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 responses in human lyme borreliosis: cytokines and IgG subclasses in relation to clinical outcome
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-26677Local ID: 11244ISBN: 91-7373-540-X (print)OAI: oai:DiVA.org:liu-26677DiVA: diva2:247226
Public defence
2003-04-04, Administrationsbyggnadens aula, Hälsouniversitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-12Bibliographically approved
List of papers
1. IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-γ-predominated disease
Open this publication in new window or tab >>IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-γ-predominated disease
Show others...
1998 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 47, no 6, 575-581 p.Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis has shown a T helper type 1 (Th1)-like immune response with high production of interferon-gamma. Since the cytokine environment seems to be important in the regulation of immunoglobulin production and in the switch between different isotypes and subclasses, and since the subclasses of IgG have different functions, we wanted to examine the IgG subclass distribution in Lyme borreliosis. We have developed an ELISA measuring flagellin-specific antibodies of the different IgG subclasses in serum and cerebrospinal fluid (CSF). Thirty-five seropositive patients with varying manifestations of Lyme borreliosis were included in the study. According to the results, the predominating subclasses in both serum and CSF were IgG1 and IgG3. In samples taken early in disease this pattern was more pronounced in patients with a subacute disease, defined as recovery within 3 months, compared to patients that later on developed chronic borreliosis. The levels of IgG2 were generally low and IgG4 was below detection level. Thus, in the IFN-gamma-predominated immune response seen in Lyme borreliosis, mainly IgG1 and IgG3 were found, i.e. the subclasses that are complement activating as well as opsonizing in humans. Increased levels of these two subclasses early in disease might contribute to recovery and counteract the development of chronicity. The absence of IgG4 is in accordance with the presumed Th1-like situation of Lyme borreliosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84546 (URN)9652826 (PubMedID)
Available from: 2012-10-12 Created: 2012-10-12 Last updated: 2017-12-07Bibliographically approved
2. Cytokines in Lyme borreliosis: lack of early tumour necrosis factor-α and transforming growth factor-β1 responses are associated with chronic neuroborreliosis
Open this publication in new window or tab >>Cytokines in Lyme borreliosis: lack of early tumour necrosis factor-α and transforming growth factor-β1 responses are associated with chronic neuroborreliosis
Show others...
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46895 (URN)10.1046/j.1365-2567.2002.01500.x (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
3. Borrelia-specific interferon-γ and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome
Open this publication in new window or tab >>Borrelia-specific interferon-γ and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome
Show others...
2004 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 189, no 10, 1881-1891 p.Article in journal (Refereed) Published
Abstract [en]

The Borrelia-specific interferon (IFN)-γ and interleukin (IL)-4 responses of 113 patients and control subjects were analyzed using the sensitive enzyme-linked immunospot method. Cerebrospinal fluid (CSF) and blood samples were obtained, during the course of disease, from patients with chronic or nonchronic neuroborreliosis (NB) and from control subjects without NB. Blood samples were obtained from patients with Lyme skin manifestations and from healthy blood donors. Early increased secretion of Borrelia-specific IFN-γ (P < .05) and subsequent up-regulation of IL-4 ( P < .05) were detected in the CSF cells of patients with nonchronic NB. In contrast, persistent Borrelia-specific IFN-γ responses were observed in the CSF cells of patients with chronic NB ( P < .05). In patients with erythema migrans, increased IFN-γ (P < .001 ) was observed in blood samples obtained early during the course of disease, whereas increased IL-4 ( P < .05) was observed after clearance. On the contrary, patients with acrodermatitis chronica atrophicans had Borrelia-specific IFN-γ (P < .001 ), but not IL-4, detected in blood samples. The present data suggest that an initial IFN-γ response, followed by up-regulation of IL-4, is associated with nonchronic manifestations, whereas a persistent IFN-γ response may lead to chronic Lyme borreliosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13800 (URN)10.1086/382893 (DOI)
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2017-12-13
4. A multicenter study on children with Lyme Neuroborreliosis: Up-regulation of Borrelia-specific IL-4 and IFN-γ secreting cells in cerebrospinal fluid and blood
Open this publication in new window or tab >>A multicenter study on children with Lyme Neuroborreliosis: Up-regulation of Borrelia-specific IL-4 and IFN-γ secreting cells in cerebrospinal fluid and blood
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The clinical course and outcome of several infectious diseases are dependent on the type of immune response elicited against the pathogen. As suggested by animal models the interleukin (IL)-4 and interferon (IFN)-γ responses seem to play a role in Lyme borreliosis. In adults with neuroborreliosis (NB), a type 1 like response with high production of Borrelia-specific IFN-γ, but no IL-4, in the cerebrospinal fluid (CSF) and blood has been reported. Since children have a more benign course of NB than adults, we wanted to investigate type 1 and type 2 like responses in children with NB. CSF and blood were collected from children during the acute stage of 'confirmed NB' (n=34), 'possible NB' (n=30) and 'non-NB' (n=10). The number of Borrelia-speciflc IL-4 and IFN-γ producing cells was measured by ELISPOT. Borrelia-specific secretion of both IL-4 and IFN-γ was increased in CSF in confirmed (p<0.05) and possible (p<0,01) NB, compared with non-NB. Furthermore, children with NB had significantly higher Borrelia-speciflc IL-4 secretion in cerebrospinal fluid than an adult reference material with NB (p<0,05). There were no differences in cytokine secretion in relation to onset or recovery of neurological symptoms. Since IL-4 is known to down-regulate the pro-inflammatory and possibly hannful. effects of prolonged IFN-γ responses, the observed prominent IL-4 response in the CNS-compartment might contribute to the more benign disease course seen in children with Lyme NB.

Keyword
Lyme neuroborreliosis, children, cerebrospinal fluid, cytokines, interleukin-4, interferon-y
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84552 (URN)
Available from: 2012-10-12 Created: 2012-10-12 Last updated: 2013-08-29Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Widhe, Mona

Search in DiVA

By author/editor
Widhe, Mona
By organisation
Clinical ImmunologyInfectious DiseasesFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1285 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