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Lyme borreliosis reinfection: might it be explained by gender difference in immune response?
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
Department of Clinical Sciences, University Hospital of Malmö, Lund University, Malmö .
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
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2006 (English)In: Immunology, ISSN 0019-2805, Vol. 118, no 2, 224-235 p.Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis is a tick-borne disease often manifesting as a circular skin lesion. This cutaneous form of the disease is known as erythema migrans. In a 5-year follow-up study in southern Sweden, 31 of 708 individuals initially diagnosed with erythema migrans and treated with antibiotics were found to be reinfected with Borrelia burgdorferi. Although men and women were tick-bitten to the same extent, 27 of the 31 reinfected individuals were women, all of whom were over 44 years of age. The aim of this study was to determine whether this discrepancy in gender distribution could be a result of differences in immunological response. Twenty single-infected and 21 reinfected women and 18 single-infected and three reinfected men were included in the study. None of the participants showed any sign of an ongoing B. burgdorferi infection, and thus the habitual response was captured. Lymphocytes were separated from blood and stimulated with antigens. The secretion of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumour necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) or Immulite. No difference was detected in cytokine secretion between single-infected and reinfected individuals. We also compared the immunological response in men and women, regardless of the number of B. burgdorferi infections. Women displayed a significantly higher spontaneous secretion of all cytokines measured. The ratios of IL-4:IFN-γ and IL-10:TNF-α were significantly higher in women. Gender differences in immune reactivity might in part explain the higher incidence of reinfection in women. The higher IL-4:IFN-γ and IL-10:TNF-α ratios seen in women indicate that postmenopausal women have T helper type 2 (Th2)-directed reactivity with impaired inflammatory responses which might inhibit the elimination of spirochetes.

Place, publisher, year, edition, pages
2006. Vol. 118, no 2, 224-235 p.
Keyword [en]
cytokine, erythema migrans, gender, Lyme borreliosis, postmenopausal
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-13802DOI: 10.1111/j.1365-2567.2006.02360.xOAI: diva2:21655
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2013-08-29
In thesis
1. Cytokine responses in human Lyme borreliosis: The role of T helper 1-like immunity and aspects of gender and co-exposure in relation to disease course
Open this publication in new window or tab >>Cytokine responses in human Lyme borreliosis: The role of T helper 1-like immunity and aspects of gender and co-exposure in relation to disease course
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lyme borreliosis was first described some 30 years ago in the USA. Today, it is the most common vector borne disease in Europe and the USA. The disease can have multiple stages and symptoms can manifest from various parts of the body; joints, skin heart and nervous system. In Europe, neuroborreliosis is the most frequent late stage diagnosis. Although Lyme borreliosis is treatable with antibiotics and the causative spirochete has not been shown to be resistant to drugs, some patients do not recover completely. They have persistent symptoms and are diagnosed with chronic or persistent Lyme borreliosis. The mechanism behind the lingering symptoms is unclear but might be due to tissue damage caused by the immune system. The aim of this thesis was to study the immunological differences between patients with different outcome of Lyme borreliosis, i.e. chronic, subacute and asymptomatic, and various factors that might influence the course of the disease.

The Borrelia-specific IFN-γ and IL-4 secretion was detected in blood and cerebrospinal fluid from patients with chronic and subacute neuroborreliosis during the course of the disease. Blood samples were also obtained from patients with erythema migrans (EM) and acrodermatitis chronicum atrophicans. An early increase of IFN-γ with a later switch to an IL-4 response was observed in patients with a subacute disease course whereas the IFN-γ secretion continued to be elevated in chronic patients.

The Borrelia-specific Th1-response was further investigated in chronic, subacute and asymptomatic individuals by studying the expression of the Th1-marker IL-12Rβ2, on a protein and mRNA level. The cytokine secretion and Foxp3, a marker for regulatory T-cells, were also analyzed. Chronic patients had a lower IL-12Rβ2 expression on CD8+ T-cells and a lower number of Borrelia-specific IFN-γ secreting cells compared to asymptomatic individuals. Chronic patients also displayed a higher expression of Borrelia-specific Foxp3 than healthy controls.

The conclusions for these tow studies were that a strong Th1-response early in the infection with a later switch to a Th2-response is beneficiary whereas a slow or weak Th1-response corresponds to a prolonged disease course.

The influence of a previous infection with another pathogen, seen to suppress the immune response in animals, and the possible gender difference in immune response was also investigated. Patients with EM were screened for antibodies to Anaplasma phagocytophilum (Ap) as a sign of a previous exposure to these tick-borne bacteria. Blood lymphocytes from Ap seronegative, Ap seropositive and healthy controls were stimulated with Borrelia antigen and the secretion of IL-4, IL-5, IL-12, IL-13 and IFN-γ was detected by ELISPOT. Ap seropositive patients had a lower number of cells responding with IL-12 secretion compared to the other groups which might indicate an inhibited Th1-response.

Reinfections with Lyme borreliosis was in a previous study, done by Bennet et al, found to be more frequent in postmenopausal women than in men. To investigate if there was an immunological explanation to the gender discrepancy, blood lymphocytes from individuals reinfected with Lyme borreliosis and individuals infected only once were stimulated with various antigens. The cytokine secretion was detected by ELISPOT, ELISA and Immulite. There were no differences between reinfected and single infected individuals. However, women, regardless of times infected, displayed a Th2-derived and anti-inflammatory spontaneous immune response compared to men.

A previous infection with the bacteria Ap might possibly have a long term effect on the immune system and might be of disadvantage when mounting a Th1-response to a Borrelia infection. Also, the Th2-derived response displayed by postmenopausal women could indicate why more women than men get reinfected with Borrelia burgdorferi.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin, 2006
Linköping University Medical Dissertations, ISSN 0345-0082 ; 938
Borrelia, human granulocytic anaplasmosis, cytokine, immunology, chronic
National Category
Immunology in the medical area
urn:nbn:se:liu:diva-6120 (URN)91-85497-73-8 (ISBN)
Public defence
2006-04-07, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (English)
On the day of the public defence date of the doctoral thesis the status of article III was Accepted; the status of article IV was Submitted and the title was "Importance of induction and secretion of interferon-gamma for optimal resolution of human Lyme borreliosis: differencesbetween different outcomes of the infection".Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2013-08-29

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