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.
