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Antibiotic Treatment-Resistant Lyme Arthritis (TRLA). An Autoimmune Disease?. NIH 2/3/04. Clinical Features. Arthritic knee (Single joint). Ixodes tick. Borrelia burgdorferi (Bb). Erythema migrans. Erythema migrans (localized and multiple) Flu-like illness . Late Lyme Disease

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Antibiotic Treatment-Resistant Lyme Arthritis (TRLA)


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slide1

Antibiotic Treatment-Resistant Lyme Arthritis

(TRLA)

AnAutoimmune Disease?

NIH

2/3/04

clinical features
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

slide3

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 toOspA (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)

slide4

3. recently infected

host

1. unfed tick

2. feeding tick, from

gut to salivary gland

A+/C-

A-/C-

A-/C+

A+/C+

Osp Expression during Transmission

slide5

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?

slide6

Bb, in vitro

chamber-grown

Bb, in vivo

chamber-grown

Flagellin, 41 kD

OspA, 31 kD

OspC, 21 kD

Western Blot Analysis of Osp Expression

In vitro vs. In vivo vs. In vivo-Inflamed

Bb, in vivo

chamber-grown,

zymosan-induced

inflammation

prolonged bb infection for the development of trla
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
  • => Initial exposure to spirochetes required
autoimmune basis for trla
Autoimmune basis for TRLA
  • Synovial samples are PCR-negative for B.burgdorferi DNA after antibiotic treatment1
  • Increased frequency of HLA-DR4 alleles: HLA-DRB1*0401, 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

molecular mimicry with ospa
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

model
Model

Generation of a strong OspA response

Antibiotics

B

T

OspA

Structurally related

Molecular Mimicry

B

T

Pathogenic Antibodies

Chronic arthritis

slide11

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

isolation of ig from single b cells
Isolation of Ig from single B cells

Stepwise introduction of somatic mutations

ospa vaccine
OspA vaccine

Is it a problem?

slide17

Modification of Main OspA T cell Epitope: Minimize Binding to HLA-DRB1*0401

Protein Sequence DR binding

B.b. B31-OspA 165-173YVLEGTLTA+ 6.5

hLFA-1aL332-340YVIEGTSKQ+ 7.3

B. afzelii OspA 165-173FTLEGKVAN- 1.3

FTK-OspA 165-173FTLEGKLTA+ 0.2

position 1 2 3 4 5 6 7 8 9

acknowledgements

Acknowledgements

Theresa Willett

Helena Crowley

Srimoyee Ghosh

Allen C. Steere

B. David Stollar

Jenifer Coburn