Franck Barrat, PhD

Education

Bachelor’s Degree in Biochemistry at University of Nice (France)

Master's Degree (Diplome d’Etude Approfondie) in Immunology at the Pasteur Institute (France)

Master's Degree in Pharmacology (Magistère) at University of Nice (France)

Ph.D. in Immunology at University of Paris 7 (France)

Selected Publications

Diana J., Simoni Y., Furio L., Beaudoin L., Agerberth B., Barrat F. and Lehuen A. (2013). Innate immune cells initiate autoimmune diabetes: Critical role for neutrophils, B-1a cells and plasmacytoid dendritic cells. Nature Med. 19(1):65-73

Garcia-Romo G., Caielli S., Vega B., Connolly J., Allantaz F., Xu Z., Punaro M., Baisch J., Guiducci C., Coffman R.L., Barrat F.J., Banchereau J. and Pascual V. (2011). Neutrophils in Systemic Lupus Erythematosus. Science Transl. Med. 3:73ra20

Guiducci C., Tripodo C., Gong M., Sangaletti S., Colombo M.P., Coffman R.L. and Barrat F.J. (2010). TLR Recognition of Self Nucleic Acids Promotes Autoimmune Skin Inflammation via Activation of Plasmacytoid Dendritic Cells. J. Exp. Med. 207:2931-42

Guiducci C., Gong M., Xu Z., Gill M., Chaussabel D., Meeker T., Chan J.H., Wright T., Punaro M., Bolland S., Soumelis V., Banchereau J., Coffman R.L., Pascual V. and Barrat F.J. (2010). TLR Recognition of Self Nucleic Acids Hampers Glucocorticoids Activity in lupus. Nature. 465:937-41

Guiducci C., Ghirelli C., Marloie-Provost  M.A., Matray T., Coffman R.L., Liu Y.J.,  Barrat F.J. and Soumelis V. (2008). PI3-Kinase is Critical for the Nuclear Translocation of IRF-7 and IFN-a Production by Human Plasmacytoid Pre-Dendritic Cells in Response to TLR Activation. J.Exp.Med. 205:315-22

Barrat F.J., Meeker T., Chan J.H., Guiducci C. and Coffman R.L. (2007). Inhibition of Both TLR7 and TLR9 in Lupus Prone Mice Lead to Reduction of Autoantibody Production and Amelioration of Disease Symptoms. Eur.J.Immunol. 37:3582-3586

Guiducci C., Ott G., Chan J.H., Damon E., Calacsan C., Matray T., Lee K.D., Coffman R.L. and Barrat F.J. (2006).  Properties Regulating the Nature of Plasmacytoid Dendritic Cells Response to TLR9 Activation. J.Exp.Med. 203:1999-2008

Barrat F.J, Meeker T., Gregorio J., Chan J.H., Uematsu S., Akira S., Chang B., Duramad O. and Coffman R.L. (2005). Nucleic Acids of Mammalian Origin Can Act as Endogenous Ligands for Toll-like Receptors and May Promote Systemic Lupus Erythematosus. J.Exp.Med. 202: 1131-1139

Duramad O., Fearon K.L., Chang B., Chan J.H., Gregorio J., Coffman R.L. and Barrat F.J. (2005).  Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation. J.Immunol. 174: 5193-5200

Duramad O., Fearon K.L., Chan J.H., Kanzler H., Marshall J.D., Coffman R.L. and Barrat F.J. (2003). IL-10 Regulates Plasmacytoid Dendritic Cell Response to CpG Containing ImmunoStimulatory Sequences. Blood 102: 4487-92

Barrat F.J., Cua D.J., Boonstra A., Richards D.F., Crain C., Savelkoul H.F., de Waal Malefyt R., Coffman R.L., Hawrylowicz C.M. and O'Garra A. (2002). In vitro generation of IL-10 producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by Th1 and Th2-inducing cytokines. J.Exp.Med. 195: 603-616       

Barrat F.J., Le Deist F., Benkerrou M., Bousso P., Feldmann J., Fischer A. and de Saint Basile G. (1999). Defective CTLA-4 cycling pathway in Chediak-Higashi Syndrome: a possible mechanism for deregulation of T lymphocyte activation. Proc Natl Acad Sci 96: 8645-8650.

Pastural E., Barrat F.J., Dufourcq Lagelouse R., Certain S., Sanal O., Jabado N., Seger R., Griscelli C., Fischer A. and de Saint Basile G. (1997). Griscelli disease maps to chromosome 15q21 and is associated with mutations in the Myosin-Va gene. Nature Genet. 16: 289-292.

For more publications, please see the PubMed listing.

Research Description

The main interest of the lab is centered on the basic understanding of nucleic acid recognition in autoimmunity and in particular on the potential clinical benefit of interfering with Toll Like Receptor (TLR) signaling in human diseases.  We are using both human and mouse approaches and have focused on the role of the nucleic-acid specific TLR7, TLR8 and TLR9 in inflammation. The other main focus of the lab is to better understand the biology of human plasmacytoid dendritic cells (PDC). 

The innate immune system faces the same fundamental challenge as the adaptive immune system -distinguishing self- from non–self-antigens. There is now considerable evidence that self-recognition through TLR can occur and can contribute significantly to sterile inflammation and autoimmunity. This seems well established for the four TLRs specific for nucleic acids and their strict compartmentalization in endosomes appears to be the major mechanism to prevent self-reactivity to host nucleic acids. This mechanism however fails when nucleic acids are not degraded fast enough, are presented to the cells in the form of immune complexes or bound to cationic peptides and when there is an excessive expression of the sensing TLR. In particular, there is a strong rationale linking the activation of TLR7&9 in lupus. The lab is working on the impact of self-nucleic acid recognition by TLR7&9 in cutaneous and systemic inflammation and we have developed novel oligonucleotide-based inhibitors of TLR7&9 which are currently being tested in a trial in lupus patients. The lab is now focusing on the function and role of TLR8 in inflammation. TLR8 signaling induces important inflammatory cytokines such as IL-6 and TNF, and TLR8 is expressed by multiple cell types involved in inflammatory diseases. However, the lack of useful rodent models - a consequence of the very different ligand specificity of human TLR8 and its rodent orthologs - has proven to be a major limitation in the study of TLR8 biology.  The lab is developing new tools to study this receptor in patients with autoimmune diseases but also in vivo using novel approaches to circumvent the lack of function in mouse models.  

Human PDC represent a link between innate and adaptive immunity. They can either produce massive amount of type I IFN and participate in anti-viral responses or they can mature, by expressing costimulatory molecules and losing their plasmacytoid morphology, to become effective antigen presenting cells that activate T cells.  We have shown that these 2 functions are induced following TLR signaling and can be differentially affected by the cytokine milieu and by the signaling molecules involved in the TLR pathway. We also described that endosomal location – not physical form or valency –is the primary determinant of the signaling pathway utilized by TLR9 in human PDC. This unique role of PDC in immunity is a main interest in the lab and is at the basis of many potential clinical applications in particular for the treatment of cancer, allergies and viral infections.

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Contact Information

Office Locations

Caspary Research Building
541 East 71st Street
New Yok, NY 10021

 

Tel: 646.797.8452

Mailing Address

Hospital for Special Surgery
535 East 70th Street
New York, New York 10021