The unusual CD21low B cells associated with different human disorders may be generated through Toll-like receptor tolerance

Proponente Milvia Casato - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Marcella Visentini Componenti strutturati del gruppo di ricerca
Stefania Basili Componenti strutturati del gruppo di ricerca
Componente Qualifica Struttura Categoria
Ramona Marrapodi post-doc Dipartimento di Medicina Traslazionale e di Precisione Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca

An unusual population of B cells that express low/neg levels of the surface receptor CD21 and atypically express CD11c (CD21lowCD11c+ B cells) is expanded in several human immunologic and infectious diseases that include HIV infection, HCV-driven lymphoproliferative disorders, common variable immunodeficiency and systemic sclerosis. CD21low B cells seem also to contribute to sepsis shock-induced immune suppression, to anti-cancer immunity and to atherosclerosis.
Recent work from the hosting laboratory showed that CD21low monoclonal B cells expanded in HCV-related lymphoproliferative disorders have the characteristics of Toll like receptor (TLR)-tolerant cells and show unresponsiveness to TLR-9 stimulation that can be restored by B cell receptor stimulation and AKT signaling. Whether the TLR9-unresponsive CD21lowCD11c+ B cells expanded in other human diseases are also TLR tolerant cells is unknown.
The objectives of this project are: (a) to determine whether human B cells are susceptible to experimentally induced TLR-tolerance and show the same features as found in HCV-related lymphoproliferation and other disorders; (b) to determine whether the CD21lowCD11c+ B cells expanded in other immunological, infectious, neoplastic and metabolic disorders are indeed TLR-tolerant cells, thus identifying a common pathogenetic mechanism for these diseases; (c) to study potential inhibitors of target molecules involved in CD21low B cells generation and maintenance (e.g. PTEN and MyD88 inhibitors).
The results of our project might untangle the role of this particular B cell population that is described in different human disorders but has a still ill-defined pathogenic role. The phenomenon of TLR-tolerance has many implications both in autoimmunity and infectious diseases and has been studied in T cell in depth. The identification of possible molecular target involved in B cell tolerance might open the door to new therapeutic strategies.

LS6_4, LS6_3, LS1_10

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