Lyme Borreliosis in Genetically Resistant and Susceptible Mice with Severe Combined Immunodeficiency

Barthold, Stephen W.; Sidman, Charles L.; Smith, Abigail L.

doi:10.4269/ajtmh.1992.47.605

Cited by 159 publications

(174 citation statements)

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“…At wk 8, both carditis and arthritis remained active in B6-Rag1 KO (Table I), but myocarditis was never observed in mice lacking both T cells and B cells. This observation confirmed the necessity of acquired immunity for disease resolution and the importance of a non-immune-mediated mechanism for initiating carditis and joint inflammation (4). As demonstrated previously, B6-Tcr␤Tcr␦ KO mice (which lack both ␣␤ ϩ T cells and ␥␦ ϩ T cells but bear B cells) developed mild carditis and synovitis that were resolved by wk 8 ( Table I), confirming that B cells were necessary and sufficient for inactivation of carditis and resolution of arthritis.…”

Section: Resultssupporting

confidence: 70%

“…Lack of consensus exists for three primary reasons. Early studies using infected SCID mice, which lack T cells and B cells, demonstrated the contribution of non-lymphocyte-based mechanisms, such as inflammatory mediators, in the development of carditis and arthritis (4,5). The course and intensity of human Lyme disease follows various patterns: short and self-limiting; treatment-sensitive neural, joint, or cardiac manifestations; recurrent episodes of inflammation; and persistent manifestations.…”

mentioning

confidence: 99%

“…Thus, analyzing the data becomes difficult, especially in light of recent findings demonstrating that a T cell-independent response mediated by B cells is critical and sufficient for resolution of Lyme disease (22). 4 The recent availability of knockout (KO) mice, with selected genes disrupted, provides an appropriate model to assess definitively the role of T cells in exacerbating, attenuating, or resolving Lyme diseaseassociated carditis and arthritis. In this study, B cell-deficient mice bearing T cells were used to ascertain the consequence of a cellmediated immune response against Bb.…”

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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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Section: Resultssupporting

confidence: 70%

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confidence: 99%

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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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“…In rodent models rheumatoid arthritis is absolutely linked to particular alleles of the MHC, 40,41 requires T cells that recognize self-antigens such as collagen presented by the MHC susceptibility allele, 42 and involves antibodies to these self-antigens. Lyme arthritis is unique in that it develops in scid and rag mice, [43][44][45][46] indicating that the adaptive immune response is not required for the initiation of arthritis. In contrast, the role of initiating antibody and/or T cells is well documented in many rodent models of rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase

Crandall

Dunn

et al. 2005

The American Journal of Pathology

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Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candi- Lyme disease is caused by the tick-borne spirochete Borrelia burgdorferi and can involve multiple organs including the joints, heart, skin, and nervous system. 1 Lyme arthritis is a consequence of bacterial invasion of joint tissue and results from localized inflammation triggered by persistent infection. 2,3 Arthritis develops weeks to months after transmission from an infected tick and is characterized by edema, inflammatory cell infiltration, and hyperproliferation of synovium. 1,4,5 In most individuals, arthritis will resolve after clearance of the bacteria, however, a subset of individuals with the most severe inflammatory arthritis have been documented to develop treatment-resistant arthritis that does not respond to antibiotic therapy. 6,7 It is suspected that in these individuals progression to an autoimmune-mediated arthritis more similar to rheumatoid arthritis has occurred. Susceptibility to treatment-resistant arthritis is associated with HLA-DR1*0401, a major histocompatibility complex (MHC) class II allele also associated with rheumatoid arthritis. 6,8,9 These studies suggest that there are two distinct stages of Lyme arthritis; an acute inflammatory arthritis dependent on bacterial invasion and persistence in joint tissues and a chronic, treatment-resistant arthritis that may represent a transition to a rheumatoid-like disease.

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“…Despite the presence of neutralizing antibodies, the host acquired immune response limits spirochete numbers but does not eradicate B. burgdorferi infection and most mice become persistently infected after needle inoculation or the bite of an infected tick. Antibody does serve to limit disease and pathogenesis, since SCID mice, which lack both the cellular and antibody components of the acquired immune response, contain much higher spirochete loads in tissues and exhibit more severely arthitic joints than normal mice [91]. The ability of the bacteria to survive in the face of an antibody response suggests that either the bacteria "hide out" in sites protected from antibodies or that the bacteria evade antibody reactivity by varying antigens or otherwise masking reactive proteins.…”

Section: Mammalian Components Affecting B Burgdorferi Infectionmentioning

confidence: 99%

Biology of Infection with Borrelia burgdorferi

Tilly

Rosa

Stewart

2008

Infectious Disease Clinics of North America

183

177

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The spirochete Borrelia burgdorferi is a tick-borne obligate parasite whose normal reservoir is a variety of small mammals [1]. Whereas infection of these natural hosts does not lead to disease, infection of humans can result in Lyme disease, as a consequence of the human immunopathological response to B. burgdorferi [2,3]. Consistent with the pathogenesis of Lyme disease, bacterial products that allow B. burgdorferi to replicate and survive, rather than true "virulence factors," appear to be primarily what is required for the bacterium to cause disease in a susceptible host. In support of this idea, the genome sequence of B31, the type strain of B. burgdorferi sensu stricto [4,5], revealed that the bacterium lacks factors common to many bacterial pathogens, such as lipopolysaccharide, toxins, and specialized secretion systems. In this chapter, we will describe the basic biology of B. burgdorferi, and some of the bacterial components required to infect and survive in the mammalian and tick hosts.

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Lyme Borreliosis in Genetically Resistant and Susceptible Mice with Severe Combined Immunodeficiency

Cited by 159 publications

References 0 publications

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

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

Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase

Biology of Infection with Borrelia burgdorferi

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