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SP0177 Lyme disease – old and new insights
  1. A. Steere
  1. Division of Rheumatology, Allergy, and Immunology, Harvard Medical School, Massachusetts General Hospital, Boston, United States

Abstract

Lyme disease was recognized as a separate entity in 1976 because of geographic clustering of children in Lyme, Connecticut who were thought to have juvenile rheumatoid arthritis, a presumed autoimmune disease. However, the clustering suggested that they had a previously unrecognized illness, most likely of infectious origin.

Lyme borreliosis is now known to be the most common vector-borne disease in the United States and Europe. This tick-borne infection is caused by 3 pathogenic species of Borrelia burgdorferi sensu lato. In the United States, it results exclusively from infection with B. burgdorferi sensu stricto (hereafter referred to as B. burgdorferi). Although all 3 species are found in Europe, most of the infection there is caused by B. afzelii or B. garinii. In the U.S., arthritis with intense joint inflammation, especially affecting knees, is a frequent late manifestation of the infection. Moreover, a small percentage of these patients have persistent proliferative synovitis for months to years after 2-3 months of oral and intravenous antibiotics, called antibiotic-refractory arthritis. In contrast, Lyme arthritis occurs infrequently in Europe. When present, it is often associated with minimal joint swelling, and it is not clear whether antibiotic-refractory arthritis is a feature of the infection there.

Antibiotic-refractory Lyme arthritis in the U.S. is associated with an increased frequency of infection with ribosomal RNA intergenic spacer type 1 (RST1) strains of B. burgdorferi, which have a high inflammatory potential. However, this outcome is not thought to result from persistent infection after antibiotic treatment. PCR and culture results for B. burgdorferi have been uniformly negative from synovial tissue obtained from therapeutic synovectomies months after antibiotic therapy. Moreover, re-emergence of infection has not been observed with the use of DMARDs, such as methotrexate or TNF inhibitors, after antibiotic treatment. Instead, risk factors for antibiotic-refractory arthritis include 1) specific HLA-DR alleles, a risk factor commonly associated with autoimmune disease; in this case, the DRB1*0401, 0101, and 1501 alleles are most common, 2) a Toll-like receptor 1 (TLR1) polymorphism that leads to exceptionally high levels of inflammatory chemokines and cytokines in affected joints, particularly, IFNγ and IFNγ-inducible chemokines, and 3) low percentages of CD4+FoxP3+Treg cells in joint fluid. For these reasons, this disease course is postulated to result from infection-induced, site-specific autoimmunity, excessive inflammation and immune dysregulation in joints.

We recently used a discovery-based approach to identify autoantigens in patients with antibiotic-refractory arthritis. Using tandem-mass spectrometry, naturally presented HLA-DR self-peptides from patients’ synovial were identified, synthesized, and reacted with the matching patient’s PBMC. In this way, we recently identified endothelial cell growth factor (ECGF) as an autoantigen that induces T and B cell responses in a subset of patients with antibiotic-refractory arthritis. However, as in rheumatoid arthritis, we suspect that other as-yet-to-be-identified autoantigens could be important in this outcome. Thus, in the U.S., Lyme arthritis is caused by an infectious agent, but in a genetically susceptible subgroup, site-specific autoimmunity may develop.

Disclosure of Interest None Declared

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