HCV proteins and immunoglobulin variable gene (IgV) subfamilies in HCV-induced type II mixed cryoglobulinemia: a concurrent pathogenetic role

Abstract

The association between hepatitis C virus (HCV) infection and type II mixed cryoglobulinemia (MCII) is well established, but the role played by distinct HCV proteins and by specific components of the anti-HCV humoral immune response remains to be clearly defined. It is widely accepted that HCV drives the expansion of few B-cell clones expressing a restricted pool of selected immunoglobulin variable (IgV) gene subfamilies frequently endowed with rheumatoid factor (RF) activity. Moreover, the same IgV subfamilies are frequently observed in HCV-transformed malignant B-cell clones occasionally complicating MCII. In this paper, we analyze both the humoral and viral counterparts at the basis of cryoglobulins production in HCV-induced MCII, with particular attention reserved to the single IgV subfamilies most frequently involved.

Figure 1

Proposed etiopathogenetic mechanisms involved in the origin of HCV-induced MCII. (a) Direct involvement of HCV infection and of specific HCV Ags in the emergence and maintenance of B-cell expansions, more frequently occurring in the liver and mostly involving RF-producing B cells. This B-cell repertoire is therefore limited and likely coded by few germline genes. These clonal expansions are invariably associated with extrahepatic manifestations, including high serum levels of polyclonal rheumatoid factor activity, cryoglobulins, monoclonal gammopathy of undetermined significance (MGUS), and eventually frank B-cell non-Hodgkin lymphoma (B-NHL). (b) The wide expression of gC1qR on the surface of blood cells, like neutrophil granulocytes, as well as of endothelial cells favors their specific binding to immune complexes containing HCV core protein and may determine their cold precipitation. Alternatively, IgM molecules are good acceptors of C1q, whose binding site is on their Fc portion and, if endowed with RF activity, may precipitate in presence of IgG molecules with specific anticore activity. (c) HCV/E2- and HCV/NS3-induced proliferation and expansion of B-cell clones producing cross-reactive Ig recognizing structures shared between these Ags and discrete Ig regions (i.e., Fc or IgV domains). (d) HCV might initiate a multistage process of lymphomagenesis by replicating in lymphoid cells and expressing proteins that associate with host cell-encoded tumor-suppressing proteins, thereby abrogating their cell-cycle checkpoint functions and predisposing the cell to genetic instability. Alternatively, HCV/E2 binding to CD81, as part of the CD19/CD21/CD81, might provide a strong proliferation signal. Moreover, HCV/E2 could behave as a B-cell super-Ag and directly stimulate proliferation and oligo/monoclonal expansion through its direct binding to BCRs encoded by specific IgV subfamilies.