Puumala hantavirus (PUUV) causes nephropathia epidemica (NE), a form of haemorrhagic fever with renal syndrome that occurs in northern and central Europe. The immunoglobulin A (IgA) response in NE patients was studied. The levels of total serum IgA in acute-phase samples from NE patients were found to be significantly elevated when compared with the levels in healthy controls. ELISAs for detection of the IgA1 and IgA2 responses against each PUUV structural protein (N, G1 and G2) were developed and evaluated. Sequential sera from NE patients (acute, convalescent, 2-year) and 10–20 year NE-convalescent sera were examined. Most patients developed detectable levels of IgA1 against N and G2, while the G1 responses were low or undetectable. Seven of nine 10–20 year sera contained virus-specific IgA1, which may indicate the prolonged presence of viral antigens after the initial infection. PEPSCAN analysis revealed several IgA-reactive antigenic regions in the N protein. Serum IgA and IgG was purified by affinity chromatography and examined by a virus-neutralization assay. Three of five sera from acute-phase NE patients contained neutralizing IgA1. The diagnostic potential of the PUUV-specific IgA1 response was evaluated. The N and G2 assays showed specificities of 100% with sensitivities of 91 and 84%, respectively, compared with an IgM μ-capture ELISA. Several NE patients, clinically diagnosed for acute PUUV infection, with borderline or undetectable levels of PUUV-specific IgM, were found to be highly positive for the presence of PUUV N-specific serum IgA1, proving the diagnostic value of IgA analysis as a complement to detection of IgM.


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  1. Asano, Y., Hiroishi, Y., Itakura, N., Hirose, S., Kajita, Y., Nagai, T., Yazaki, T. & Takahashi, M. (1987). Immunoglobulin subclass antibodies to varicella-zoster virus.Pediatrics 80, 933-936. [Google Scholar]
  2. Asano, Y., Hiroishi, Y., Itakura, N., Hirose, S., Kajita, Y., Suga, S. & Yazaki, T. (1988). Placental transfer of IgG subclass-specific antibodies to varicella-zoster virus.Journal of Medical Virology 26, 1-6.[CrossRef] [Google Scholar]
  3. Beverley, P. C. (1990). Is T-cell memory maintained by crossreactive stimulation?Immunology Today 11, 203-205.[CrossRef] [Google Scholar]
  4. Bogdanov, S. B., Gavrilovskaia, I. N., Boiko, V. A., Prokhorova, I. A. & Linev, M. B. (1987). Persistent infection caused by haemorrhagic fever with renal syndrome virus in bank voles (Clethrionomys glareolus) – the natural host of the virus. Mikrobiologicheskii Zhurnal 49, 99–106 (in Russian). [Google Scholar]
  5. Brus-Sjölander, K., Elgh, F., Kallio-Kokko, H., Vapalahti, O., Hägglund, M., Palmcrantz, V., Juto, P., Vaheri, A., Niklasson, B. & Lundkvist, Å. (1997). Evaluation of serological methods for diagnosis of Puumala hantavirus infection (nephropathia epidemica).Journal of Clinical Microbiology 35, 3264-3268. [Google Scholar]
  6. Coulson, B. S., Grimwood, K., Masendycz, P. J., Lund, J. S., Mermelstein, N., Bishop, R. F. & Barnes, G. L. (1990). Comparison of rotavirus immunoglobulin A coproconversion with other indices of rotavirus infection in a longitudinal study in childhood.Journal of Clinical Microbiology 28, 1367-1374. [Google Scholar]
  7. Dohmae, K. & Nishimune, Y. (1998). Maternal transfer of hantavirus antibodies in rats.Laboratory Animal Science 48, 395-397. [Google Scholar]
  8. Dohmae, K., Koshimizu, U. & Nishimune, Y. (1993). In utero and mammary transfer of hantavirus antibody from dams to infant rats.Laboratory Animal Science 43, 557-561. [Google Scholar]
  9. Elgh, F., Linderholm, M., Wadell, G. & Juto, P. (1996). The clinical usefulness of a Puumala virus recombinant nucleocapsid protein based enzyme-linked immunosorbent assay in the diagnosis of nephropathia epidemica as compared with an immunofluorescence assay.Clinical and Diagnostic Virology 6, 17-26.[CrossRef] [Google Scholar]
  10. Elgh, F., Linderholm, M., Wadell, G., Tärnvik, A. & Juto, P. (1998). Development of humoral cross-reactivity to the nucleocapsid protein of heterologous hantaviruses in nephropathia epidemica.FEMS Immunology and Medical Microbiology 22, 309-315.[CrossRef] [Google Scholar]
  11. Friedman, M. G. & Eichler, A. W. (1991). The use of serum IgA as a diagnostic marker in viral infections.Immunology & Infectious Diseases 1, 223-234. [Google Scholar]
  12. Friedman, M. G., Phillip, M. & Dagan, R. (1989). Virus-specific IgA in serum, saliva, and tears of children with measles.Clinical and Experimental Immunology 75, 58-63. [Google Scholar]
  13. Geysen, H. M., Rodda, S. J., Mason, T. J., Tribbick, G. & Schoofs, P. G. (1987). Strategies for epitope analysis using peptide synthesis.Journal of Immunological Methods 102, 259-274.[CrossRef] [Google Scholar]
  14. Groen, J., Gerding, M., Jordans, J. G., Clement, J. P. & Osterhaus, A. D. (1994). Class and subclass distribution of hantavirus-specific serum antibodies at different times after the onset of nephropathia epidemica.Journal of Medical Virology 43, 39-43.[CrossRef] [Google Scholar]
  15. Groen, J., Gerding, M., Koeman, J. P., Roholl, P. J., van Amerongen, G., Jordans, H. G., Niesters, H. G. & Osterhaus, A. D. (1995). A macaque model for hantavirus infection.Journal of Infectious Diseases 172, 38-44.[CrossRef] [Google Scholar]
  16. Heyman, P., Vervoort, T., Colson, P., Chu, Y. K., Avsic-Zupanc, T. & Lundkvist, Å. (1999). A major outbreak of hantavirus infection in Belgium in 1995 and 1996.Epidemiology and Infection 122, 447-453.[CrossRef] [Google Scholar]
  17. Hörling, J., Lundkvist, Å., Huggins, J. W. & Niklasson, B. (1992). Antibodies to Puumala virus in humans determined by neutralization test.Journal of Virological Methods 39, 139-147.[CrossRef] [Google Scholar]
  18. Hörling, J., Lundkvist, Å., Persson, K., Mullaart, M., Dzagurova, T., Dekonenko, A., Tkachenko, E. & Niklasson, B. (1995). Detection and subsequent sequencing of Puumala virus from human specimens by PCR.Journal of Clinical Microbiology 33, 277-282. [Google Scholar]
  19. Johansen, K., Granqvist, L., Karlén, K., Stintzing, G., Uhnoo, I. & Svensson, L. (1994). Serum IgA immune response to individual rotavirus polypeptides in young children with rotavirus infection.Archives of Virology 138, 247-259.[CrossRef] [Google Scholar]
  20. Kanerva, M., Vaheri, A., Mustonen, J. & Partanen, J. (1998). High-producer allele of tumour necrosis factor-alpha is part of the susceptibility MHC haplotype in severe Puumala virus-induced nephropathia epidemica.Scandinavian Journal of Infectious Diseases 30, 532-534.[CrossRef] [Google Scholar]
  21. Lundkvist, Å. & Niklasson, B. (1992). Bank vole monoclonal antibodies against Puumala virus envelope glycoproteins: identification of epitopes involved in neutralization.Archives of Virology 126, 93-105.[CrossRef] [Google Scholar]
  22. Lundkvist, Å. & Niklasson, B. (1994). Haemorrhagic fever with renal syndrome and other hantavirus infections.Reviews in Medical Virology 4, 177-184.[CrossRef] [Google Scholar]
  23. Lundkvist, Å., Fatouros, A. & Niklasson, B. (1991). Antigenic variation of European haemorrhagic fever with renal syndrome virus strains characterized using bank vole monoclonal antibodies.Journal of General Virology 72, 2097-2103.[CrossRef] [Google Scholar]
  24. Lundkvist, Å., Hörling, J. & Niklasson, B. (1993a). The humoral response to Puumala virus infection (nephropathia epidemica) investigated by viral protein specific immunoassays.Archives of Virology 130, 121-130.[CrossRef] [Google Scholar]
  25. Lundkvist, Å., Björsten, S. & Niklasson, B. (1993b). Immunoglobulin G subclass responses against the structural components of Puumala virus.Journal of Clinical Microbiology 31, 368-372. [Google Scholar]
  26. Lundkvist, Å., Björsten, S., Niklasson, B. & Ahlborg, N. (1995). Mapping of B-cell determinants in the nucleocapsid protein of Puumala virus: definition of epitopes specific for acute immunoglobulin G recognition in humans.Clinical and Diagnostic Laboratory Immunology 2, 82-86. [Google Scholar]
  27. Lundkvist, Å., Hukic, M., Hörling, J., Gilljam, M., Nichol, S. & Niklasson, B. (1997). Puumala and Dobrava viruses cause hemorrhagic fever with renal syndrome in Bosnia-Herzegovina: evidence of highly cross-neutralizing antibody responses in early patient sera.Journal of Medical Virology 53, 51-59.[CrossRef] [Google Scholar]
  28. McBride, B. W. & Ward, K. A. (1987). Herpes simplex-specific IgG subclass response in herpetic keratitis.Journal of Medical Virology 21, 179-189.[CrossRef] [Google Scholar]
  29. Mazanec, M. B., Nedrud, J. G. & Lamm, M. E. (1987). Immunoglobulin A monoclonal antibodies protect against Sendai virus.Journal of Virology 61, 2624-2626. [Google Scholar]
  30. Mazanec, M. B., Kaetzel, C. S., Lamm, M. E., Fletcher, D. & Nedrud, J. G. (1992). Intracellular neutralization of virus by immunoglobulin A antibodies.Proceedings of the National Academy of Sciences, USA 89, 6901-6905.[CrossRef] [Google Scholar]
  31. Morris, G. E., Coleman, R. M., Best, J. M., Benetato, B. B. & Nahmias, A. J. (1985). Persistence of serum IgA antibodies to herpes simplex, varicella-zoster, cytomegalovirus, and rubella virus detected by enzyme-linked immunosorbent assays.Journal of Medical Virology 16, 343-349.[CrossRef] [Google Scholar]
  32. Nilsen, I., Flaegstad, T. & Traavik, T. (1991). Detection of specific IgA antibodies against BK virus by ELISA.Journal of Medical Virology 33, 89-94.[CrossRef] [Google Scholar]
  33. Page, G. S., Mosser, A. G., Hogle, J. M., Filman, D. J., Rueckert, R. R. & Chow, M. (1988). Three-dimensional structure of poliovirus serotype 1 neutralizing determinants.Journal of Virology 62, 1781-1794. [Google Scholar]
  34. Patnaik, M., Velosa, J. A. & Peter, J. B. (1999). Hantavirus-specific IgG, IgM, and IgA in acute and chronic renal disease versus congenital renal disease in the United States.American Journal of Kidney Diseases 33, 734-737.[CrossRef] [Google Scholar]
  35. Plyusnin, A., Vapalahti, O. & Vaheri, A. (1996). Hantaviruses: genome structure, expression and evolution.Journal of General Virology 77, 2677-2687.[CrossRef] [Google Scholar]
  36. Plyusnin, A., Hörling, J., Kanerva, M., Mustonen, J., Cheng, Y., Partanen, J., Vapalahti, O., Kukkonen, S. K., Niemimaa, J., Henttonen, H., Niklasson, B., Lundkvist, Å. & Vaheri, A. (1997). Puumala hantavirus genome in patients with nephropathia epidemica: correlation of PCR positivity with HLA haplotype and link to viral sequences in local rodents.Journal of Clinical Microbiology 35, 1090-1096. [Google Scholar]
  37. Plyusnin, A., Nemirov, K., Apekina, N., Plyusnina, A., Lundkvist, Å. & Vaheri, A. (1999). Dobrava hantavirus in Russia.Lancet 353, 207.[CrossRef] [Google Scholar]
  38. Pozzetto, B., Gaudin, O. G., Lucht, F. R., Hafid, J. & Ros, A. (1990). Detection of immunoglobulin G, M, and A antibodies to enterovirus structural proteins by immunoblot technique in echovirus type 4-infected patients.Journal of Virological Methods 29, 143-155.[CrossRef] [Google Scholar]
  39. Renegar, K. B. & Small, P. A.Jr (1991). Passive transfer of local immunity to influenza virus infection by IgA antibody.Journal of Immunology 146, 1972-1978. [Google Scholar]
  40. Sällberg, M., Norder, H. & Magnius, L. O. (1990). Comparison of class and subclass distribution of antibodies to the hepatitis B core and B e antigens in chronic hepatitis B.Journal of Medical Virology 30, 1-6.[CrossRef] [Google Scholar]
  41. Schmaljohn, C. S. (1996). The Bunyaviridae. In Molecular Biology of Hantaviruses, pp. 63-90. Edited by R. Elliott. New York: Plenum Press.
  42. Tew, J. G., Phipps, R. P. & Mandel, T. E. (1980). The maintenance and regulation of the humoral immune response: persisting antigen and the role of follicular antigen-binding dendritic cells as accessory cells.Immunological Reviews 53, 175-201.[CrossRef] [Google Scholar]
  43. Vapalahti, O., Kallio-Kokko, H., Salonen, E.-M., Brummer-Korvenkontio, M. & Vaheri, A. (1992). Cloning and sequencing of Puumala virus Sotkamo strain S and M RNA segments: evidence for strain variation in hantaviruses and expression of the nucleocapsid protein.Journal of General Virology 73, 829-838.[CrossRef] [Google Scholar]
  44. Vapalahti, O., Kallio-Kokko, H., Narvanen, A., Julkunen, I., Lundkvist, Å., Plyusnin, A., Lehvaslaiho, H., Brummer-Korvenkontio, M., Vaheri, A. & Lankinen, H. (1995). Human B-cell epitopes of Puumala virus nucleocapsid protein, the major antigen in early serological response.Journal of Medical Virology 46, 293-303.[CrossRef] [Google Scholar]
  45. Wang, M. L. (1986). Production of IgA monoclonal antibodies against influenza A virus.Journal of Virological Methods 13, 21-26.[CrossRef] [Google Scholar]
  46. Zöller, L., Yang, S., Gott, P., Bautz, E. K. & Darai, G. (1993). Use of recombinant nucleocapsid proteins of the Hantaan and nephropathia epidemica serotypes of hantaviruses as immunodiagnostic antigens.Journal of Medical Virology 39, 200-207.[CrossRef] [Google Scholar]

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