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.
ReviewHepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations
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
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