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B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients.

ABSTRACT: Autoimmune regulator (Aire)-deficient mice and humans have circulating autoantibodies against a multitude of organs and multiorgan autoinflammatory infiltrates. It is not known to what extent autoantibodies or their source, B lymphocytes, are required for disease onset or progression. We show in this research that B cells must be present for Aire-deficient mice to develop fulminant infiltrates. We found no evidence that autoantibodies were directly pathogenic; rather, B cells appeared to play a critical early role in T cell priming or expansion. A therapeutic reagent directed against B cells, Rituximab, induced remission of the autoimmune disease in Aire-deficient mice, raising the hope of applying it to human patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

SUBMITTER: Gavanescu I

PROVIDER: S-EPMC2529049 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients.

Gavanescu Irina I Benoist Christophe C Mathis Diane D

Proceedings of the National Academy of Sciences of the United States of America 20080828 35

Autoimmune regulator (Aire)-deficient mice and humans have circulating autoantibodies against a multitude of organs and multiorgan autoinflammatory infiltrates. It is not known to what extent autoantibodies or their source, B lymphocytes, are required for disease onset or progression. We show in this research that B cells must be present for Aire-deficient mice to develop fulminant infiltrates. We found no evidence that autoantibodies were directly pathogenic; rather, B cells appeared to play a ...[more]

PMID: 18755889

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Project description:Despite all epidemiological, clinical, and experimental research efforts, therapeutic concepts in sepsis and sepsis-induced multi-organ dysfunction syndrome (MODS) remain limited and unsatisfactory. Currently, gene expression data sets are widely utilized to discover new biomarkers and therapeutic targets in diseases. In the present study, we analyzed MODS expression profiles (comprising 13 sepsis and 8 control samples) retrieved from NCBI-GEO and found 359 differentially expressed genes (DEGs), among which 170 were downregulated and 189 were upregulated. Next, we employed the weighted gene co-expression network analysis (WGCNA) to establish a MODS-associated gene co-expression network (weighted) and identified representative module genes having an elevated correlation with age. Based on the results, a turquoise module was picked as our hub module. Further, we constructed the PPI network comprising 35 hub module DEGs. The DEGs involved in the highest-confidence PPI network were utilized for collecting pathway and gene ontology (GO) terms using various libraries. Nucleotide di- and triphosphate biosynthesis and interconversion was the most significant pathway. Also, 3 DEGs within our PPI network were involved in the top 5 significantly enriched ontology terms, with hypercortisolism being the most significant term. PRKAR1A was the overlapping gene between top 5 significant pathways and GO terms, respectively. PRKAR1A was considered as a therapeutic target in MODS, and 2992 ligands were screened for binding with PRKAR1A. Among these ligands, 3 molecules based on CDOCKER score (molecular dynamics simulated-based score, which allows us to rank the binding poses according to their quality and to identify the best pose for each system) and crucial interaction with human PRKAR1A coding protein and protein kinase-cyclic nucleotide binding domains (PKA RI alpha CNB-B domain) via active site binding residues, viz. Val283, Val302, Gln304, Val315, Ile327, Ala336, Ala337, Val339, Tyr373, and Asn374, were considered as lead molecules.

Project description:BackgroundMedullary thymic epithelial cells (mTECs) are characterized by ectopic expression of self-antigens during the establishment of central tolerance. The autoimmune regulator (Aire), which is specifically expressed in mTECs, is responsible for the expression of a large repertoire of tissue-restricted antigens (TRAs) and plays a role in the development of mTECs. However, Aire-deficient mTECs still express TRAs. Moreover, a subset of mTECs, which are considered to be at a stage of terminal differentiation, exists in the Aire-deficient thymus. The phenotype of a specific cell type in a multicellular organism is governed by the epigenetic regulation system. DNA methylation modification is an important component of this system. Every cell or tissue type displays a DNA methylation profile, consisting of tissue-dependent and differentially methylated regions (T-DMRs), and this profile is involved in cell-type-specific genome usage. The aim of this study was to examine the DNA methylation profile of mTECs by using Aire-deficient mTECs as a model.ResultsWe identified the T-DMRs of mTECs (mTEC-T-DMRs) via genome-wide DNA methylation analysis of Aire(-/-) mTECs by comparison with the liver, brain, thymus, and embryonic stem cells. The hypomethylated mTEC-T-DMRs in Aire(-/-) mTECs were associated with mTEC-specific genes, including Aire, CD80, and Trp63, as well as other genes involved in the RANK signaling pathway. While these mTEC-T-DMRs were also hypomethylated in Aire(+/+) mTECs, they were hypermethylated in control thymic stromal cells. We compared the pattern of DNA methylation levels at a total of 55 mTEC-T-DMRs and adjacent regions and found that the DNA methylation status was similar for Aire(+/+) and Aire(-/-) mTECs but distinct from that of athymic cells and tissues.ConclusionsThese results indicate a unique DNA methylation profile that is independent of Aire in mTECs. This profile is distinct from other cell types in the thymic microenvironment and is indicated to be involved in the differentiation of the mTEC lineage.

Dataset Information

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients.

Publications

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients.

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