Review
Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations

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Summary

Several viruses are involved in the development of systemic vasculitides. Hepatitis C virus (HCV) has been shown to be closely related to mixed cryoglobulinaemia, an immune complex-mediated vasculitis. HCV particles and non-enveloped nucleocapsid protein participate in the formation of immune complexes. Once formed, immune complexes precipitate in many organs, including the skin, kidneys, and peripheral nerve fibres. Viral proteins confer peculiar physical and chemical properties on cryoimmunoglobulins. Since expansion of rheumatoid factor-synthesising B cells is the biological hallmark of mixed cryoglobulinaemia, it may be that the combination of rheumatoid factor activity and cryoprecipitability is responsible for the vasculitis. B-cell clonal expansion occurs primarily in the liver and correlates with a high intrahepatic viral load, pointing to a major role for HCV in the emergence and maintenance of B-cell clonalities. Recognition of HCV as an aetiological factor in most cryoglobulinaemic vasculitides has dramatically changed the approach to their treatment. Emphasis, in fact, is now placed on abatement of the viral load and deletion of B-cell clonalities.

Section snippets

Hepatitis C virus

HCV is a small, enveloped, single-stranded positive-sense RNA virus, belonging to the Flaviviridae family, hepacivirus genus.14, 15 Phylogenetic analysis of its core, E1, and NS5 (non-structural) region has identified six major genotypes (1–6) with more closely related variants (subtypes).16 The approximately 9600 nucleotide HCV genome contains highly conserved non-coding regions (NCRs) at both the 5′ and the 3′ termini that flank a large open reading frame (ORF), which codes for a protein of

Cryoglobulins

Cryoglobulins are single or mixed immunoglobulins that reversibly precipitate at low temperatures, conventionally classified according to their immunochemical composition as type I (monoclonal immunoglobulins only), type II mixed cryoglobulins (a mixture of monoclonal and polyclonal immunoglobulins), and type III mixed cryoglobulins (polyclonal immunoglobulins only).22

The mechanisms of in-vitro protein cryoprecipitation are poorly understood. The solubility of proteins depends on various

Pathophysiology of cryoprecipitation

Cryoglobulins in HCV-infected patients are the product of virus–host interactions. Production of IgM rheumatoid factor molecules is a crucial point in the cryoprecipitating process. Most of the molecules exhibit the WA (named after the patient in whom it was first identified) cross-idiotype40 and are almost always associated with the light chain cross-idiotype 17-109 and the heavy chain cross-idiotype G6, which are postulated to be the product of the restricted expression of germline genes.5

A

Cryoglobulinaemic vasculitis

Cryoglobulinaemic vasculitis is most frequently evident in the skin (figure 4), though any organ may be affected (table 1). Palpable purpura is evident in more than 90% of mixed cryoglobulinaemia patients, and is usually the first sign of cryoglobulinaemia, raising an immediate suspicion of cryoglobulinaemic vasculitis and foreshadowing systemic complications.4

Chronic leg ulcers are relatively frequent above the malleoli, and are always associated with purpura, often appearing in the absence of

Cryoglobulinaemic nephropathy

Kidney involvement is a frequent feature of systemic vasculitis. Even so, cryoglobulinaemic nephropathy is now emerging as a distinct clinical and pathological entity.45 The association between HCV infection and renal disease is mainly supported by epidemiological evidence. Indeed, prevalence of HCV infection in nephropathies varies geographically, ranging from 10–20% in USA60 to 60% in Japan.61

Chronic glomerulonephritis shows a greater prevalence of HCV infection compared with other renal

Cryoglobulinaemic neuropathy

Increasingly, HCV is being recognised as the cause of a variety of neurological disorders.69 Participation of the nervous system in people with HCV-related mixed cryoglobulinaemia has been variably emphasised in the literature, and its incidence may exceed 60%.70 Involvement of the peripheral nervous system presents as sensory-motor neuropathy, especially in the lower limbs, often as painful paresthesias with loss of strength.71, 72, 73 Central nervous system involvement with transient

Molecular features of B-cell clonal expansion

HCV-related mixed cryoglobulinaemia is based strictly on a benign lymphoproliferative disorder whose molecular features have been primarily determined in the liver.76, 77 Data from our laboratory have demonstrated that the intrahepatic B cells of HCV-infected patients undergo massive clonal expansion. Those derived from clonal expansions of the same founder were less frequently detected in the circulation and bone marrow.78

The liver is obviously the main target of HCV infection and the site of

Treatment

The discovery of high HCV prevalence in people with cryoglobulinaemic vasculitis has shifted treatment of the condition away from the usual combination of steroids and cyclophosphamide.96 Indeed, the effectiveness of interferon alfa in the management of mixed cryoglobulinaemia was recognised before the demonstration of its close relation with HCV.97 In responsive patients, reduction of HCV RNA to non-measurable levels precedes reduction of the cryocrit.43, 98, 99 By analogy with the treatment

Conclusions

Tremendous progress has been made in the characterisation of HCV pathobiology in both hepatic and extrahepatic diseases. These insights have illustrated HCV's major role in the production of cryoglobulins and vasculitis-related damage. However, there are many dark areas in the comprehension of several aspects of their pathogenetic mechanism(s). For example, why are cryoglobulins produced only in a subgroup of HCV-infected individuals? The nature of the process during which B cells expand with

Search strategy and selection criteria

Data for this review were identified by searches of Medline, PubMed, and references from relevant articles, using the search terms “cryoglobulinaemia”, “hepatitis C virus”, and “lymphoproliferation”. Only papers published from 1966 to 2004 were chosen. Human studies and experimental models were selected and references from relevant articles were retrieved.

References (106)

  • JD Tissot et al.

    Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide

    Immunol Methods

    (1994)
  • F Dammacco et al.

    Natural interferon-alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study

    Blood

    (1994)
  • M Pascual et al.

    Complement in human diseases: looking towards the 21st century

    Immunol Today

    (1995)
  • L Daghestani et al.

    Renal manifestations of hepatitis C infection

    Am J Med

    (1999)
  • RB Sim et al.

    Interaction of C1q and the collectins with the potential receptors calreticulin (cC1qR/collectin receptor) and megalin

    Immunobiology

    (1998)
  • B Ghebrehiwet et al.

    Structure and function of gC1q-R: a multiligand binding cellular protein

    Immunobiology

    (1998)
  • D Sansonno et al.

    Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia

    Hepatology

    (1995)
  • R Lemoine et al.

    Induction of “wire-loop” lesions by murine monoclonal IgG3 cryoglobulins

    Kidney Int

    (1992)
  • G D'Amico

    Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis

    Kidney Int

    (1998)
  • F Lunel et al.

    Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage

    Gastroenterology

    (1994)
  • D Sansonno et al.

    Detection and distribution of hepatitis C virus-related proteins in lymph nodes of patients with type II mixed cryoglobulinemia and neoplastic or non-neoplastic lymphoproliferation

    Blood

    (1996)
  • L Bonomo et al.

    Treatment of idiopathic mixed cryoglobulinemia with alpha interferon

    Am J Med

    (1987)
  • M Casato et al.

    Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia

    Blood

    (1991)
  • C Ferri et al.

    Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial

    Blood

    (1993)
  • GM Laver et al.

    Hepatitis C virus infection

    N Engl J Med

    (2001)
  • B Rehermann

    Interaction between the hepatitis C virus and the immune system

    Semin Liver Dis

    (2000)
  • DR Nelson et al.

    The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C

    J Immunol

    (1997)
  • F Dammacco et al.

    The cryoglobulins: an overview

    Eur J Clin Invest

    (2001)
  • PD Gorevic et al.

    Mixed cryoglobulinemia cross-reactive idiotypes: implications for the relationship of MC to rheumatic and lymphoproliferative diseases

    Semin Hematol

    (1991)
  • M Pascual et al.

    Hepatitis C virus in patients with cryoglobulinemia type II

    J Infect Dis

    (1990)
  • C Ferri et al.

    Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia

    Arthritis Rheum

    (1991)
  • V Agnello et al.

    A role for hepatitis C virus infection in type II cryoglobulinemia

    N Engl J Med

    (1992)
  • F Dammacco et al.

    Antibodies to hepatitis C virus in essential mixed cryoglobulinaemia

    Clin Exp Immunol

    (1992)
  • M Trendelenburg et al.

    Cryoglobulins are not essential

    Ann Rheum Dis

    (1998)
  • AR Magalini et al.

    Clonality of B-cells in portal lymphoid infiltrates of HCV-infected livers

    J Pathol

    (1998)
  • D Sansonno et al.

    Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia

    J Immunol

    (1998)
  • QL Choo et al.

    Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome

    Science

    (1989)
  • BD Lindenbach et al.

    Flaviviridae: the viruses and their replication

  • F Penin et al.

    Structural biology of hepatitis C virus

    Hepatology

    (2004)
  • LP Beales et al.

    The internal ribosome entry site (IRES) of hepatitis C virus visualized by electron microscopy

    RNA

    (2001)
  • CM Spahn et al.

    Hepatitis C virus IRES RNA-induced changes in the conformation of the 40s ribosomal subunit

    Science

    (2001)
  • AA Kolykhalov et al.

    Identification of a highly conserved sequence element at the 3′ terminus of hepatitis C virus genome RNA

    J Virol

    (1996)
  • T Tanaka et al.

    Structure of the 3′ terminus of the hepatitis C virus genome

    J Virol

    (1996)
  • F Dammacco et al.

    Cryoglobulins and pyroglobulins: an overview

    Ric Clin Lab

    (1986)
  • Y Pastore et al.

    An experimental model of cryoglobulin-associated vasculitis in mice

    Springer Semin Immunopathol

    (2001)
  • PH Saulk et al.

    Studies on the cryoprecipitation of a human IgG3 cryoglobulin: the effects of temperature-induced conformational changes on the primary interaction

    Immunochemistry

    (1975)
  • S Kikuchi et al.

    A transgenic mouse model of autoimmune glomerulonephritis and necrotizing arteritis associated with cryoglobulinemia

    J Immunol

    (2002)
  • G Montagnino

    Reappraisal of the clinical expression of mixed cryoglobulinemia

    Springer Semin Immunopathol

    (1988)
  • M Trendelenburg et al.

    Cryoglobulins in chronic hepatitis C virus infection

    Clin Exp Immunol

    (2003)
  • IG McFarlane

    Immunological abnormalities and hepatotropic viral infections

    Clin Exp Immunol

    (1992)
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