Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and an important cause of short and long-term disability. Systemic Onset Juvenile Idiopathic Arthritis (SoJIA) represents up to 20percent of all the cases of JIA. This disease does not respond to conventional therapies or anti-TNF agents and it leads to serious disabilities in a large proportion of patients. During the past 4 years we have addressed most of the aims that were included in our original application. This has resulted in the following advances: 1) identification of Interleukin-1 as a major mediator of the systemic phase of the disease, 2) resolution of clinical symptoms upon initiation of IL-1 blockade, 3) identification of a signature specific to the initial, systemic phase of the disease that permits to establish the diagnosis against a panel of other febrile illnesses, 4) identification of the cell type that gives rise to this SoJIA-specific signature, 5) identification of environmental agents that trigger a dysregulated IL-1B production by SoJIA blood cells, 6) identification of the neutrophil as a potential major source of IL-1B in SoJIA, 7) identification of transcripts that are differentially regulated in SoJIA versus healthy controls in response to environmental agents. These transcripts represent candidates for genetic analysis. Our hypothesis is that SoJIA arises as the result of an inappropriate response of the innate immune system to an environmental insult. This inappropriate response very likely has a genetic basis. Having identified one of the potential triggers of IL-1 overproduction, and counting on an in vitro assay to test the effect of these and novel triggers on cells from patients and controls, we are now in a good position to select candidate genes for genetic and functional analyses.
The specific aims of our current application are: 1. To confirm and extend our observations that candidate blood gene signatures are SoJIA-specific and can be used as diagnostic tools. 2. To further characterize the cell type(s) giving rise to the unique SoJIA gene signature. 3. To characterize the role of infectious agents in the initial stage and acute exacerbations/flare-ups of patients with SoJIA. Completion of these studies will set the stage for future experiments aimed at characterizing candidate genes at the genetic level and at ascertaining their contribution to IL-1B dysregulation. To perform these studies, we have secured collaborations with infectious disease experts, statisticians, geneticists and experts in the biology and regulation of IL-1 activation. The results of these studies will have immediate clinical and basic immunology applications and should contribute to improve the outlook of children suffering from this often devastating disease.

Public Health Relevance

The successful accomplishment of this project would have significant consequences on SoJIA patients, including the availability of a simple diagnostic test and the identification of potential environmental triggers that may lead to novel therapeutic and/or preventive approaches. These studies will also set the stage for future discovery of susceptibility genes that could be used for screening and diagnostic purposes as well. Understanding the basis of IL-1 dysregulation might shed light on very basic aspects of cytokine biology and help finding novel therapeutic targets for this disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Wang, Yan Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor Research Institute
United States
Zip Code
Cepika, Alma-Martina; Banchereau, Romain; Segura, Elodie et al. (2017) A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med 214:3449-3466
Simonini, Gabriele; Xu, Zhaohui; Caputo, Roberto et al. (2013) Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis Rheum 65:513-8
Xu, Wei; Joo, HyeMee; Clayton, Sandra et al. (2012) Macrophages induce differentiation of plasma cells through CXCL10/IP-10. J Exp Med 209:1813-23, S1-2
Banchereau, Romain; Jordan-Villegas, Alejandro; Ardura, Monica et al. (2012) Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. PLoS One 7:e34390
Banchereau, Jacques; Pascual, Virginia; O'Garra, Anne (2012) From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol 13:925-31
Boisson, Bertrand; Laplantine, Emmanuel; Prando, Carolina et al. (2012) Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 13:1178-86
Garcia-Romo, Gina S; Caielli, Simone; Vega, Barbara et al. (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3:73ra20
Pascual, Virginia; Chaussabel, Damien; Banchereau, Jacques (2010) A genomic approach to human autoimmune diseases. Annu Rev Immunol 28:535-71
Berry, Matthew P R; Graham, Christine M; McNab, Finlay W et al. (2010) An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466:973-7
Obermoser, G; Pascual, V (2010) The interferon-alpha signature of systemic lupus erythematosus. Lupus 19:1012-9

Showing the most recent 10 out of 18 publications