Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia

Abstract

Objective. To investigate the role of hepatitis C virus (HCV) in the pathogenesis of the cutaneous vasculitis in patients with type I1 cryoglobulinemia.Methods. Using in situ hybridization detection of HCV, we studied 6 test patients and various control subjects. Serum HCV was quantitated, cryoglobulins were analyzed by column chromatography at 37"C, and lowdensity lipoprotein (LDL) receptors on keratinocytes were detected using LDL labeled with fluorescent dye.Results. In the cutaneous vasculitic lesions from test patients, but not control subjects, the HCV virion was found in association with IgM and IgG. HCV alone was detected in some vessel walls, and in skin and ductal epithelium and vascular endothelium in inflamed, but not normal, skin. Cryoglobulins showed HCV, monomeric IgM, and monomeric IgG, with little or no immune complexes. The extent of the lesions correlated with levels of viremia. Up-regulation of LDL receptors on keratinocytes was detected in inflamed, but not normal, skin.Conclusion. HCV was present in the cutaneous vasculitic lesions, most likely in complexes with IgM and IgG formed in situ. These findings and the correlation of the severity of the rash with the level of viremia suggest that HCV plays a major role in the pathogenesis of cutaneous vasculitis in these patients and strength- The hallmark of type TI cryoglobulinemia is palpable purpura, a cutaneous vasculitis thought to be caused by the deposition of the components of cryoglobulins, polyclonal IgG, and monoclonal rheumatoid factor (RF) in the vessel walls (1). A strong association of hepatitis C virus (HCV) infection and type I1 cryoglobulinemia has been established (2,3), and the virus is specifically concentrated in the cryoglobulins (4). These findings suggest that HCV is the etiologic agent for the disease and that the virus may be involved in the pathogenesis of the systemic vasculitis that occurs in these patients.HCV is a single-stranded RNA virus, and both the positive strand, the putative virion RNA, and the negative strand, the putative replicative RNA, have been detected in hepatocytes of infected patients by polymerase chain reaction (PCR) assays ( 5 ) and by in situ hybridization and in situ PCR (6). HCV RNA has not been reported to be localized in cutaneous vasculitic lesions, but HCV has been detected in RNA extracted from these lesions using a PCR assay (7). However, because of the exquisite sensitivity of the PCR assay, the extraction technique does not distinguish between HCV RNA in the lesion and HCV RNA that may be present in small amounts of residual serum in unaffected blood vessels.We investigated the role of HCV in the pathogenesis of the cutaneous vasculitis in type I1 cryoglobulinemia by examining biopsy specimens of the palpable purpuric lesions from patients with type I1

Does the hepatitis C virus replicate in cells of the hematopoietic lineage?

“…41 Again, however, contradictory data have been reported: immunohistochemistry has failed to stain non-structural HCV proteins in the skin of cryoglobulinemic, chronic hepatitis C patients, 42 and a careful RT-PCR study has suggested the absence of HCV RNA in salivary gland epithelial cells. 43 Finally, the presence of HCV in the brain has only been anecdotally reported 44 and awaits confirmation.…”

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C

“…15 Furthermore, it has been demonstrated that low-density lipoprotein re- ceptors are upregulated on keratinocytes in cutaneous vasculitis lesions of HCV-infected patients compared with normal skin. 22 A higher proinflammatory cytokine production (i.e., tumor necrosis factor ␣) has been observed in the peripheral blood and liver of HCV-cryoglobulinemic patients compared with their cryoglobulin-negative couterparts. 23,24 Hence, upregulation of low-density lipoprotein receptors associated with inflammation may result in lipid accumulation in the liver of HCV-cryoglobulinemic patients.…”

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

“…It has been shown that the endocytosis of viral particles is associated with LDLR activity, based upon the correlation of cells positive for HCV and for LDLR. 38 Furthermore, continued stimulation of LDLR expression enhanced virus replication in vitro. 39 The serum concentration of beta-lipoproteins is thought to influence HCV concentration, as the former could inhibit the binding of the virus to its proposed receptor, the LDLR.…”