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Mapping of T-cell subsets in relation to disease course in experimental Borrelia burgdorferi infection
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Department of Molecular Biology, Umeå University, Umeå, Sweden.
Department of Molecular Biology, Umeå University, Umeå, Sweden.
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2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Resolution of Lyme borreliosis has previously been shown to be associated with a strong initial Th1 response, followed by a subsequent Th2 response,  shutting off inflammation. We mapped markers for Th1, Th2, Th17, cytotoxic and T regulatory subsets in a murine model, where the outcome of Borrelia (B.) burgdorferi sensu stricto (s.s.) infection was altered by immune-deviation towards Th2 by exposure to a subtoxic dose of mercury. Twenty-one B. burgdorferi s.s.-infected (Bb), 21 immune-deviated B. burgdorferi s.s.-infected (BbId), and seven control C3H/HeN mice were sacrificed on days 15, 28 and 43 post-infection (p.i.) with B. burgdorferi s.s. BbId mice had increased joint swelling compared with Bb at the height of the disease (28 p.i.), and also showed a trend for increased spirochaetal load that became significant on day 43 p.i. BbId had an increased histopathology score on day 28 p.i. compared with both earlier and later time points. mRNA expression of IL-4 (p=0.018), IL-10 (p=0.018) and EBI-3 (p=0.009) decreased in Bb mice, but not in BbId, over the course of infection. A trend for higher expression of IL-12p40 mRNA in Bb mice compared with BbId was seen late in the disease course, while BbId showed trends for higher levels of Foxp3 and GM-CSF. At the protein level, BbId showed decreased levels of CXCL9 compared to the Bb group on day 15 p.i (p=0.007). Bb mice showed increases of CXCL9 and CXCL10 at all time points compared with day 0 p.i. (p≤0.014), whereas BbId mice showed an initial decrease in both chemokines at day 15 p.i. compared with day 0 (p≤0.008). In conclusion, both the clinical signs of infection and the trends for increased expression of pro-inflammatory GM-CSF and T-regulatory marker Foxp3 in BbId mice suggested ongoing inflammation. Although our findings support the need for a strong Th1 response followed by anti-inflammatory response for optimal resolution, the anti-inflammatory response seems to be more complex than only dampening the inflammation by a Th1-antagonistic Th2 response.

Place, publisher, year, edition, pages
2012.
Keyword [en]
Borrelia burgdorferi sensu lato, T-cell subsets, disease outcome, arthritis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-86266OAI: oai:DiVA.org:liu-86266DiVA: diva2:576158
Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2013-08-29Bibliographically approved
In thesis
1. Immune mechanisms in Borrelia burgdorferi sensu lato infection in relation to clinical outcome
Open this publication in new window or tab >>Immune mechanisms in Borrelia burgdorferi sensu lato infection in relation to clinical outcome
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lyme borreliosis (LB) is the most common tick-borne disease in the northern hemisphere. The infection is caused by spirochaetes from the Borrelia (B.) burgdorferi sensu lato (s.l.) group. The clinical outcome after B. burgdorferi s.l. infection differs between individuals from asymptomatic infection without history of LB to individuals who experience persistent symptoms post-treatment for more than six months after treatment. The difference in clinical outcome is not thought to be associated with persistent infection, but could instead be affected by the host’s ability to mount an optimal immune response to the spirochaete.

The hypothesis of this thesis was that a strong inflammatory Th1-like immune response is required in the early stage of infection in order to achieve both an optimal eradication of the B. burgdorferi s.l. bacteria and a good clinical outcome. The inflammatory response must be down-regulated by an anti-inflammatory response in order to avoid excessive immune responses that will end in tissue injury. The proper down-regulation will also protect against development of a chronic Th1-like inflammatory response, with activated cytotoxic cells, which may lead to LB with persistent symptoms post-treatment.

The thesis aimed to investigate the immunological mechanisms behind the optimal resolution of human B. burgdorferi s.l. infection and to define the aberrant mechanisms leading to development of persisting symptoms.

prospective study on newly tick-bitten individuals showed that although 25% of the collected ticks were infected with B. burgdorferi s.l. very few individuals bitten by infected ticks developed LB (3.7%). In addition, 4.9% of the individuals bitten by infected ticks developed asymptomatic infection, i.e. B. burgdorferi s.l.-specific antibody seroconversion without LB. Approximately one third of all tick-bitten study subjects reported self-experienced symptoms possibly associated with LB. Individuals bitten by infected ticks were more likely to report experience of symptoms than those bitten by uninfected ticks. Thus, only 8.6% of the individuals bitten by B. burgdorferi s.l.-infected ticks were infected, verified by seroconversion, and out of them 57% were asymptomatic.

A prospective study on EM patients showed that a good clinical outcome was associated with a strong early Th1 immune response since EM patients with persistent symptoms six months after treatment had reduced expression of Th1 cytokines in their EM lesions compared with EM patients without symptoms.

The investigation of blood samples from newly tick-bitten individuals, for detection of possible early immune biomarkers indicating good clinical outcome of LB, showed that none of the investigated markers clearly discriminated between the individuals who developed LB, asymptomatic individuals, or non-infected individuals. However, tick-bitten individuals who developed asymptomatic infection showed an increase of early Th1-associated biomarkers in blood compared to individuals who developed clinical LB.

In an experimental study, Th2-immune-deviated mice had more pronounced clinical signs of infection and could not eradicate the spirochaete as efficiently as non-deviated B. burgdorferi sensu stricto (s.s.)-infected mice. Non-deviated B. burgdorferi s.s.-infected mice showed a decrease of mRNA expression associated with Th2, anti-inflammatory and Treg/Th1 responses during the course of infection, which suggested a termination of the inflammatory response – something that was not seen in the immune-deviated mice. Trends for increased expression of pro-inflammatory GM-CSF and Treg marker Foxp3 in immune-deviated mice suggested on-going inflammation. Non-deviated B. burgdorferi s.s.-infected mice showed increased systemic expression of the Th1-associated CXCL9 and CXCL10 during the course of infection, while immune-deviated mice showed an initial decrease in both chemokines at day 15 p.i. compared with day 0 p.i.

In conclusion, the risk of developing LB after a tick bite is low, and no infection or asymptomatic infection are the most common outcomes after a tick bite. The early immune response in humans and the immune response towards B. burgdorferi s.s. infection in mice support the hypothesis that a strong pro-inflammatory Th1 response is needed for an optimal clinical outcome and eradication of bacteria.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 96 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1347
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-86269 (URN)978-91-7519-734-0 (ISBN)
Public defence
2013-01-18, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2013-08-29Bibliographically approved

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Fryland, LindaHavarinasab, SaidHultman, PerEkerfelt, Christina

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