Change search
ReferencesLink to record
Permanent link

Direct link
Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
Show others and affiliations
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. Vol. 6, no 3, 0018220- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-67829DOI: 10.1371/journal.pone.0018220ISI: 000289057200045OAI: oai:DiVA.org:liu-67829DiVA: diva2:413601
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
In thesis
1. Clinical and Immunological Aspects of Lyme borreliosis
Open this publication in new window or tab >>Clinical and Immunological Aspects of Lyme borreliosis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lyme borreliosis (LB) is a tick-borne infection caused by spirochetes of the Borrelia (B.) burgdorferi sensu lato complex. The infection is associated with several clinical features, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common in Europe. The prognosis after antibiotic therapy is generally good. However, some patients may have residual symptoms post-treatment. The cause of the delayed convalescence is unclear. There are several factors that may affect the clinical outcome of LB, for example, the early interaction between the host’s immune response and B. burgdorferi, the spirochete genotype, antibiotic therapy, as well as the host’s vulnerability.

This thesis aimed to explore the type of early immune response that is generated to B. burgdorferi and its importance for the clinical outcome of LB, and to study the condition of persistent symptoms post-NB from clinical, immunological and diagnostic perspectives. In total, 125 adult patients with different clinical features and outcomes of LB and 23 healthy controls were included.

In a prospective follow-up study of EM, we confirmed that the prognosis of EM is good after antibiotic therapy, and that B. afzelii is the most common B. burgdorferi genotype associated with EM in the Nordic countries. Seven patients (8%) reported persistent symptoms more than six months post-treatment. These patients had also a decreased early expression of inflammatory, Th1-type cytokines in the EM lesions, suggesting an importance of early, local Th1-type immunity to B. burgdorferi for a successful clinical outcome of LB. No correlation between clinical characteristics, allergic predisposition, B. burgdorferi genotype or serology and the development of symptoms post-treatment was found.

Asymptomatic B. burgdorferi-seropositive individuals are interesting from clinical and immunological points of view, since they apparently have encountered B. burgdorferi without developing symptoms of LB. In this thesis, asymptomatic individuals were shown to display an enhanced innate inflammatory immune response to live B. garinii spirochetes, induced by dendritic cells and whole blood cells, in comparison with patients with a history of subacute NB and healthy controls. Whether this is the optimal immune response to B. burgdorferi remains to be determined.

A randomized, placebo-controlled cross-over study showed that three weeks of doxycycline therapy did not significantly improve objective neurological signs, subjective symptoms or quality of life in NB patients with persistent symptoms post-treatment. Nor could any doxycycline-mediated effects on systemic cytokine responses be demonstrated.

Brain magnetic resonance imaging (MRI) findings in NB patients with persistent symptoms post-treatment were shown to be nonspecific and to correlate with age, but not with the duration of symptoms.

In conclusion, this thesis shows that there is an association between the early immune response to B. burgdorferi sensu lato and the clinical outcome of LB. The cause of prolonged convalescence post-treatment remains unknown and needs further investigation. However, repeated treatment with doxycycline does not lead to improvement of the persistent symptoms; nor does brain MRI facilitate diagnosis of, or provide an explanation for the post-treatment symptoms.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 134 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1225
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68745 (URN)978-91-7393-237-0 (ISBN)
Public defence
2011-05-06, Elsa Brändströms sal, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2013-08-29Bibliographically approved
2. 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

Open Access in DiVA

fulltext(287 kB)277 downloads
File information
File name FULLTEXT01.pdfFile size 287 kBChecksum SHA-512
fb69c96393466a97a6d4bbcc6a03ff3d302f5c7be8fad1771a7fdd079148fdd00a3c5dd9dff30919efa3124f2a42edc66ed587680d828e52158d2a0319fd2c1d
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Sjöwall, JohannaFryland, LindaSjögren, FlorenceErnerudh, JanForsberg, PiaEkerfelt, Christina
By organisation
Faculty of Health SciencesInfectious DiseasesClinical ImmunologyDermatology and VenerologyDepartment of Clinical Immunology and Transfusion MedicineDepartment of Infectious Diseases in Östergötland
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 277 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

Altmetric score

Total: 242 hits
ReferencesLink to record
Permanent link

Direct link