Clonal CD27+ CD19+ B cell expansion through inhibition of FCγIIR in HCV+ cryoglobulinemic patients: A model

Persistent HCV infection may be associated with extrahepatic manifestations such as type II mixed cryoglobulinemia (II-MC), a clonal B cell proliferative disorder. In persistent HCV infection without II-MC, an increase in serum immunoglobulins (Ig) is commonly observed. This increase is polyclonal and is determined primarily by increased levels of IgG which include both HCV-specific and nonspecific antibodies. Nonetheless, memory CD27⁺ B cells do not accumulate. This paradoxical phenomenon depends on heightened sensitivity of memory B cells to BCR-independent noncognate T cell help, which speeds up their terminal differentiation into antibody-secreting cells and makes them more prone to apoptosis. In persistent HCV infection with II-MC, serum Ig elevation is also a general occurrence, and characteristically includes IgM antibodies with rheumatoid factor activity, which are essential for the development of circulating, cryoprecipitable immune complexes. Hypergammaglobulinemia is sustained by a peripheral expansion of IgM⁺k⁺IgD ^low/negCD21^lowCD27⁺ B cells. These cells exhibit marked V_H, J_H, and V_K gene segment usage restriction, indicating that a limited number of antigens drive their proliferation through BCR interaction. Recently, two epitopes, one of the human IgG and the second of the HCV_NS3 protein, had been identified and demonstrated able to link the BCR exposed on II-MC subjects. Based on the above findings, we propose a model whereby BCR binding the IgM/IgG/HCV_NS3 immune complexes deprives FcγIIR 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 II-MC.