It is well established that leukocyte infiltration of the central nervous system (CNS) is a critical early step in the development of the demyelinating autoimmune disease, multiple sclerosis (MS) however the mechanistic details of this process remain poorly understood. Blocking leukocyte infiltration and destruction of the CNS in a targeted manner remains a significant clinical challenge. The long-term objectives are to develop therapeutics that restore immune tolerance and control autoimmune-mediated destruction of target organs. The obiective of this proposal is to define how stromal cells regulate autoimmune inflammation of the CNS. Stromal cells create inflammatory microenvironments, attract T cells and antigen presenting cells (APCs) into the CNS, create three-dimensional reticular structures that infiltrating leukocytes crawl on, and produce proinflammatory cytokines through interactions with Th17 cells. Moreover, stromal cells can function as APCs and regulate the function of activated T cells in close proximity. The central hvpothesis is that a stromal cell network is essential for the formation of chronic inflammatory lesions in MS. This hypothesis is based on emerging evidence from the literature and preliminary data generated in the applicants'laboratories. The rationale for the proposed research is that elucidating the mechanisms by which stromal cells interact with T cells and APCs at the blood brain barrier and in the CNS parenchyma may illuminate mechanistic insight into this pathogenic process.
Two specific aims will be carried out to test this hypothesis: 1) Define the role of PDPN expression by stromal, cells in leukocyte infiltration of the CNS. and 2) Elucidate the impact of stromal cell-leukocyte cross-talk in the inflamed CNS. As part of the first aim, human brain tissue from MS patients and healthy subjects will be studied to evaluate the interactions between leukocytes and PDPN-expressing stromal cells in lesions. In addition, novel conditional knockout mice will be used to evaluate whether PDPN expression by stromal cells and CLEC-2 expression by dendritic ceils and B ceils affects leukocytic infiltration of the CNS during EAE. In the second aim the impact of autoimmune tissue inflammation on stromal cell interactions with T cells and APCs will be evaluated. Furthermore, the mechanism by which the inflammatory milieu converts FRCs from immunosuppressive to proinflammatory cells will be interrogated. The proposed research is innovative because the contribution of stromal cells to the pathogenesis of MS is an understudied field and the role ofthe PDPN-CLEC-2 axis in leukocyte infiltration of inflamed tissues has not been previously addressed. The study is significant because elucidation ofthe mechanisms by which stromal cells influence APC and T cell function may offer new opportunities for intervention.
Stromal cells create inflammatory microenvironments, attract T cells and antigen presenting cells (APCs) into the central nervous system, create three-dimensional reticular structures that infiltrating leukocytes crawl on, and produce proinflammatory cytokines through interactions with Thi 7 cells. Moreover, stromal cells can function as APCs and regulate the function of activated T cells in close proximity. The contribution of stromal cells to the pathogenesis of multiple sclerosis is an understudied field, and elucidation of the mechanisms by which they interact with APCs and T cells may offer new opportunities for intervention.
|Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang et al. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337-43|
|Fletcher, Anne L; Elman, Jessica S; Astarita, Jillian et al. (2014) Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis. Sci Transl Med 6:249ra109|
|Stern, Joel N H; Yaari, Gur; Vander Heiden, Jason A et al. (2014) B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med 6:248ra107|
|Manzel, Arndt; Muller, Dominik N; Hafler, David A et al. (2014) Role of "Western diet" in inflammatory autoimmune diseases. Curr Allergy Asthma Rep 14:404|
|Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W et al. (2014) Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118-23|
|Zhou, Penghui; Shaffer, Donald R; Alvarez Arias, Diana A et al. (2014) In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 506:52-7|
|Sollid, Ludvig M; Pos, Wouter; Wucherpfennig, Kai W (2014) Molecular mechanisms for contribution of MHC molecules to autoimmune diseases. Curr Opin Immunol 31:24-30|
|Elpek, Kutlu G; Cremasco, Viviana; Shen, Hua et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2:655-67|
|Woodruff, Matthew C; Heesters, Balthasar A; Herndon, Caroline N et al. (2014) Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine. J Exp Med 211:1611-21|
|Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita et al. (2014) Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. J Clin Invest 124:2513-22|
Showing the most recent 10 out of 84 publications