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Clinical, epidemiological and immunological aspects of Lyme borreliosis with special focus on the role of the complement system
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere. The infection is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and it is transmitted to humans by ticks. LB is associated with several clinical manifestations, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common inEurope. The course of the disease is usually benign, but can vary between individuals. The underlying pathogenic mechanisms are not fully understood, but the prognosis is probably determined by a complex interplay between the bacteria and the host’s immune response. Previous studies have indicated that a strong initial T helper (Th) 1-response followed by a Th2 response is beneficial for the clinical outcome in LB.

The aims of this thesis were to follow the incidence of NB inJönköping County,Sweden, over time, to search for clinical and laboratory markers associated with the risk of developing long-lasting post-treatment symptoms, and to explore the role of the complement system as well as the relative balance between Th-associated cytokine/chemokine responses in LB.

The number of NB cases, diagnosed by cerebrospinal fluid (CSF) analysis, increased from 5 to 10/100,000 inhabitants/year in Jönköping County during 2000-2005. Post-treatment symptoms persisting more than 6 months occurred in 13 %, and were associated with higher age, longer-lasting symptoms prior to treatment, higher levels of Borrelia-specific IgG in CSF, and reported symptoms of radiculitis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients.

Complement activation occurred both locally in the skin in EM and in CSF of NB patients. However, no activation could be detected in blood in NB patients. Elevated levels of C1q, C4 and C3a in CSF, along with correlation between C1q and C3a levels, suggest complement activation via the classical pathway locally in the central nervous system in NB. In vitro experiments with two clinical Borrelia isolates revealed that B. garinii LU59 induced higher complement activation in human plasma compared to B. afzelii K78 that recruited more of complement regulator factor H. To elucidate the role of complement in the phagocytosis process, experiments were performed using whole blood from healthy donors incubated with fluorescence-labelled spirochetes and different complement inhibitors. The results illustrated a central role of complement for phagocytosis of Borrelia spirochetes.

We also studied the relative contribution of different Th-associated cytokines/chemokine responses in NB. The results support the notion that early NB is dominated by a Th1 response, eventually accompanied by a Th2 response. IL-17A was increased in CSF in half of the patients with confirmed NB, suggesting a hitherto unknown role of Th17 in NB.

In conclusion, the risk of developing long-lasting post-treatment symptoms tend to increase mainly with age and duration of symptoms prior to treatment in NB. The complement system seems to play an important role in host defence to recognize and kill Borrelia spirochetes. However, complement activation in inappropriate sites or to an excessive degree may cause tissue damage, and therefore, the role of complement in relation to disease course needs to be studied further. Likewise, the role of Th17 in LB pathogenesis and host defence should be further evaluated in prospective studies.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 116 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1255
Keyword [en]
Lyme borreliosis, neuroborreliosis, clinical, epidemiology, inflammation, complement, cytokine, chemokine
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:liu:diva-71117ISBN: 978-91-7393-097-0 (print)OAI: oai:DiVA.org:liu-71117DiVA: diva2:444748
Public defence
2011-11-25, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-10-03 Created: 2011-09-30 Last updated: 2012-03-23Bibliographically approved
List of papers
1. Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden
Open this publication in new window or tab >>Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden
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2010 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 16, no 8, 1245-1251 p.Article in journal (Refereed) Published
Abstract [en]

We studied retrospectively the medical records of all patients (n = 150) diagnosed, by cerebrospinal fluid (CSF) analysis, with neuroborreliosis (NB) in Jonkoping County, Sweden during 2000-2005. The number of NB cases increased from 5/100 000 to 10/100 000 inhabitants/year. In 17% of the patients, anti-Borrelia antibodies were found in CSF but not in serum at the time of diagnosis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients. Post-treatment symptoms persisting for more than 6 months occurred in 13%, and the patients concerned were significantly older, had longer-lasting symptoms prior to treatment, had higher levels of Borrelia-specific IgG in CSF, and more often had radiculitis. The total cost of NB-related healthcare was estimated to be euro500 000 for the entire study group (euro3300 per patient), and the cost of social benefits was estimated to be euro134 000 (euro2000 per patient). CSF analysis is necessary for the diagnosis of NB, because some patients develop antibodies in serum later than in CSF. Early diagnosis of borreliosis would result in reduced human suffering and in economic gain.

Place, publisher, year, edition, pages
Blackwell Publishing Ltd, 2010
Keyword
Clinical, epidemiology, healthcare economy, Lyme disease, neuroborreliosis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-58536 (URN)10.1111/j.1469-0691.2009.03059.x (DOI)000280359900034 ()
Note
This is the pre-reviewed version of the following article: A J Henningsson, Bo-Eric Malmvall, Jan Ernerudh, A Matussek and Pia Forsberg, Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden, 2010, CLINICAL MICROBIOLOGY AND INFECTION, (16), 8, 1245-1251. which has been published in final form at: http://dx.doi.org/10.1111/j.1469-0691.2009.03059.x Copyright: Blackwell Publishing Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html Available from: 2010-08-13 Created: 2010-08-13 Last updated: 2017-12-12Bibliographically approved
2. Complement activation in Lyme neuroborreliosis - Increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS
Open this publication in new window or tab >>Complement activation in Lyme neuroborreliosis - Increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS
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2007 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 183, no 01-Feb, 200-207 p.Article in journal (Refereed) Published
Abstract [en]

A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.

Keyword
complement, neuroborreliosis, inflammation, Lyme borreliosis, cerebrospinal fluid
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-45964 (URN)10.1016/j.jneuroim.2006.10.022 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
3. Early Immune Responses to Borrelia garinii and Borrelia afzeliiin Lyme Borreliosis: Local Complement Activation in Erythema Migrans and in vitro Studies ofComplement Activation, Phagocytosis and Cytokine Profile
Open this publication in new window or tab >>Early Immune Responses to Borrelia garinii and Borrelia afzeliiin Lyme Borreliosis: Local Complement Activation in Erythema Migrans and in vitro Studies ofComplement Activation, Phagocytosis and Cytokine Profile
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

An optimal eradication of spirochetes in Lyme borreliosis depends on the early immune response, including the potent actions of the complement system. We here assessed possible differences between two Borrelia burgdorferi genospecies in their ability to activate complement, and the consequences of complement activation in terms of phagocytosis and induction of cytokines.

Early local complement activation was assessed immunohistochemically in skin biopsies from patients with erythema migrans (EM) caused by B. afzelii or B. garinii. Complement activation, phagocytosis and early cytokine and chemokine release were studied in vitro by incubating clinical isolates of B. afzelii (K78 from a human skin biopsy) and B. garinii (LU59 from human cerebrospinal fluid) in human whole blood.

B. afzelii and B. garinii were detected in skin biopsies from EM and deposition of C3-fragments and IgG was found adjacent to the spirochetes. In vitro, B. garinii LU59 induced higher complement activation (measured as the generation of C3a and C5b-9), while B. afzelii K78 recruited more factor H. Phagocytosis by granulocytes and monocytes was demonstrated to be largely dependent on complement activation since phagocytosis was substantially reduced by addition of the C3 inhibitor compstatin or a C5a receptor antagonist. The early cytokine and chemokine release in human blood in response to live spirochetes revealed a rapid and pronounced pro-inflammatory response, mainly associated with the Th1- and Th17-types.

We conclude that complement is activated locally in the skin in EM, and that B. garinii LU59 activates complement more than B. afzelii K78. Complement activation is pivotal for efficient phagocytosis of Borrelia spirochetes, especially in early infection before specific antibodies are produced. Both B. garinii LU59 and B. afzelii K78 induce proinflammatory cytokines rapidly, but no clear differences were seen between the two genospecies in this respect.

Keyword
Lyme borreliosis, erythema migrans, inflammation, complement, cytokine, chemokine, phagocytosis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-71065 (URN)
Available from: 2011-09-29 Created: 2011-09-29 Last updated: 2012-08-23Bibliographically approved
4. Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study
Open this publication in new window or tab >>Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study
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2011 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 8, no 36Article in journal (Refereed) Published
Abstract [en]

Background: Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB) is associated with a strong T helper (Th) 1-type cytokine response in the cerebrospinal fluid (CSF) followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown. Methods: To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker), CCL22 (Th2 marker), IL-17 (Th17 marker) and CXCL8 (general inflammation marker), in serum and in CSF from untreated patients with confirmed NB (n = 133), and non-NB patients (n = 96), and related the findings to clinical data. Samples from patients with possible early NB (n = 15) and possible late NB (n = 19) were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17), where CSF was obtained at spinal anaesthesia. Results: The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p andlt; 0.0001 for all comparisons). Patients in the early NB group, showing a short duration of symptoms, had lower CCL22 levels in CSF than did the confirmed NB group (p andlt; 0.0001). Furthermore, patients within the confirmed NB group showing a duration of symptoms andlt; 2 weeks, tended to have lower CCL22 levels in CSF than did those with longer symptom duration (p = 0.023). Cytokine/chemokine levels were not correlated with clinical parameters or to levels of anti-Borrelia-antibodies. Conclusion: Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.

Place, publisher, year, edition, pages
BioMed Central, 2011
Keyword
Lyme neuroborreliosis, cerebrospinal fluid, T helper cell, cytokine, chemokine
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-69177 (URN)10.1186/1742-2094-8-36 (DOI)000291317900001 ()
Note

Original Publication: Anna J Henningsson, Ivar Tjernberg, Bo-Eric Malmvall, Pia Forsberg and Jan Ernerudh, Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study, 2011, JOURNAL OF NEUROINFLAMMATION, (8), 36. http://dx.doi.org/10.1186/1742-2094-8-36 Licensee: BioMed Central http://www.biomedcentral.com/

Available from: 2011-06-17 Created: 2011-06-17 Last updated: 2017-12-11Bibliographically approved

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