Persistent arthritis in Borrelia burgdorferi-infected HLA-DR4-positive CD28-negative mice post-antibiotic treatment

Arthritis Rheum. 2008 Dec;58(12):3892-901. doi: 10.1002/art.24028.

Abstract

Objective: The immunologic events that lead to persistent joint inflammation in certain patients with Lyme arthritis post-antibiotic treatment have been elusive so far. The prevalence of this condition is highest in individuals with rheumatoid arthritis-associated HLA-DR alleles. This study was undertaken to generate a murine model with persistent arthritis post-antibiotic treatment.

Methods: We have previously shown that CD28(-/-) mice develop intermittent monarticular Lyme arthritis that is responsive to antibiotics. Since there seems to be a link in humans between persistent arthritic manifestations post-antibiotic treatment and the HLA-DR4 allele, we generated DR4+/+CD28(-/-)MHCII(-/-) mice, infected them with Borrelia burgdorferi, and subsequently treated them with antibiotics.

Results: Thirty-eight percent of the B burgdorferi-infected DR4+/+CD28(-/-)MHCII(-/-) mice, but none of the B burgdorferi-infected CD28(-/-)MHCII(-/-) mice, remained arthritic post-antibiotic treatment. A significant fraction (36%) of these mice, but none of the mice in which arthritis resolved, had serum antibodies to outer surface protein A of B burgdorferi. After abrogation of active B burgdorferi infection, the inflammatory reaction in mice with persistent joint inflammation was restricted to the joints, since their draining lymph nodes were no longer enlarged. Increased CD20 and interferon-gamma messenger RNA expression in the inflamed joints of these mice suggested a possible role of B cells and inflammatory cytokines in the pathogenesis of persistent arthritis post-antibiotic treatment.

Conclusion: The establishment of this murine model allows, for the first time, the elucidation of the immunologic events that lead to persistent Lyme arthritis post-antibiotic therapy in genetically susceptible individuals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antibodies, Bacterial / blood
  • Antigens, CD20 / genetics
  • Antigens, Surface / immunology
  • Arthritis, Infectious / epidemiology
  • Arthritis, Infectious / immunology
  • Arthritis, Infectious / microbiology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / microbiology
  • Bacterial Outer Membrane Proteins / immunology
  • Bacterial Vaccines / immunology
  • Borrelia burgdorferi*
  • CD28 Antigens / genetics*
  • Disease Models, Animal
  • Female
  • Genes, MHC Class II / genetics
  • HLA-DR4 Antigen / genetics*
  • Humans
  • Interferon-gamma / genetics
  • Lipoproteins / immunology
  • Lyme Disease / complications*
  • Lyme Disease / drug therapy
  • Lyme Disease / immunology
  • Lymph Nodes / immunology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • RNA, Messenger / metabolism
  • Seroepidemiologic Studies

Substances

  • Anti-Bacterial Agents
  • Antibodies, Bacterial
  • Antigens, CD20
  • Antigens, Surface
  • Bacterial Outer Membrane Proteins
  • Bacterial Vaccines
  • CD28 Antigens
  • HLA-DR4 Antigen
  • Lipoproteins
  • OspA protein
  • RNA, Messenger
  • Interferon-gamma