Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations  Domenico Sansonno, Franco Dammacco  The Lancet Infectious Diseases  Volume 5, Issue 4, Pages 227-236 (April 2005) DOI: 10.1016/S1473-3099(05)70053-0 Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 1 Structure and genetic organisation of the hepatitis C virus genome. The Lancet Infectious Diseases 2005 5, 227-236DOI: (10.1016/S1473-3099(05)70053-0) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 2 Tentative scheme of HCV replication cycle in the hepatocyte. The HCV particle binds the cell membrane via a specific interaction between envelope glycoproteins (E1 and E2) and an unknown specific receptor. The bound particle is internalised by receptor-mediated endocytosis. The viral genome is then uncoated from the nucleocapsid and translated at the level of the rough endoplasmic reticulum. Formation of membrane vesicles serves as a scaffold for the viral replication complex. After genome amplification and protein expression, progeny virions are assembled and released. HCV particles circulate free or complexed with specific antibodies. In addition, they can interact with lymphocytes mainly through CD81. The upper right panel of the figure shows a schematic representation of the HCV particle. ss=single-stranded. The Lancet Infectious Diseases 2005 5, 227-236DOI: (10.1016/S1473-3099(05)70053-0) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 3 Proposed model of the cryoprecipitating immune complex in HCV-related cryoglobulinaemia. HCV core protein is linked to IgG molecules with specific anticore reactivity, which in turn are bound to IgM molecules with rheumatoid factor activity. Multimolecular complexes are good acceptors of C1q protein, and this results in specific binding to endothelial cells via the C1q receptor (C1qR). In boxes, the relative proportions of IgG, IgM, and complement proteins in relation to cryoprecipitate and supernatant phases are depicted. The Lancet Infectious Diseases 2005 5, 227-236DOI: (10.1016/S1473-3099(05)70053-0) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 4 Features of HCV-related cryoglobulinaemic vasculitis. (A) Whitish cryoprecipitate after keeping a Wintrobe tube at 4°C for 7 days and centrifuging at 1400 rpm for 10 min at 4°C. (B) Purpuric eruptions involving the lower part of the legs. (C) Torpid cutaneous perimalleolar ulcer. (D) Light microscopy of skin biopsy from a patient with cryoglobulinaemic vasculitis. Note: necrotising arteritis with fibrinoid necrosis of the intima and inflammatory infiltrates throughout the entire thickness of the vessel wall and perivascularly. (E) Immunohistochemistry reveals HCV core protein in skin immunodeposits of papillary vessels. Note intraluminal deposits (red arrows), and involvement of perivascular spaces (blue arrows). The Lancet Infectious Diseases 2005 5, 227-236DOI: (10.1016/S1473-3099(05)70053-0) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 5 Demonstration of HCV core protein and IgM molecules in a kidney biopsy of a cryoglobulinaemic patient. (A) Immunohistochemical detection of HCV core protein in glomerular vascular structures. (B) Bright granular capillary wall location of IgM molecules detected by fluorescein-labelled antihuman IgM antibody. The Lancet Infectious Diseases 2005 5, 227-236DOI: (10.1016/S1473-3099(05)70053-0) Copyright © 2005 Elsevier Ltd Terms and Conditions