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Cytokines in Lyme borreliosis: lack of early tumour necrosis factor-α and transforming growth factor-β1 responses are associated with chronic neuroborreliosis
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-3993-9985
Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Department of Neuroscience and Locomotion, Neurophysiology. Linköping University, Faculty of Health Sciences.
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2002 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 107, no 1, 46-55 p.Article in journal (Refereed) Published
Abstract [en]

The clinical outcome of the tick born infection Lyme borreliosis seems to be influenced by the type of immune response mounted during the disease, as suggested by various animal models. Here we report the serum and cerebrospinal fluid levels of tumour necrosis factor-α (TNF-α), transforming growth factor β1 (TGF-β1) and interleukin-6 (IL-6) in samples drawn at different disease intervals during the course of non-chronic neuroborreliosis (n=10), chronic neuroborreliosis (n=15), erythema migrans (n=8, serum only) and controls (n=7). When comparing early neuroborreliosis cerebrospinal fluid samples, significantly higher levels of TNF-α were found in non-chronic patients than in chronic patients (P<0·05). Moreover, TGF-β1 was increased in the early serum samples of non-chronic patients, as compared to chronic patients (P<0·01). Elevated serum levels of TGF-β1 were also found in erythema migrans as compared to neuroborreliosis and controls (P<0·05). The high TNF-α levels noted in early cerebrospinal fluid samples of non-chronic patients only, possibly reflects an ongoing pro-inflammatory immune response in the central nervous system, which could be beneficial in eliminating disease. High serum levels of TGF-β1 probably mirror an anti-inflammatory response, which might play a role in controlling the systemic immune response.

Place, publisher, year, edition, pages
2002. Vol. 107, no 1, 46-55 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-46895DOI: 10.1046/j.1365-2567.2002.01500.xOAI: oai:DiVA.org:liu-46895DiVA: diva2:267791
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Immune responses in human lyme borreliosis: cytokines and IgG subclasses in relation to clinical outcome
Open this publication in new window or tab >>Immune responses in human lyme borreliosis: cytokines and IgG subclasses in relation to clinical outcome
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Lyme borreliosis is a tick-borne infectious disease caused by the spirochete Borrelia burgdorferi sensu lato. The disease is characterised by several disease stages, where multiple organ systems might be affected, e.g. the skin, nervous system, heart or joints. The disease might lead to chronic symptoms of e.g. the nervous system, so called chronic neuroborreliosis (NB). The clinical features are often less severe in children, as compared to adults. The mechanisms responsible for the development of chronic symptoms are not fully established, but several factors might be involved. Probably the type of immune response elicited against the Borrelia spirochete during infection has implications on the clinical outcome, including development of chronic symptoms. Pro-inflammatory and type 1 responses are known to be efficient for elimination of pathogens, but may also be disease generating, whereas anti-inflammatory and type 2 responses are believed to regulate inflammation and possible tissue-harm, and have been reported in relation to resolution of symptoms in inflammatory diseases. In human Lyme borreliosis, mostly pro-inflammatory and type 1 responses have been reported previously.

Aim: To examine selected aspects of the immune response- i.e. type 1/type 2 responses and pro-/anti-inflammatory responses - during the course of human Lyme borreliosis in patients with chronic and non-chronic manifestations, and in children vs. adults with NB, and to relate the type of immune response to the clinical outcome.

Material and methods: Adult patients with the non-chronic manifestations erythema migrans and non-chronic NB or the chronic manifestations chronic NB and acrodermatitis chronica atrophicans (ACA), and children with NB were included in the study. Some of the adult patients were followed during the course of the disease. The Borrelia-specific cytokine production of interferon (IFN)-γ and interleukin (IL)-4 and the Borrelia-specific IgG subclass distribution were analysed as a measure of type 1 and type 2 responses, and the cytokinelevels of tumour necrosis factor (TNF)-α, IL-6 and transforming growth factor (TGF)-ß1 were analysed as a measure of the pro- and anti-inflammatory responses. IFN-γ and IL-4 were measured as number of cytokine secreting cells, using the sensitive method ELISPOT. Mononuclear cells were separated from blood and cerebrospinal fluid (CSF) and stimulated with a Borrelia antigen containing outer surface protein (Osp)A and OspB. Borrelia-specific IgG subclasses were measured in serum and CSF by ELISA using a flagellin-containing antigen. Levels of TNF-α, IL-6 and total TGF-ß1 were measured in serum and CSF by ELISA.

Results: Adult patients with non-chronic NB showed a strong initial TNF-α and IFN-γ response in the CSF with production of the complement-activating and opsonizing IgG1 and IgG3. Subsequently, this inflammatory response seemed to be down-regulated by an upregulation of IL-4. TGF-ß1 was expressed during the entire follow-up period. Patients with EM showed the same pattern, with an early IFN-γ response, elevated levels of TGF-ß1 and a late up-regulation of IL-4. In addition, the children with early stage NB had elevated production of both IFN-γ and IL-4. The chronic NB patients, however, lacked early TNF-α in CSF and the subsequent up-regulation of IL-4, but showed persistent expression of IFN-γ. Furthermore, they did not show IgG3 or early TGF-ß1 in serum. Furthermore, ACA patients showed elevated IFN-γ late in disease.

Conclusions: Altogether, the results suggest that good prognosis of human Lyme borreliosis is associated with a strong initial pro-inflammatory type 1 response, effective for elimination of Borrelia spirochetes, which is subsequently down-regulated by up-regulation of a type-2 response, and whose possible harmful effects might also be limited by TGF-ß1. Chronic manifestations, on the contrary, seem to be associated with lack of early pro-inflammatory responses, plausibly limiting their ability to eradicate the pathogen, followed by persistent inflammatory type 1 response, which might be self-destructive and disease-generating. In addition, the relative absence of type-2 responses in chronic manifestations may reduce the ability to limit the possibly harmful effects generated by long-standing IFN-γ. The results may have implications on future development of immuomodulatory treatments of chronic Lyme neuroborreliosis.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 94 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 778
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26677 (URN)11244 (Local ID)91-7373-540-X (ISBN)11244 (Archive number)11244 (OAI)
Public defence
2003-04-04, Administrationsbyggnadens aula, Hälsouniversitet, Linköping, 09:00 (Swedish)
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Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-12Bibliographically approved

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Widhe, MonaEkerfelt, ChristinaVrethem, MagnusForsberg, PiaErnerudh, Jan

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