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Antibiotic Treatment-Resistant Lyme Arthritis (TRLA)

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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  1. Antibiotic Treatment-Resistant Lyme Arthritis (TRLA) AnAutoimmune Disease? NIH 2/3/04

  2. 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

  3. 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)

  4. 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

  5. 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?

  6. 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

  7. 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

  8. 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

  9. 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

  10. Model Generation of a strong OspA response Antibiotics B T OspA Structurally related Molecular Mimicry B T Pathogenic Antibodies Chronic arthritis

  11. 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

  12. Isolation of Ig from single B cells Stepwise introduction of somatic mutations

  13. Patient ID: DCSample ID: 3-1Rearranged kappa light chain Common CDR3

  14. Patient ID: DCSample ID: 2-1Rearranged gamma chain

  15. Patient ID: DCSample ID: 2-1Rearranged kappa light chain

  16. OspA vaccine Is it a problem?

  17. 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

  18. Acknowledgements Theresa Willett Helena Crowley Srimoyee Ghosh Allen C. Steere B. David Stollar Jenifer Coburn

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