Abstract
The brain parenchyma affords immune privilege to tissue grafts, but it is not known whether the same is true for intracerebral viral infections. Using stereotactically guided microinjection, we have confined infection with influenza virus A/NT/60/68 to either the brain parenchyma or the cerebrospinal fluid (CSF). A/NT/60/68 infection in the CSF elicited a comparable immune response to intranasal infection, with the production of antiviral serum antibody, priming of antiviral cytotoxic T-cell precursors, and an antiviral proliferative response in the draining lymph nodes. The response to virus in the CSF was detectable sooner after inoculation than the response to intranasal virus and also involved a prolonged production of virus-specific immunoglobulin A in the CSF. In contrast, there was no detectable immune response to virus infection in the brain parenchyma by any of the parameters measured for at least 10 days after inoculation. Over the next 80 days, 46% of the mice given parenchymal virus developed low-level immune responses that did not involve CSF antibody production, while the remaining 54% had no detectable response at any time. Thus, a virus infection confined to the parenchymal substance of the brain primed the immune system inefficiently or not at all.
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- CAIRNS H. J. F. Intracerebral inoculation of mice; fate of the inoculum. Nature. 1950 Nov 25;166(4230):910–911. doi: 10.1038/166910b0. [DOI] [PubMed] [Google Scholar]
- Cserr H. F., Knopf P. M. Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol Today. 1992 Dec;13(12):507–512. doi: 10.1016/0167-5699(92)90027-5. [DOI] [PubMed] [Google Scholar]
- Gerhard W., Iwasaki Y., Koprowski H. The central nervous system-associated immune response to parainfluenza type I virus in mice. J Immunol. 1978 Apr;120(4):1256–1260. [PubMed] [Google Scholar]
- Gordon L. B., Knopf P. M., Cserr H. F. Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites. J Neuroimmunol. 1992 Sep;40(1):81–87. doi: 10.1016/0165-5728(92)90215-7. [DOI] [PubMed] [Google Scholar]
- Griffin D. E. Immunoglobulins in the cerebrospinal fluid: changes during acute viral encephalitis in mice. J Immunol. 1981 Jan;126(1):27–31. [PubMed] [Google Scholar]
- Harling-Berg C., Knopf P. M., Merriam J., Cserr H. F. Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid. J Neuroimmunol. 1989 Dec;25(2-3):185–193. doi: 10.1016/0165-5728(89)90136-7. [DOI] [PubMed] [Google Scholar]
- Hart D. N., Fabre J. W. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med. 1981 Aug 1;154(2):347–361. doi: 10.1084/jem.154.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones P. D., Ada G. L. Influenza virus-specific antibody-secreting cells in the murine lung during primary influenza virus infection. J Virol. 1986 Nov;60(2):614–619. doi: 10.1128/jvi.60.2.614-619.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kawaoka Y. Equine H7N7 influenza A viruses are highly pathogenic in mice without adaptation: potential use as an animal model. J Virol. 1991 Jul;65(7):3891–3894. doi: 10.1128/jvi.65.7.3891-3894.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lynch F., Doherty P. C., Ceredig R. Phenotypic and functional analysis of the cellular response in regional lymphoid tissue during an acute virus infection. J Immunol. 1989 May 15;142(10):3592–3598. [PubMed] [Google Scholar]
- MIMS C. A. Intracerebral injections and the growth of viruses in the mouse brain. Br J Exp Pathol. 1960 Feb;41:52–59. [PMC free article] [PubMed] [Google Scholar]
- PANDA J. N., DALE H. E., LOAN R. W., DAVIS L. E. IMMUNOLOGIC RESPONSE TO SUBARACHNOID AND INTRACEREBRAL INJECTION OF ANTIGENS. J Immunol. 1965 May;94:760–764. [PubMed] [Google Scholar]
- Ravenholt R. T., Foege W. H. 1918 influenza, encephalitis lethargica, parkinsonism. Lancet. 1982 Oct 16;2(8303):860–864. doi: 10.1016/s0140-6736(82)90820-0. [DOI] [PubMed] [Google Scholar]
- Reinacher M., Bonin J., Narayan O., Scholtissek C. Pathogenesis of neurovirulent influenza A virus infection in mice. Route of entry of virus into brain determines infection of different populations of cells. Lab Invest. 1983 Dec;49(6):686–692. [PubMed] [Google Scholar]
- SCHLESINGER R. W. Incomplete growth cycle of influenza virus in mouse brain. Proc Soc Exp Biol Med. 1950 Jul;74(3):541–548. doi: 10.3181/00379727-74-17966. [DOI] [PubMed] [Google Scholar]
- Santos T. Q., Valdimarsson H. T-dependent antigens are more immunogenic in the subarachnoid space than in other sites. J Neuroimmunol. 1982 Jun;2(3-4):215–222. doi: 10.1016/0165-5728(82)90056-x. [DOI] [PubMed] [Google Scholar]
- Sloan D. J., Wood M. J., Charlton H. M. The immune response to intracerebral neural grafts. Trends Neurosci. 1991 Aug;14(8):341–346. doi: 10.1016/0166-2236(91)90159-r. [DOI] [PubMed] [Google Scholar]
- Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
- Thomas D. B., Skehel J. J., Mills K. H., Graham C. M. A single amino acid substitution in influenza hemagglutinin abrogates recognition by monoclonal antibody and a spectrum of subtype-specific L3T4+ T cell clones. Eur J Immunol. 1987 Jan;17(1):133–136. doi: 10.1002/eji.1830170122. [DOI] [PubMed] [Google Scholar]
- Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
- Tyor W. R., Griffin D. E. Virus specificity and isotype expression of intraparenchymal antibody-secreting cells during Sindbis virus encephalitis in mice. J Neuroimmunol. 1993 Oct;48(1):37–44. doi: 10.1016/0165-5728(93)90056-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Webster R. G., Laver W. G., Air G. M., Schild G. C. Molecular mechanisms of variation in influenza viruses. Nature. 1982 Mar 11;296(5853):115–121. doi: 10.1038/296115a0. [DOI] [PubMed] [Google Scholar]
- Widner H., Möller G., Johansson B. B. Immune response in deep cervical lymph nodes and spleen in the mouse after antigen deposition in different intracerebral sites. Scand J Immunol. 1988 Nov;28(5):563–571. doi: 10.1111/j.1365-3083.1988.tb01488.x. [DOI] [PubMed] [Google Scholar]
- Yolken R. H., Torrey E. F. Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev. 1995 Jan;8(1):131–145. doi: 10.1128/cmr.8.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]