liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Immune mechanisms in Borrelia burgdorferi sensu lato infection in relation to clinical outcome
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-86269ISBN: 978-91-7519-734-0 (print)OAI: oai:DiVA.org:liu-86269DiVA: diva2:576184
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
List of papers
1. Low risk of developing Borrelia burgdorferi infection in the south-east of Sweden after being bitten by a Borrelia burgdorferi-infected tick
Open this publication in new window or tab >>Low risk of developing Borrelia burgdorferi infection in the south-east of Sweden after being bitten by a Borrelia burgdorferi-infected tick
Show others...
2011 (English)In: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, ISSN 1201-9712, Vol. 15, no 3, E174-E181 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The risk of developing Lyme borreliosis (LB) from Borrelia burgdorferi sensu lato (Bb)-infected ticks in Sweden is largely unknown. In the current study, we investigated the prevalence of Bb in ticks that had bitten humans and the risk of developing LB from Bb-infected ticks. Methods: Health questionnaires, blood samples, and ticks were collected from 394 tick-bitten study subjects in the County of Ostergotland, Sweden, at the time of the tick bite. Questionnaires and blood samples were also collected 3 months later. Ticks were screened for Bb DNA with PCR, while sera were analyzed for antibodies against Bb using two ELISA assays. Seroconversion, i.e., an at least two-fold increase in anti-Bb antibodies after 3 months, was confirmed using a Strip-Immunoassay. Results: Seventy-five of 397 ticks collected from the study subjects were determined to be Bb-positive. Sixty-four of the tick-bitten subjects had been bitten by Bb-infected ticks. Four of them showed seroconversion and were therefore considered to have an active Bb infection. None of these four subjects had sought health care due to symptoms, but one reported symptoms. Conclusions: Our data suggest that the risk of developing LB after being bitten by a Bb-infected tick is low, and asymptomatic Bb infections appear to be more frequent than symptomatic infections.

Place, publisher, year, edition, pages
Elsevier Science B. V., Amsterdam, 2011
Keyword
Borrelia burgdorferi sensu lato, Lyme borreliosis, Tick-bite, Anti-Borrelia antibodies, Clinical outcome
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66879 (URN)10.1016/j.ijid.2010.10.006 (DOI)000287967500004 ()
Note
Original Publication: Linda Fryland, Peter Wilhelmsson, Per-Eric Lindgren, Dag Nyman, Christina Ekerfelt and Pia Forsberg, Low risk of developing Borrelia burgdorferi infection in the south-east of Sweden after being bitten by a Borrelia burgdorferi-infected tick, 2011, INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, (15), 3, E174-E181. http://dx.doi.org/10.1016/j.ijid.2010.10.006 Copyright: Elsevier Science B. V., Amsterdam http://www.elsevier.com/Available from: 2011-03-22 Created: 2011-03-21 Last updated: 2013-08-29
2. Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans
Open this publication in new window or tab >>Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans
Show others...
2011 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 3, 0018220- p.Article in journal (Refereed) Published
Abstract [en]

Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67829 (URN)10.1371/journal.pone.0018220 (DOI)000289057200045 ()
Note
Original Publication: Johanna Sjöwall, Linda Fryland, Marika Nordberg, Florence Sjögren, Ulf Garpmo, Christian Jansson, Sten-Anders Carlsson, Sven Bergstrom, Jan Ernerudh, Dag Nyman, Pia Forsberg and Christina Ekerfelt, Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans, 2011, PLOS ONE, (6), 3, 0018220. http://dx.doi.org/10.1371/journal.pone.0018220 Copyright: Public Library of Science (PLoS) http://www.plos.org/Available from: 2011-04-29 Created: 2011-04-29 Last updated: 2013-08-29
3. Mapping of T-cell subsets in relation to disease course in experimental Borrelia burgdorferi infection
Open this publication in new window or tab >>Mapping of T-cell subsets in relation to disease course in experimental Borrelia burgdorferi infection
Show others...
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.

Keyword
Borrelia burgdorferi sensu lato, T-cell subsets, disease outcome, arthritis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86266 (URN)
Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2013-08-29Bibliographically approved
4. Biomarkers in blood a few days after a bite by a Borrelia burgdorferi infected tick:: Asymptomatic Borrelia burgdorferi-infected subjects show higher Th1-associated response compared with subjects who later develop Lyme borreliosis
Open this publication in new window or tab >>Biomarkers in blood a few days after a bite by a Borrelia burgdorferi infected tick:: Asymptomatic Borrelia burgdorferi-infected subjects show higher Th1-associated response compared with subjects who later develop Lyme borreliosis
Show others...
2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

The clinical outcome following infection with Borrelia (B.) burgdorferi sensu lato (s.l.) differs between individuals, ranging from asymptomatic infection to Lyme borreliosis (LB) with persistent symptoms post-treatment. Previous studies in mice and humans have generated the hypothesis that a successful outcome of B. burgdorferi s.l. infection is associated with an early strong pro-inflammatory T helper (Th)1-like immune response. The aim of this study was to assess the early course of events in B. burgdorferi s.l.-associated inflammation by screening for possible early immune biomarkers in peripheral blood from newly tick-bitten persons. The study subjects bitten by B. burgdorferi s.l.-infected ticks were divided into (1) those later developing clinical LB, (2) those who developed anti-B. burgdorferi s.l. antibodies but not clinical LB, (3) those who neither developed antibodies nor clinical LB. A fourth group consisted of bitten study subjects without development of antibodies or clinical LB. Two sets of samples, both comprising all four groups, were collected in order to repeat the analyses and confirm the data. Sera or plasma collected a few days after the tick bite were analysed for 18 biomarkers (IL-1β, IL-6, CXCL8/IL-8, IL-12p70, IL-17A, IL-27, TNF, CCL18, CCL20, CCL22, CXCL1, CXCL9, CXCL10, CXCL11, calprotectin, MMP-3, MMP-8, MMP-9) by multiplex bead assay and ELISA. In the first set of samples, the neutrophil activation marker calprotectin was increased in subjects who developed clinical LB compared with subjects who developed antibodies against B. burgdorferi s.l. but did not develop LB. However, the finding could not be confirmed in the second set of samples, thus the study failed to identify an early prognostic marker for development of clinical LB. Interestingly, both sets of samples showed increases in two different Th1-associated markers, CXCL10 and IL-12p70, respectively, in subjects who following a bite by a B. burgdorferi s.l.-infected tick developed antibodies against B. burgdorferi s.l. but did not develop LB compared with subjects who developed clinical LB, thus supporting the hypothesis of an early strong Th1-response being important for optimal resolution of B. burgdorferi s.l. infection.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86267 (URN)
Note

TBD Sting study group (Tick-Borne Diseases Sting study group) consists of: Clas Ahlm,Johan Berglund, Sven Bergström, Sten-Anders Carlsson, Ingvar Eliasson, Mats Haglund,Anna J Henningsson, Christian Jansson, Liselott Lindvall, Peter Nolskog, Marika Nordberg,Susanne Olausson, Katarina Ornstein, Johanna Sjöwall, Barbro Hedin Skogman, IvarTjernberg, Mari-Anne Åkeson.

Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2013-08-29Bibliographically approved

Open Access in DiVA

Immune mechanisms in Borrelia burgdorferi sensu lato infection in relation to clinical outcome(1167 kB)810 downloads
File information
File name FULLTEXT01.pdfFile size 1167 kBChecksum SHA-512
cf851f5e26bdbb63f05defcbb820ddc5178077c5c87159e5cf87b3ce99c9596f9dc8b3bd23fb994e6bddb157c514be9d1e2eb48c1fa121f4e8d1351857129b0a
Type fulltextMimetype application/pdf
omslag(155 kB)95 downloads
File information
File name COVER01.pdfFile size 155 kBChecksum SHA-512
b3d3f6307ada8556d45e03a7923028c32910d03adbd79f9347baab6c6bd01772aa18f8753644e5a4705c397b14d366557caddc37dee00556438a17d056771a07
Type coverMimetype application/pdf

Authority records BETA

Fryland, Linda

Search in DiVA

By author/editor
Fryland, Linda
By organisation
Clinical ImmunologyFaculty of Health Sciences
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 810 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1670 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf