homo sapiens

SUBMITTER: David Dolan

PROVIDER: E-MTAB-11630 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. Methods: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. Results: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. Conclusions: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Project description:Down syndrome (DS) patients frequently develop organ-specific autoimmune disorders, particularly endocrinopathies and coeliac disease, as well as an increased susceptibility to mucosal candidiasis. These clinical features resemble APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy), a monogenic condition due to mutations in the AIRE gene, located on 21q22.3 and already described as down-regulated in 21 trisomy. Here we investigated AIRE expression and global gene expression profiles in surgically removed thymuses from 14 DS infants and children with congenital heart defects and from 42 age-matched individuals with cardiac defect as an isolated malformation. Immunohistochemistry revealed significantly reduced AIRE expression in DS thymuses (70.48M-BM-149.59 positive cells/mm2 in DS X 154.70M-BM-161.16 in controls, p<0.0001). qPCR confirmed the lower expression of AIRE in DS thymuses. Global thymic RNA profiles from DS patients and controls revealed 407 genes significantly hypoexpressed in DS. Network transcriptional analysis showed that hypoexpressed genes are related to biological processes such as antigen processing and presentation of endogenous antigen (ERAP2, CD1D), negative (PRDX2) and positive (CD3D, CD74) thymic T-cell selection and homeostasis of number of cells (PRDX2). Altogether these findings may explain the high prevalence of autoimmune phenomena in DS patients. Moreover, our data are in accordance with previous findings of thymic abnormal development in DS patients, characterized by lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation. Global gene profiles indicate that in DS patients, the trisomic imbalance probably leads to thymic hypofunction. In conclusion, lower AIRE expression and the impairment of other crucial pathways for central tolerance could well explain the high prevalence of organ-specific autoimmune disorders in DS. Among the 14 DS infants and 42 age-matched individuals with cardiac defect, only 4 from each group provided enough biological material (thymus fragments) for isolation of high-quality RNA to perform array analysis. Eight thymic samples were analyzed: C1, C2, C3 and C4 are controls, and D1, D2, D3 and D4 are from patients with Down syndrome.

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Microarray of blood samples of APS-1 patients and matched healthy controls

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