Vitiligo and pigmentary disorders associated with inflammation
keywords: Vitiligo, pigmentation, inflammation
The main goal of the immuno-dermatology project is to develop basic and translational research programs on vitiligo and pigmentary changes associated with skin inflammation, and to consolidate the collaboration with the department of dermatology (National Reference Center for Skin Diseases) and the clinical research program already internationally well recognized in the field.
Vitiligo remains to date the major depigmenting disorder with a real social impact and without effective treatment. The classical hallmark of vitiligo is the disappearance of melanocytes. While several theories have been proposed to explain the pathomechanism of the disease, intrinsic defects of melanocytes with local increased production of ROS, associated with an exaggerated immune response, appear important.
The impact of the immune response in vitiligo will be based on the new concepts of skin immune surveillance. Several immune cell types populate human healthy skin, including dendritic cells, which have a crucial role at the interface between the environment, the epithelium, and adaptive immune cells. In addition, recent progresses have been made in the description and function of skin immune T cells and the newly described skin resident effector memory T cells (TRM). Skin TRM are characterized by the expression of CD69 and CD103 and have the capacity to locally proliferate in skin, and produce large amount of multiple cytokines under local stimulation. Precisely, our project investigates the role of T, especially TRM cell subsets and the soluble factors produced in the process leading to melanocyte loss in vitiligo through both clinical and fundamental research studies. A particular attention is given to the phenotype and function of these cells. Ultimately, our goal, based on our ongoing research, is to define a specific target that will eventually lead to novel therapeutic interventions to improve vitiligo management.
Additionally, we aim to decipher the role of the immune response leading to melanocyte loss, particularly on the function, survival, and adhesion of melanocytes. Understanding the interplay between the immune response and the deregulation of the function and phenotype of melanocytes remain important. This interaction between the immune response and melanocytes is better studied using epidermal reconstruction with melanocytes and in-vivo models, which has allowed the modelization of the melanocytorrhagy hypothesis formulated by our group in 2003. Our recently published research identifies new mechanisms for the understanding of the mechanism leading to the loss of melanocytes in vitiligo (patents: WO2018109222A1 and EP 3336175 A1, JCI insight 2020). We showed that the combined activity of two pro-inflammatory cytokines interferon (IFN)-g and tumor necrosis factor (TNF)-a induces melanocyte detachment rather than death in vitro and in vivo and this phenomenon is dependent of the increased expression of activated matrix metalloproteinase 9 (MMP9), leading to the cleavage of E-cadherin, important for the stability of melanocytes.
Moreover, we are developing models useful for the understanding of pigmentary disorders associated with inflammation that could be seen during the course of chronic inflammatory diseases such as psoriasis, atopic dermatitis or scleroderma.
Watch the Pr Julien Seneschal’s talk at the last European for Dermatological Research meeting in 2017 in the link below.
Pr Julien Seneschal’s talk at the ESDR meeting 2017
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- Type-1 Cytokines Regulate Matrix metalloprotease-9 Production and E-cadherin Disruption to Promote Melanocyte Loss in Vitiligo Boukhedouni N, Martins C, Darrigade AS, Drullion C, Rambert J, Barrault C, Garnier J, Jacquemin C, Thiolat D, Lucchese F, Morel F, Ezzedine K, Taieb A, Bernard FX, Seneschal J, Boniface K. JCI Insight ()
- Phenotype and Function of Circulating Memory T Cells in Human Vitiligo Martins C, Darrigade AS, Jacquemin C, Barnetche T, Taieb A, Ezzedine K, Boniface K, Seneschal J. Br J Dermatol ()
- NKG2D defines a subset of skin effector memory CD8 T cells with pro-inflammatory functions in vitiligo: Skin NKG2D+ CD8+ TEM cells in human vitiligo. Jacquemin C, Martins C, Lucchese F, Thiolat D, Taieb A, Seneschal J, Boniface K J Investit Dermatol ()
- Association of skin hyperpigmentation disorders with digital ulcers in systemic sclerosis: Analysis of a cohort of 239 patients. V. Leroy, P. Henrot, T. Barnetche, M. Cario, A.S. Darrigade, P. Manicki, M.S. Doutre, E. Lazaro, J. Constans, D. Barcat, J.P. Vernhes, C. Richez, A. Taieb, M.E. Truchetet, J. Seneschal; Fédération Hospitalo-Universitaire–Aquitaine's Care and Research Organisation for Inflammatory and Immune-Mediated Diseases. J Am Acad Dermatol ()
- Vitiligo as a skin memory disease: The need for early intervention with immunomodulating agents and a maintenance therapy to target resident memory T cells. K. Boniface, J. Seneschal Exp Dermatol ()
- Imbalance of peripheral follicular helper T lymphocyte subsets in active vitiligo. Jacquemin C, Taieb A, Boniface K, Seneschal J Pigment Cell Melanoma Res () 2018
- Vitiligo: Focus on Clinical Aspects, Immunopathogenesis, and Therapy. Boniface K, Seneschal J, Picardo M, Taïeb A Clin Rev Allergy Immunol. () DOI: 10.1007/s12016-017-8622
- Vitiligo Skin Is Imprinted with Resident Memory CD8 T Cells Expressing CXCR3. Boniface K, Jacquemin C, Darrigade AS, Dessarthe B, Martins C, Boukhedouni N, Vernisse C, Grasseau A, Thiolat D, Rambert J, Lucchese F, Bertolotti A, Ezzedine K, Taieb A, Seneschal J. J Invest Dermatol () PMID: 28927891
- Vitiligo-like lesions in patients receiving anti-programmed cell death-1 therapies are distinct from spontaneously occurring active vitiligo. Boniface K, Dutriaux C, Prey S, Taieb A, Seneschal J. J Am Acad Dermatol. () PMID: 29241800
- Toxicity profiles of immunotherapy. Cousin S, Seneschal J, Italiano A. Pharmacol Ther. () PMID: 28716652
- HSP70 potentiates interferon-alpha production by plasamcytoid dendritic cells : relevance for cutaneous lupus and vitiligo pathogenesis. C. Jacquemin, J. Rambert, S. Guillet, D. Thiolat, N Boukhedouni, MS Doutre, AS Darrigade, K Ezzedine, P. Blanco, A. Taieb, K. Boniface, J Seneschal. Brit J Dermatol ()
- Vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies are clinically and biologically distinct from vitiligo M. Larsabal*, A. Marti1* , C. Jacquemin, J. Rambert, D. Thiolat, L. Dousset, A. Taieb, C. Dutriaux, S. Prey, K. Boniface*, J. Seneschal. *equally contribution J Am Acad Dermatol () DOI: 10.1016/j.jaad.2016.10.
- OX40 Ligand Contributes to the Pathogenesis of Autoiimunity by Promoting T follicular Helper Response. * equally contribution C. Jacquemin*, N. Schmitt*, C. Contin-Bordes*, Y. Liu, P. Narayanan, J. Seneschal, T. Maurouard, D. Dougall, E. Spence Davizon, H. Dumortier, I. Douchet, L. Raffray, C. Richez, E. Lazaro, P. Duffau, M.E. Truchetet, L. Khoryati, P. Mercié, L. Couzi, P. Merville, T. Schaeverbeke, J.F. Viallard, J.L. Pellegrin, J.F. Moreau, S. Muller, R.L. Coffman, V. Pascual, H. Ueno* and P. Blanco*. *equally contribution Immunity () 42;1159-70
- Type I Interferon signature in the initiation of the immune response in vitiligo. A. Bertolotti, K. Boniface, B. Vergier, MD. Mossalayi, A. Taieb, K. Ezzedine, J. Seneschal. Pigment Cell Melanom Res. () 27:398-407
- Human Epidermal Langerhans Cells Maintain Immune Homeostasis in Skin by Activating Skin Resident Regulatory T Cells. J. Seneschal, R.A.Clark, A. Gehad, Clare M. Baecher-Allan, T.S. Kupper. Immunity. () 873-8
- Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic-AMP and EP2/EP4 receptor signaling Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, McKenzie BS, Kastelein RA, Cua DJ, de Waal Malefyt R. J. Exp. Med. () 206(3):535-548.
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