LYME ARTHRITIS: A NEW EPIDEMIC DISEASE

Summary

Principal Investigator: Allen Steere
Abstract: DESCRIPTION (provided by applicant): Lyme disease, which is caused by the tick-borne spirochete Borrelia burgdorferi, can usually be treated successfully with 2-4 week courses of oral or intravenous antibiotic therapy. However, approximately 10% of patients with Lyme arthritis have persistent synovial inflammation despite such courses of therapy. To explain antibiotic-refractory Lyme arthritis after 2-3 month courses of oral and IV antibiotics, the competing hypotheses of persistent infection or infection-induced autoimmunity have been proposed. In the absence of an animal model, clinical correlations in human patients are required to address these hypotheses. To date, most patients with antibiotic-refractory Lyme arthritis have had negative PCR results for B. burgdorferi DNA in joint fluid after antibiotic treatment;they have had HLA-DRB molecules that bind the OspA163-i75 epitope of the spirochete, particularly the DRB1*0401, 0404 and 0101 molecules, and T cell reactivity with this epitope. Our goals in the next grant cycle include an assessment of antibody responses to lipid and carbohydrate antigens of B. burgdorferi to determine whether a decline in one of these responses after antibiotic therapy might serve as a practical surrogate marker for spirochetal killing in Lyme disease. The precursor frequencies of T cells specific for OspA163-i75 or implicated autoantigens will be determined in both the infectious and post-antibiotic periods of the illness, the clonal characteristics of these cells will be delineated, and the numbers and function of T regulatory cells will be determined during active arthritis through arthritis resolution. To broaden the search for candidate autoantigens beyond those identified by sequence homology with the OspA-,63-175 epitope, B cell epitopes of putative autoantigens will be sought using patient sera to screen a large array of expressed human proteins, and T cell epitopes will be sought using patient synovial tissue as a source of naturally processed MHC complexes from which peptides will be eluted and identified using tandem mass spectrometry. The knowledge gained from these studies is likely to aid in more accurate diagnosis and more effective treatment of antibiotic-refractory Lyme arthritis. Of greater general importance, antibiotic-refractory Lyme arthritis, which shares similar HLA associations with rheumatoid arthritis, may serve as a model of infection-induced autoimmunity. Furthermore, this work brings us closer to the long-term goal of direct comparisons of antigens in Lyme arthritis and rheumatoid arthritis synovia.
Funding Period: ----------------1987 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide
    Allen C Steere
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    J Exp Med 203:961-71. 2006
  2. pmc Tick-specific borrelial antigens appear to be upregulated in American but not European patients with Lyme arthritis, a late manifestation of Lyme borreliosis
    Xin Li
    Department of Veterinary Biosciences, The Ohio State University, Columbus, USA
    J Infect Dis 208:934-41. 2013
  3. pmc Dysregulation of CD4+CD25(high) T cells in the synovial fluid of patients with antibiotic-refractory Lyme arthritis
    Nalini K Vudattu
    Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Arthritis Rheum 65:1643-53. 2013
  4. pmc A novel human autoantigen, endothelial cell growth factor, is a target of T and B cell responses in patients with Lyme disease
    Elise E Drouin
    Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Arthritis Rheum 65:186-96. 2013
  5. pmc Borrelia burgdorferi stimulation of chemokine secretion by cells of monocyte lineage in patients with Lyme arthritis
    Junghee J Shin
    Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
    Arthritis Res Ther 12:R168. 2010
  6. ncbi Borrelia burgdorferi NapA-driven Th17 cell inflammation in lyme arthritis
    Gaia Codolo
    Venetian Institute of Molecular Medicine, and University of Padua, Padua, Italy
    Arthritis Rheum 58:3609-17. 2008
  7. pmc A genome-wide proteome array reveals a limited set of immunogens in natural infections of humans and white-footed mice with Borrelia burgdorferi
    Alan G Barbour
    Pacific Southwest Center for Research on Emerging Infections, University of California Irvine, 3012 Hewitt, Irvine, CA 92697 4028, USA
    Infect Immun 76:3374-89. 2008
  8. pmc Searching for borrelial T cell epitopes associated with antibiotic-refractory Lyme arthritis
    Elise E Drouin
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Mol Immunol 45:2323-32. 2008
  9. ncbi Higher mRNA levels of chemokines and cytokines associated with macrophage activation in erythema migrans skin lesions in patients from the United States than in patients from Austria with Lyme borreliosis
    Kathryn L Jones
    Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Clin Infect Dis 46:85-92. 2008
  10. ncbi High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis
    Junghee J Shin
    Massachusetts General Hospital, and Harvard Medical School, Boston, Massachussets 02114, USA
    Arthritis Rheum 56:1325-35. 2007

Scientific Experts

  • Klemen Strle
  • Allen Steere
  • Elise E Drouin
  • Lisa J Glickstein
  • Kathryn L Jones
  • Xin Li
  • Junghee J Shin
  • Robert J Seward
  • Gail McHugh
  • Catherine E Costello
  • Gail A McHugh
  • Lisa Glickstein
  • Nitin Damle
  • Vijay K Sikand
  • Nalini K Vudattu
  • Konstantin Yakimchuk
  • Shiqian Shen
  • Andrew D Luster
  • Gaia Codolo
  • Gerald T Nepom
  • Alan G Barbour
  • William W Kwok
  • Priya Kannian
  • Aruna K Behera
  • David I Acosta
  • Franc Strle
  • Chunxiang Yao
  • Diana Londoño
  • Nikhil Sikand
  • Peng Wang
  • Kianoosh Katchar
  • Carsten Kirschning
  • Victor Pena-Cruz
  • Tan Yun Cheng
  • D Branch Moody
  • Kelly G Magalhaes
  • Annemieke de Jong
  • Carme Roura-Mir
  • Scott R Granter
  • Anne G Kasmar
  • Ralph Budd
  • Gil Ben-Menachem
  • Vittorio Sambri
  • Marshall Lee
  • Philip L Felgner
  • Cosima Tatiana Baldari
  • Marisa Benagiano
  • Matthew A Kayala
  • Pierre Baldi
  • Cesare Montecucco
  • Mario Milco D'Elios
  • D Huw Davies
  • Elena Papinutto
  • Terry K Means
  • Alessandra Polenghi
  • Silvia Rossi Paccani
  • Andrea Cappon
  • Marina de Bernard
  • Gianfranco Del Prete
  • Robert R Muellegger
  • Amedeo Amedei
  • Giuseppe Zanotti
  • Algimantas Jasinskas
  • Barbara J B Johnson
  • Rendi M Bacon
  • Han Hwa Hung
  • Robert Kalish
  • George Perides
  • Alisa E Koch
  • Alan J Grodzinsky
  • Jon Szafranski
  • Linden T Hu
  • Robert Lafyatis
  • Ethan Hildebrand

Detail Information

Publications26

  1. pmc Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide
    Allen C Steere
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    J Exp Med 203:961-71. 2006
    ..4; P < 0.001). We conclude that binding of a single spirochetal peptide to certain DRB molecules is a marker for antibiotic-refractory Lyme arthritis and might play a role in the pathogenesis of the disease...
  2. pmc Tick-specific borrelial antigens appear to be upregulated in American but not European patients with Lyme arthritis, a late manifestation of Lyme borreliosis
    Xin Li
    Department of Veterinary Biosciences, The Ohio State University, Columbus, USA
    J Infect Dis 208:934-41. 2013
    ..This suggests that infection with American but not European Borrelia strains often leads to concerted upregulation or derepression of tick-specific spirochetal antigens in these patients. ..
  3. pmc Dysregulation of CD4+CD25(high) T cells in the synovial fluid of patients with antibiotic-refractory Lyme arthritis
    Nalini K Vudattu
    Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Arthritis Rheum 65:1643-53. 2013
    ....
  4. pmc A novel human autoantigen, endothelial cell growth factor, is a target of T and B cell responses in patients with Lyme disease
    Elise E Drouin
    Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Arthritis Rheum 65:186-96. 2013
    ..In this study we aimed to identify autoantigens in patients with antibiotic-refractory Lyme arthritis, in which infection-induced autoimmunity is thought to play an important role...
  5. pmc Borrelia burgdorferi stimulation of chemokine secretion by cells of monocyte lineage in patients with Lyme arthritis
    Junghee J Shin
    Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
    Arthritis Res Ther 12:R168. 2010
    ..We hypothesized that B. burgdorferi stimulates chemokine secretion from monocytes/macrophages in multiple ways, thereby linking innate and adaptive immune responses...
  6. ncbi Borrelia burgdorferi NapA-driven Th17 cell inflammation in lyme arthritis
    Gaia Codolo
    Venetian Institute of Molecular Medicine, and University of Padua, Padua, Italy
    Arthritis Rheum 58:3609-17. 2008
    ..This study was undertaken to evaluate the role of the innate and acquired immune responses elicited by the neutrophil-activating protein A (NapA) of B burgdorferi in patients with Lyme arthritis...
  7. pmc A genome-wide proteome array reveals a limited set of immunogens in natural infections of humans and white-footed mice with Borrelia burgdorferi
    Alan G Barbour
    Pacific Southwest Center for Research on Emerging Infections, University of California Irvine, 3012 Hewitt, Irvine, CA 92697 4028, USA
    Infect Immun 76:3374-89. 2008
    ..These results indicate that the majority of deduced proteins of B. burgdorferi do not elicit antibody responses during infection and that the limited sets of immunogens are similar for two different host species...
  8. pmc Searching for borrelial T cell epitopes associated with antibiotic-refractory Lyme arthritis
    Elise E Drouin
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Mol Immunol 45:2323-32. 2008
    ..Therefore, while additional Bb epitopes may be involved in the development of antibiotic-refractory Lyme arthritis, recognition of OspA(163-175) remains the only known Bb epitope associated with this disease course...
  9. ncbi Higher mRNA levels of chemokines and cytokines associated with macrophage activation in erythema migrans skin lesions in patients from the United States than in patients from Austria with Lyme borreliosis
    Kathryn L Jones
    Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Clin Infect Dis 46:85-92. 2008
    ..afzelii infection in Europe. However, reasons for these differences are not yet known...
  10. ncbi High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis
    Junghee J Shin
    Massachusetts General Hospital, and Harvard Medical School, Boston, Massachussets 02114, USA
    Arthritis Rheum 56:1325-35. 2007
    ..To investigate the possible role of chemokines and cytokines in the pathogenesis of Lyme arthritis...
  11. pmc Borrelia burgdorferi genetic markers and disseminated disease in patients with early Lyme disease
    Kathryn L Jones
    Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Disease, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, CNY 149 8301, Boston, MA 02114, USA
    J Clin Microbiol 44:4407-13. 2006
    ..We conclude that B. burgdorferi strains vary in their capacity to disseminate, but almost all strains isolated from EM lesions sometimes caused disseminated disease...
  12. pmc Human homologues of a Borrelia T cell epitope associated with antibiotic-refractory Lyme arthritis
    Elise E Drouin
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Mol Immunol 45:180-9. 2008
    ..However, molecular mimicry due to sequence homology between OspA(165-173) and a human peptide seems unlikely to be the critical mechanism...
  13. ncbi Role of aggrecanase 1 in Lyme arthritis
    Aruna K Behera
    Tupper Research Institute, Tufts University School of Medicine, Boston, Massachusetts, USA
    Arthritis Rheum 54:3319-29. 2006
    ..The role of aggrecanases in Lyme arthritis has not yet been determined. We therefore sought to delineate the contribution of aggrecanases to joint destruction in Lyme arthritis...
  14. ncbi Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis
    Allen C Steere
    Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Arthritis Rheum 54:3079-86. 2006
  15. ncbi Antibody responses to Borrelia burgdorferi in patients with antibiotic-refractory, antibiotic-responsive, or non-antibiotic-treated Lyme arthritis
    Priya Kannian
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
    Arthritis Rheum 56:4216-25. 2007
    ..To compare the pattern of antibody responses to Borrelia burgdorferi in patients with antibiotic-refractory, antibiotic-responsive, or non-antibiotic-treated Lyme arthritis as an indirect measure of spirochetal persistence or eradication...
  16. pmc Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis
    Klemen Strle
    Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Arthritis Rheum 64:1497-507. 2012
    ..This study was undertaken to assess the frequency and functional outcomes of these polymorphisms in patients with Lyme disease...
  17. pmc Borrelia burgdorferi RST1 (OspC type A) genotype is associated with greater inflammation and more severe Lyme disease
    Klemen Strle
    Division of Rheumatology, Allergy and Immunology, the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Am J Pathol 178:2726-39. 2011
    ..Thus, the B. burgdorferi RST1 (OspC type A) genotype, followed by the RST3 (OspC type I) genotype, causes greater inflammation and more severe disease, establishing a link between spirochetal virulence and host inflammation...
  18. ncbi Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis
    Xin Li
    Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA
    Arthritis Rheum 63:2238-47. 2011
    ..To determine the burden and viability of Borrelia burgdorferi in the skin and joints of patients with Lyme disease...
  19. pmc Borrelia burgdorferi infection regulates CD1 expression in human cells and tissues via IL1-β
    Konstantin Yakimchuk
    Division of Rheumatology, Immunology and Allergy, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Eur J Immunol 41:694-705. 2011
    ..burgdorferi infection and suggests a stepwise mechanism whereby bacterial cell walls, TLR activation and cytokine release cause DC precursors to express group 1 CD1 proteins...
  20. pmc Relationship between immunity to Borrelia burgdorferi outer-surface protein A (OspA) and Lyme arthritis
    Allen C Steere
    Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, USA
    Clin Infect Dis 52:s259-65. 2011
    ..Thus, a vaccine-induced immune response to OspA does not replicate the sequence of events needed in the natural infection to induce antibiotic-refractory Lyme arthritis...
  21. pmc Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis
    Robert J Seward
    Center for Biomedical Mass Spectrometry, Department of Biochemistry, Boston University School of Medicine, and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02118, USA
    Mol Cell Proteomics 10:M110.002477. 2011
    ..New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions...
  22. pmc Treg cell numbers and function in patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis
    Shiqian Shen
    Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Arthritis Rheum 62:2127-37. 2010
    ..In a murine model of antibiotic-refractory Lyme arthritis, the numbers of Treg cells are dramatically reduced. The aim of this study was to examine Treg cell numbers and function in patients with antibiotic-refractory Lyme arthritis...
  23. pmc Analysis of Borrelia burgdorferi genotypes in patients with Lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis
    Kathryn L Jones
    Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Arthritis Rheum 60:2174-82. 2009
    ..The goal of this study was to determine the B burgdorferi genotypes in the joints of patients with Lyme arthritis...
  24. pmc Strong IgG antibody responses to Borrelia burgdorferi glycolipids in patients with Lyme arthritis, a late manifestation of the infection
    Kathryn L Jones
    Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Clin Immunol 132:93-102. 2009
    ..Thus, almost all patients with Lyme arthritis have strong IgG antibody responses to B. burgdorferi glycolipid antigens...
  25. pmc Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii
    Klemen Strle
    Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    J Infect Dis 200:1936-43. 2009
    ..These results demonstrate in vitro and in vivo that B. burgdorferi has greater inflammatory potential than B. afzelii and B. garinii, which may account in part for variations in the clinical manifestations of Lyme borreliosis...