The Autoimmunity Center of Excellence based at the Baylor Institute for Immunology Research in Dallas, Texas aims at 1) advancing the knowledge of pathways and mechanisms that contribute to the development and amplification of Human Systemic Autoimmunity, and 2) developing assays and tools to monitor these dysfunctional pathways in patients. The specific proposed research focuses on characterizing triggers, sensors and helpers of systemic autoimmunity. It capitalizes on the availability of samples from pediatric patients, who manifest disease early in life, often present extreme phenotypes and lack co-morbidities that confound the phenotypes. It will focus on diseases where breakdown of tolerance to Nucleic Acids (NAs) and dysregulated production of Type I Interferon (IFN) and/or Follicular Helper T cells (Tfh) play central pathogenic roles. While the initial focus will be the study of patients with Systemic Lupus Erythematosus (SLE), extrapolation of the Center findings to other systemic autoimmune disease scenarios will be pursued. To this end, BIIR has gathered a highly integrated multidisciplinary team composed of scientists (including immunologists, molecular biologists, bioinformaticians, software engineers) and Physician- Scientists/Clinicians. This multidisciplinary team has worked efficiently together for several years at bed-to bench and bench-to-bed translation to meet the challenges of Human Immunology and Medicine. BIIR has also established strong national and international collaborations. The Center will employ in vitro culture techniques using patient cells and knock-down assays of cell lines and primary human cells, immune profiling strategies reflecting human immune status and function, and an extensive infrastructure to support patient-based studies. Throughout the performance of these mechanistic studies, BIIR recognized the fundamental value of data sharing, data integration and data visualization. Thus, significant efforts have been placed at developing the right bioinformatics and software tools to make possible that clinical and research data provide the most useful information to advance clinical and basic discoveries.
The ACE at Baylor aims at 1) advancing the knowledge of mechanisms that contribute to the development and amplification of Human Systemic Autoimmunity, and 2) developing tools to monitor these dysfunctional pathways in patients. The proposed research focuses on triggers, sensors, and helpers of systemic autoimmunity and capitalizes on the availability of samples from pediatric patients who often have extreme cases of autoimmune disease. Principal Project: Novel Pathogenic Roles for Interferon and Autoantibodies in Human SLE Project Leader (PL): Virginia Pascual DESCRIPTION (as provided by applicant): Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation and development of autoantibodies against nucleic acids (NAs). SLE pathogenesis is not fully understood but genomic studies support an interplay between innate and adaptive immunity. Pathogenic loops involving immune complex(IC)-containing NAs that activate innate immune cells such as dendritic cells (DCs), platelets and neutrophils through the endosomal TLR pathway result in plasmacytoid DC (pDC) activation and release of type I IFN. Excessive production and/or sensing of NAs is emerging as a fundamental and upstream event in SLE, and over-expression of IFN-inducible transcriptional signatures is a universal finding, especially in early onset SLE. We and others recently reported that neutrophils release DNA-protein complexes that activate pDCs, thus acting as Danger-Associated Molecular Patterns (DAMPs). DAMPS are extruded upon neutrophil activation with SLE immune complexes (ICs) and directly activate pDCs in an FcB-independent and TLR9-dependent manner. Our preliminary data now show that these DAMPs are composed of damaged (oxidized) mitochondrial DNA-protein complexes (mtDAMPs) released upon type I IFN and anti-Sm/RNP mediated endosomal TLR7 activation of neutrophils. This combination of stimuli impairs the detoxification of oxidized mtDNA through lysosomal degradation, which is a fundamental step leading to the extrusion of interferogenic mtDAMPs. Here, we propose 1) to characterize the basic mechanisms that lead to neutrophil mitochondrial damage and release of mtDAMPs in SLE, 2) to identify the interferogenic components of mtDAMPs and the mechanisms responsible for their internalization in pDCs, and 3) to characterize the effects of SLE mtDAMPs on non-hemopoietic cells that become the target of inflammation in SLE, especially endothelial cells. Overall, these studies will provide a better understanding of how breakdown of tolerance to NAs and dysregulation of the IFN pathway are interconnected and amplify each other. These studies will bring novel insight into SLE autoantibody pathogenic roles and perpetuation of IFN-amplification loops.
Our work supports a previously unsuspected role for neutrophils as a link between lupus-specific nucleic acid-recognizing antibodies and amplification loops for type I IFN production and eventually B cell help. Completion of the project goals will lead to better understanding of these pathways and to the identification of novel therapeutic targets.
|Weng, Leiyun; Mitoma, Hiroki; Trichot, Coline et al. (2014) The E3 ubiquitin ligase tripartite motif 33 is essential for cytosolic RNA-induced NLRP3 inflammasome activation. J Immunol 193:3676-82|
|Rodriguez-Pla, Alicia; Patel, Pinakeen; Maecker, Holden T et al. (2014) IFN priming is necessary but not sufficient to turn on a migratory dendritic cell program in lupus monocytes. J Immunol 192:5586-98|
|Lu, Hongbo; Lu, Ning; Weng, Leiyun et al. (2014) DHX15 senses double-stranded RNA in myeloid dendritic cells. J Immunol 193:1364-72|
|Chiche, Laurent; Jourde-Chiche, Noémie; Whalen, Elizabeth et al. (2014) Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol 66:1583-95|
|Schmitt, Nathalie; Bentebibel, Salah-Eddine; Ueno, Hideki (2014) Phenotype and functions of memory Tfh cells in human blood. Trends Immunol 35:436-42|
|Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2014) The cytokine TGF-? co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat Immunol 15:856-65|
|Banchereau, Romain; Cepika, Alma-Martina; Pascual, Virginia (2013) Systems approaches to human autoimmune diseases. Curr Opin Immunol 25:598-605|
|Bentebibel, Salah-Eddine; Lopez, Santiago; Obermoser, Gerlinde et al. (2013) Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med 5:176ra32|
|Schmitt, Nathalie; Bustamante, Jacinta; Bourdery, Laure et al. (2013) IL-12 receptor ?1 deficiency alters in vivo T follicular helper cell response in humans. Blood 121:3375-85|
|Schmitt, Nathalie; Ueno, Hideki (2013) Human T follicular helper cells: development and subsets. Adv Exp Med Biol 785:87-94|
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