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Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum
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.
Department of Clinical Microbiology, Kalmar County Hospital, Sweden .
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
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2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 2, 322-328 p.Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis and human granulocytic ehrlichiosis are tick-borne diseases caused by Borrelia burgdorferi and Anaplasma phagocytophilum, respectively. Infection with A. phagocytophilum has been observed to induce immunosuppression and animal studies suggest that the bacteria might also have prolonged inhibitory effects on immune cells. The aim of this study was to investigate the cytokine secretion in patients exposed previously to A. phagocytophilum and currently infected with B. burgdorferi compared with patients infected with B. burgdorferi and seronegative for A. phagocytophilum. Eight patients with erythema migrans and antibodies against A. phagocytophilum, 15 patients with erythema migrans and negative A. phagocytophilum serology and 15 non-exposed healthy individuals were included in the study. Blood mononuclear cells were stimulated with Borrelia-antigen and the number of cytokine [interleukin (IL)-4, IL-5, IL-12, IL-13 and interferon (IFN)-γ]-secreting cells was detected by enzyme-linked immunospot (ELISPOT). This study shows that patients with a previous exposure to A. phagocytophilum and a current infection with B. burgdorferi have a lower number of Borrelia-specific cells secreting IL-12 compared to Ap seronegative patients infected with B. burgdorferi (P < 0·001), indicating impairment in the ability to mount strong Th1-responses. We suggest that this mirrors a reduced Th1 response caused by A. phagocytophilum which could influence the outcome of the Borrelia infection and, speculatively, may also have implications in other conditions.

Place, publisher, year, edition, pages
2006. Vol. 143, no 2, 322-328 p.
Keyword [en]
HGE, human granulocytic ehrlichiosis, interleukin-12, Lyme disease, tick-borne
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13801DOI: 10.1111/j.1365-2249.2005.02993.xOAI: oai:DiVA.org:liu-13801DiVA: diva2:21654
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2013-08-29Bibliographically approved
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
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 938
Keyword
Borrelia, human granulocytic anaplasmosis, cytokine, immunology, chronic
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-6120 (URN)91-85497-73-8 (ISBN)
Public defence
2006-04-07, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (English)
Opponent
Supervisors
Note
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
2. Tick-Borne Infections in Humans: Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum
Open this publication in new window or tab >>Tick-Borne Infections in Humans: Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The tick-borne infectious agents, B. burgdorferi, A. phagocytophilum and the TBE-virus, can all cause clinical disease in humans and may all initially give rise to myalgia, arthralgia, headache and fever. The clinical manifestations of the infections range from subclinical or mild to severe, in some cases with a postinfectious sequel, and mixed infections may occur, confusing the clinical picture.

The aim of this thesis was to investigate the occurrence and co-existence of these infections in a Scandinavian context. A further aim was to study aspects of the immunopathogenesis of B. burgdorferi infection and possible effects on the immune response when previously exposed to A. phagocytophilum. Finally, an attempt was made to improve the laboratory diagnosis of Lyme neuroborreliosis (LNB).

In a prospective clinical study, patients were recruited based on two independent inclusion criteria; 1) patients with unspecific symptoms or fever, and 2) patients with erythema migrans (EM). Among 206 patients, we found 186 cases of Lyme borreliosis (LB) (174 with EM), 18 confirmed and two probable cases of human granulocytic anaplasmosis (HGA), and two cases of Tick-borne encephalitis (TBE). Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a subclinical co-infection with A. phagocytophilum, based on serology. Both TBE cases had co-infections, one with B. burgdorferi and one with A. phagocytophilum.

In another investigation, IL-12p70 secretion in patients with current LB was compared in patients with or without previous A. phagocytophilum infection. Patients with serological evidence of previous exposure to A. phagocytophilum had a lower B. burgdorferi-induced IL-12p70 secretion. Since IL-12p70 induces the Th1 response, this finding indicates a reduced Th1 response, possibly caused by A. phagocytophilum. In a separate study, we showed that patients with LNB had increased levels of cytokines associated with cytotoxicity in cerebrospinal fluid (CSF), including the recently described cytokine IL-17.

Since it is known that the adaptive immune system, especially the T cells, is activated during an infection with B. burgdorferi, a modified ELISPOT assay using cells from CSF was evaluated to be a useful complementary test in diagnosing LNB. However, we found that the diagnostic performance was too weak in our setting, and we could not recommend it for use in clinical laboratories at this stage.

In conclusion, tick-borne co-infections are probably quite common in Sweden. Our HGA cases were most often discovered as co-infections with LB and would probably have been missed during a routine consultation. They presented with mild symptoms and often without fever, which in previous reports has been part of the disease definition.

The immune response in LNB was shown to be compartmentalized to the target organ, also in terms of cytokine response. Furthermore, we found indications of possible long-term effects of A. phagocytophilum infection, demonstrated as a reduced IL-12p70 secretion in patients with ongoing LB. This could be a disadvantage when mounting a Th1 response to infection with B. burgdorferi. If this is so, the inter-play of these infectious agents in co-infections or consecutive infections may be of importance to clinical outcome.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 131 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1315
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80260 (URN)978-91-7519-852-1 (ISBN)
Public defence
2012-09-07, Berzeliussalen, ingång 65, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2013-08-29Bibliographically approved

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Jarefors, SaraKarlsson, MarikaForsberg, PiaErnerudh, JanEkerfelt, Christina

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