CD28 Deficiency Exacerbates Joint Inflammation upon <i>Borrelia burgdorferi</i> Infection, Resulting in the Development of Chronic Lyme Arthritis

Iliopoulou, Bettina P.; Alroy, Joseph; Huber, Brigitte

doi:10.4049/jimmunol.179.12.8076

Cited by 19 publications

(20 citation statements)

References 39 publications

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“…All 18 patients met the Centers for Disease Control and Prevention (CDC) criteria for the diagnosis of Lyme disease (17); they were entered into a study called “Immunity in Lyme Arthritis”. PCR testing for B. burgdorferi DNA and serum antibody responses to B. burgdorferi were determined as previously described (18,19). They received antibiotic therapy according to the guidelines of the Infectious Diseases Society of America (IDSA) (20).…”

Section: Methodsmentioning

confidence: 99%

“…In this model, both the human HLA-DR4 transgene, which is associated with antibiotic-refractory arthritis, and lack of the CD28 co-receptor, which leads to dramatically reduced numbers of T regulatory cells (Treg) (18), are necessary for persistent synovitis after antibiotic therapy. Mice that lack only the CD28 co-receptor, without the HLA-DR4 transgene, do not develop persistent synovitis after treatment (19); and similarly, mice that lack the CD28 co-receptor and have the human HLA-DR11 transgene, which is associated with antibiotic-responsive arthritis, do not develop post-treatment synovitis (20). These outcomes in mice support the HLA-DR findings in human patients with Lyme arthritis (8), but Treg numbers and function have not yet been examined in human Lyme arthritis.…”

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confidence: 99%

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Treg cell numbers and function in patients with antibiotic‐refractory or antibiotic‐responsive lyme arthritis

Shen¹,

Shin²,

Strle³

et al. 2010

Arthritis & Rheumatism

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Objective. In a murine model of antibioticrefractory Lyme arthritis, the numbers of Treg cells are dramatically reduced. The aim of this study was to examine Treg cell numbers and function in patients with antibiotic-refractory Lyme arthritis.Methods. CD4؉ T cell subsets were enumerated in the peripheral blood (PB) and synovial fluid (SF) of 12 patients with antibiotic-refractory arthritis and 6 patients with antibiotic-responsive arthritis. Treg cell function was examined using Borrelia-specific and nonspecific Treg cell proliferation assays.Results. In both patient groups, interferon-␥-positive Th1 cells in SF were abundant and enriched (ϳ50% of CD4؉ T cells). In patients with antibioticrefractory arthritis, the median percentages of FoxP3-positive Treg cells were significantly higher in SF than in PB (12% versus 6%; P ‫؍‬ 0.03) or in SF from patients with antibiotic-responsive arthritis (12% versus 5%; P ‫؍‬ 0.04). Moreover, in the antibiotic-refractory group, a higher percentage of Treg cells in SF correlated with a shorter duration until resolution of arthritis (r ‫؍‬ ؊0.74, P ‫؍‬ 0.006). In contrast, patients with fewer Treg cells had suboptimal responses to disease-modifying antirheumatic drugs and a longer duration of arthritis after antibiotic treatment, and they often required synovectomies for arthritis resolution. In each group, Treg cells in SF dampened Borrelia burgdorferi-specific proliferative responses, and in 2 patients with antibioticrefractory arthritis, Treg cells were functional in nonspecific suppression assays.Conclusion. Treg cells were functional in patients with antibiotic-refractory arthritis, and in some patients, higher numbers of these cells in SF appeared to participate in arthritis resolution. However, as in the murine model, patients with antibiotic-refractory arthritis and lower numbers of Treg cells seemed unable to achieve resolution of synovial inflammation.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Treg cell numbers and function in patients with antibiotic‐refractory or antibiotic‐responsive lyme arthritis

Shen¹,

Shin²,

Strle³

et al. 2010

Arthritis & Rheumatism

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“…An autoimmune reaction as a result of molecular mimicry between OspA of B. burgdorferi and human leukocyte function-associated antigen 1 (hLFA-1) was proposed as a mechanism of this persistent arthritis [27,28], although further work has not confirmed hLFA-1 as a relevant autoantigen [29]. Current hypotheses to explain this condition include bystander activation of autoreactive T cells due to an increased inflammatory response [30][31][32].…”

Section: Clinical Featuresmentioning

confidence: 99%

Lyme Disease: A Review

Marques

2010

Curr Allergy Asthma Rep

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Lyme disease is the most common vector-borne illness in the United States and is also endemic in Europe and Asia. It is caused by the spirochete Borrelia burgdorferi and transmitted by the bite of the Ixodes (deer) tick. It occurs most frequently during spring and summer and may involve the skin, nervous system, heart, and joints. This article reviews the pathogenesis, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of Lyme disease.

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“…Multiple gene-targeted knockouts are available on this background, and thus, the B6 model provides an opportunity to explore specific deficiencies of acute and chronic inflammatory responses and mediators that may exacerbate Lyme arthritis (29–35). IL-10 deficiency in B6 mice is one such knockout model, and this deficiency results in increased arthritis severity, even with 5–10 fold fewer spirochetes in the joint tissues of infected mice than observed in B6 mice (36).…”

Section: Introductionmentioning

confidence: 99%

Localized Production of IL-10 Suppresses Early Inflammatory Cell Infiltration and Subsequent Development of IFN-γ–Mediated Lyme Arthritis

Sonderegger

Maylor-Hagan

et al. 2012

The Journal of Immunology

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IL-10 is a non-redundant inflammatory modulator that suppresses arthritis development in Borrelia burgdorferi infected mice. Infected B6 IL-10−/− mice were previously found to have a prolonged interferon-inducible response in joint tissue. Infection of B6 IL-10 reporter mice identified macrophages and CD4+ T cells as the primary sources of IL-10 in the infected joint tissue, suggesting that early local production of IL-10 dampened the pro-arthritic interferon response. Treatment of B6 IL-10−/− mice with anti-IFN-γ reduced the increase in arthritis severity and suppressed interferon-inducible transcripts to wild type levels, thereby linking dysregulation of IFN-γ to disease in the B6 IL-10−/− mouse. Arthritis in B6 IL-10−/− mice was associated with elevated numbers of NK cell, NKT cell, α/β T cell, and macrophage infiltration of the infected joint. FACS lineage sorting revealed NK cells and CD4+ T cells as sources of IFN-γ in the joint tissue of B6 IL-10−/− mice. These findings suggest the presence of a positive feedback loop in the joint tissue of infected B6 IL-10−/− mice, where production of inflammatory chemokines, infiltration of IFN-γ producing cells, and additional production of inflammatory cytokines result in arthritis. This mechanism of arthritis is in contrast to that seen in C3H mice, where arthritis development is linked to transient production of Type I interferon, and develops independently of IFN-γ. Due to the sustained interferon response driven by NK cells and T cells, we propose the B6 IL-10−/− mouse as a potential model to study the persistent arthritis observed in some human Lyme disease patients.

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CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis

Cited by 19 publications

References 39 publications

Treg cell numbers and function in patients with antibiotic‐refractory or antibiotic‐responsive lyme arthritis

Treg cell numbers and function in patients with antibiotic‐refractory or antibiotic‐responsive lyme arthritis

Lyme Disease: A Review

Localized Production of IL-10 Suppresses Early Inflammatory Cell Infiltration and Subsequent Development of IFN-γ–Mediated Lyme Arthritis

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