Carditis in Lyme Disease Susceptible and Resistant Strains of Laboratory Mice Infected with Borrelia Burgdorferi

Armstrong, Audrey L.; Barthold, Stephen W.; Persing, David H.; Beck, Deborah S.

doi:10.4269/ajtmh.1992.47.249

Cited by 143 publications

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“…The finding of increased numbers of T cells, plasma cells (Table 3, Figure 1c and d), and macrophages (Figure 2) in the heart is consistent with previous observations in small animal models of Lyme carditis. [20][21][22] Plasma cells were more abundant in IS-NHPs (Table 3), which was also the group with the highest expression of BLC ( Figure 6) and the highest tissue deposition of IgM (Figure 4, panel b). This suggests that one of the consequences of persistent B. burgdorferi infection of the heart is upregulation of the B-cell chemokine BLC leading to infiltration by plasma cells and production and deposition of large amounts of IgM.…”

Section: Discussionmentioning

confidence: 96%

Cardiac involvement in non-human primates infected with the Lyme disease spirochete Borrelia burgdorferi

Cadavid

Bai

Hodzic

et al. 2004

Laboratory Investigation

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To investigate cardiac involvement in the non-human primate (NHP) model of Lyme disease, we inoculated 39 adult Macaca mulatta with Borrelia burgdorferi sensu stricto strains N40 (BbN40) by needle (N ¼ 22, 14 immunocompetent (IC), seven permanently immunosuppressed (IS), and four transiently immunosuppressed (TISP)) or by tick-bite (N ¼ 4, all TISP) or strain 297 (Bb297) by needle (N ¼ 2 IS), or with B. garinii strains Pbi (N ¼ 4, 2 TISP and 2 IS), 793 (N ¼ 2, TISP) or Pli (N ¼ 2, TISP). Five uninfected NHPs were used as controls. Infection and inflammation was studied in the hearts and the aorta removed at necropsy 2-32 months after inoculation by (1) H&E and trichrome-staining; (2) immunohistochemistry and digital image analysis; (3) Western blot densitometry; and (4) TaqMan RT-PCR. All NHPs inoculated with BbN40 became infected and showed carditis at necropsy. The predominant cells were T cells, plasma cells, and macrophages. There was increased IgG and IgM in the heart independent of immunosuppression. The B-cell chemokine BLC was significantly increased in IS-NHPs. There was increased deposition of the complement membrane attack complex (MAC) in TISP and IS-NHPs. The spirochetal load was very high in all BbN40-inoculated IS-NHPs but minimal if any in IC or TISP NHPs. Double-immunostaining revealed that many spirochetes in the heart of BbN40-IS NHPs had MAC on their membranes. We conclude that carditis in NHPs infected with B. burgdorferi is frequent and can persist for years but is mild unless they are immunosupressed.

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Section: Discussionmentioning

confidence: 96%

Cardiac involvement in non-human primates infected with the Lyme disease spirochete Borrelia burgdorferi

Cadavid

Bai

Hodzic

et al. 2004

Laboratory Investigation

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“…To evaluate the relative contribution of T cells in the pathology of Bb infection, Lyme disease-associated carditis and arthritis in diseaseresistant C57BL/6J (B6) immunocompetent mice (25,27) were compared with disease in congenic B6-Igh6 KO mice (which lack B cells but bear T cells) and B6-Rag1 KO mice devoid of both T and B cells ( Table I). As expected, B6 mice developed mild carditis and arthritis 3 wk postinoculation (p.i.)…”

Section: Resultsmentioning

confidence: 99%

“…Values of arthritis severity are the mean scores from the most inflamed tibiotarsal joint of individual mice in each group Ϯ the SD, assessed on a scale of 0 (negative) to 3 (severe), as described (26). Sagittal sections of the heart through the aortic valve were examined for inflammation and scored as active (ϩ) or inactive (Ϫ) carditis, as described (25). In addition, these studies revealed a novel lesion (myocarditis) heretofore not described in the mouse model.…”

Section: Histologymentioning

confidence: 99%

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

McKisic

Redmond

Barthold

2000

The Journal of Immunology

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Even in the absence of an appropriate model or direct evidence, T cells have been hypothesized to exacerbate the manifestations of Lyme disease. To define definitely the role of T cells in Lyme disease, the course of disease in immunocompetent and B cell-deficient mice was compared. By 8 wk postinoculation, immunocompetent mice resolved both carditis and arthritis, whereas foci of myocarditis and severe destructive arthritis characterized disease of B cell-deficient mice. Cell transfer experiments using infected B6-Rag1 knock out mice demonstrated that: 1) innate immunity mediated the initial sequelae of infection, 2) transferring both naive T cells and B cells induced resolution of carditis and arthritis, 3) infected mice reconstituted with T cells developed myocarditis and severe destructive arthritis, and 4) CD4+ T cells were responsible for the observed immune-mediated pathology. These data demonstrate directly the deleterious effect of T cells in Lyme disease.

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“…The joints were scored for arthritis severity on a scale of 0 (negative) to 3 (severe) in a blinded fashion as described previously (10). Carditis was considered active when acute inflammatory cell infiltrates were seen in the heart base tissues (5).…”

Section: Methodsmentioning

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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Carditis in Lyme Disease Susceptible and Resistant Strains of Laboratory Mice Infected with Borrelia Burgdorferi

Cited by 143 publications

References 0 publications

Cardiac involvement in non-human primates infected with the Lyme disease spirochete Borrelia burgdorferi

Cardiac involvement in non-human primates infected with the Lyme disease spirochete Borrelia burgdorferi

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

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

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