Clonal CD27+ CD19+ B-Cell Expansion through Inhibition of FCgIIR in HCV+ Lymphorpoliferative Disorders

Abstract

HCV infection may or may not be associated with extra-hepatic manifestations such as type-II mixed cryoglobulinemia (MC), a clonal B cell proliferative disorder. In persistent HCV infection without MC a increase in serum immunoglobulins (Ig) is commonly observed. We found this increase is polyclonal and is determined primarily by increased levels of both HCV-specific and nonspecific IgG. Despite this hypergammaglobulinemia, memory CD27+ do not accumulate, depending on a heightened sensitivity of memory B cells to BCR-independent noncognate T cell help which speeds up their terminal differentiation into antibody secreting cells and make them more prone to activation induced cell death. In persistent HCV infection with MC, elevation of Ig is a general occurrence too. However, it is attributable to IgG and IgM. The latter include antibodies with rheumatoid factor (RF) activity, which are essential for the development of circulating, cryoprecipitable immune complexes. We found Hypergammaglobulinemia is sustained by a peripheral expansion of IgMk+restriction indicating that a limited number of antigens drives their proliferation through BCR interaction. We shown that IgM RF and their counterparts on the surface of bone marrow-resident monoclonal B cells react against a Fc-epitope of IgG and the HCV-NS3 protein. Based on the above findings, we propose a model whereby BCR, by binding the Fc of IgM/IgG/HCVNS3 immune complexes deprives FcgIIR of its natural ligand. This takes the brake off RF+CD27+ B cell proliferation and promotes their selective accumulation which is otherwise prevented by increased apoptosis susceptibility in persistent HCV infection without MC. By confocal microscopy analysis we found that both Fc and NS3 peptides are able to clusterize BCR. Cytofluorimetric analysis found activation of both SYK/ERK phosphorilation pathways. Both these observations are in agreement with the hypothesis of BCR activation in these samples. Data regarding FcR are in course.