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Direct-Acting Antiviral Therapy and Immune
Tolerance in Hepatitis C Virus-Induced Vasculitis
  Gastroenterology June 2017 -
Direct-acting antiviral therapy effectively treats hepatitis C cryoglobulinemia vasculitis by hepatitis C viral clearance, reduction in pathologic autoimmune memory B cells, and restoration of T-cell homeostasis.
Mixed cryoglobulins frequently circulate in patients chronically infected with hepatitis C (HCV). Cryoglobulinemia-induced vasculitis (HCV-CV) occurs in the minority of these patients but is associated with significant morbidity and reduced survival. The pathologic mechanism leading to HCV-CV is thought to be due to B-cell activation resulting in the generation of pathologic M- and G-type immunoglobulins. Rituximab, targeting pathologic B cells, is an effective therapy; however, not surprisingly, frequent relapses occur unless HCV is also treated. Recent studies have indicated that direct-acting antivirals (DAA), used in the treatment of chronic HCV, are highly effective in treating HCV-CV and that this correlates with a reduction in hepatitis C viral titers. Prior studies identified defects in regulatory T cells (Tregs) and the expansion of memory B cells in patients with HCV-CV. What occurs to these autoreactive immune subsets after DAA therapy is unknown. In this issue of Gastroenterology, Comarmond et al evaluated immunologic outcomes in patients with HCV-CV successfully treated with DAAs. Pretreatment reductions in Tregs and increased numbers of circulating IgM+CD21-/low memory B cells were observed, consistent with prior observations. In addition increases in several other immune subsets such as T follicular helper cells was observed. After therapy, peripheral autoreactive memory B cells and circulating cryoglobulin levels were reduced, and the numbers of Tregs and T follicular helper cells were increased and improved T cell homeostasis. Interestingly, abnormalities in other immune subsets did not reverse with DAA therapy. No changes in memory B cells or Tregs were observed in patients who did not have HCV-CV or did not respond to therapy. This study demonstrates that clearance of the virus leads to remission of autoimmune manifestations of chronic HCV infection in those suffering from cryoglobulinemia vasculitis via reductions in autoreactive memory B cells and through restoring Th1/Th17 balances.

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