The arthritic form of Lyme disease was first reported in the 1970s by Allen Steere, who described the condition in a group of children (and a few adults) residing in and around the town of Lyme, Connecticut. Lyme arthritis can strike when Borrelia burgdorferi introduced into the skin by an Ixodes tick burrows into deeper tissues and ends up in the joints, usually the knee. Swelling results from an inflammatory response to B. burgdorferi residing in the joint. Lyme arthritis is treated with antibiotics, which destroy the bacteria driving inflammation. Unfortunately, arthritic symptoms endure in ~10% of treated patients despite the complete or almost complete eradication of the infection, as determined by negative PCR tests for B. burgdorferi DNA in joint fluid. Such cases are called antibiotic-refractory Lyme arthritis, which can persist for months or sometimes years. In severe cases cartilage and bone erode. Although the pathogenesis of antibiotic-refractory Lyme arthritis could involve persistence of small numbers of B. burgdorferi (or their antigens) in the joints, investigators have been seeking an autoimmune mechanism to explain the prolonged attack on joint tissue by the immune system after the spirochetes have been cleared.
Many autoimmune diseases are linked to variants of HLA
(immunity) genes such as those encoding the MHC class II complex.
Antibiotic-refractory Lyme arthritis is associated with MHC class II variants
that are able to bind to fragments of the B. burgdorferi protein OspA (outer
surface protein A) encompassing amino acid residues 165 through 173.
Antigen-presenting cells whose MHC class II molecules display OspA165-173
peptides on their surface stimulate T cells that recognize the OspA peptide. How
OspA165-173-reactive T cells cause autoimmunity has been an area of intensive
research, yet a clear answer has not emerged.
One potential pathway to
autoimmunity is molecular mimicry, in which a cross-reactive host protein in the
joint continues to stimulate OspA165-173-specific T cells even after the
eradication of B. burgdorferi by antibiotics. Although the simplicity of the
molecular mimicry model is appealing, exhaustive efforts to find a
cross-reactive autoantigen that stimulates OspA165-173-specific T cells have
failed. Moreover, levels of OspA165-173-reactive T cells decline soon after
initiation of antibiotic therapy despite continuing arthritis following
treatment. Thus, chronic arthritis does not seem to involve molecular mimicry
driven by a cross reaction between the OspA165-173 epitope and a self-antigen in
the joint. It is possible that molecular mimicry involves another B. burgdorferi
antigen that is able to bind the MHC class II variants found in genetically
Other potential routes to autoimmunity in
antibiotic-refractory Lyme arthritis patients emphasize the role of the high
levels of key proinflammatory cytokines and chemokines found in their joint
fluid, levels even higher than those found in treatment-responsive patients
prior to initiation of antibiotic therapy:
In a model known as bystander
activation, the immune response to OspA165-173 (or another B. burgdorferi
antigen) causes an excessive inflammatory response that activates other T cells
that react to autoantigens in the joint.
The immune system is unable to turn
off the intense inflammatory response associated with OspA165-173 after the
spirochetes are cleared from the joint.
Although much attention has been
focused on the role of host genetics, a recent study indicates that the genetics
of the pathogen could also influence the course of Lyme arthritis. In the July
2009 issue of Arthritis and Rheumatism, Allen Steere and his collaborators
showed that antibiotic-refractory Lyme arthritis is associated with different
strains of B. burgdorferi. The strains were typed from joint fluid samples
collected before or during antibiotic treatment. Among the methods available to
group B. burgdorferi isolates, they used the 16S-23S ribosomal RNA intergenic
spacer type (RST), of which there are three. Antibiotic-refractory arthritis was
defined as joint swelling lasting for at least 3 months after the start of
antibiotic treatment. Antibiotic treatment consisted of 8 weeks of oral
antibiotics or up to 4 weeks of antibiotics administered intravenously. Joint
fluid from all 17 patients in the study tested positive by PCR for B.
burgdorferi DNA prior to or during antibiotic treatment.
found that all 7 Lyme arthritis patients infected with RST1 strains had the
antibiotic-refractory form. Joint fluid was obtained after antibiotic treatment
from 5 of the 7 patients; all 5 samples tested negative for B. burgdorferi DNA
by PCR. In contrast, 2 of 6 and 3 of 4 infected with RST2 and RST3 strains,
respectively, were successfully treated with antibiotics (see the table below
from the Jones et al. 2009 article). A larger number of samples is needed to
demonstrate that the difference observed between RST1 and RST2 strains is
statistically significant, but there is a clear trend towards RST1 infections
having the greatest association with antibiotic treatment failure and RST3
having the least, with RST2 having an intermediate effect. The duration of
arthritis also depended on the infecting RST strain.
How do RST1 strains
cause arthritis to persist even after the apparent eradication of the
spirochetes by the recommended course of antibiotics? The investigators proposed
that RST1 strains provoke a stronger inflammatory response in the joint than
RST2 or RST3 strains. Coupled with an immune response to OspA165-173 in
genetically susceptible patients, this could cause inflammation to continue at
high levels even after elimination of the spirochetes from the joints. RST1
strains may be more likely than the other genotypes to spark intense joint
inflammation even in patients who are not genetically prone to
In future studies, it would be
interesting to see if proinflammatory cytokine levels are related to the RST
type that infects the joint. Ultimately, researchers need to identify the B.
burgdorferi gene or genes whose variation among the RSTs causes the different
treatment outcomes of Lyme arthritis.