1. Lyme Arthritis
In 1976 Lyme arthritis was described by Allen Steere and colleagues in a group of children clustered in the town of Lyme, Connecticut who were initially diagnosed with juvenile rheumatoid arthritis. Since 1982, the etiologic agent of Lyme arthritis, a tick-borne spirochete Borrelia burgdorferi, has been known with certainty.
2. Clinical and Laboratory Findings
Lyme disease is a complex illness that usually occurs in stages over a period of years, with remissions and exacerbations and different clinical manifestations at each stage. A patient infected with B. burgdorferi may proceed through all stages of disease, be completely asymptomatic or present with stage 2 or 3 disease without having had symptomatic earlier stage disease.
2.1. Stage 1
The infection usually begins in the late spring or summer with a characteristic skin lesion, erythema migrans (stage 1), which occurs at the site of a deer tick (ixodes scapularis) bite. The skin lesion may be accompanied by flu-like symptoms.
2.2. Stage 2
Days to weeks later (stage 2), some patients develop cardiac or neurologic abnormalities or migratory musculoskeletal pain.
2.3. Stage 3
Months to years later (stage 3), patients may develop Lyme arthritis or chronic involvement of the nervous system or joints.
Lyme arthritis, which occurs in about 60% of untreated patients with B. burgdorferi infection, is characterized by intermittent attacks of swelling and pain in one or a few joints at a time, generally large joints and especially the knee. The onset of arthritis occurs a mean of 6 months after the tick bite and is usually seen in individuals who were asymptomatic in the earlier stages or had nonspecific symptoms of early disease and were not diagnosed and treated at that time. The severity of Lyme arthritis ranges from short episodes of mild joint pain, to intermittent attacks of arthritis over several years, to chronic persistent arthritis, which occurs in about 10% of patients with arthritis and almost always affects one or both knees. Thus, the majority of patients exposed to B. burgdorferi in the United States develop joint symptoms. However, the wide spectrum of joint involvement suggests that host factors play a major role in determining the severity and duration of Lyme arthritis.
B. burgdorferi spreads to the joint early in the illness, but arthritis does not usually develop until months later within the context of a strong cellular and humoral immune response to the spirochete. The synovial lesions of Lyme disease and rheumatoid arthritis are nearly identical. In both diseases, T cells, predominantly of the helper/inducer subset, are distributed diffusely in subsynovial lining areas, often with nodular aggregates of tightly intermixed T and B cells. Outside the aggregates, many plasma cells, high endothelial venules, scattered macrophages, and a few dendritic macrophages are found. HLA-DR expression is intense throughout the lesion. T cells and macrophages in the synovial tissue secrete primarily pro-inflammatory cytokines.
Although it has not been possible to routinely culture B. burgdorferi from synovial tissue, PCR testing has shown that the spirochete is in the joint prior to antibiotic therapy. Of joint fluid samples from 73 patients obtained prior to treatment, 70 (94%) had positive PCR test results. Thus, in Lyme arthritis, the antigenic stimulus for chronic synovial inflammation in untreated patients would appear to be a small number of spirochetes. Lyme arthritis may therefore serve as an excellent model to study the pathogenesis of idiopathic inflammatory arthritides such as rheumatoid arthritis.
4. Autoimmunity in Lyme Arthritis
The first clue that autoimmune phenomena may sometimes occur in the joints of patients with Lyme arthritis came from studies of antibiotic treatment of this infection. Most patients with Lyme arthritis can be treated successfully with oral doxycycline or amoxicillin. However, a small percentage of patients fail to respond. After antibiotic treatment, these patients have negative PCR results for B. burgdorferi DNA in joint fluid, suggesting that the spirochete has been eradicated from the joint and that the ongoing inflammatory response does not require the presence of live bacteria.
5. Immunogenetic Susceptibility
Patients with Lyme arthritis have been tested for the frequency of various class II MHC alleles. As with patients with rheumatoid arthritis, those with treatment-resistant Lyme arthritis have an increased frequency of HLA-DRB1*0401 or related alleles. However, in contrast with rheumatoid arthritis in which the cause is not known, it has been possible to determine whether particular spirochetal immune responses are associated with treatment-resistant Lyme arthritis.
6. Cellular Immunity
The immune response in Lyme disease is complex. B. burgdorferi expresses as many as 30 immunogenic proteins, and has at least 10 outer-surface or membrane lipoproteins. Outer-surface protein A (OspA) is ordinarily expressed primarily in the tick and not in the human host. Therefore an immune response is not usually seen in patients with Lyme disease, particularly early in the disease. However, about 70% of patients with arthritis develop a response to OspA near the beginning of prolonged attacks of arthritis. In genetically susceptible individuals, this response is strongly associated with treatment-resistant Lyme arthritis, and antigen-specific T cells that react with OspA are concentrated in the inflamed joints of such patients.
7. Molecular Mimicry
Several years ago, an MD/PhD student at Tufts, and the student's advisor, used this information to identify a candidate autoantigen in Lyme arthritis. Using transgenic mice that expressed the human HLA-DRB1*0401 allele, they identified the dominant T cell epitope of OspA, which is located between amino acids (aa) 165-173. In a search of the GCG genebank database, this peptide sequence was found to have significant homology with human lymphocyte function associated antigen (LFA-1)(aa 332-340), suggesting it as a candidate autoantigen. Moreover, LFA-1 provoked T helper cell reactivity in most patients with treatment-resistant Lyme arthritis, but not in those with treatment-responsive disease or in other forms of chronic inflammatory arthritis. LFA-1 is an integrin receptor on T cells that binds to intracellular adhesion molecule-1 (ICAM-1) on macrophages. This interaction is thought to be important in anchoring these cells during the interaction of the T cell receptor with the MHC-peptide complex. Molecular mimicry between LFA-1 and OspA would provide a possible explanation for persistent joint inflammation in genetically susceptible human subjects after the apparent eradication of the spirochete from the joint. However, LFA-1 may not be the only autoantigen or even the most important one in treatment-resistant Lyme arthritis and the above mechanism must still be further validated.
8. Implications for Rheumatic Disease
In summary, in the chronic inflammatory arthritides, it has been hypothesized that infectious agents may trigger, in genetically susceptible persons, an autoimmune response that leads to chronic arthritis. The current work on Lyme arthritis provides support for this hypothesis. This experience lends greater credibility to the possibility that an infectious agent may be important in rheumatoid arthritis.
- Steere AC. Lyme disease. N Engl J Med 2001; 345:115-125.
- Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med 1987; 107:725-31.
- Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid in Lyme arthritis. N Engl J Med 1994; 330:229-34.
- Gross DM, Forsthuber T, Tary-Lehmann M, Etling C, Kouichi I, Nagy ZA, Field JA, Steere AC, Huber BT. Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science 1998; 281:703-6.