Role of innate immune cells in the development of autoimmune disorders

Data inizio
1 luglio 2011
Durata (mesi) 
48
Responsabili (o referenti locali)
Scapini Patrizia

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex and unclear etiology that is thought to result from the interaction between genetic and environmental factors. Most studies of this disease have focused on defects of B and T cell selection/tolerance as an underlying cause of the disorder. Recently, greater attention has been given to investigate the role of myeloid cells in SLE pathogenesis. However, the majority of the data supporting this concept were obtained either from correlative studies on the phenotype of myeloid cells in SLE patients (where the type of observations that can be maid are of course limited and also often altered by the effects of the drug treatment these patients are receiving), or from studies on murine models of SLE where disease development is mainly the result of the effects of genetic modifications that typically affect multiple different cell types simultaneously. In these conditions, the understanding of the contribution of a specific cell type to the overall disease has been difficult. In the past years, Dr. Patrizia Scapini, Principal Investigator of the study, has been working on a murine model of autoimmunity caused by the lack of Lyn, a Src-family kinase mainly expressed in B and myeloid cells. This model is particularly attractive because the disease arises from a single gene defect whose instracelllular signal transduction functions are well characterized. Recent data obtained by Dr. Scapini and her collaborators, suggest an important role of innate immune cells in the development of lupus-like disease in lyn-/- mice. However, several questions still remain to be addressed. In particular it is not clear which myeloid cell subtype/s is/are mainly involved in these phenomena and whether impaired functions of innate immune cells are sufficient to initiate spontaneous SLE development. Furthermore, the initial triggers lyn-/- myeloid cells might be responding to and the mechanisms through which these cells might induce disease onset are also mostly unknown. In order to address these questions, by taking advantage of the innovative loxP-Cre technology, that results in cell lineage-dependent deletion in specific target molecules, we have recently generated Lyn flox/flox conditional knockout mice that, combined with cell-type specific Cre-loxP lines, have allowed us to selectively genetically delete Lyn in different types of myeloid cells, such as neutrophils, monocytes/macrophages, dendritic cells (DCs) and mast cells (MCs). The goal of this study is therefore to investigate the specific contribution of these different myeloid cell types to the development of autoimmunity in this model. In this context, preliminary data, suggest that lyn-/- myeloid cells are hyper-responsive to Toll-like receptor (TLR) stimulation. In view of the important role of TLRs in autoimmune responses and tissue injury, we are particularly interested in verifying the contribution of this phenomenon not only during spontaneous disease development but also in response to inflammatory stimuli known to induce/accelerate SLE in mice. Finally, even though the main focus of this study will be on SLE development, it is our intention to extend our observation to other models of inflammatory autoimmune diseases, such as rheumatoid arthritis (RA) and multiple-sclerosis (MS) in which an important pathological role of innate immune cells and TLRs has also been shown.

Enti finanziatori:

MIUR - FIRB
Finanziamento: assegnato e gestito dal Dipartimento

Partecipanti al progetto

Federica Calzetti
Tecnico-Amministrativo
Patrizia Scapini
Professore associato
Pubblicazioni
Titolo Autori Anno
B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice Scapini P; Lamagna C; Hu Y; Lee K; Tang Q; Defranco AL; Lowell CA 2011
Myeloid cells, BAFF, and IFN-gamma establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice Scapini P; Hu Y; Chu CL; Migone TS; Defranco AL; Cassatella MA; Lowell CA 2010
The Ubiquitin Modifying Enzyme A20 Restricts B Cell Survival and Prevents Autoimmunity Tavares RM; Turer EE; Liu CL; Advincula R; Scapini P; Rhee L; Barrera J; Lowell CA; Utz PJ; Malynn BA; Ma A 2010

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