Cytoplasmic Rods and Rings Autoantibodies Developed during Pegylated Interferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

Abstract

Background

Serum autoantibodies are frequently detected in patients with chronic HCV infection, reflecting the wide spectrum of immune reactions related to this virus. In the present study, a novel autoantibody to cytoplasmic rods and rings (RR) in chronic HCV patients was characterized.

Methods

Sera from 75 previously untreated HCV patients were investigated by indirect immunofluorescence using HEp-2 cell substrate before and during pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. HEp-2 cells were cultured and fixed either following standard protocols or with the addition of RBV in culture medium.

Results

In 15 out of 75 (20%) patients, analysis revealed the presence of antibodies to rod-like cytoplasmic structures ranging approximately 3–10 mm in length and rings approximately 2–5 μm in diameter. These RR structures became detectable in >95% of cells after addition of RBV in culture medium, whereas they were absent in untreated cells. Anti-RR antibodies were found in sera collected during PEG-IFN/RBV treatment only, but never detected before antiviral therapy nor in control groups. More importantly, these anti-RR antibodies were more often detected in non-responder/relapsers than in responder patients (33% versus 11%; P-value =0.037).

Conclusions

An RBV-induced autoantibody was identified to a new cytoplasmic autoantigenic structure developed in HCV patients after PEG-IFN/RBV and this same structure can be induced by RBV in in vitro culture. Owing to the onset of anti-RR antibodies in PEG-IFN/RBV-treated patients and their association with a treatment failure, studies are deemed necessary to clarify whether anti-RR plays a role in the response to PEG-IFN/RBV therapy.

References

Abuaf

, Lunel

, Giral

Non-organ specific autoantibodies associated with chronic C virus hepatitis. J Hepatol 1993; 18: 359–364.

Cassani

, Cataleta

, Valentini

Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile. Hepatology 1997; 26: 561–566.

Clifford

B.D.

, Donahue

, Smith

High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995; 21: 613–619.

Covini

, von Muhlen

C.A.

, Pacchetti

Diversity of antinuclear antibody responses in hepatocellular carcinoma. J Hepatol 1997; 26: 1255–1265.

Fried

M.W.

, Draguesku

J.O.

, Shindo

Clinical and serological differentiation of autoimmune and hepatitis C virus-related chronic hepatitis. Dig Dis Sci 1993; 38: 631–636.

Lenzi

, Bellentani

, Saccoccio

Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort. Gut 1999; 45: 435–441.

Lenzi

, Johnson

P.J.

, McFarlane

I.G.

Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity. Lancet 1991; 338: 277–280.

Preziati

, La Rosa

, Covini

Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol 1995; 132: 587–593.

Tran

, Quaranta

J.F.

, Benzaken

High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 1993; 18: 253–257.

10.

Williams

M.J.

, Lawson

, Neal

K.R.

Autoantibodies in chronic hepatitis C virus infection and their association with disease profile. J Viral Hepat 2009; 16: 325–331.

11.

Maecker

H.T.

, Do

M.S.

, Levy

CD81 on B cells promotes interleukin 4 secretion and antibody production during T helper type 2 immune responses. Proc Natl Acad Sci U S A 1998; 95: 2458–2462.

12.

Pileri

, Uematsu

, Campagnoli

Binding of hepatitis C virus to CD81. Science 1998; 282: 938–941.

13.

Gregorio

G.V.

, Choudhuri

, Ma

Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection. Clin Exp Immunol 2003; 133: 404–413.

14.

Kammer

A.R.

, van der Burg

S.H.

, Grabscheid

Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition. J Exp Med 1999; 190: 169–176.

15.

Sutti

, Vidali

, Mombello

Breaking self-tolerance toward cytochrome P4502E1 (CYP2E1) in chronic hepatitis C: possible role for molecular mimicry. J Hepatol 2010; 53: 431–438.

16.

Yamamoto

A.M.

, Cresteil

, Boniface

Identification and analysis of cytochrome P450IID6 antigenic sites recognized by anti-liver-kidney microsome type-1 antibodies (LKM1). Eur J Immunol 1993; 23: 1105–1111.

17.

Dalekos

G.N.

, Wedemeyer

, Obermayer-Straub

Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during alpha-interferon treatment. J Hepatol 1999; 30: 366–375.

18.

Fabbri

, Jaboli

M.F.

, Giovanelli

Gastric autoimmune disorders in patients with chronic hepatitis C before, during and after interferon-alpha therapy. World J Gastroenterol 2003; 9: 1487–1490.

19.

Fabris

, Betterle

, Floreani

Development of type 1 diabetes mellitus during interferon alfa therapy for chronic HCV hepatitis. Lancet 1992; 340: 548.

20.

Fabris

, Betterle

, Greggio

N.A.

Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. J Hepatol 1998; 28: 514–517.

21.

García-Buey

, Garcia-Monzon

, Rodriguez

Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 1995; 108: 1770–1777.

22.

Imagawa

, Itoh

, Hanafusa

Antibodies to glutamic acid decarboxylase induced by interferon-alpha therapy for chronic viral hepatitis. Diabetologia 1996; 39: 126.

23.

Papo

, Marcellin

, Bernuau

Autoimmune chronic hepatitis exacerbated by alpha-interferon. Ann Intern Med 1992; 116: 51–53.

24.

Shindo

, Di Bisceglie

A.M.

, Hoofnagle

J.H.

Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C. Gastroenterology 1992; 102: 1406–1408.

25.

Todros

, Saracco

, Durazzo

Efficacy and safety of interferon alfa therapy in chronic hepatitis C with autoantibodies to liver-kidney microsomes. Hepatology 1995; 22: 1374–1378.

26.

Wesche

, Jaeckel

, Trautwein

Induction of autoantibodies to the adrenal cortex and pancreatic islet cells by interferon alpha therapy for chronic hepatitis C. Gut 2001; 48: 378–383.

27.

Baron

, Tyring

S.K.

, Fleischmann

W.R.

Jr. . The interferons. Mechanisms of action and clinical applications. JAMA 1991; 266: 1375–1383.

28.

Fried

M.W.

, Shiffman

M.L.

, Reddy

K.R.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–982.

29.

Kogure

, Ueno

, Fukushima

Fulminant hepatic failure in a case of autoimmune hepatitis in hepatitis C during peg-interferon-alpha 2b plus ribavirin treatment. World J Gastroenterol 2007; 13: 4394–4397.

30.

Narciso-Schiavon

J.L.

, Freire

F.C.

, Suarez

M.M.

Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon?

Eur J Gastroenterol Hepatol 2009; 21: 440–446.

31.

Ferri

, Muratori

, Quarneti

Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C. J Hepatol 2009; 50: 1093–1101.

32.

Gatselis

N.K.

, Georgiadou

S.P.

, Koukoulis

G.K.

Clinical significance of organ- and non-organ-specific autoantibodies on the response to anti-viral treatment of patients with chronic hepatitis C. Aliment Pharmacol Ther 2006; 24: 1563–1573.

33.

Wasmuth

H.E.

, Stolte

, Geier

The presence of non-organ-specific autoantibodies is associated with a negative response to combination therapy with interferon and ribavirin for chronic hepatitis C. BMC Infect Dis 2004; 4: 4.

34.

Yee

L.J.

, Kelleher

, Goldin

R.D.

Antinuclear antibodies (ANA) in chronic hepatitis C virus infection: correlates of positivity and clinical relevance. J Viral Hepat 2004; 11: 459–464.

35.

Dienstag

J.L.

, McHutchison

J.G.

American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006; 130: 231–264.

36.

Alvarez

, Berg

P.A.

, Bianchi

F.B.

International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31: 929–938.

37.

Jakymiw

, Pauley

K.M.

, Li

The role of GW/P-bodies in RNA processing and silencing. J Cell Sci 2007; 120: 1317–1323.

38.

Homberg

J.C.

, Andre

, Abuaf

A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin Exp Immunol 1984; 55: 561–570.

39.

Matsuda

, Saitoh

, Gotoh

High prevalence of anti-phospholipid antibodies and anti-thyroglobulin antibody in patients with hepatitis C virus infection treated with interferon-alpha. Am J Gastroenterol 1995; 90: 1138–1141.

40.

Stroffolini

, Colloredo

, Gaeta

G.B.

Does an ‘autoimmune’ profile affect the clinical profile of chronic hepatitis C? An Italian multicentre survey. J Viral Hepat 2004; 11: 257–262.

41.

Tan

E.M.

Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 1989; 44: 93–151.

42.

Tan

E.M.

Autoantibodies in pathology and cell biology. Cell 1991; 67: 841–842.