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. 1996 Sep;70(9):5968–5974. doi: 10.1128/jvi.70.9.5968-5974.1996

Effects of the route of infection on immunoglobulin G subclasses and specificity of the reovirus-specific humoral immune response.

A S Major 1, C F Cuff 1
PMCID: PMC190617  PMID: 8709219

Abstract

Reovirus serotype 1, strain Lang (T1/L), a well characterized enteric virus, elicits humoral and cellular immune responses in mice. Although orally and intradermally induced infections generate comparable reovirus-specific serum antibody titers, little is known about the effects of the route of infection on the systemic immunoglobulin G (IgG) response. To assess whether the route of exposure affects virus-specific humoral immunity, we infected various strains of mice with reovirus T1/L by the oral or intradermal routes. At day 10 following infection, virus-specific serum antibody titers and IgG subclasses were determined by enzyme-linked immunosorbent assay. Serum IgG2a and IgG2b antibodies were detected in all mouse strains independent of the route of infection. Mice of the H-2d haplotype that received an intradermal infection also had high levels of reovirus-specific serum IgG1. This dichotomy of responses was not associated with differences in the types of cytokine produced by draining peripheral lymph nodes. However, peripheral lymph node lymphocytes from C3H mice produced significantly higher levels of gamma interferon than did BALB/c, C57BL/6, and B10.D2 mice. Additionally, peripheral lymph node lymphocytes from all strains of mice produced only low levels of interleukin-5, with no detectable level of interleukin-4 or interleukin-6. Analysis of specific antibody at inductive sites of the immune response showed that orally infected Peyer's patches produced predominantly IgA and intradermally infected peripheral lymph nodes produced predominantly IgG2a. Western blot (immunoblot) analysis showed that virus-specific IgA, IgG1, and IgG2a reacted with reovirus structural proteins. These data suggest that the route of infection affects the isotype and IgG subclasses, but not the antigen specificity, of the local antibody response. In addition, virus-specific IgG1 generated following an intradermally induced infection is linked to the H-2d major histocompatibility complex haplotype.

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Selected References

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  1. Armstrong S. J., Outlaw M. C., Dimmock N. J. Morphological studies of the neutralization of influenza virus by IgM. J Gen Virol. 1990 Oct;71(Pt 10):2313–2319. doi: 10.1099/0022-1317-71-10-2313. [DOI] [PubMed] [Google Scholar]
  2. Barkon M. L., Haller B. L., Virgin H. W., 4th Circulating immunoglobulin G can play a critical role in clearance of intestinal reovirus infection. J Virol. 1996 Feb;70(2):1109–1116. doi: 10.1128/jvi.70.2.1109-1116.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernstein D. I., Kacica M. A., McNeal M. M., Schiff G. M., Ward R. L. Local and systemic antibody response to rotavirus WC3 vaccine in adult volunteers. Antiviral Res. 1989 Dec;12(5-6):293–300. doi: 10.1016/0166-3542(89)90056-9. [DOI] [PubMed] [Google Scholar]
  4. Cebra J. J., Bos N. A., Cebra E. R., Cuff C. F., Deenen G. J., Kroese F. G., Shroff K. E. Development of components of the mucosal immune system in SCID recipient mice. Adv Exp Med Biol. 1994;355:255–259. doi: 10.1007/978-1-4615-2492-2_43. [DOI] [PubMed] [Google Scholar]
  5. Chatfield S. N., Strugnell R. A., Dougan G. Live Salmonella as vaccines and carriers of foreign antigenic determinants. Vaccine. 1989 Dec;7(6):495–498. doi: 10.1016/0264-410x(89)90271-5. [DOI] [PubMed] [Google Scholar]
  6. Coffin S. E., Klinek M., Offit P. A. Induction of virus-specific antibody production by lamina propria lymphocytes following intramuscular inoculation with rotavirus. J Infect Dis. 1995 Sep;172(3):874–878. doi: 10.1093/infdis/172.3.874. [DOI] [PubMed] [Google Scholar]
  7. Conner M. E., Gilger M. A., Estes M. K., Graham D. Y. Serologic and mucosal immune response to rotavirus infection in the rabbit model. J Virol. 1991 May;65(5):2562–2571. doi: 10.1128/jvi.65.5.2562-2571.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coutelier J. P., van der Logt J. T., Heessen F. W., Vink A., van Snick J. Virally induced modulation of murine IgG antibody subclasses. J Exp Med. 1988 Dec 1;168(6):2373–2378. doi: 10.1084/jem.168.6.2373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coutelier J. P., van der Logt J. T., Heessen F. W., Warnier G., Van Snick J. IgG2a restriction of murine antibodies elicited by viral infections. J Exp Med. 1987 Jan 1;165(1):64–69. doi: 10.1084/jem.165.1.64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Craig S. W., Cebra J. J. Peyer's patches: an enriched source of precursors for IgA-producing immunocytes in the rabbit. J Exp Med. 1971 Jul 1;134(1):188–200. doi: 10.1084/jem.134.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cuff C. F., Cebra C. K., Lavi E., Molowitz E. H., Rubin D. H., Cebra J. J. Protection of neonatal mice from fatal reovirus infection by immune serum and gut derived lymphocytes. Adv Exp Med Biol. 1991;310:307–315. doi: 10.1007/978-1-4615-3838-7_40. [DOI] [PubMed] [Google Scholar]
  12. Cuff C. F., Lavi E., Cebra C. K., Cebra J. J., Rubin D. H. Passive immunity to fatal reovirus serotype 3-induced meningoencephalitis mediated by both secretory and transplacental factors in neonatal mice. J Virol. 1990 Mar;64(3):1256–1263. doi: 10.1128/jvi.64.3.1256-1263.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. De Becker G., Sornasse T., Nabavi N., Bazin H., Tielemans F., Urbain J., Leo O., Moser M. Immunoglobulin isotype regulation by antigen-presenting cells in vivo. Eur J Immunol. 1994 Jul;24(7):1523–1528. doi: 10.1002/eji.1830240710. [DOI] [PubMed] [Google Scholar]
  14. Denis O., Latinne D., Nisol F., Bazin H. Resting B cells can act as antigen presenting cells in vivo and induce antibody responses. Int Immunol. 1993 Jan;5(1):71–78. doi: 10.1093/intimm/5.1.71. [DOI] [PubMed] [Google Scholar]
  15. Doherty P. C., Allan J. E., Lynch F., Ceredig R. Dissection of an inflammatory process induced by CD8+ T cells. Immunol Today. 1990 Feb;11(2):55–59. doi: 10.1016/0167-5699(90)90019-6. [DOI] [PubMed] [Google Scholar]
  16. Evengård B., Wolowczuk I., Marguerite M., Hammarström L., Smith E., Auriault C. IgG subclass-associated differences in anti-schistosomal antibody specificity. Scand J Immunol. 1994 Dec;40(6):618–622. doi: 10.1111/j.1365-3083.1994.tb03513.x. [DOI] [PubMed] [Google Scholar]
  17. Farstad I. N., Halstensen T. S., Fausa O., Brandtzaeg P. Heterogeneity of M-cell-associated B and T cells in human Peyer's patches. Immunology. 1994 Nov;83(3):457–464. [PMC free article] [PubMed] [Google Scholar]
  18. Feng N., Burns J. W., Bracy L., Greenberg H. B. Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus. J Virol. 1994 Dec;68(12):7766–7773. doi: 10.1128/jvi.68.12.7766-7773.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Finkelman F. D., Katona I. M., Mosmann T. R., Coffman R. L. IFN-gamma regulates the isotypes of Ig secreted during in vivo humoral immune responses. J Immunol. 1988 Feb 15;140(4):1022–1027. [PubMed] [Google Scholar]
  20. Finkelman F. D., Katona I. M., Urban J. F., Jr, Holmes J., Ohara J., Tung A. S., Sample J. V., Paul W. E. IL-4 is required to generate and sustain in vivo IgE responses. J Immunol. 1988 Oct 1;141(7):2335–2341. [PubMed] [Google Scholar]
  21. George A., Kost S. I., Witzleben C. L., Cebra J. J., Rubin D. H. Reovirus-induced liver disease in severe combined immunodeficient (SCID) mice. A model for the study of viral infection, pathogenesis, and clearance. J Exp Med. 1990 Mar 1;171(3):929–934. doi: 10.1084/jem.171.3.929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Heusser C. H., Anderson C. L., Grey H. M. Receptors for IgG: subclass specificity of receptors on different mouse cell types and the definition of two distinct receptors on a macrophage cell line. J Exp Med. 1977 May 1;145(5):1316–1327. doi: 10.1084/jem.145.5.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Holmgren J., Lycke N., Czerkinsky C. Cholera toxin and cholera B subunit as oral-mucosal adjuvant and antigen vector systems. Vaccine. 1993 Sep;11(12):1179–1184. doi: 10.1016/0264-410x(93)90039-z. [DOI] [PubMed] [Google Scholar]
  24. Ishizaka S. T., Piacente P., Silva J., Mishkin E. M. IgG subtype is correlated with efficiency of passive protection and effector function of anti-herpes simplex virus glycoprotein D monoclonal antibodies. J Infect Dis. 1995 Oct;172(4):1108–1111. doi: 10.1093/infdis/172.4.1108. [DOI] [PubMed] [Google Scholar]
  25. Islam D., Wretlind B., Ryd M., Lindberg A. A., Christensson B. Immunoglobulin subclass distribution and dynamics of Shigella-specific antibody responses in serum and stool samples in shigellosis. Infect Immun. 1995 May;63(5):2054–2061. doi: 10.1128/iai.63.5.2054-2061.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kaetzel C. S., Robinson J. K., Lamm M. E. Epithelial transcytosis of monomeric IgA and IgG cross-linked through antigen to polymeric IgA. A role for monomeric antibodies in the mucosal immune system. J Immunol. 1994 Jan 1;152(1):72–76. [PubMed] [Google Scholar]
  27. Khoury C. A., Moser C. A., Speaker T. J., Offit P. A. Oral inoculation of mice with low doses of microencapsulated, noninfectious rotavirus induces virus-specific antibodies in gut-associated lymphoid tissue. J Infect Dis. 1995 Sep;172(3):870–874. doi: 10.1093/infdis/172.3.870. [DOI] [PubMed] [Google Scholar]
  28. Klaus G. G., Pepys M. B., Kitajima K., Askonas B. A. Activation of mouse complement by different classes of mouse antibody. Immunology. 1979 Dec;38(4):687–695. [PMC free article] [PubMed] [Google Scholar]
  29. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  30. Lambkin R., McLain L., Jones S. E., Aldridge S. L., Dimmock N. J. Neutralization escape mutants of type A influenza virus are readily selected by antisera from mice immunized with whole virus: a possible mechanism for antigenic drift. J Gen Virol. 1994 Dec;75(Pt 12):3493–3502. doi: 10.1099/0022-1317-75-12-3493. [DOI] [PubMed] [Google Scholar]
  31. Langley J. G., Kariuki H. C., Hammersley A. P., Ouma J. H., Butterworth A. E., Dunne D. W. Human IgG subclass responses and subclass restriction to Schistosoma mansoni egg antigens. Immunology. 1994 Dec;83(4):651–658. [PMC free article] [PubMed] [Google Scholar]
  32. Lazdins I., Coulson B. S., Kirkwood C., Dyall-Smith M., Masendycz P. J., Sonza S., Holmes I. H. Rotavirus antigenicity is affected by the genetic context and glycosylation of VP7. Virology. 1995 May 10;209(1):80–89. doi: 10.1006/viro.1995.1232. [DOI] [PubMed] [Google Scholar]
  33. Letvin N. L., Kauffman R. S., Finberg R. T lymphocyte immunity to reovirus: cellular requirements for generation and role in clearance of primary infections. J Immunol. 1981 Dec;127(6):2334–2339. [PubMed] [Google Scholar]
  34. Logan A. C., Chow K. P., George A., Weinstein P. D., Cebra J. J. Use of Peyer's patch and lymph node fragment cultures to compare local immune responses to Morganella morganii. Infect Immun. 1991 Mar;59(3):1024–1031. doi: 10.1128/iai.59.3.1024-1031.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. London S. D., Cebra-Thomas J. A., Rubin D. H., Cebra J. J. CD8 lymphocyte subpopulations in Peyer's patches induced by reovirus serotype 1 infection. J Immunol. 1990 Apr 15;144(8):3187–3194. [PubMed] [Google Scholar]
  36. London S. D., Cebra J. J., Rubin D. H. Intraepithelial lymphocytes contain virus-specific, MHC-restricted cytotoxic cell precursors after gut mucosal immunization with reovirus serotype 1/Lang. Reg Immunol. 1989 Mar-Apr;2(2):98–102. [PubMed] [Google Scholar]
  37. London S. D., Rubin D. H., Cebra J. J. Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer's patches. J Exp Med. 1987 Mar 1;165(3):830–847. doi: 10.1084/jem.165.3.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mahon B. P., Katrak K., Nomoto A., Macadam A. J., Minor P. D., Mills K. H. Poliovirus-specific CD4+ Th1 clones with both cytotoxic and helper activity mediate protective humoral immunity against a lethal poliovirus infection in transgenic mice expressing the human poliovirus receptor. J Exp Med. 1995 Apr 1;181(4):1285–1292. doi: 10.1084/jem.181.4.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Manickan E., Francotte M., Kuklin N., Dewerchin M., Molitor C., Gheysen D., Slaoui M., Rouse B. T. Vaccination with recombinant vaccinia viruses expressing ICP27 induces protective immunity against herpes simplex virus through CD4+ Th1+ T cells. J Virol. 1995 Aug;69(8):4711–4716. doi: 10.1128/jvi.69.8.4711-4716.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Milich D. R., Peterson D. L., Schödel F., Jones J. E., Hughes J. L. Preferential recognition of hepatitis B nucleocapsid antigens by Th1 or Th2 cells is epitope and major histocompatibility complex dependent. J Virol. 1995 May;69(5):2776–2785. doi: 10.1128/jvi.69.5.2776-2785.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Mo X. Y., Sangster M., Sarawar S., Coleclough C., Doherty P. C. Differential antigen burden modulates the gamma interferon but not the immunoglobulin response in mice that vary in susceptibility to Sendai virus pneumonia. J Virol. 1995 Sep;69(9):5592–5598. doi: 10.1128/jvi.69.9.5592-5598.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  43. Nguyen L., Knipe D. M., Finberg R. W. Mechanism of virus-induced Ig subclass shifts. J Immunol. 1994 Jan 15;152(2):478–484. [PubMed] [Google Scholar]
  44. Outlaw M. C., Armstrong S. J., Dimmock N. J. Mechanisms of neutralization of influenza virus in tracheal epithelial and BHK cells vary according to IgG concentration. Virology. 1990 Oct;178(2):478–485. doi: 10.1016/0042-6822(90)90345-r. [DOI] [PubMed] [Google Scholar]
  45. Outlaw M. C., Dimmock N. J. Insights into neutralization of animal viruses gained from study of influenza virus. Epidemiol Infect. 1991 Apr;106(2):205–220. doi: 10.1017/s0950268800048354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Outlaw M. C., Dimmock N. J. Mechanisms of neutralization of influenza virus on mouse tracheal epithelial cells by mouse monoclonal polymeric IgA and polyclonal IgM directed against the viral haemagglutinin. J Gen Virol. 1990 Jan;71(Pt 1):69–76. doi: 10.1099/0022-1317-71-1-69. [DOI] [PubMed] [Google Scholar]
  47. Paya C. V., Kenmotsu N., Schoon R. A., Leibson P. J. Tumor necrosis factor and lymphotoxin secretion by human natural killer cells leads to antiviral cytotoxicity. J Immunol. 1988 Sep 15;141(6):1989–1995. [PubMed] [Google Scholar]
  48. Richardson S. C., Bishop R. F. Homotypic serum antibody responses to rotavirus proteins following primary infection of young children with serotype 1 rotavirus. J Clin Microbiol. 1990 Sep;28(9):1891–1897. doi: 10.1128/jcm.28.9.1891-1897.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Rubin D. H., Kornstein M. J., Anderson A. O. Reovirus serotype 1 intestinal infection: a novel replicative cycle with ileal disease. J Virol. 1985 Feb;53(2):391–398. doi: 10.1128/jvi.53.2.391-398.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schrader C. E., George A., Kerlin R. L., Cebra J. J. Dendritic cells support production of IgA and other non-IgM isotypes in clonal microculture. Int Immunol. 1990;2(6):563–570. doi: 10.1093/intimm/2.6.563. [DOI] [PubMed] [Google Scholar]
  51. Scott P., Natovitz P., Coffman R. L., Pearce E., Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. doi: 10.1084/jem.168.5.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Selb B., Weber B. A study of human reovirus IgG and IgA antibodies by ELISA and western blot. J Virol Methods. 1994 Apr;47(1-2):15–25. doi: 10.1016/0166-0934(94)90062-0. [DOI] [PubMed] [Google Scholar]
  53. Shaw R. D., Groene W. S., Mackow E. R., Merchant A. A., Cheng E. H. VP4-specific intestinal antibody response to rotavirus in a murine model of heterotypic infection. J Virol. 1991 Jun;65(6):3052–3059. doi: 10.1128/jvi.65.6.3052-3059.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
  55. Spalding D. M., Griffin J. A. Different pathways of differentiation of pre-B cell lines are induced by dendritic cells and T cells from different lymphoid tissues. Cell. 1986 Feb 14;44(3):507–515. doi: 10.1016/0092-8674(86)90472-1. [DOI] [PubMed] [Google Scholar]
  56. Spalding D. M., Williamson S. I., Koopman W. J., McGhee J. R. Preferential induction of polyclonal IgA secretion by murine Peyer's patch dendritic cell-T cell mixtures. J Exp Med. 1984 Sep 1;160(3):941–946. doi: 10.1084/jem.160.3.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Stevens T. L., Bossie A., Sanders V. M., Fernandez-Botran R., Coffman R. L., Mosmann T. R., Vitetta E. S. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature. 1988 Jul 21;334(6179):255–258. doi: 10.1038/334255a0. [DOI] [PubMed] [Google Scholar]
  58. Tamer C. M., Lamm M. E., Robinson J. K., Piskurich J. F., Kaetzel C. S. Comparative studies of transcytosis and assembly of secretory IgA in Madin-Darby canine kidney cells expressing human polymeric Ig receptor. J Immunol. 1995 Jul 15;155(2):707–714. [PubMed] [Google Scholar]
  59. Tyler K. L., Mann M. A., Fields B. N., Virgin H. W., 4th Protective anti-reovirus monoclonal antibodies and their effects on viral pathogenesis. J Virol. 1993 Jun;67(6):3446–3453. doi: 10.1128/jvi.67.6.3446-3453.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Tyler K. L., Virgin H. W., 4th, Bassel-Duby R., Fields B. N. Antibody inhibits defined stages in the pathogenesis of reovirus serotype 3 infection of the central nervous system. J Exp Med. 1989 Sep 1;170(3):887–900. doi: 10.1084/jem.170.3.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Virgin H. W., 4th, Mann M. A., Tyler K. L. Protective antibodies inhibit reovirus internalization and uncoating by intracellular proteases. J Virol. 1994 Oct;68(10):6719–6729. doi: 10.1128/jvi.68.10.6719-6729.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Virgin H. W., 4th, Tyler K. L. Role of immune cells in protection against and control of reovirus infection in neonatal mice. J Virol. 1991 Oct;65(10):5157–5164. doi: 10.1128/jvi.65.10.5157-5164.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Weinstein P. D., Cebra J. J. The preference for switching to IgA expression by Peyer's patch germinal center B cells is likely due to the intrinsic influence of their microenvironment. J Immunol. 1991 Dec 15;147(12):4126–4135. [PubMed] [Google Scholar]
  64. Zhaori G., Sun M., Faden H. S., Ogra P. L. Nasopharyngeal secretory antibody response to poliovirus type 3 virion proteins exhibit different specificities after immunization with live or inactivated poliovirus vaccines. J Infect Dis. 1989 Jun;159(6):1018–1024. doi: 10.1093/infdis/159.6.1018. [DOI] [PubMed] [Google Scholar]
  65. Zhaori G., Sun M., Ogra P. L. Characteristics of the immune response to poliovirus virion polypeptides after immunization with live or inactivated polio vaccines. J Infect Dis. 1988 Jul;158(1):160–165. doi: 10.1093/infdis/158.1.160. [DOI] [PubMed] [Google Scholar]

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