Abstract
Borrelia burgdorferi produces potent cell-activating molecules capable of stimulating polyclonal proliferation and immunoglobulin production by murine B lymphocytes and cytokine production by a variety of cell types. These stimulatory molecules function in infected mice, resulting in elevated levels of circulating immunoglobulins and serum interleukin-6. We have recently demonstrated that the purified outer surface lipoproteins OspA and OspB possess these properties. To assess their possible involvement in human disease, we determined whether cells from normal human donors could respond to these activities. Normal human B lymphocytes but not T lymphocytes proliferated when incubated with either sonicated B. burgdorferi or purified OspA. Sonicated B. burgdorferi was efficient at stimulating immunoglobulin M production by human mononuclear cell cultures; however, purified OspA was relatively inactive. Both sonicated B. burgdorferi and purified OspA stimulated production of high levels of interleukin-6 by mononuclear cells. These findings extend our observations with the mouse model and suggest that the stimulatory lipoproteins could indeed be involved in the symptoms and pathologies of human infection with B. burgdorferi.
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- Barbour A. G., Tessier S. L., Todd W. J. Lyme disease spirochetes and ixodid tick spirochetes share a common surface antigenic determinant defined by a monoclonal antibody. Infect Immun. 1983 Aug;41(2):795–804. doi: 10.1128/iai.41.2.795-804.1983. [DOI] [PMC free article] [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]
- Barthold S. W., Persing D. H., Armstrong A. L., Peeples R. A. Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice. Am J Pathol. 1991 Aug;139(2):263–273. [PMC free article] [PubMed] [Google Scholar]
- Beck G., Benach J. L., Habicht G. S. Isolation of interleukin 1 from joint fluids of patients with Lyme disease. J Rheumatol. 1989 Jun;16(6):800–806. [PubMed] [Google Scholar]
- Bundoc V. G., Barbour A. G. Clonal polymorphisms of outer membrane protein OspB of Borrelia burgdorferi. Infect Immun. 1989 Sep;57(9):2733–2741. doi: 10.1128/iai.57.9.2733-2741.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burgdorfer W., Barbour A. G., Hayes S. F., Benach J. L., Grunwaldt E., Davis J. P. Lyme disease-a tick-borne spirochetosis? Science. 1982 Jun 18;216(4552):1317–1319. doi: 10.1126/science.7043737. [DOI] [PubMed] [Google Scholar]
- Defosse D. L., Johnson R. C. In vitro and in vivo induction of tumor necrosis factor alpha by Borrelia burgdorferi. Infect Immun. 1992 Mar;60(3):1109–1113. doi: 10.1128/iai.60.3.1109-1113.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fikrig E., Barthold S. W., Kantor F. S., Flavell R. A. Long-term protection of mice from Lyme disease by vaccination with OspA. Infect Immun. 1992 Mar;60(3):773–777. doi: 10.1128/iai.60.3.773-777.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Habicht G. S., Katona L. I., Benach J. L. Cytokines and the pathogenesis of neuroborreliosis: Borrelia burgdorferi induces glioma cells to secrete interleukin-6. J Infect Dis. 1991 Sep;164(3):568–574. doi: 10.1093/infdis/164.3.568. [DOI] [PubMed] [Google Scholar]
- Katona L. I., Beck G., Habicht G. S. Purification and immunological characterization of a major low-molecular-weight lipoprotein from Borrelia burgdorferi. Infect Immun. 1992 Dec;60(12):4995–5003. doi: 10.1128/iai.60.12.4995-5003.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keffer J., Probert L., Cazlaris H., Georgopoulos S., Kaslaris E., Kioussis D., Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991 Dec;10(13):4025–4031. doi: 10.1002/j.1460-2075.1991.tb04978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Ma Y., Weis J. J. Borrelia burgdorferi outer surface lipoproteins OspA and OspB possess B-cell mitogenic and cytokine-stimulatory properties. Infect Immun. 1993 Sep;61(9):3843–3853. doi: 10.1128/iai.61.9.3843-3853.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller L. C., Isa S., Vannier E., Georgilis K., Steere A. C., Dinarello C. A. Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist. J Clin Invest. 1992 Sep;90(3):906–912. doi: 10.1172/JCI115966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morrison D. C., Jacobs D. M. Binding of polymyxin B to the lipid A portion of bacterial lipopolysaccharides. Immunochemistry. 1976 Oct;13(10):813–818. doi: 10.1016/0019-2791(76)90181-6. [DOI] [PubMed] [Google Scholar]
- Nawata Y., Eugui E. M., Lee S. W., Allison A. C. IL-6 is the principal factor produced by synovia of patients with rheumatoid arthritis that induces B-lymphocytes to secrete immunoglobulins. Ann N Y Acad Sci. 1989;557:230-8, discussion 239. doi: 10.1111/j.1749-6632.1989.tb24016.x. [DOI] [PubMed] [Google Scholar]
- Pachner A. R., Delaney E., Ricalton N. S. Murine Lyme borreliosis: route of inoculation determines immune response and infectivity. Reg Immunol. 1992 Nov-Dec;4(6):345–351. [PubMed] [Google Scholar]
- Radolf J. D., Norgard M. V., Brandt M. E., Isaacs R. D., Thompson P. A., Beutler B. Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis. Analysis using a CAT reporter construct. J Immunol. 1991 Sep 15;147(6):1968–1974. [PubMed] [Google Scholar]
- Schaible U. E., Kramer M. D., Museteanu C., Zimmer G., Mossmann H., Simon M. M. The severe combined immunodeficiency (scid) mouse. A laboratory model for the analysis of Lyme arthritis and carditis. J Exp Med. 1989 Oct 1;170(4):1427–1432. doi: 10.1084/jem.170.4.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schoenfeld R., Araneo B., Ma Y., Yang L. M., Weis J. J. Demonstration of a B-lymphocyte mitogen produced by the Lyme disease pathogen, Borrelia burgdorferi. Infect Immun. 1992 Feb;60(2):455–464. doi: 10.1128/iai.60.2.455-464.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sigal L. H. Lyme disease, 1988: immunologic manifestations and possible immunopathogenetic mechanisms. Semin Arthritis Rheum. 1989 Feb;18(3):151–167. doi: 10.1016/0049-0172(89)90058-9. [DOI] [PubMed] [Google Scholar]
- Sigal L. H., Steere A. C., Dwyer J. M. In vivo and in vitro evidence of B cell hyperactivity during Lyme disease. J Rheumatol. 1988 Apr;15(4):648–654. [PubMed] [Google Scholar]
- Simon M. M., Schaible U. E., Kramer M. D., Eckerskorn C., Museteanu C., Müller-Hermelink H. K., Wallich R. Recombinant outer surface protein a from Borrelia burgdorferi induces antibodies protective against spirochetal infection in mice. J Infect Dis. 1991 Jul;164(1):123–132. doi: 10.1093/infdis/164.1.123. [DOI] [PubMed] [Google Scholar]
- Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
- Sădziene A., Rosa P. A., Thompson P. A., Hogan D. M., Barbour A. G. Antibody-resistant mutants of Borrelia burgdorferi: in vitro selection and characterization. J Exp Med. 1992 Sep 1;176(3):799–809. doi: 10.1084/jem.176.3.799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tedder T. F., Clement L. T., Cooper M. D. Expression of C3d receptors during human B cell differentiation: immunofluorescence analysis with the HB-5 monoclonal antibody. J Immunol. 1984 Aug;133(2):678–683. [PubMed] [Google Scholar]
- Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [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]
- Zoschke D. C., Skemp A. A., Defosse D. L. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease. Ann Intern Med. 1991 Feb 15;114(4):285–289. doi: 10.7326/0003-4819-114-4-285. [DOI] [PubMed] [Google Scholar]
- de Souza M. S., Fikrig E., Smith A. L., Flavell R. A., Barthold S. W. Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens. J Infect Dis. 1992 Mar;165(3):471–478. doi: 10.1093/infdis/165.3.471. [DOI] [PubMed] [Google Scholar]


