Antibiotic TreatmentResistant Lyme Arthritis

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Antibiotic Treatment-Resistant Lyme Arthritis
(TRLA)
An Autoimmune Disease?
NIH 2/3/04
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Clinical Features
Arthritic knee (Single joint)
Ixodes tick
Borrelia burgdorferi (Bb)
Erythema migrans

• Erythema migrans
• (localized and multiple)
• Flu-like illness

• Late Lyme Disease
• Neurologic peripheral
• neuropathy,
• encephalopathy
• Chronic arthritis

• Early Disseminated Lyme Disease
• Neurologic cranial neuropathy,
• meningitis, radiculoneuropathy
• Joint Acute, inflammatory large
• joint arthritis
• Carditis

Early Lyme Disease
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Acute Inflammatory vs. Chronic Arthritis

• Develops after a prolonged period of
• latency/minimally symptomatic disease
• Defined as one year or more of persistent
• joint inflammation, usually the knee
• Does not subside in response to antibiotic
• therapy
• Correlates with the development of a strong
• immune response to OspA (Outer Surface
• Protein A)

• Early attacks - within weeks to a few
• months after disease onset
• Sudden pain, swelling with massive
• effusions
• Mostly intermittent
• Remits after a few days/weeks
• sometimes without antibiotic therapy

Treatment Resistant Lyme Arthritis (TRLA)
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Osp Expression during Transmission
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Evidence for OspA Upregulation In Vivo
Bb transmitted to the host express little or no
OspA.
Later in the course of infection, patients
develop strong spiking titers of OspA
antibodies coinciding with periods of arthritis
(Kalish 1995).
If these responses indicate OspA upregulation,
then are inflammatory cues stimulating OspA
expression by Bb?
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Western Blot Analysis of Osp Expression In vitro
vs. In vivo vs. In vivo-Inflamed
Bb, in vivo chamber-grown, zymosan-induced
inflammation
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Prolonged Bb infection for the development of
TRLA

• Antibiotic treatment in the first couple of
  weeks
  after exposure eliminates development of TRLA
• Antibiotic treatment later on has no effect
• gt Initial exposure to spirochetes required

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Autoimmune basis for TRLA

• Synovial samples are PCR-negative for
  B.burgdorferi DNA after antibiotic treatment1
• Increased frequency of HLA-DR4 alleles
  HLA-DRB10401, 0404 and 0101, 0102 in the
  affected population2

1.Carlson et al., Arthritis Rheumatism 42(12)
1999 2.Steere et al., New Engl Journal of Med.161
1990
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Molecular mimicry with OspA?

• Strong T-cell response to OspA
• 1. OspA-reactive T-cells in synovial fluid1
• 2. Human LFA-1? candidate T-cell autoantigen2

1.Meyer et al. PNAS 97(21), 2000 2. Gross et al.
Science 281, 1998
A Shift in Paradigm 1. Linked T-B recognition
of autoantigen (GPI) RA mouse model 2.
Ectopic germinal centers in RA synovium
1.Matsumoto et al.Science 286,1999 2. Kim et al.
J Immunol. 162(5), 1999
Strong B-cell response to OspA
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Model
Generation of a strong OspA response
Antibiotics
B
T
OspA
Structurally related
Molecular Mimicry
B
T
Pathogenic Antibodies
Chronic arthritis
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Antibodies in Lyme Arthritis

• 1. Increased Titers of OspA antibodies
• IgG response to OspA develops later in the course
  of infection
• High titers of OspA antibodies coincide with
  periods of maximal arthritis
• Mark the transition from episodic to chronic
  arthritis
• Persist after treatment
• 2. Germinal centers in inflamed synovium
• 2222222
• Tightly intermixed B- T-cells
• Follicular dendritic cells
• Activated germinal center B-cells
• Plasma cells

Kalish et al., Infection and Immunity 61(7), 1993
Akin et al., Infection and Immunity, 67(1),1998
Steere et al., Arthritis and Rheumatism, .31 (4),
1988
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Isolation of Ig from single B cells
Stepwise introduction of somatic mutations
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Patient ID DCSample ID 3-1Rearranged kappa
light chain
Common CDR3
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Patient ID DCSample ID 2-1Rearranged gamma
chain
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Patient ID DCSample ID 2-1Rearranged kappa
light chain
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OspA vaccine
Is it a problem?
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Modification of Main OspA T cell Epitope
Minimize Binding to HLA-DRB10401
Protein Sequence DR binding
B.b. B31-OspA 165-173 YVLEGTLTA 6.5
hLFA-1a L332-340 YVIEGTSKQ 7.3
B. afzelii OspA 165-173 FTLEGKVAN - 1.3
FTK-OspA 165-173 FTLEGKLTA
0.2 position 1 2 3 4 5 6 7 8 9
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Acknowledgements
Theresa Willett Helena Crowley Srimoyee Ghosh

• Allen C. Steere
• B. David Stollar
• Jenifer Coburn