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Genetic variants of the IgA Fc receptor (FcαR, CD89) promoter in chronic hepatitis C patients

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Abstract

Fc receptor for IgA (FcαR, CD89) is capable of triggering IgA-mediated immune responses to pathogens and has been proposed to function in circulating IgA clearance. Because inheritable variations modifying individual immune responses or immunoglobulin catabolism may affect the chronicity of viral infection, we investigated whether promoter polymorphisms of the FcαR gene (FCAR) affect chronic hepatitis C virus (HCV) infection and its disease progression. The two −311T/C and −142T/C single-nucleotide polymorphisms (SNPs) were studied by direct DNA sequencing in 177 Japanese patients with chronic hepatitis C (CHC). Both −311CC and −142CC genotypes were more frequent in CHC patients (15.9 and 18.6%) compared with 210 healthy controls (5.7 and 10.0%) [p = 0.001, odds ratio (OR) = 3.10, 95% confidence interval CI) = 1.53–6.30 and p = 0.014, OR = 2.06, 95% CI = 1.14–3.72, respectively], and were associated with infection with HCV genotype 2a/2b (p = 0.019 and p = 0.005, respectively). Conversely, −311CC and −142CC were decreased in 59 patients at advanced stages of disease as assessed on the basis of hepatic fibrosis markers such as decreased platelet count (PLT) ( < 150,000/μl) (5.1 and 8.5%) compared with 91 patients with normal PLT ( ≥ 150,000/μl) (24.2 and 26.4%) (p = 0.006 and p = 0.005, respectively). Moreover, among the patients with normal PLT (but not with decreased PLT), −311CC or −142CC was significantly associated with decreased serum IgA levels (p = 0.023 or p = 0.007, respectively). These results suggest that the FCAR promoter SNPs may be related to chronic HCV infection and disease progression in Japanese CHC, which might be explained by altered FcαR expression affecting IgA-mediated immune responses and/or IgA catabolism.

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Abbreviations

ADCC:

antibody-dependent cell-mediated cytotoxicity

ΔPLT:

changes in PLT

CHC:

chronic hepatitis C

FcαR:

FcR for IgA

FcR:

Fc receptor

HC:

healthy controls

HCV:

hepatitis C virus

IgAN:

IgA nephropathy

PLT:

platelet count

SNP:

single-nucleotide polymorphism

References

  • Arthur RR, Hassan NF, Abdallah MY, el-Sharkawy MS, Saad MD, Hackbart BG, Imam IZ (1997) Hepatitis C antibody prevalence in blood donors in different governorates in Egypt. Trans R Soc Trop Med Hyg 91:271–274

    Article  PubMed  CAS  Google Scholar 

  • Bertoletti A, Ferrari C (2003) Kinetics of the immune response during HBV and HCV infection. Hepatology 38:4–13

    Article  PubMed  CAS  Google Scholar 

  • Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S (1961) The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clin Sci 21:43–57

    PubMed  CAS  Google Scholar 

  • Coverdale SA, Samarasinghe DA, Lin R, Kench J, Byth K, Khan MH, Crewe E, Liddle C, George J, Farrell GC (2003) Changes in antipyrine clearance and platelet count, but not conventional liver tests, correlate with fibrotic change in chronic hepatitis C: value for predicting fibrotic progression. Am J Gastroenterol 98:1384–1390

    Article  PubMed  CAS  Google Scholar 

  • Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19:1513–1520

    Article  PubMed  CAS  Google Scholar 

  • Geissmann F, Launay P, Pasquier B, Lepelletier Y, Leborgne M, Lehuen A, Brousse N, Monteiro RC (2001) A subset of human dendritic cells expresses IgA Fc receptor (CD89), which mediates internalization and activation upon cross-linking by IgA complexes. J Immunol 166:346–352

    PubMed  CAS  Google Scholar 

  • Gowans EJ, Jones KL, Bharadwaj M, Jackson DC (2004) Prospects for dendritic cell vaccination in persistent infection with hepatitis C virus. J Clin Virol 30:283–290

    Article  PubMed  CAS  Google Scholar 

  • Grossetete B, Viard JP, Lehuen A, Bach JF, Monteiro RC (1995) Impaired Fcα receptor expression is linked to increased immunoglobulin A levels and disease progression in HIV-1-infected patients. AIDS 9:229–234

    Article  PubMed  CAS  Google Scholar 

  • Grossetete B, Launay P, Lehuen A, Jungers P, Bach JF, Monteiro RC (1998) Down-regulation of Fcα receptors on blood cells of IgA nephropathy patients: evidence for a negative regulatory role of serum IgA. Kidney Int 53:1321–1335

    Article  PubMed  CAS  Google Scholar 

  • Guechot J, Poupon RE, Giral P, Balkau B, Giboudeau J, Poupon R (1994) Relationship between procollagen III aminoterminal propeptide and hyaluronan serum levels and histological fibrosis in primary biliary cirrhosis and chronic viral hepatitis C. J Hepatol 20:388–393

    Article  PubMed  CAS  Google Scholar 

  • Halfon P, Bourliere M, Penaranda G, Deydier R, Renou C, Botta-Fridlund D, Tran A, Portal I, Allemand I, Rosenthal-Allieri A, Ouzan D (2005) Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus. Comp Hepatol 4:6

    Article  PubMed  CAS  Google Scholar 

  • Heystek HC, Moulon C, Woltman AM, Garonne P, van Kooten C (2002) Human immature dendritic cells efficiently bind and take up secretory IgA without the induction of maturation. J Immunol 168:102–107

    PubMed  CAS  Google Scholar 

  • Hoofnagle JH (2002) Course and outcome of hepatitis C. Hepatology 36:S21–S29

    Article  PubMed  Google Scholar 

  • Janoff EN, Wahl SM, Thomas K, Smith PD (1995) Modulation of human immunodeficiency virus type 1 infection of human monocytes by IgA. J Infect Dis 172:855–858

    PubMed  CAS  Google Scholar 

  • Kerr MA (1990) The structure and function of human IgA. Biochem J 271:285–296

    PubMed  CAS  Google Scholar 

  • Kozlowski PA, Black KP, Shen L, Jackson S (1995) High prevalence of serum IgA HIV-1 infection-enhancing antibodies in HIV-infected persons. Masking by IgG. J Immunol 154:6163–6173

    PubMed  CAS  Google Scholar 

  • Lamm ME (1997) Interaction of antigens and antibodies at mucosal surfaces. Annu Rev Microbiol 51:311–340

    Article  PubMed  CAS  Google Scholar 

  • Launay P, Grossetete B, Arcos-Fajardo M, Gaudin E, Torres SP, Beaudoin L, Patey-Mariaud de Serre N, Lehuen A, Monteiro RC (2000) Fcα receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger’s disease). Evidence for pathogenic soluble receptor-IgA complexes in patients and CD89 transgenic mice. J Exp Med 191:1999–2009

    Article  PubMed  CAS  Google Scholar 

  • Lerat H, Rumin S, Habersetzer F, Berby F, Trabaud MA, Trepo C, Inchauspe G (1998) In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 91:3841–3849

    PubMed  CAS  Google Scholar 

  • Maliszewski CR, March CJ, Schoenborn MA, Gimpel S, Shen L (1990) Expression cloning of a human Fc receptor for IgA. J Exp Med 172:1665–1672

    Article  PubMed  CAS  Google Scholar 

  • Marino R, Deibis L, De Sanctis JB, Bianco NE, Toro F (2005) Interaction of immune complexes isolated from hepatitis C virus-infected individuals with human cell lines. Med Microbiol Immunol (Berl) 194:73–80

    Article  CAS  Google Scholar 

  • Maruoka T, Nagata T, Kasahara M (2004) Identification of the rat IgA Fc receptor encoded in the leukocyte receptor complex. Immunogenetics 55:712–716

    Article  PubMed  CAS  Google Scholar 

  • Monteiro RC, van de Winkel JG (2003) IgA Fc receptors. Annu Rev Immunol 21:177–204

    Article  PubMed  CAS  Google Scholar 

  • Monteiro RC, Cooper MD, Kubagawa H (1992) Molecular heterogeneity of Fcα receptors detected by receptor-specific monoclonal antibodies. J Immunol 148:1764–1770

    PubMed  CAS  Google Scholar 

  • Monteiro RC, Hostoffer RW, Cooper MD, Bonner JR, Gartland GL, Kubagawa H (1993) Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals. J Clin Invest 92:1681–1685

    PubMed  CAS  Google Scholar 

  • Morton HC, van Egmond M, van de Winkel JG (1996) Structure and function of human IgA Fc receptors (FcαR). Crit Rev Immunol 16:423–440

    PubMed  CAS  Google Scholar 

  • Muller HM, Pfaff E, Goeser T, Kallinowski B, Solbach C, Theilmann L (1993) Peripheral blood leukocytes serve as a possible extrahepatic site for hepatitis C virus replication. J Gen Virol 74(Pt 4):669–676

    PubMed  Google Scholar 

  • Murawaki Y, Koda M, Okamoto K, Mimura K, Kawasaki H (2001) Diagnostic value of serum type IV collagen test in comparison with platelet count for predicting the fibrotic stage in patients with chronic hepatitis C. J Gastroenterol Hepatol 16:777–781

    Article  PubMed  CAS  Google Scholar 

  • Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane Y, Sugai Y, Tanaka T, Sato K, Tsuda F, Miyakawa Y, Mayumi M (1992) Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol 73(Pt 3):673–679

    Article  PubMed  CAS  Google Scholar 

  • Otten MA, van Egmond M (2004) The Fc receptor for IgA (FcαRI, CD89). Immunol Lett 92:23–31

    Article  PubMed  CAS  Google Scholar 

  • Papatheodoridis GV, Delladetsima JK, Katsoulidou A, Sypsa V, Albrecht M, Michel G, Hatzakis A, Tassopoulos NC (1997) Significance of IgM anti-HCV core level in chronic hepatitis C. J Hepatol 27:36–41

    Article  PubMed  CAS  Google Scholar 

  • Pasquier B, Lepelletier Y, Baude C, Hermine O, Monteiro RC (2004) Differential expression and function of IgA receptors (CD89 and CD71) during maturation of dendritic cells. J Leukoc Biol 76:1134–1141

    Article  PubMed  CAS  Google Scholar 

  • Patry C, Sibille Y, Lehuen A, Monteiro RC (1996) Identification of Fcα receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages. J Immunol 156:4442–4448

    PubMed  CAS  Google Scholar 

  • Peng XX, Wang SY, Zhang JY, Zhu H (2002) Analysis of HCV-immunoglobulin isotype complexes provide new insights into antibody response to HCV. Scand J Immunol 56:94–100

    Article  PubMed  CAS  Google Scholar 

  • Pohl A, Behling C, Oliver D, Kilani M, Monson P, Hassanein T (2001) Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am J Gastroenterol 96:3142–3146

    Article  PubMed  CAS  Google Scholar 

  • Poynard T, Bedossa P, Opolon P (1997) Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 349:825–832

    Article  PubMed  CAS  Google Scholar 

  • Sato S, Fujiyama S, Tanaka M, Goto M, Taura Y, Kawano S, Sato T, Yasuo H (1994) IgM and IgA antibodies generated against hepatitis C virus core antigen in patients with acute and chronic HCV infection. Dig Dis Sci 39:2022–2031

    Article  PubMed  CAS  Google Scholar 

  • Shen L, van Egmond M, Siemasko K, Gao H, Wade T, Lang ML, Clark M, van De Winkel JG, Wade WF (2001) Presentation of ovalbumin internalized via the immunoglobulin-A Fc receptor isenhanced through Fc receptor γ-chain signaling. Blood 97:205–213

    Article  PubMed  CAS  Google Scholar 

  • Shimokawa T, Ra C (2003) C/EBPα and Ets protein family members regulate the human myeloid IgA Fc receptor (FcαR, CD89) promoter. J Immunol 170:2564–2572

    PubMed  CAS  Google Scholar 

  • Shimokawa T, Ra C (2005) C/EBPα functionally and physically interacts with GABP to activate the human myeloid IgA Fc receptor (FcαR, CD89) gene promoter. Blood 106:2534–2542

    Article  PubMed  CAS  Google Scholar 

  • Shimokawa T, Tsuge T, Okumura K, Ra C (2000) Identification and characterization of the promoter for the gene encoding the human myeloid IgA Fc receptor (FcαR, CD89). Immunogenetics 51:945–954

    Article  PubMed  CAS  Google Scholar 

  • Silvain C, Patry C, Launay P, Lehuen A, Monteiro RC (1995) Altered expression of monocyte IgA Fc receptors is associated with defective endocytosis in patients with alcoholic cirrhosis. Potential role for IFN-g. J Immunol 155:1606–1618

    PubMed  CAS  Google Scholar 

  • Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, Brechot C, Brouwer JT, Chan SW, Chayama K, Chen DS et al (1994) A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology 19:1321–1324

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Sato S, Fujiyama S, Kawano S, Taura Y, Chikazawa H, Honda Y, Shibata J, Sato T (1995) Clinical study of IgA antibody against hepatitis C virus core antigen in patients with type C chronic liver disease. Dig Dis Sci 40:457–464

    Article  PubMed  CAS  Google Scholar 

  • Togo S, Shimokawa T, Fukuchi Y, Ra C (2003) Alternative splicing of myeloid IgA Fc receptor (FcαR, CD89) transcripts in inflammatory responses. FEBS Lett 535:205–209

    Article  PubMed  CAS  Google Scholar 

  • Tsuge T, Shimokawa T, Horikoshi S, Tomino Y, Ra C (2001) Polymorphism in promoter region of Fcα receptor gene in patients with IgA nephropathy. Hum Genet 108:128–133

    Article  PubMed  CAS  Google Scholar 

  • van Egmond M, van Garderen E, van Spriel AB, Damen CA, van Amersfoort ES, van Zandbergen G, van Hattum J, Kuiper J, van de Winkel JG (2000) FcαRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 6:680–685

    Article  PubMed  Google Scholar 

  • Wang JT, Sheu JC, Lin JT, Wang TH, Chen DS (1992) Detection of replicative form of hepatitis C virus RNA in peripheral blood mononuclear cells. J Infect Dis 166:1167–1169

    PubMed  CAS  Google Scholar 

  • Watt K, Uhanova J, Gong Y, Kaita K, Doucette K, Pettigrew N, Minuk GY (2004) Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection. J Viral Hepat 11:251–256

    Article  PubMed  CAS  Google Scholar 

  • Woof JM, van Egmond M, Kerr MA (2005) Fc receptors. In: Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayer L (eds) Mucosal Immunology, 3rd edn. Academic, New York, pp 251–265

    Google Scholar 

  • Yabu K, Kiyosawa K, Mori H, Matsumoto A, Yoshizawa K, Tanaka E, Furuta S (1994) Serum collagen type IV for the assessment of fibrosis and resistance to interferon therapy in chronic hepatitis C. Scand J Gastroenterol 29:474–479

    PubMed  CAS  Google Scholar 

  • Zein NN (2000) Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 13:223–235

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan to promote advanced scientific research, a Grant-in-Aid for scientific research from the Japanese Society for the Promotion of Science, a grant from Nihon University School of Medicine, and a grant from the Uehara Memorial Foundation.

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Authors and Affiliations

  1. Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan

    Azuma Watanabe, Toshibumi Shimokawa & Chisei Ra

  2. Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    Azuma Watanabe, Mitsuhiko Moriyama, Fumihiko Komine, Shuichi Amaki & Yasuyuki Arakawa

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  1. Azuma Watanabe
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  2. Toshibumi Shimokawa
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  3. Mitsuhiko Moriyama
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Correspondence to Chisei Ra.

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Watanabe, A., Shimokawa, T., Moriyama, M. et al. Genetic variants of the IgA Fc receptor (FcαR, CD89) promoter in chronic hepatitis C patients. Immunogenetics 58, 937–946 (2006). https://doi.org/10.1007/s00251-006-0159-5

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  • DOI: https://doi.org/10.1007/s00251-006-0159-5

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