The T helper cell response in Lyme arthritis: differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis.

Lengl-Janssen, B; Strauss, Ann; Steere, Allen C.; Kamradt, Thomas

doi:10.1084/jem.180.6.2069

Cited by 121 publications

(82 citation statements)

References 60 publications

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“…Local inflammation initiated by OSPs, particularly OspA, is a potential major mechanism in the acute phase of Lyme arthritis. In addition to the experimental evidence presented here and previously (13), development of arthritis in humans during B burgdorferi infection is associated with humoral and cellular immune responses to borrelial antigens, including OspA (37)(38)(39). A temporal relationship between the appearance of antibody to OspA and the onset of joint inflammation was previously reported (40).…”

Section: Discussionmentioning

confidence: 95%

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Batsford

Dunn

Mihatsch³

2004

Arthritis & Rheumatism

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Objective. To examine the ability of bacterial lipoproteins from the spirochete Borrelia burgdorferi to cause in vivo tissue injury (arthritis).Methods. Outer surface proteins (OSPs) from B burgdorferi were used in a rat model of antigen-induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology.Results. Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam 3 Cys-SerLys 4 -OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens but vary greatly with respect to their injury-inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic.Conclusion. This is the first study to demonstrate that individual lipoproteins from B burgdorferi can induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.Lipoproteins are now being recognized as prime virulence factors of bacteria. For many decades this group of molecules played the role of poor relation to the lipopolysaccharides (LPS), but particularly the discovery that lipoproteins can act as ligands for the Toll-like receptor (TLR) complex has rekindled interest (1). In earlier studies, a number of naturally occurring bacterial lipoproteins and their synthetic lipopeptide analogs were shown to possess impressive biologic activities. The Braun protein, a prototype lipoprotein, can stimulate lymphocytes (2), and the corresponding synthetic lipopeptide is in fact now used as an adjuvant (3). Membrane lipoproteins and the corresponding lipopeptides from mycoplasma could induce mononuclear phagocytes to secrete cytokines; a particular lipopeptide from Mycoplasma fermentans, macrophage activating lipopeptide 2, was effective even at concentrations in the picogram range (4). The outer surface lipoproteins (OSPs) of Borrelia burgdorferi have been shown to exhibit similar stimulatory effects (5-8).Results of recent in vitro studies indicated that the lipid moiety plays a key role, and that the CD14/ TLR-2 receptors can be involved (9-11). Lipoproteins have been shown to be capable of inducing tissue injury in animals, mimicking certain common clinical manifestations of the corresponding infection in man. First, synthetic lipopeptide analogs of treponemal and...

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Section: Discussionmentioning

confidence: 95%

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Batsford

Dunn

Mihatsch³

2004

Arthritis & Rheumatism

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“…Initial studies linked antibiotic-refractory Lyme arthritis with HLA-DR4 alleles (8) and with cellular and humoral immune responses to outer surface protein A (OspA) 3 of B. burgdorferi (9,10). The core immunodominant epitope of OspA presented by the DRB1*0401 molecule was identified as OspA [165][166][167][168][169][170][171][172][173] (11), and patients with an antibiotic-refractory course often had T cell reactivity with this epitope (11)(12)(13)(14).…”

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confidence: 99%

Decline in the Frequencies of Borrelia burgdorferi OspA161–175-Specific T Cells after Antibiotic Therapy in HLA-DRB1*0401-Positive Patients with Antibiotic-Responsive or Antibiotic-Refractory Lyme Arthritis

Kannian

Drouin

Glickstein

et al. 2007

The Journal of Immunology

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Synovitis in patients with antibiotic-refractory Lyme arthritis persists for months to several years after antibiotic therapy. This course, which may result from infection-induced autoimmunity, is associated with T cell recognition of Borrelia burgdorferi outer surface protein A (OspA161–175) and with HLA-DR molecules that bind this epitope, including the DRB1*0401 molecule. In this study, we used tetramer reagents to determine the frequencies of OspA161–175-specific T cells in samples of PBMC and synovial fluid mononuclear cells (SFMC) from 13 DRB1*0401-positive patients with antibiotic-responsive or antibiotic-refractory arthritis. Initially, three of the six patients (50%) with antibiotic-responsive arthritis and four of the seven patients (57%) with antibiotic-refractory arthritis had frequencies of OspA161–175-specific CD4+ T cells in peripheral blood above the cutoff value of 4 per 105 cells. Among the five patients with concomitant PBMC and SFMC, four (80%) had OspA tetramer-positive cells at both sites, but the mean frequency of such cells was 16 times higher in SFMC, reaching levels as high as 1,177 per 105 cells. In the two patients in each patient group in whom serial samples were available, the frequencies of OspA161–175-specific T cells declined to low or undetectable levels during or soon after antibiotic therapy, months before the resolution of synovitis in the two patients with antibiotic-refractory arthritis. Thus, the majority of patients with Lyme arthritis initially have increased frequencies of OspA161–175-specific T cells. However, the marked decline in the frequency of such cells with antibiotic therapy suggests that persistent synovitis in the refractory group is not perpetuated by these cells.

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“…Both spirochete virulence and the host response to B. burgdorferi can influence the outcome of infection (3)(4)(5)(6)(7)(8). CD4 ϩ T cell differentiation affects the course of disease in humans and mice (4, 5, 8 -12).…”

mentioning

confidence: 99%

Borrelia burgdorferi-Induced Inflammation Facilitates Spirochete Adaptation and Variable Major Protein-Like Sequence Locus Recombination

Anguíta

Thomas

Samanta

et al. 2001

The Journal of Immunology

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Spirochete adaptation in vivo is associated with preferential Borrelia burgdorferi gene expression. In this paper, we show that the administration of B. burgdorferi-immune sera to IFN-γR-deficient mice that have been infected with B. burgdorferi N40 for 4 days causes spirochete clearance. In contrast, immune sera-mediated clearance of B. burgdorferi N40 is not apparent in immunocompetent mice, suggesting a role for IFN-γ-mediated responses in B. burgdorferi N40 host adaptation. B. burgdorferi-immune sera also induces clearance of B. burgdorferi N40 that have been passaged in vitro 75 times (B. burgdorferi N40-75), a derivative of B. burgdorferi N40 that does not rapidly adapt in vivo in immunocompetent mice. B. burgdorferi N40-75 produce lower levels of IFN-γ and IL-12 in mice than does B. burgdorferi N40, and the administration of these cytokines to B. burgdorferi N40-75-infected mice results in an increased spirochetal burden, further indicating that IFN-γ-mediated events promote B. burgdorferi survival. Differential immunoscreening and RT-PCR demonstrate that IFN-γ-mediated signals facilitate spirochete recombination at the variable major protein like sequence locus, a site for early antigenic variation in vivo, and that recombination rates by B. burgdorferi N40 are lower in IFN-γR-deficient mice than in control animals. These results suggest that the murine immune response can promote the in vivo adaptation of B. burgdorferi.

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The T helper cell response in Lyme arthritis: differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis.

Cited by 121 publications

References 60 publications

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Decline in the Frequencies of Borrelia burgdorferi OspA161–175-Specific T Cells after Antibiotic Therapy in HLA-DRB1*0401-Positive Patients with Antibiotic-Responsive or Antibiotic-Refractory Lyme Arthritis

Borrelia burgdorferi-Induced Inflammation Facilitates Spirochete Adaptation and Variable Major Protein-Like Sequence Locus Recombination

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