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.
B lymphocytes are multifunctional cells playing a pivotal role in both innate and adaptive immune responses. Although mostly known for their role in the humoral immune response through secretion of specific Igs, B lymphocytes are also presenting cells that can activate T cells and can also gain immunoregulatory properties. In disease B cells present a pathogenic role in different clinical settings and targeting B cells related factors has result as successful strategies.
A particular population of B cells with recurrent phenotypical (CD21low CD11c+) and functional features of anergic and exhausted cells has been described in a wide range of human disorders, but their pathogenic role remains still elusive.
This project aims to further untangle the nature of CD21low B cells by analyzing the possible role of TLR tolerance in their development and maintenance and our findings might reveal some molecular targets that could be exploited for future therapeutic strategies. We expand our studies not only to a multitude of immunological disorders but include also patients affected by other diseases (neoplasia, sepsis, metabolic diseases) to identify a common mechanism of TLR tolerance characterized by expansion of TLR9-unresposive CD21lowCD11cpos innate-like B cells.
In melanoma patients CD21low B cells expand after combination checkpoint blockade targeting inhibitory CTLA4 and PD1 receptors and their expansion correlate with the timing of immune related adverse events. Therefore preemptive strategies targeting these B cells might be beneficial for some patients. In sepsis immune dysregulation increases mortality because of secondary infections and CD21low B cells have been implicated in sepsis-induced immune suppression. Again targeting the molecular pathway implicated in CD21low expansion in severe infections might be a successful strategy. In this view, we will analyze in vitro the role of inhibitory molecules possibly implicated in CD21low B cell generation.
The results of our project may identify the common molecular trait of a particular B cell population implicated in several chronic and severe human diseases with an ill-defined role. Different authors have described the expansion of CD21low B cells in a widespread of disease without revealing the nature of these cells. Our project has the ambitious aim to study CD21low B cells in different human disorders and to find a common denominator for their expansion and contribution in disease development or progression.