Etiopathogenesis

A possible role for hepatotropic viruses in the pathogenesis of the MC has long been hypothesized on the basis of the frequent liver involvement observed during the clinical course of the disease (Gorevic et al., 1980; Gorevic and Frangione, 1991; Ferri et al., 2002a; Levo et al., 1977; Bombardieri et al., 1979). First, a role for hepatitis B virus (HBV) even in MC was investigated during the 1970s, following the example of poly-arteritis nodosa, another systemic vasculitis, frequently associated with this virus (Levo et al., 1977; Bombardieri et al., 1979; Gocke et al., 1970). Since HBV antigenemia was rarely recorded, it can be estimated that HBV can represent a causative factor of MC in less than 5% of individuals (Ferri et al., 2004). With the discovery of hepatitis C virus (HCV) as the major etiologic agent of non-A-non-B chronic hepatitis (Choo et al., 1989), an increasing number of epidemiological studies suggested an important role for HCV in the pathogenesis of MC (Choo et al., 1989; Ferri et al., 1991, 1993a; Abel et al., 1993; Dammacco et al., 2001). HCV seropositivity in MC varies from 70% to 100% of individuals in different patient populations (Ferri et al., 1993a) and it is almost constantly associated to HCV viremia (Ferri et al., 1991). In addition, HCV RNA is often markedly concentrated (1000-fold) in the cryoprecipitates compared to supernatants (Abel et al., 1993). The pathogenic role of HCV infection in MC syndrome has been definitely demonstrated by a large body of clinico-epidemiological and laboratory investigations (Ferri et al., 1993a, 2002a, 2004; Abel et al., 1993; Dammacco et al., 2001). A direct involvement of HCV antigens in immune-complex-mediated cryoglobulinemic (MC) vascu-litis has also been suggested, on the basis of immunohistochemical and molecular biological studies, including HCV RNA detection by in situ hybridization (Ferri et al., 2002a; Sansonno et al., 1996, Agnello and Abel, 1997). Therefore, the term 'essential' no longer seems to be appropriate for the majority of MC patients (Ferri et al., 2002a, 2004).

Low levels of circulating mixed cryoglobulins can be detected in over 50% HCV-infected individuals; however, overt MC syndrome develops in only a minority of cases (Lunel et al., 1994; Pawlotsky et al., 1994). On the other hand, the large diffusion of HCV infection worldwide contrasts with the geographical heterogeneity observed in the prevalence of HCV-related MC (Ferri et al., 1993a, 2002a), suggesting a role for particular HCV genotypes, unknown environmental and/or genetic co-factors. However, the actual role of the above co-factors still remains to be demonstrated (Ferri et al., 2000, 2002a).

The histopathological hallmark of MC is the leukocytoclastic vasculitis (Fig. 2) of small-sized vessels, including arterioles, capillaries, and venules (Gorevic et al., 1980; Gorevic and Frangione, 1991; Ferri et al., 2002a; Dammacco et al., 2001; Agnello and Abel, 1997). Leuko-cytoclastic vasculitis is secondary to the vessel deposition of circulating immune-complexes, mainly the cryoglobulins, and complement. This is a necrotizing vasculitis characterized by extensive fibrinoid necrosis of the vessel wall with permeation of the wall by disintegrating neutrophils (Fig. 2). The consequence of vasculitis is the ischemic organ damage responsible for typical clinical manifestations of MC syndrome: skin purpura and ulcers (Figs. 3 and 4), peripheral neuropathy, glomerulo-nephritis, lung alveolitis, endocrine disorders, and diffuse vasculitis (Gorevic et al., 1980; Gorevic and Frangione, 1991; Ferri et al., 2002a; Table 1).

Both epidemiological and clinico-pathological observations suggest that MC is the result of a multifactorial and multistep pathogenetic process (Ferri et al., 2002a). The immune-complex-mediated vasculitis is the result of this complex process, while B-lymphocyte expansion (Gorevic and Frangione, 1991) may represent the remote disorder responsible for autoantibodies and immune-complex production and in some instances for malignant lymphomas complicating the MC syndrome.

A direct role of HCV, both hepato- and lympho-tropic virus (Ferri et al., 2000, 2002a; Zignego et al., 1992, 1995; Ferri et al., 1993b), in the B-cell expansion has been initially hypothesized on the basis of the high frequency of HCV-RNA positive lymphocytes in peripheral blood and bone marrow of cryoglobulinemic patients (Zignego et al., 1992, 1995; Ferri et al., 1993b), as well as the significant percentage of individuals developing malignant lymphomas (Ferri et al., 2000, 2002a). In patients with type II MC, the B-cell infection precedes tumoral transformation, possibly playing a major

Figure 2. Severe necrotizing leukocytoclastic vasculitis: extensive fibrinoid necrosis of the vessel wall with permeation of the wall by disintegrating neutrophils. Leukocytoclastic vasculitis is secondary to the vessel deposition of circulating immune-complexes, mainly the cryoglobulins, and complement.

Figure 2. Severe necrotizing leukocytoclastic vasculitis: extensive fibrinoid necrosis of the vessel wall with permeation of the wall by disintegrating neutrophils. Leukocytoclastic vasculitis is secondary to the vessel deposition of circulating immune-complexes, mainly the cryoglobulins, and complement.

role in the lymphomagenesis, while anaplastic cells are no longer completely permissive to HCV replication (Sansonno et al., 1996).

Being HCV an RNA virus without reverse trascriptase activity, viral genome cannot integrate in the host genome. Probably, HCV may exert its oncogenic potential, indirectly, through viral proteins, particularly the core protein (Koike, 2002); even if the expression of core protein did not appear to significantly modify the main intracellular signalling transduction pathways (Giannini et al., 2002). The chronic stimulation of the lymphatic system might be exerted through viral epitopes, autoantigen production, and/or molecular mimicry mechanism (Ferri et al., 2000, 2002a).

Alternatively, HCV in association with very low-density lipoprotein (VLDL) would induce a T-independent primordial B-cell population producing monoclonal Ig with WA idiotype (Abel et al., 1993; Agnello, 1997). The RF activity of WA clones would be a consequence of somatic mutations induced after the stimulation by HCV-VLDL complexes. In this context, the possible evolution to B-NHL might be the consequence of the accumulation of stochastic genetic aberrations (Abel et al., 1993; Agnello, 1997).

A chronic stimulation of the B-cell by HCV epitopes may lead to the expansion of some B-cell subpopulations with favourable and/or dominant genetic characteristics (Ferri et al., 2000, 2002a; Zignego et al., 1997). The in vitro observation that HCV E2 protein is able to bind to CD81 molecule on the surface of B-cell (Pileri et al., 1998) suggested that this interaction may be responsible for the strong and sustained polyclonal stimulation of B lymphocytes (Zignego et al., 1997).

The significantly high frequency of t (14; 18) translocation or bcl-2 rearrangement observed in B cells may represent an important step of HCV-related lymphoproliferation (Zignego et al., 2000, 2002). The consequence is the abnormally elevated expression of Bcl-2 protein with consequent inhibition of apoptosis and abnormal B-cell survival (Zignego et al., 2002; Giannelli et al., 2003). In conclusion, it is possible to hypothesize that during chronic HCV infection, several factors, including the interaction between HCV E2 protein and CD81 molecule, the high viral variability, and the persistent infection of both hepatic and lymphatic cells, may favour a sustained and strong B-cell activation. The latter may in turn favour the apparition of t (14; 18) translocation with Bcl-2

Figure 3. Cutaneous cryoglobulinemia vasculitis: recent onset, palpable purpura on the legs with both isolated and confluent purpuric lesions (above); ochreous coloration of the skin with sock-like distribution due to chronic hemosiderin deposits in two patient with long-lasting mixed cryoglobulinemia syndrome (below).

Figure 3. Cutaneous cryoglobulinemia vasculitis: recent onset, palpable purpura on the legs with both isolated and confluent purpuric lesions (above); ochreous coloration of the skin with sock-like distribution due to chronic hemosiderin deposits in two patient with long-lasting mixed cryoglobulinemia syndrome (below).

protein overexpression responsible for abnormally prolonged B-cell survival, which ultimately may favour the development of MC syndrome. Similarly, the prolonged B-cell survival may represent a predisposing condition for further genetic aberrations responsible for frank B-cell malignancy

(Ferri et al., 2000, 2002a, 2004). This later may develop in patients with type II MC, usually after a long-term follow-up (Ferri et al., 2000, 2002a). It can vary from diffuse large B-cell lymphoma (observed in 40-50% of cases) to marginal-zone lymphoma (extranodal, nodal, or splenic) or, more

Figure 4. Perimalleolar torpid ulcers with diffuse hyperpigmentation of the surrounding skin (above, left); large and torpid ulcer (above, right); severe skin ulcers in a patient with cryoglobulinemic vasculitis before (bottom, left) and after (bottom, right) prolonged plasma exchange treatment.

rarely, B-cell chronic lymphocytic leukaemia (B-CLL) and lymphoplasmacytic lymphoma/ immunocytoma (LPL/Ic) (Trejo et al., 2003; Ramos-Casals et al., 2004). The malignancy may be related to peripheral B-cell expansion (Ferri et al., 2000, 2002a) and to lymphoid infiltrates observed in the liver and bone marrow of MC patients (38). These infiltrates have been regarded as 'early lymphomas', since they are sustained by lymphoid components indistinguishable from those of B-CLL and LPL/Ic (Monteverde et al., 1997). However, unlike frank malignant lymphomas, they tend to remain unmodified for years or even decades and are followed by overt lymphoid tumours in about 10% of cases (Monteverde et al., 1997; Ferri et al., 2000). These characteristics justify the proposed term of 'monotypic lymphopro-liferative disorder of undetermined significance (MLDUS)' (Monteverde et al., 1997; Ferri et al., 2000). Of interest, type II MC-related MLDUS has its highest incidence in the same geographic areas where about 30% of 'idiopathic' BCL patients also display HCV-positivity, and where an increased prevalence of HCV genotype 2a/c has been observed in both MC and BCL (Ferri et al., 2000; Zignego et al., 1996).

Type II MC-associated MLDUS presents two main pathological patterns; namely B-CLL-like and LPL/Ic-like, often detectable as lymphoid infiltrates in the liver and bone marrow (Ferri et al., 2000; Harris et al., 1994). In serial biopsies, these infiltrates tend to remain unmodified in the bone marrow and may undergo spontaneous re gression in the liver in case of cirrhotic evolution (Monteverde et al., 1997).

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