Abstract
The immunoglobulin G (IgG) antibody response to outer surface protein A (OspA) of Borrelia burgdorferi has been reported to occur late in the course of Lyme disease. To learn when reactivity to particular epitopes of OspA develops and whether the strength of particular responses correlates with the duration of arthritis and HLA-DR specificities, we determined the IgM and IgG responses by enzyme-linked immunosorbent assay in 128 patients with various manifestations of Lyme disease to full-length recombinant OspA and three OspA fragments which divided the protein approximately into thirds. Among the 10 patients who were followed serially, an early IgM response was often found to epitopes in all three fragments of OspA, sometimes accompanied by a weak IgG response, primarily to an epitope in the middle third of the protein. Months to years later, the seven patients who had prolonged or moderate episodes of arthritis developed strong IgG responses to OspA, especially to epitopes in the N-terminal and C-terminal fragments, that paralleled the course of the arthritis. In single serum samples from 128 patients, a similar pattern of IgM and IgG reactivity with OspA epitopes was seen in patients with early or late manifestations of the illness. Of the 80 patients with arthritis, 62 (78%) had IgG responses to OspA, usually with the strongest reactivity to the C-terminal fragment. In these patients, the strength of the IgG response to OspA correlated with the duration of arthritis; in HLA-DR4-positive patients, most of whom had chronic arthritis, this association was attributable to reactivity with the C-terminal fragment. Thus, patients with Lyme disease often have early responses to OspA, but those with prolonged arthritis do not develop IgG responses to certain epitopes of the protein until late in the illness. In patients with HLA-DR4, the strength of IgG reactivity with one or more epitopes in the C-terminal fragment of OspA correlates with the duration of arthritis.
Full Text
The Full Text of this article is available as a PDF (315.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Barbour A. G., Burgdorfer W., Grunwaldt E., Steere A. C. Antibodies of patients with Lyme disease to components of the Ixodes dammini spirochete. J Clin Invest. 1983 Aug;72(2):504–515. doi: 10.1172/JCI110998. [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]
- Craft J. E., Grodzicki R. L., Steere A. C. Antibody response in Lyme disease: evaluation of diagnostic tests. J Infect Dis. 1984 May;149(5):789–795. doi: 10.1093/infdis/149.5.789. [DOI] [PubMed] [Google Scholar]
- Dressler F., Whalen J. A., Reinhardt B. N., Steere A. C. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis. 1993 Feb;167(2):392–400. doi: 10.1093/infdis/167.2.392. [DOI] [PubMed] [Google Scholar]
- Erdile L. F., Brandt M. A., Warakomski D. J., Westrack G. J., Sadziene A., Barbour A. G., Mays J. P. Role of attached lipid in immunogenicity of Borrelia burgdorferi OspA. Infect Immun. 1993 Jan;61(1):81–90. doi: 10.1128/iai.61.1.81-90.1993. [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., Barthold S. W., Marcantonio N., Deponte K., Kantor F. S., Flavell R. A. Roles of OspA, OspB, and flagellin in protective immunity to Lyme borreliosis in laboratory mice. Infect Immun. 1992 Feb;60(2):657–661. doi: 10.1128/iai.60.2.657-661.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fung B. P., McHugh G. L., Leong J. M., Steere A. C. Humoral immune response to outer surface protein C of Borrelia burgdorferi in Lyme disease: role of the immunoglobulin M response in the serodiagnosis of early infection. Infect Immun. 1994 Aug;62(8):3213–3221. doi: 10.1128/iai.62.8.3213-3221.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Howe T. R., Mayer L. W., Barbour A. G. A single recombinant plasmid expressing two major outer surface proteins of the Lyme disease spirochete. Science. 1985 Feb 8;227(4687):645–646. doi: 10.1126/science.3969554. [DOI] [PubMed] [Google Scholar]
- Janeway C. A., Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994 Jan 28;76(2):275–285. doi: 10.1016/0092-8674(94)90335-2. [DOI] [PubMed] [Google Scholar]
- Kalish R. A., Leong J. M., Steere A. C. Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun. 1993 Jul;61(7):2774–2779. doi: 10.1128/iai.61.7.2774-2779.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keller D., Koster F. T., Marks D. H., Hosbach P., Erdile L. F., Mays J. P. Safety and immunogenicity of a recombinant outer surface protein A Lyme vaccine. JAMA. 1994 Jun 8;271(22):1764–1768. [PubMed] [Google Scholar]
- Krause A., Burmester G. R., Rensing A., Schoerner C., Schaible U. E., Simon M. M., Herzer P., Kramer M. D., Wallich R. Cellular immune reactivity to recombinant OspA and flagellin from Borrelia burgdorferi in patients with Lyme borreliosis. Complexity of humoral and cellular immune responses. J Clin Invest. 1992 Sep;90(3):1077–1084. doi: 10.1172/JCI115923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lengl-Janssen B., Strauss A. F., Steere A. C., Kamradt T. The T helper cell response in Lyme arthritis: differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis. J Exp Med. 1994 Dec 1;180(6):2069–2078. doi: 10.1084/jem.180.6.2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leong J. M., Fournier R. S., Isberg R. R. Identification of the integrin binding domain of the Yersinia pseudotuberculosis invasin protein. EMBO J. 1990 Jun;9(6):1979–1989. doi: 10.1002/j.1460-2075.1990.tb08326.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lim L. C., England D. M., DuChateau B. K., Glowacki N. J., Creson J. R., Lovrich S. D., Callister S. M., Jobe D. A., Schell R. F. Development of destructive arthritis in vaccinated hamsters challenged with Borrelia burgdorferi. Infect Immun. 1994 Jul;62(7):2825–2833. doi: 10.1128/iai.62.7.2825-2833.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lim L. C., England D. M., DuChateau B. K., Glowacki N. J., Schell R. F. Borrelia burgdorferi-specific T lymphocytes induce severe destructive Lyme arthritis. Infect Immun. 1995 Apr;63(4):1400–1408. doi: 10.1128/iai.63.4.1400-1408.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Logigian E. L., Kaplan R. F., Steere A. C. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990 Nov 22;323(21):1438–1444. doi: 10.1056/NEJM199011223232102. [DOI] [PubMed] [Google Scholar]
- McAlister H. F., Klementowicz P. T., Andrews C., Fisher J. D., Feld M., Furman S. Lyme carditis: an important cause of reversible heart block. Ann Intern Med. 1989 Mar 1;110(5):339–345. doi: 10.7326/0003-4819-110-5-339. [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]
- Pachner A. R., Steere A. C. The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology. 1985 Jan;35(1):47–53. doi: 10.1212/wnl.35.1.47. [DOI] [PubMed] [Google Scholar]
- Schmitz J. L., Schell R. F., Lovrich S. D., Callister S. M., Coe J. E. Characterization of the protective antibody response to Borrelia burgdorferi in experimentally infected LSH hamsters. Infect Immun. 1991 Jun;59(6):1916–1921. doi: 10.1128/iai.59.6.1916-1921.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schubach W. H., Mudri S., Dattwyler R. J., Luft B. J. Mapping antibody-binding domains of the major outer surface membrane protein (OspA) of Borrelia burgdorferi. Infect Immun. 1991 Jun;59(6):1911–1915. doi: 10.1128/iai.59.6.1911-1915.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schutzer S. E., Coyle P. K., Dunn J. J., Luft B. J., Brunner M. Early and specific antibody response to OspA in Lyme Disease. J Clin Invest. 1994 Jul;94(1):454–457. doi: 10.1172/JCI117346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sears J. E., Fikrig E., Nakagawa T. Y., Deponte K., Marcantonio N., Kantor F. S., Flavell R. A. Molecular mapping of Osp-A mediated immunity against Borrelia burgdorferi, the agent of Lyme disease. J Immunol. 1991 Sep 15;147(6):1995–2000. [PubMed] [Google Scholar]
- Shanafelt M. C., Anzola J., Soderberg C., Yssel H., Turck C. W., Peltz G. Epitopes on the outer surface protein A of Borrelia burgdorferi recognized by antibodies and T cells of patients with Lyme disease. J Immunol. 1992 Jan 1;148(1):218–224. [PubMed] [Google Scholar]
- Steere A. C., Bartenhagen N. H., Craft J. E., Hutchinson G. J., Newman J. H., Rahn D. W., Sigal L. H., Spieler P. N., Stenn K. S., Malawista S. E. The early clinical manifestations of Lyme disease. Ann Intern Med. 1983 Jul;99(1):76–82. doi: 10.7326/0003-4819-99-1-76. [DOI] [PubMed] [Google Scholar]
- Steere A. C., Dwyer E., Winchester R. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med. 1990 Jul 26;323(4):219–223. doi: 10.1056/NEJM199007263230402. [DOI] [PubMed] [Google Scholar]
- Steere A. C., Levin R. E., Molloy P. J., Kalish R. A., Abraham J. H., 3rd, Liu N. Y., Schmid C. H. Treatment of Lyme arthritis. Arthritis Rheum. 1994 Jun;37(6):878–888. doi: 10.1002/art.1780370616. [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]
- Steere A. C., Schoen R. T., Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987 Nov;107(5):725–731. doi: 10.7326/0003-4819-107-5-725. [DOI] [PubMed] [Google Scholar]
- Stover C. K., Bansal G. P., Hanson M. S., Burlein J. E., Palaszynski S. R., Young J. F., Koenig S., Young D. B., Sadziene A., Barbour A. G. Protective immunity elicited by recombinant bacille Calmette-Guerin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine. J Exp Med. 1993 Jul 1;178(1):197–209. doi: 10.1084/jem.178.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tai K. F., Ma Y., Weis J. J. Normal human B lymphocytes and mononuclear cells respond to the mitogenic and cytokine-stimulatory activities of Borrelia burgdorferi and its lipoprotein OspA. Infect Immun. 1994 Feb;62(2):520–528. doi: 10.1128/iai.62.2.520-528.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilske B., Preac-Mursic V., Jauris S., Hofmann A., Pradel I., Soutschek E., Schwab E., Will G., Wanner G. Immunological and molecular polymorphisms of OspC, an immunodominant major outer surface protein of Borrelia burgdorferi. Infect Immun. 1993 May;61(5):2182–2191. doi: 10.1128/iai.61.5.2182-2191.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
