A major project which involves the TIS is the definition of molecular biomarkers for autoimmune and autoinflammatory diseases. In collaboration NHGRI investigators we have observed that monocytes of normal individuals carrying the protective allele, we reported abeing associated with Behcet's disease, express lower levels of IL-23R, and we are now investigating a correlation with the different monocyte populations. Furthemore, we are analyzing the expression of IL-23R in monocytes from patients suffering from Ankylosing Spondilitys (in collaboration with Dr. Mike Ward). In collaboration with the Kastner group, we have also performed whole blood stimulation assays followed by cytokines measurement to support the recently published study that identified patients carrying mutations in the in CECR1 gene, encoding adenosine deaminase 2 (ADA2). Mutation in this gene results in a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy and/or vasculitis. With the Goldbach-Mansky group, studied patients with early onset systemic inflammation, vasculitis, and pulmonary inflammation (SAVI) who were shown to have de novo gain of function mutations in TMEM173 (encoding STimulator of Interferon Genes (STING)). The TIS was responsible for measuring patients serum cytokine levels, which show increase in type I IFNs as well as chemokines such as IP-10 and CCL5. We assessed gene expression in patients fibroblasts stimulated with STING ligands with or without the Jak inhibitor tofacitinib. Interestingly, reduced expression of IFN-regulated genes (CXCL10, MX1 and OAS3) was observed upon drug treatment suggesting a possible therapeutic approach. We are also continuing our collaboration with NHGRI investigators assessing the cytokine-secreting capabilities of patients with Erdheim-Chester Disease (ECD), a rare, non-familial multisystem disorder characterized by proliferation and infiltration of non-Langerhans histocytes into multiple organs. We are comparing the cytokine secretion levels of ECD patients with normal controls after stimulation of PBMCs. Furthermore, the TIS has been investigating novel approaches for the treatment of autoimmune diseases. In collaboration with the O'Shea's group, the Kaplans group, and Pfizer (via a CRADA), we evaluated the efficacy of tofacitinib on a murine model of systemic lupus erythematous (SLE) the MRL/lpr mouse. Tofacitinib treatment results in a significant amelioration of SLE phenotype, including increased serum autoantibody level, nephritis, skin inflammation and inflammatory cytokines including IL-17, IFN-gamma, and TNF-alpha. We found that tofacitinib mitigates the dysregulation of neutrophil function and induced significant improvements in endothelium-dependent vasorelaxation, which is relevant to vascular health. These data supports the concept that tofacitinib may be beneficial in SLE patients. The TIS has continued the project generating inducible pluripotent stem cells (iPS). We generated iPS cells from a patient with HLA B-27+ Ankylosing Spondilitys and one patient with CANDLE as well as one normal control. We have demonstrated their pluripotency and we differentiated iPSCs into MSC and osteoblasts. MSC-derived osteoblasts from patients showed greater mineralization capacity comparing with normal control. We started an iPS gene-editing project . Crispr-CAS9 techniques are applied to change B*27:04 into B*27:06 (non disease-associated allele). The purpose of the project is to assess role of the gene in the disease process. The TIS is also providing support to several projects carried out at NIAMS to improve the understanding of the genetic determinants of autoimmune, autoinflammatory and musculoskeletal diseases using the Illumina HiSeq 2500 and the MiSeq for ultra high-throughput DNA sequencing. With Aster Juan in Sartorellis group we continue working on the hyperactive Ezh2 project by checking the H3K27 methylation status using ChIP-seq and RNA-seq. We also check the global Notch binding in ES cells by ChIP-seq. Also with Hong Jun Wang, we study how Spt6 regulates H3K27me3 by counteracting PRC2 complex in mESC. Pei-Fang Tsai project is to determine localization of the enhancer RNAs by comparing RNAs from different cell fractions and to identify the possible isoforms performing ChIP-seq, RNA-seq, and GRO-seq for the project. Xuesong Feng continues studying the function of Ezh2 in regulating embryonic cerebellum development to dissect the role of Ezh2 on the cerebellar gene expression.. Also Dr. Sartorelli and Stan Wang are collaborating with Sir John Gurdons (University of Cambridge) to study the effects of epigenetic modification on nuclear reprogramming. They have performed nuclear transfer with samples pre-treated with various factors that remove DNA methylation, deubiquitinate histone H2A, or remove other histone marks.. This work provides insight into the fundamental mechanisms that restrict the ability for cells to be reprogrammed. With Dr. OShea and Yuka Kanno our efforts are focused on analyzing genomic organization of T lymphocytes to understand gene regulatory mechanism for T helper cell fate specification and function. We recently introduced ATAC-seq to understand chromatin accessibility among T helper subsets and innate lymphocytes. We have also extended our catalogue of transcription factor mapping and histone epigenetic mapping to create chromatin state map for T cells and innate lymphocytes. We reported progressive opening of IL-10 locus in natural killer cells following virus infection and also we have explored the role of type I IFN in regulating T helper subset called follicular helper T cells. With Dr. Casellas and Kyong-Rim Kieffer we investigate to what extent epigenetic feature is dynamically changed during cellular activation of B-cells and how such modulation impacts cellular activation. We measure and compare various histone marks, nucleosome binding, transcription factor binding, DNA (de) methylation and nascent transcript along the activation using sequencing technology. With Dr. Morasso we study Dlx3's functions in inflammation. We investigate the genes altered immediately after dlx3 deletion before the skin diseases is observed. With Olivier Duverger we use DNA sequencing facility to investigate the function of Dlx3 in enamel formation. RNA-seq is also used to characterize the transcriptome of enamel organs in which Dlx3 was deleted using a conditional knockout approach Also ChIP-seq analysis is being used to identify direct targets of Dlx3 in the same tissue and two different ameloblast cell lines. With Dr. Leon Nesti and Youngmi Ji we perfomed RNA-Seq studies to elucidate how activation via injury affects the mesenchymal progenitor cells and if trauma contributes to pathological differentiation of these cells and formation of heterotopic ossification. With Dr. Goldbach-Mansky and Adriana Almeida de Jesus we evaluate whole blood gene expression profiles in pediatric autoinflammatory diseases patients. The pathways most significantly contributing to the disease were also determined through IPA. Patients presenting with an undifferentiated clinical phenotype were evaluated individually. Andres Canela in Dr. Nussenzweig group (NCI, studies the role of MLL4 in lymphomagenesis using a conditional mouse model in B-cells. We are using genomic approaches primary B-cells and lymphomas to study and gain more insights of the changes that in the absence of MLL4 give rise to lymphomagenesis. With Dr. Aksentijevich and Qing Zhou we performed targeted deep re-sequencing of NLRP3 in 19 patients with late onset urticaria. The nine exons of NLRP3 were covered by twelve amplicons. Samples were sequenced using single and pair-end sequencing and data showed that all of 19 patients dont have somatic mutation in NLRP3 gene.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
City
State
Country
Zip Code
Gadina, Massimo; Gazaniga, Nathalia; Vian, Laura et al. (2017) Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases. J Autoimmun 85:20-31
Layh-Schmitt, Gerlinde; Lu, Shajia; Navid, Fatemeh et al. (2017) Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors. Clin Rheumatol 36:143-154
Demirkaya, Erkan; Zhou, Qing; Smith, Carolyne K et al. (2017) Brief Report: Deficiency of Complement 1r Subcomponent in Early-Onset Systemic Lupus Erythematosus: The Role of Disease-Modifying Alleles in a Monogenic Disease. Arthritis Rheumatol 69:1832-1839
Banerjee, Shubhasree; Biehl, Ann; Gadina, Massimo et al. (2017) JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs 77:521-546
Sciumè, Giuseppe; Le, Mimi T; Gadina, Massimo (2017) HiJAKing Innate Lymphoid Cells? Front Immunol 8:438
Takeuchi, Masaki; Mizuki, Nobuhisa; Meguro, Akira et al. (2017) Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat Genet 49:438-443
Furumoto, Yasuko; Smith, Carolyne K; Blanco, Luz et al. (2017) Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction. Arthritis Rheumatol 69:148-160
Rodriguez-Smith, Jackeline; Lin, Yen-Chih; Tsai, Wanxia Li et al. (2017) Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood-Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Centra Arthritis Rheumatol 69:1325-1336
Zhou, Qing; Yu, Xiaomin; Demirkaya, Erkan et al. (2016) Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A 113:10127-32
Andriani, Grasiella Angelina; Almeida, Vinnycius Pereira; Faggioli, Francesca et al. (2016) Whole Chromosome Instability induces senescence and promotes SASP. Sci Rep 6:35218

Showing the most recent 10 out of 40 publications