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. 1997 Aug;65(8):3037–3041. doi: 10.1128/iai.65.8.3037-3041.1997

B7-1 and B7-2 monoclonal antibodies modulate the severity of murine Lyme arthritis.

J Anguita 1, R Roth 1, S Samanta 1, R J Gee 1, S W Barthold 1, M Mamula 1, E Fikrig 1
PMCID: PMC175428  PMID: 9234751

Abstract

We assessed the role of B7-1 and B7-2 costimulatory molecules on the course of murine Lyme borreliosis because experimental Lyme arthritis is dependent, at least partially, upon the development of the host immune response and these costimulatory molecules have been implicated in CD4+ T-cell differentiation. We demonstrated that Borrelia burgdorferi infection upregulated the surface expression of B7-1 and B7-2 in macrophages and B7-2 expression in B cells. Anti-B7-2 monoclonal antibody (MAb) or both anti-B7-2 and anti-B7-1 MAbs produced a dose-dependent increase in the severity of Lyme arthritis in C3H/HeN mice. In contrast, the administration of an anti-B7-1 MAb reduced the degree of arthritis. These effects occurred independently of significant alteration in B. burgdorferi-specific immune responses, including splenocyte proliferative responses to B. burgdorferi, B. burgdorferi antibody levels and specificity, and mRNA levels of gamma interferon, interleukin-4 (IL-4), IL-10, and IL-12 in the spleen. These results demonstrate that signaling delivered by B7-1 and B7-2 plays a role in determining the severity of acute murine Lyme arthritis.

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Selected References

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  1. Anderson J. F., Barthold S. W., Magnarelli L. A. Infectious but nonpathogenic isolate of Borrelia burgdorferi. J Clin Microbiol. 1990 Dec;28(12):2693–2699. doi: 10.1128/jcm.28.12.2693-2699.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armstrong A. L., Barthold S. W., Persing D. H., Beck D. S. Carditis in Lyme disease susceptible and resistant strains of laboratory mice infected with Borrelia burgdorferi. Am J Trop Med Hyg. 1992 Aug;47(2):249–258. doi: 10.4269/ajtmh.1992.47.249. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Barthold S. W., Sidman C. L., Smith A. L. Lyme borreliosis in genetically resistant and susceptible mice with severe combined immunodeficiency. Am J Trop Med Hyg. 1992 Nov;47(5):605–613. doi: 10.4269/ajtmh.1992.47.605. [DOI] [PubMed] [Google Scholar]
  6. Barthold S. W., de Souza M. S., Janotka J. L., Smith A. L., Persing D. H. Chronic Lyme borreliosis in the laboratory mouse. Am J Pathol. 1993 Sep;143(3):959–971. [PMC free article] [PubMed] [Google Scholar]
  7. Barthold S. W., deSouza M., Feng S. Serum-mediated resolution of Lyme arthritis in mice. Lab Invest. 1996 Jan;74(1):57–67. [PubMed] [Google Scholar]
  8. Brown D. R., Green J. M., Moskowitz N. H., Davis M., Thompson C. B., Reiner S. L. Limited role of CD28-mediated signals in T helper subset differentiation. J Exp Med. 1996 Sep 1;184(3):803–810. doi: 10.1084/jem.184.3.803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Böggemeyer E., Stehle T., Schaible U. E., Hahne M., Vestweber D., Simon M. M. Borrelia burgdorferi upregulates the adhesion molecules E-selectin, P-selectin, ICAM-1 and VCAM-1 on mouse endothelioma cells in vitro. Cell Adhes Commun. 1994 Jun;2(2):145–157. doi: 10.3109/15419069409004433. [DOI] [PubMed] [Google Scholar]
  10. Chen C., Faherty D. A., Gault A., Connaughton S. E., Powers G. D., Godfrey D. I., Nabavi N. Monoclonal antibody 2D10 recognizes a novel T cell costimulatory molecule on activated murine B lymphocytes. J Immunol. 1994 Mar 1;152(5):2105–2114. [PubMed] [Google Scholar]
  11. Chen C., Gault A., Shen L., Nabavi N. Molecular cloning and expression of early T cell costimulatory molecule-1 and its characterization as B7-2 molecule. J Immunol. 1994 May 15;152(10):4929–4936. [PubMed] [Google Scholar]
  12. Chen C., Nabavi N. In vitro induction of T cell anergy by blocking B7 and early T cell costimulatory molecule ETC-1/B7-2. Immunity. 1994 May;1(2):147–154. doi: 10.1016/1074-7613(94)90108-2. [DOI] [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. Corry D. B., Reiner S. L., Linsley P. S., Locksley R. M. Differential effects of blockade of CD28-B7 on the development of Th1 or Th2 effector cells in experimental leishmaniasis. J Immunol. 1994 Nov 1;153(9):4142–4148. [PubMed] [Google Scholar]
  15. Dressler F., Yoshinari N. H., Steere A. C. The T-cell proliferative assay in the diagnosis of Lyme disease. Ann Intern Med. 1991 Oct 1;115(7):533–539. doi: 10.7326/0003-4819-115-7-533. [DOI] [PubMed] [Google Scholar]
  16. Fikrig E., Barthold S. W., Flavell R. A. OspA vaccination of mice with established Borrelia burgdorferi infection alters disease but not infection. Infect Immun. 1993 Jun;61(6):2553–2557. doi: 10.1128/iai.61.6.2553-2557.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Fikrig E., Tao H., Kantor F. S., Barthold S. W., Flavell R. A. Evasion of protective immunity by Borrelia burgdorferi by truncation of outer surface protein B. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4092–4096. doi: 10.1073/pnas.90.9.4092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Freeman G. J., Boussiotis V. A., Anumanthan A., Bernstein G. M., Ke X. Y., Rennert P. D., Gray G. S., Gribben J. G., Nadler L. M. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity. 1995 May;2(5):523–532. doi: 10.1016/1074-7613(95)90032-2. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Jones N. C., Germain A., Riley K. E., Bautista C., Taylor W., Wells A. F. Borrelia burgdorferi decreases hyaluronan synthesis but increases IL-6 production by fibroblasts. Microb Pathog. 1994 Apr;16(4):261–267. doi: 10.1006/mpat.1994.1027. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Kaye P. M., Rogers N. J., Curry A. J., Scott J. C. Deficient expression of co-stimulatory molecules on Leishmania-infected macrophages. Eur J Immunol. 1994 Nov;24(11):2850–2854. doi: 10.1002/eji.1830241140. [DOI] [PubMed] [Google Scholar]
  24. Keane-Myers A., Nickell S. P. Role of IL-4 and IFN-gamma in modulation of immunity to Borrelia burgdorferi in mice. J Immunol. 1995 Aug 15;155(4):2020–2028. [PubMed] [Google Scholar]
  25. Keane-Myers A., Nickell S. P. T cell subset-dependent modulation of immunity to Borrelia burgdorferi in mice. J Immunol. 1995 Feb 15;154(4):1770–1776. [PubMed] [Google Scholar]
  26. Kuchroo V. K., Das M. P., Brown J. A., Ranger A. M., Zamvil S. S., Sobel R. A., Weiner H. L., Nabavi N., Glimcher L. H. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell. 1995 Mar 10;80(5):707–718. doi: 10.1016/0092-8674(95)90349-6. [DOI] [PubMed] [Google Scholar]
  27. Lenschow D. J., Su G. H., Zuckerman L. A., Nabavi N., Jellis C. L., Gray G. S., Miller J., Bluestone J. A. Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11054–11058. doi: 10.1073/pnas.90.23.11054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Matyniak J. E., Reiner S. L. T helper phenotype and genetic susceptibility in experimental Lyme disease. J Exp Med. 1995 Mar 1;181(3):1251–1254. doi: 10.1084/jem.181.3.1251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Miller L. C., Lynch E. A., Isa S., Logan J. W., Dinarello C. A., Steere A. C. Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet. 1993 Jan 16;341(8838):146–148. doi: 10.1016/0140-6736(93)90006-3. [DOI] [PubMed] [Google Scholar]
  32. Paul W. E., Seder R. A. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. doi: 10.1016/0092-8674(94)90332-8. [DOI] [PubMed] [Google Scholar]
  33. Powers G. D., Faherty D. A., Connaughton S. E., Biondi D. A., Godfrey D. I., Gault A., Chen C. Y., Nabavi N. Expression and functional analysis of murine B7 delineated by a novel monoclonal antibody. Cell Immunol. 1994 Feb;153(2):298–311. doi: 10.1006/cimm.1994.1030. [DOI] [PubMed] [Google Scholar]
  34. Reiner S. L., Zheng S., Corry D. B., Locksley R. M. Constructing polycompetitor cDNAs for quantitative PCR. J Immunol Methods. 1993 Sep 27;165(1):37–46. doi: 10.1016/0022-1759(93)90104-f. [DOI] [PubMed] [Google Scholar]
  35. Roth R., Nakamura T., Mamula M. J. B7 costimulation and autoantigen specificity enable B cells to activate autoreactive T cells. J Immunol. 1996 Oct 1;157(7):2924–2931. [PubMed] [Google Scholar]
  36. Saha B., Das G., Vohra H., Ganguly N. K., Mishra G. C. Macrophage-T cell interaction in experimental mycobacterial infection. Selective regulation of co-stimulatory molecules on Mycobacterium-infected macrophages and its implication in the suppression of cell-mediated immune response. Eur J Immunol. 1994 Nov;24(11):2618–2624. doi: 10.1002/eji.1830241108. [DOI] [PubMed] [Google Scholar]
  37. Saha B., Das G., Vohra H., Ganguly N. K., Mishra G. C. Macrophage-T cell interaction in experimental visceral leishmaniasis: failure to express costimulatory molecules on Leishmania-infected macrophages and its implication in the suppression of cell-mediated immunity. Eur J Immunol. 1995 Sep;25(9):2492–2498. doi: 10.1002/eji.1830250913. [DOI] [PubMed] [Google Scholar]
  38. Schaible U. E., Gern L., Wallich R., Kramer M. D., Prester M., Simon M. M. Distinct patterns of protective antibodies are generated against Borrelia burgdorferi in mice experimentally inoculated with high and low doses of antigen. Immunol Lett. 1993 May;36(2):219–226. doi: 10.1016/0165-2478(93)90056-8. [DOI] [PubMed] [Google Scholar]
  39. Schaible U. E., Vestweber D., Butcher E. G., Stehle T., Simon M. M. Expression of endothelial cell adhesion molecules in joints and heart during Borrelia burgdorferi infection of mice. Cell Adhes Commun. 1994 Dec;2(6):465–479. doi: 10.3109/15419069409014211. [DOI] [PubMed] [Google Scholar]
  40. Schaible U. E., Wallich R., Kramer M. D., Nerz G., Stehle T., Museteanu C., Simon M. M. Protection against Borrelia burgdorferi infection in SCID mice is conferred by presensitized spleen cells and partially by B but not T cells alone. Int Immunol. 1994 May;6(5):671–681. doi: 10.1093/intimm/6.5.671. [DOI] [PubMed] [Google Scholar]
  41. Steere A. C., Batsford W. P., Weinberg M., Alexander J., Berger H. J., Wolfson S., Malawista S. E. Lyme carditis: cardiac abnormalities of Lyme disease. Ann Intern Med. 1980 Jul;93(1):8–16. doi: 10.7326/0003-4819-93-1-8. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Thompson C. B. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell. 1995 Jun 30;81(7):979–982. doi: 10.1016/s0092-8674(05)80001-7. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Yssel H., Nakamoto T., Schneider P., Freitas V., Collins C., Webb D., Mensi N., Soderberg C., Peltz G. Analysis of T lymphocytes cloned from the synovial fluid and blood of a patient with Lyme arthritis. Int Immunol. 1990;2(11):1081–1089. doi: 10.1093/intimm/2.11.1081. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. 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]
  48. 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]

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