Abstract
Infection of inbred mice with Borrelia burgdorferi results in strain- specific variation in the severity of pathogen-induced arthritis: BALB/c mice develop only mild disease whereas C3H/HeJ mice develop severe arthritis. The immunologic basis for varying host susceptibility has yet to be defined. We modified experimental Lyme disease to facilitate measurement of antigen-specific cytokine production in resistant and susceptible mice. The analysis revealed highly polarized lymphokine patterns directly linked to differing disease outcomes. Among the inbred strains of mice challenged with B. burgdorferi, production of interleukin 4 (IL-4) correlated to resistance whereas production of interferon gamma (IFN-gamma) correlated to susceptibility. We also demonstrate that production of IL-4 or IFN- gamma regulates the severity of arthritis after infection. Neutralization of IL-4 in resistant BALB/c mice resulted in more severe arthritis whereas neutralization of IFN-gamma in susceptible C3H/HeJ mice attenuated the severity of disease. These results suggest a primary relationship between T helper cell phenotype and the genetic basis for susceptibility to experimental Lyme borreliosis.
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Selected References
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- Asch E. S., Bujak D. I., Weiss M., Peterson M. G., Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol. 1994 Mar;21(3):454–461. [PubMed] [Google Scholar]
- Barthold S. W., Beck D. S., Hansen G. M., Terwilliger G. A., Moody K. D. Lyme borreliosis in selected strains and ages of laboratory mice. J Infect Dis. 1990 Jul;162(1):133–138. doi: 10.1093/infdis/162.1.133. [DOI] [PubMed] [Google Scholar]
- Else K. J., Finkelman F. D., Maliszewski C. R., Grencis R. K. Cytokine-mediated regulation of chronic intestinal helminth infection. J Exp Med. 1994 Jan 1;179(1):347–351. doi: 10.1084/jem.179.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fikrig E., Barthold S. W., Kantor F. S., Flavell R. A. Protection of mice against the Lyme disease agent by immunizing with recombinant OspA. Science. 1990 Oct 26;250(4980):553–556. doi: 10.1126/science.2237407. [DOI] [PubMed] [Google Scholar]
- Fikrig E., Bockenstedt L. K., Barthold S. W., Chen M., Tao H., Ali-Salaam P., Telford S. R., Flavell R. A. Sera from patients with chronic Lyme disease protect mice from Lyme borreliosis. J Infect Dis. 1994 Mar;169(3):568–574. doi: 10.1093/infdis/169.3.568. [DOI] [PubMed] [Google Scholar]
- Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ma Y., Seiler K. P., Tai K. F., Yang L., Woods M., Weis J. J. Outer surface lipoproteins of Borrelia burgdorferi stimulate nitric oxide production by the cytokine-inducible pathway. Infect Immun. 1994 Sep;62(9):3663–3671. doi: 10.1128/iai.62.9.3663-3671.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moody K. D., Barthold S. W., Terwilliger G. A. Lyme borreliosis in laboratory animals: effect of host species and in vitro passage of Borrelia burgdorferi. Am J Trop Med Hyg. 1990 Jul;43(1):87–92. doi: 10.4269/ajtmh.1990.43.87. [DOI] [PubMed] [Google Scholar]
- Nocton J. J., Dressler F., Rutledge B. J., Rys P. N., Persing D. H., Steere A. C. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med. 1994 Jan 27;330(4):229–234. doi: 10.1056/NEJM199401273300401. [DOI] [PubMed] [Google Scholar]
- Romani L., Mencacci A., Cenci E., Spaccapelo R., Mosci P., Puccetti P., Bistoni F. CD4+ subset expression in murine candidiasis. Th responses correlate directly with genetically determined susceptibility or vaccine-induced resistance. J Immunol. 1993 Feb 1;150(3):925–931. [PubMed] [Google Scholar]
- Schaible U. E., Kramer M. D., Eichmann K., Modolell M., Museteanu C., Simon M. M. Monoclonal antibodies specific for the outer surface protein A (OspA) of Borrelia burgdorferi prevent Lyme borreliosis in severe combined immunodeficiency (scid) mice. Proc Natl Acad Sci U S A. 1990 May;87(10):3768–3772. doi: 10.1073/pnas.87.10.3768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shih C. M., Telford S. R., 3rd, Pollack R. J., Spielman A. Rapid dissemination by the agent of Lyme disease in hosts that permit fulminating infection. Infect Immun. 1993 Jun;61(6):2396–2399. doi: 10.1128/iai.61.6.2396-2399.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang L., Ma Y., Schoenfeld R., Griffiths M., Eichwald E., Araneo B., Weis J. J. Evidence for B-lymphocyte mitogen activity in Borrelia burgdorferi-infected mice. Infect Immun. 1992 Aug;60(8):3033–3041. doi: 10.1128/iai.60.8.3033-3041.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang L., Weis J. H., Eichwald E., Kolbert C. P., Persing D. H., Weis J. J. Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues. Infect Immun. 1994 Feb;62(2):492–500. doi: 10.1128/iai.62.2.492-500.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yssel H., Shanafelt M. C., Soderberg C., Schneider P. V., Anzola J., Peltz G. Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis. J Exp Med. 1991 Sep 1;174(3):593–601. doi: 10.1084/jem.174.3.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Souza M. S., Smith A. L., Beck D. S., Terwilliger G. A., Fikrig E., Barthold S. W. Long-term study of cell-mediated responses to Borrelia burgdorferi in the laboratory mouse. Infect Immun. 1993 May;61(5):1814–1822. doi: 10.1128/iai.61.5.1814-1822.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]