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IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-γ-predominated disease
Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland, Transfusionsmedicin och klinisk immunologi. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-3993-9985
Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
Department of Microbiology, University of Umeå, Umeå, Sweden.
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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.

Place, publisher, year, edition, pages
1998. Vol. 47, no 6, 575-581 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-84546PubMedID: 9652826OAI: diva2:560185
Available from: 2012-10-12 Created: 2012-10-12 Last updated: 2013-08-29Bibliographically 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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 778
National Category
Medical and Health Sciences
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)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-12Bibliographically approved

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Widhe, MonaEkerfelt, ChristinaForsberg, PiaErnerudh, Jan
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