Cutting Edge: T Cell-Mediated Pathology in Murine Lyme Borreliosis

McKisic, M D; Redmond, William L.; Barthold, Stephen W.

doi:10.4049/jimmunol.164.12.6096

Cited by 70 publications

(57 citation statements)

References 23 publications

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“…Cell transfer experiments by these investigators showed that CD4 ϩ T cells were responsible for the aggravated carditis. 21 However, one can also speculate that the greater inflammation in Igh6 Ϫ/Ϫ mice was attributable to the loss of some regulatory effect of B cells on T cells. Unlike the Lyme disease model, we observed worsening of the disease across all of the clinical measures, including arthritis, conjunctivitis, ruffled fur, vestibular dysfunction, and weight loss (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…One mechanism by which T cells may have exacerbated disease is by dampening the surge in IL-10 production by the innate immune system in response to rising pathogen loads, as seen in the Rag1 Ϫ/Ϫ mice. In the B. burgdorferi murine model of Lyme disease, McKisic and colleagues 21 found evidence that the presence of ␥␦ T cells worsens carditis but not arthritis. Cell transfer experiments by these investigators showed that CD4 ϩ T cells were responsible for the aggravated carditis.…”

Section: Discussionmentioning

confidence: 99%

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Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

Gelderblom

Schmidt

Londoño

et al. 2007

The American Journal of Pathology

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Relapsing fever is an infection characterized by peaks of spirochetemia attributable to antibody selection against variable serotypes. In the absence of B cells, serotypes cannot be cleared, resulting in persistent infection. We previously identified differences in spirochetemia and disease severity during persistent infection of severe combined immunodeficiency mice with isogenic serotypes 1 (Bt1) or 2 (Bt2) of Borrelia turicatae. To investigate this further, we studied pathogen load, clinical disease, cytokine/chemokine production, and inflammation in mice deficient in B (Igh6 ؊/؊ ) or B and T (Rag1 ؊/؊ ) cells persistently infected with Bt1 or Bt2. The results showed that Igh6 ؊/؊ mice, despite lower spirochetemia, had a significantly aggravated disease course compared with Rag1 ؊/؊ mice. Measurement of cytokines revealed a significant positive correlation between pathogen load and interleukin (IL)-10 in blood, brain, and heart. Bt2-infected Rag1 ؊/؊ mice harbored the highest spirochetemia and, at the same time, displayed the highest IL-10 plasma levels. In the brain, Bt1, which was five times more neurotropic than Bt2, caused higher IL-10 production. Activated microglia were the main source of IL-10 in brain. IL-10 injected systemically reduced disease and spirochetemia. The results suggest IL-10 plays a protective role as a downregulator of inflammation and pathogen load during infection with relapsing fever spirochetes. (Am J

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

Gelderblom

Schmidt

Londoño

et al. 2007

The American Journal of Pathology

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“…More recently, Iliopoulou et al (21) reported that C57BL/6 mice deficient for CD28-mediated costimulation develop chronic joint inflammation and have increased titers of anti-OspA antibodies. However, the results from another study (22), relying on adoptive transfer of cells to immune deficient mice, suggested that CD4 ϩ T cells, in the absence of B lymphocytes, exacerbate arthritis and carditis. Last, with regard to the regulation of inflammation and disease resolution, a recent study has shown that T-independent antibodies from marginal zone (MZ) B cells have a major role, because their depletion leads to reduced B. burgdorferi-specific IgM and IgG titers, enhanced pathogen burden and more severe arthritis (23).…”

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confidence: 97%

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

Tupin

Benhnia

Kinjo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR ␣ chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using V␣14i NKT cell-deficient (J␣18 ؊/؊ ) BALB/c mice. On tick inoculation with B. burgdorferi, J␣18 ؊/؊ mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. V␣14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from V␣14i NKT cells. V␣14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFN␥ in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of V␣14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution.cytokines ͉ glycolipids ͉ Lyme disease ͉ spirochetes

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confidence: 99%

“…For this animal model, disease is believed to reflect the innate immune response to spirochetes because histopathology reveals mainly neutrophils and macrophages within inflamed joints and hearts, respectively, and arises in the absence of adaptive immunity (11,26,33,35). B. burgdorferi infections of severe combined immunodeficiency (SCID) and rag-deficient mice, which lack both T and B cells (11,26,33,35), or of mice deficient in B cells alone (13,26) result in higher pathogen burdens but do not have altered disease incidence. In contrast to the disease in immunocompetent mice, however, neither carditis nor arthritis regresses in mice that are deficient in B and T cells (11).…”

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confidence: 99%

Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation inBorrelia burgdorferi-Infected Mice

et al. 2004

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The spirochete Borrelia burgdorferi causes acute inflammation in mice that resolves with the development of pathogen-specific adaptive immunity. B. burgdorferi lipoproteins activate innate immune cells via Toll-like receptor 2 (TLR2), but TLR2-deficient mice are not resistant to B. burgdorferi-induced disease, suggesting the involvement of other TLRs or non-TLR mechanisms in the induction of acute inflammation. For this study, we used mice that were deficient in the intracellular adapter molecule myeloid differentiation antigen 88 (MyD88), which is required for all TLR-induced inflammatory responses, to determine whether the interruption of this pathway would alter B. burgdorferi-induced disease. Infected MyD88 ؊/؊ mice developed carditis and arthritis, similar to the disease in wild-type (WT) mice analyzed at its peak (days 14 and 28) and during regression (day 45). MyD88 ؊/؊ macrophages produced tumor necrosis factor alpha only when spirochetes were opsonized, suggesting a role for B. burgdorferi-specific antibody in disease expression. MyD88 ؊/؊ mice produced stronger pathogen-specific Th2-dependent immunoglobulin G1 (IgG1) responses than did WT mice, and their IgM titers remained significantly elevated through 90 days of infection. Despite specific antibodies, the pathogen burden was 250-fold higher in MyD88 ؊/؊ mice than in WT mice 45 days after infection; by 90 days of infection, the pathogen burden had diminished substantially in MyD88 ؊/؊ mice, but it was still elevated compared to that in WT mice. The elevated pathogen burden may be explained in part by the finding that MyD88 ؊/؊ peritoneal macrophages could ingest spirochetes but degraded them more slowly than WT macrophages. Our results show that MyD88-dependent signaling pathways are not required for B. burgdorferi-induced inflammation but are necessary for the efficient control of the pathogen burden by phagocytes.Infection of humans with the Lyme disease spirochete, Borrelia burgdorferi, results in a characteristic pattern of skin lesions, arthritis, carditis, and neurologic abnormalities that can resolve over time despite the incomplete eradication of the pathogen (12). In the murine model of Lyme borreliosis, spirochetes inoculated into the skin disseminate within days to infect all organ systems, but disease is primarily manifested in the joints and heart (8). The severity of inflammation peaks at these sites about 2 to 4 weeks after infection and then regresses in the presence of B. burgdorferi-specific adaptive immune responses. For this animal model, disease is believed to reflect the innate immune response to spirochetes because histopathology reveals mainly neutrophils and macrophages within inflamed joints and hearts, respectively, and arises in the absence of adaptive immunity (11,26,33,35). B. burgdorferi infections of severe combined immunodeficiency (SCID) and rag-deficient mice, which lack both T and B cells (11,26,33,35

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Cutting Edge: T Cell-Mediated Pathology in Murine Lyme Borreliosis

Cited by 70 publications

References 23 publications

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation inBorrelia burgdorferi-Infected Mice

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