Relationship Between Cryoglobulinemia-associated Nephritis and HCV Infection

Dario Roccatello; Osvaldo Giachino; Elisa Menegatti; Simone Baldovino

Disclosures

Expert Rev Clin Immunol. 2008;4(4):515-524. 

In This Article

Pathogenesis of HCV-related Cryoglobulinemia

It is presently believed that HCV infects B lymphocytes while infecting hepatocytes due to the shared expression of CD81 receptors. Lymphocytes that are chronically stimulated by HCV are prone to widespread autoantibody production related to HCV-induced lowering of the cell-activation threshold. This favors the development of a number of immune manifestations associated with HCV infection, which are variously assembled in clinical pictures we collectively call the 'HCV syndrome'. The HCV syndrome includes manifestations that are apparently unrelated to the characteristic picture of MC, such as thyroiditis, sicca syndrome, thrombocytopenia and pulmonary fibrosis.

Furthermore, B cells, which are protected from apoptosis by a HCV-dependent gene translocation, develop oligoclonal monotypic lymphoproliferations.[6] Distinct lymphoid infiltrates with cells expressing oligo- or monoclonal rheumatoid factor in the portal tracts, spleen and bone marrow (on occasion, evolving towards an overt B-cell non-Hodgkin's lymphoma) can be detected in these patients.

The pathogenetic implication of HCV in the formation, transport and removal from the circulation of cryoprecipitable immune complexes (ICs) in MC has been studied extensively in recent years. Figure 1 summarizes the cascade of putative pathological events.

Pathogenesis of tissue injury in mixed cryoglobulinemia. HCV infects B lymphocytes while infecting hepatocytes due to the common expression of the CD81 receptors. A HCV-dependent gene translocation able to protect cells against apoptosis sustains the oligoclonal monotypic lymphoproliferation that occurs in mixed cryoglobulinemia. Cryoprecipitable ICs, formed by HCV, anti-HCV polyclonal IgG and monoclonal IgM (usually IgMκ sharing rheumatoid activity), escape the erythrocyte transport system (E) due to the presence in the megacomplex of IgM rheumatoid factor that provides an obstacle to the incorporation of the complement factor C3b into the cryocomplexes (which should allow IC binding to the CR1 erythrocyte surface receptor). IgMκ-IgG anti-HCV complexes remain free to circulate and, thus, to saturate the phagocyte's ability to remove ICs from the blood. Phagocyte blockade is favored by HCV infection, which makes cells unable to digest cryoglobulins following phagocytosis. Cryoprecipitable ICs, which remain free to circulate in the bloodstream in non-neutralized conditions (i.e., unbound to erythrocytes) can easily deposit in tissues and promote the inflammatory cascade. Monocytes, engulfed with cryoglobulins, are unable to digest phagocytosed immune material due to abnormalities in the biogenesis of lysosomal enzymes, but participate in inflammation and perivascular infiltration. E: Erythrocyte transport system; HCV: Hepatitis C virus; IC: Immune complex.

Under the trigger effects of chronic HCV infection, oligo- or monoclonal IgM sharing rheumatoid activity is synthesized, thus favoring the appearance in the circulation of ICs (formed by HCV, anti-HCV polyclonal IgG and the monoclonal IgM itself), which is critical for tissue (especially renal) deposition because of the particular affinity of monoclonal IgM to fibronectin and other mesangial components.[7] Moreover, due to the clonally restricted IgM, these cryoprecipitable ICs also escape the erythrocyte transport system[1] and directly impact hepatic and splenic macrophages, which are unable to process them due to abnormalities in the biogenesis of lysosomal enzymes.[8] The same abnormality (possibly due to HCV infection of phagocyte cells) is likely to occur at the level of circulating monocytes, which are usually found to be engulfed with cryoglobulins when examined by electron microscopy, but are unable to process digestion of phagocytosed immune material.[8]

Therefore, the pathogenetic scenario of the disease is dominated by the following:

  • Chronic stimulation by HCV infection, sustaining the synthesis of IgM rheumatoid factor and, consequently, of cryoprecipitable ICs;

  • The abnormal kinetics and easy deposition of the HCV-containing ICs;

  • A subclinical smoldering lymphoproliferative disorder.

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