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Jarefors, Sara
Publications (9 of 9) Show all publications
Widhe, M., Ekerfelt, C., Jarefors, S., Hedin-Skogman, B., Peterson, E. M., Bergstrom, S., . . . Ernerudh, J. (2009). T-Cell Epitope Mapping of the Borrelia garinii Outer Surface Protein A in Lyme Neuroborreliosis. SCANDINAVIAN JOURNAL OF IMMUNOLOGY, 70(2), 141-148
Open this publication in new window or tab >>T-Cell Epitope Mapping of the Borrelia garinii Outer Surface Protein A in Lyme Neuroborreliosis
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2009 (English)In: SCANDINAVIAN JOURNAL OF IMMUNOLOGY, ISSN 0300-9475, Vol. 70, no 2, p. 141-148Article in journal (Refereed) Published
Abstract [en]

We studied the T-cell reactivity to overlapping peptides of B. garinii OspA, in order to locate possible immunodominant T-cell epitopes in neuroborreliosis. Cells from cerebrospinal fluid (CSF) and blood from 39 patients with neuroborreliosis and 31 controls were stimulated with 31 overlapping peptides, and interferon-gamma secreting cells were detected by ELISPOT. The peptides OspA(17-36), OspA(49-68), OspA(105-124), OspA(137-156), OspA(193-212) and OspA(233-252) showed the highest frequency of positive responses, being positive in CSF from 38% to 50% of patients with neuroborreliosis. These peptides also elicited higher responses in CSF compared with controls (P = 0.004). CSF cells more often showed positive responses to these peptides than blood cells (P = 0.001), in line with a compartmentalization to the central nervous system. Thus, a set of potential T-cell epitopes were identified in CSF cells from patients with neuroborreliosis. Further studies may reveal whether these epitopes can be used diagnostically and studies involving HLA interactions may show their possible pathogenetic importance.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20130 (URN)10.1111/j.1365-3083.2009.02285.x (DOI)
Available from: 2009-08-31 Created: 2009-08-31 Last updated: 2013-11-07
Jarefors, S., Janefjord, C., Forsberg, P., Jenmalm, M. & Ekerfelt, C. (2007). Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals. Clinical and Experimental Immunology, 147(1), 18-27
Open this publication in new window or tab >>Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals
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2007 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 1, p. 18-27Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rβ2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rβ2 and FoxP3 mRNA expression was analysed with real-time reverse transcription–polymerase chain reaction (RT–PCR). The protein expression of IL-12Rβ2 on CD3+, CD4+, CD8+ and CD56+ cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-γ, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rβ2 on CD8+ cells and also a lower number of Borrelia-specific IFN-γ-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.

Keywords
chronic, cytokine, FoxP3, IL-12Rβ2, Lyme borreliosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13803 (URN)10.1111/j.1365-2249.2006.03245.x (DOI)
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2017-12-13
Jarefors, S. (2006). 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. (Doctoral dissertation). Institutionen för molekylär och klinisk medicin
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
Keywords
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: 2018-01-13
Jarefors, S., Bennet, L., You, E., Forsberg, P., Ekerfelt, C., Berglund, J. & Ernerudh, J. (2006). Lyme borreliosis reinfection: might it be explained by gender difference in immune response?. Immunology, 118(2), 224-235
Open this publication in new window or tab >>Lyme borreliosis reinfection: might it be explained by gender difference in immune response?
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2006 (English)In: Immunology, ISSN 0019-2805, Vol. 118, no 2, p. 224-235Article 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.

Keywords
cytokine, erythema migrans, gender, Lyme borreliosis, postmenopausal
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13802 (URN)10.1111/j.1365-2567.2006.02360.x (DOI)
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2013-08-29
Jarefors, S., Karlsson, M., Eliasson, I., Forsberg, P., Ernerudh, J. & Ekerfelt, C. (2006). Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum. Clinical and Experimental Immunology, 143(2), 322-328
Open this publication in new window or tab >>Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum
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2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 2, p. 322-328Article 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.

Keywords
HGE, human granulocytic ehrlichiosis, interleukin-12, Lyme disease, tick-borne
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13801 (URN)10.1111/j.1365-2249.2005.02993.x (DOI)
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2017-12-13Bibliographically approved
Widhe, M., Hedin Skogman, B., Bergström, S., Forsberg, P., Ernerudh, J., Jarefors, S., . . . Croner, S. (2005). Up-regulation of Borrelia-specific IL-4 and IFN-gamma secreting cells in cerebrospinal fluid from children with Lyme neuroborreliosis. International Immunology, 17(10), 1283-1291
Open this publication in new window or tab >>Up-regulation of Borrelia-specific IL-4 and IFN-gamma secreting cells in cerebrospinal fluid from children with Lyme neuroborreliosis
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2005 (English)In: International Immunology, ISSN 0953-8178, Vol. 17, no 10, p. 1283-1291Article in journal (Refereed) Published
Abstract [en]

The clinical course and outcome of several infectious diseases are dependent on the type of immune response elicited against the pathogen. In adults with neuroborreliosis (NB), a type 1 response with high production of Borrelia-specific IFN-, but no IL-4, has been reported. Since children have a more benign course of NB than adults, we wanted to investigate type 1 and type 2 responses in children with NB. Cerebrospinal fluid (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-specific IL-4- and IFN--secreting cells was measured by enzyme-linked immunospot assay. Borrelia-specific secretion of both IL-4 and IFN- was increased in CSF in confirmed (P < 0.05) and possible (P < 0.01) NB, when compared with non-NB controls. Furthermore, children with NB had significantly higher Borrelia-specific IL-4 secretion in CSF 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 harmful effects of prolonged IFN- responses, the prominent IL-4 response observed in the central nervous system compartment might contribute to the more benign disease course seen in children with Lyme NB.

Keywords
cytokines, IL-4, IFN-{gamma}, immune response, ELISPOT
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13161 (URN)10.1093/intimm/dxh304 (DOI)
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2013-08-29
Widhe, M., Jarefors, S., Ekerfelt, C., Vrethem, M., Bergström, S., Forsberg, P. & Ernerudh, J. (2004). Borrelia-specific interferon-γ and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome. Journal of Infectious Diseases, 189(10), 1881-1891
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
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2004 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 189, no 10, p. 1881-1891Article 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
Ekerfelt, C., Jarefors, S., Tynngard, N., Hedlund, M., Sander, B., Bergström, S., . . . Ernerudh, J. (2003). Phenotypes indicating cytolytic properties of Borrelia-specific interferon-? secreting cells in chronic Lyme neuroborreliosis. Journal of Neuroimmunology, 145(1-2), 115-126
Open this publication in new window or tab >>Phenotypes indicating cytolytic properties of Borrelia-specific interferon-? secreting cells in chronic Lyme neuroborreliosis
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2003 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 145, no 1-2, p. 115-126Article in journal (Refereed) Published
Abstract [en]

The immuno-pathogenetic mechanisms underlying chronic Lyme neuroborreliosis are mainly unknown. Human Borrelia burgdorferi (Bb) infection is associated with Bb-specific secretion of interferon-? (IFN-?), which may be important for the elimination of Bb, but this may also cause tissue injury. In order to increase the understanding of the pathogenic mechanisms in chronic neuroborreliosis, we investigated which cell types that secrete IFN-?. Blood mononuclear cells from 13 patients with neuroborreliosis and/or acrodermatitis chronicum atrophicans were stimulated with Bb antigen and the phenotypes of the induced IFN-?-secreting cells were analyzed with three different approaches. Cells expressing CD8 or TCR?d, which both have cytolytic properties, were the main phenotypes of IFN-?-secreting cells, indicating that tissue injury in chronic neuroborreliosis may be mediated by cytotoxic cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26423 (URN)10.1016/j.jneuroim.2003.08.037 (DOI)10965 (Local ID)10965 (Archive number)10965 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13
Widhe, M., Hedin Skogman, B., Jarefors, S., Eknefelt, M., Eneström, G., Nordwall, M., . . . Ernerudh, J.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
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(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.

Keywords
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
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