Research Projects Study of the role of the cytoskeleton and motor proteins during immune responses in autoimmune diseases
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases characterized by muscle inflammation. Based on clinical, histopathological, and immunological features, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM) are the major IIM forms. DM is characterized by a complement-mediated microangiopathy affecting skin and muscle, PM and IBM are T cell-mediated diseases, where clonally expanded cytotoxic T cells invade single non-necrotic muscle fibers MHC-I+, leading to fiber necrosis. In IIMs, muscle cells appear to possess the necessary requirements for antigen presentation, behaving as non-professional antigen-presenting cells (APCs) and therefore participating to the formation of the immunological synapse (IS) with T cells. The IS set up requires the remodeling of cytoskeleton, comprising microtubule-organizing center (MTOC) translocation towards T cell/APC interface, reorganization of lipid rafts for the constitution of supramolecular activation clusters (SMACs), intracellular antero or retrograde trafficking of molecules and vesicles.
Aim of the present project is to elucidate the role of the cytoskeletal dynamics in the formation, organization and functionality of the IS between muscle fiber and T cell. A better comprehension of the molecular interactions between muscle fibers and T cells might be of help in identifying new targets for innovative therapeutic interventions aimed to reduce muscular injury and to improve clinical conditions of IIM patient.
Study of the role of histamine in immune regulation in EAE (experimental autoimmune encephalomyelitis) and MS (multiple sclerosis)
Histamine is one of the main mediators of human and murine anaphylaxis, but it can modulate the cytokine network, and influence T helper 1 and T helper 2 balance and antibody-isotype switching. Thus, pharmacological blockade or genetic deletion of specific histamine receptors have been shown to reduce the severity of experimental autoimmune encephalomyelitis (EAE), a prototypic Th1 mediated disease with similarities to human multiple sclerosis (MS).
Aims of the present work are: i. to study the comprehensive contribution of endogenous histamine to the expression of EAE in histidine decarboxylase (HDC)-deficient mice, which are genetically unable to make histamine; ii. to study how the specific histamine receptors (H1R, H2R, H3R, H4R) modulate the cellular response in vitro on a T cell line activated against a myelin peptide by evaluating the effects of specific receptors agonists and antagonists.
Understanding which receptors are involved in the effects mediated by histamine in the EAE model might help in designing new treatments for EAE and, possibly, for MS.
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