| 1. |
- Henningsson, Anna J, 1972-
(författare)
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Clinical, epidemiological and immunological aspects of Lyme borreliosis with special focus on the role of the complement system
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere. The infection is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and it is transmitted to humans by ticks. LB is associated with several clinical manifestations, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common inEurope. The course of the disease is usually benign, but can vary between individuals. The underlying pathogenic mechanisms are not fully understood, but the prognosis is probably determined by a complex interplay between the bacteria and the host’s immune response. Previous studies have indicated that a strong initial T helper (Th) 1-response followed by a Th2 response is beneficial for the clinical outcome in LB.The aims of this thesis were to follow the incidence of NB inJönköping County,Sweden, over time, to search for clinical and laboratory markers associated with the risk of developing long-lasting post-treatment symptoms, and to explore the role of the complement system as well as the relative balance between Th-associated cytokine/chemokine responses in LB.The number of NB cases, diagnosed by cerebrospinal fluid (CSF) analysis, increased from 5 to 10/100,000 inhabitants/year in Jönköping County during 2000-2005. Post-treatment symptoms persisting more than 6 months occurred in 13 %, and were associated with higher age, longer-lasting symptoms prior to treatment, higher levels of Borrelia-specific IgG in CSF, and reported symptoms of radiculitis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients.Complement activation occurred both locally in the skin in EM and in CSF of NB patients. However, no activation could be detected in blood in NB patients. Elevated levels of C1q, C4 and C3a in CSF, along with correlation between C1q and C3a levels, suggest complement activation via the classical pathway locally in the central nervous system in NB. In vitro experiments with two clinical Borrelia isolates revealed that B. garinii LU59 induced higher complement activation in human plasma compared to B. afzelii K78 that recruited more of complement regulator factor H. To elucidate the role of complement in the phagocytosis process, experiments were performed using whole blood from healthy donors incubated with fluorescence-labelled spirochetes and different complement inhibitors. The results illustrated a central role of complement for phagocytosis of Borrelia spirochetes.We also studied the relative contribution of different Th-associated cytokines/chemokine responses in NB. The results support the notion that early NB is dominated by a Th1 response, eventually accompanied by a Th2 response. IL-17A was increased in CSF in half of the patients with confirmed NB, suggesting a hitherto unknown role of Th17 in NB.In conclusion, the risk of developing long-lasting post-treatment symptoms tend to increase mainly with age and duration of symptoms prior to treatment in NB. The complement system seems to play an important role in host defence to recognize and kill Borrelia spirochetes. However, complement activation in inappropriate sites or to an excessive degree may cause tissue damage, and therefore, the role of complement in relation to disease course needs to be studied further. Likewise, the role of Th17 in LB pathogenesis and host defence should be further evaluated in prospective studies.
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| 2. |
- Fryland, Linda
(författare)
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Immune mechanisms in Borrelia burgdorferi sensu lato infection in relation to clinical outcome
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme borreliosis (LB) is the most common tick-borne disease in the northern hemisphere. The infection is caused by spirochaetes from the Borrelia (B.) burgdorferi sensu lato (s.l.) group. The clinical outcome after B. burgdorferi s.l. infection differs between individuals from asymptomatic infection without history of LB to individuals who experience persistent symptoms post-treatment for more than six months after treatment. The difference in clinical outcome is not thought to be associated with persistent infection, but could instead be affected by the host’s ability to mount an optimal immune response to the spirochaete.The hypothesis of this thesis was that a strong inflammatory Th1-like immune response is required in the early stage of infection in order to achieve both an optimal eradication of the B. burgdorferi s.l. bacteria and a good clinical outcome. The inflammatory response must be down-regulated by an anti-inflammatory response in order to avoid excessive immune responses that will end in tissue injury. The proper down-regulation will also protect against development of a chronic Th1-like inflammatory response, with activated cytotoxic cells, which may lead to LB with persistent symptoms post-treatment.The thesis aimed to investigate the immunological mechanisms behind the optimal resolution of human B. burgdorferi s.l. infection and to define the aberrant mechanisms leading to development of persisting symptoms.prospective study on newly tick-bitten individuals showed that although 25% of the collected ticks were infected with B. burgdorferi s.l. very few individuals bitten by infected ticks developed LB (3.7%). In addition, 4.9% of the individuals bitten by infected ticks developed asymptomatic infection, i.e. B. burgdorferi s.l.-specific antibody seroconversion without LB. Approximately one third of all tick-bitten study subjects reported self-experienced symptoms possibly associated with LB. Individuals bitten by infected ticks were more likely to report experience of symptoms than those bitten by uninfected ticks. Thus, only 8.6% of the individuals bitten by B. burgdorferi s.l.-infected ticks were infected, verified by seroconversion, and out of them 57% were asymptomatic.A prospective study on EM patients showed that a good clinical outcome was associated with a strong early Th1 immune response since EM patients with persistent symptoms six months after treatment had reduced expression of Th1 cytokines in their EM lesions compared with EM patients without symptoms.The investigation of blood samples from newly tick-bitten individuals, for detection of possible early immune biomarkers indicating good clinical outcome of LB, showed that none of the investigated markers clearly discriminated between the individuals who developed LB, asymptomatic individuals, or non-infected individuals. However, tick-bitten individuals who developed asymptomatic infection showed an increase of early Th1-associated biomarkers in blood compared to individuals who developed clinical LB.In an experimental study, Th2-immune-deviated mice had more pronounced clinical signs of infection and could not eradicate the spirochaete as efficiently as non-deviated B. burgdorferi sensu stricto (s.s.)-infected mice. Non-deviated B. burgdorferi s.s.-infected mice showed a decrease of mRNA expression associated with Th2, anti-inflammatory and Treg/Th1 responses during the course of infection, which suggested a termination of the inflammatory response – something that was not seen in the immune-deviated mice. Trends for increased expression of pro-inflammatory GM-CSF and Treg marker Foxp3 in immune-deviated mice suggested on-going inflammation. Non-deviated B. burgdorferi s.s.-infected mice showed increased systemic expression of the Th1-associated CXCL9 and CXCL10 during the course of infection, while immune-deviated mice showed an initial decrease in both chemokines at day 15 p.i. compared with day 0 p.i.In conclusion, the risk of developing LB after a tick bite is low, and no infection or asymptomatic infection are the most common outcomes after a tick bite. The early immune response in humans and the immune response towards B. burgdorferi s.s. infection in mice support the hypothesis that a strong pro-inflammatory Th1 response is needed for an optimal clinical outcome and eradication of bacteria.
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| 3. |
- Gyllemark, Paula, 1975-
(författare)
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Tick-borne diseases and the central nervous system : clinical and immunological aspects
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme neuroborreliosis (LNB) is the dominating form of disseminated infection by the tick-borne bacteria Borrelia (B.) burgdorferi in Sweden as well as in Europe. The diagnosis of the manifestation is based on typical symptoms, together with elevated mononuclear cell count in the cerebrospinal fluid (CSF) and elevated levels of Borrelia-specific antibodies in the CSF. The diagnostic arsenal has, in recent years, been complemented by analysis of the chemokine CXCL13 in the CSF, with increasing levels in the early phase of the disease, even before antibodies can be detected in the CSF. Most patients recover within a couple of months after antibiotic treatment, but a few can suffer from residual symptoms. The mechanisms behind this are still puzzling, but there are indications that the host´s immune response may play a role. Prognostic markers would be desirable and in-creased understanding of pathogenetic mechanisms may provide a basis for development of new treatment strategies. Other agents besides B. burgdorferi have, however, also been detected in ticks collected in Sweden, but the knowledge of their impact on human health and their ability to invade the central nervous system (CNS) is limited. The aims of this thesis were to investigate a set of cytokines and chemokines associated with Th1 (CXCL10), Th2 (CCL22), Th17 (IL-17A, CXCL1, CCL20) and B cell (APRIL, BAFF, CXCL13) -related im-munity and its association with recovery in patients with LNB included both retrospectively and prospectively. The chemokine CXCL13 was further analysed, comparing the performance of two different diagnostic methods. In a large cohort of patients investigated for LNB we investigated signs of other tick-borne diseases by analysing serum and CSF using both molecular and serological techniques. In the retrospective cytokine/chemokine study, all investigated cytokines and chemokines; namely, APRIL, BAFF, CXCL13, IL-17A, CXCL1, and CCL20 could be detected at elevated levels in patients with LNB compared to controls. Patients with recovery > 3 months had higher levels of APRIL, BAFF, and IL-17A. In the prospective study, patients with short recovery (< 1 month) had lower levels of CCL20 and patients with prolonged recovery (> 6 months) had higher levels of IL-17A. The analysis of the chemokine CXCL13 with both an enzyme-linked immunosorbent assay (ELISA) with a best-performanced cut-off of 56 pg/mL and bead-based (Luminex) method with a best-performance cut-off of 158 pg/mL (both assays with 100% sensitivity and specificity) displayed the im-portance of different cut-offs depending on which method that is used.In 600 patients, we analysed serum and CSF with PCR for the different tick-borne agents Ana-plasma phagocytophilum, B. burgdorfer spp. (including B. miyamotoi), Neoehrlichia (N.) mikurensis, Rickettsia spp., Babesia spp. and tick-borne encephalitis virus. N. mikurensis and B. burgdorferi could be detected by PCR in sera from two patients. Neither PCR, nor serological analysis could detect any potential co-infections.In conclusion, we can corroborate the Th17-related immunity in the pathogenesis of LNB where IL-17A and CCL20 are plausible prognostic markers. Other tick-borne pathogens with possible dissemination to the CNS seems to be uncommon in south-eastern Sweden.
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| 4. |
- Lindblom, Pontus, 1982-
(författare)
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Epidemiological and Ecological Studies of Tick-borne Encephalitis Virus
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ticks are blood-sucking parasites that are an inconvenience for both humans and animals. The tick by itself is normally harmless unless they attack in excessive numbers. The harm from ticks stems from them being excellent vectors for other parasites, in the form of bacteria and virus that via the ticks are provided a bridge to move across the blood streams of different animals, including humans.One of the most pathogenic tick-borne disease for humans is caused by a flavivirus, the tick-borne encephalitis virus (TBEV). Each year approximately 10 000 individuals on the Eurasian continent develop neurological disease, in the form of meningitis, encephalitis, myelitis and radiculitis, following a bite by a TBEV infected tick.To evaluate the risk of TBEV infection after a tick-bite, we have developed a study to investigate ticks that have bitten humans and to follow up the tick-bitten humans to investigate if they get infected, and if they develop symptoms, and further trace the virus back to the tick that is infected with TBEV. Ticks, blood samples, and questionnaires were collected in collaboration with 34 primary health care centers in Sweden and on the Åland Islands during 2008 and 2009.Several demographical and biological factors were investigated regarding the interaction between ticks and humans. The main finding was that men removed the ticks later than women, and that both older men and older women removed the ticks later than younger individuals. This could in part explain why older individuals in general, and men in particular, are at greater risk of acquiring tick-borne encephalitis (TBE).Furthermore, the prevalence of TBEV in ticks that have bitten humans were investigated, in order to correlate the copy number of TBEV in the tick and the tick feeding-time to the risk of developing symptomatic and asymptomatic infection. This entailed the development of new methodology for tick analysis and TBEV real-time PCR. The result showed a very low risk of TBEV infection in the studied areas, only 5 of 2167 investigated ticks contained TBEV. Three of the individuals bitten by TBEV infected ticks were vaccinated and did not develop symptoms of TBEV infection. One unvaccinated individual got bitten by a tick containing 1800 virus copies, with a feeding-time of 12-24h, and interestingly showed no signs of infection. Another unvaccinated individual got bitten by a tick containing 7.7 million virus copies, with a feedingtime of >60h. This individual developed symptoms consistent with a 1st phase of TBE, including fever and headache, but did not develop the 2nd neurological phase of TBEV infection. Despite only finding 5 ticks infected with TBEV, a correlation between the virus load in the tick and the tick feeding-time was observed. In 2 other individuals, TBEV antibody seroconversion was detected during the 3 month study period, one without symptoms, while the other experienced symptoms consistent with the 1st phase of TBE. These observations support the hypothesis that a higher virus amount in the tick and a longer feeding time increases the risk of TBEV infection.To further examine TBEV in ticks that have bitten humans and find factors that may predict the risk of human infection and development of TBE, we characterized several TBEV strains genetically. Including TBEV strains isolated from ticks that have bitten human, from questing field-collected ticks, and TBEV strains isolated from patients with TBE. In one of the ticks detached from a human after >60h of feeding, there was a heterogeneous population of TBEV quasispecies with varying poly(A) length in the 3’ untranslated region of the genome was observed. These variations might have implications for differences in virulence between TBEV strains, and the heterogeneous quasispecies population observed could be the virus adapting from replication in tick cells to mammalian cells.We also investigated the response to TBEV vaccination in relation to 14 health-related factors in a population of older individuals on the Åland Islands. Blood samples, questionnaires, and vaccination records were collected from 533 individuals. Three different serological assays to characterize antibody response to TBEV vaccination were used. The main finding was that the number of vaccine doses in relation to age was the most important factor determining successful vaccination. The response to each vaccination dose declined linearly with age, and as much as 47% of individuals 50 years or older that had taken 3 vaccine doses were seronegative, compared to 23% that had taken 4 doses and 6% with 5 doses. Comparison between the serological assays revealed that the cutoffs determining the balance between sensitivity and specificity differed, but not the overall accuracy.Taken together, these results contribute to a better understanding of the TBEV epidemiology and can provide tools in the prevention of TBE.
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| 5. |
- Wilhelmsson, Peter
(författare)
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A STING from a Tick : Epidemiology, Ecology and Clinical Aspects of Lyme Borreliosis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme borreliosis (LB) is the most common tick-borne disease in the Northern Hemisphere and the number of LB cases is increasing. The infection is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and is, in Europe, transmitted to humans by Ixodes ricinus ticks.To gain a deeper knowledge of the interactions between ticks, humans and Borrelia bacteria, we investigated temporal differences in exposure to tick bites in different parts of Sweden and the Åland Islands, Finland during the years 2008 and 2009. We also investigated the site of tick attachment on the human body and the time it takes for a person to detected and remove such ticks. Furthermore, the distribution of Borrelia species and the number of Borrelia cells in the ticks were investigated. Sera taken from the tick-bitten persons at study inclusion were analyzed for the presence of Borrelia antibodies. Three months later, the clinical outcome and the serological response of the tick-bitten persons were investigated. A total of 2154 I. ricinus ticks and 1546 participants were included in the studies.Participants were exposed to tick bites between April and November, but temporal and spatial differences in exposure to ticks was found. The majority of the tick bites were caused by nymphs (70%) and most tick bites took place on the legs (50%). The site of tick attachment on the body as well as the age and gender of the participant influenced how soon a tick was detected. The majority of participants removed “their” ticks later than 24 hours of attachment. Of all ticks, 26% was Borrelia-infected, but the prevalence varied between the life stages of the tick and between the studied areas. Six species of the B. burgdorferi sensu lato complex and one Borrelia species that may cause tick-borne relapsing fever were detected. Adult ticks that had fed more than 36 hours contained a lower number of Borrelia cells than adult ticks that had fed less than 36 hours. The seroprevalence among the participants varied between genders as well as between the studied areas. Of all participants, 2% was diagnosed with LB and 2.5% seroconverted without an LB diagnose. A correlation between seroconversion and duration time of tick attachment was found, but the number of Borrelia cells in the tick, did not explain the risk of infection for the bitten person.A deeper knowledge and a better understanding of the interactions between ticks, humans and Borrelia bacteria may contribute reducing the risk for tick bites and the risk of developing LB after a tick bite.
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| 6. |
- Tjernberg, Ivar, 1973-
(författare)
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Laboratory Diagnosis of Lyme Borreliosis : Anti-Borrelia Antibodies and the Chemokine CXCL13
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme borreliosis (LB), the most common tick-borne disease in Europe and North America, is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. The spirochetes can invade several different organs, thereby causing many different symptoms and signs. Diagnosis of LB relies on patient history, physical examination, and detection of anti-Borrelia antibodies. However, anti-Borrelia antibodies are not always detectable, and they commonly persist even after LB is successfully treated or spontaneously healed.The aim of my work was to study diagnostic aspects on clinical cases of LB and control subjects in an area endemic to LB, with a focus on newly developed anti-Borrelia antibody tests. A total of 617 patients with symptoms and/or signs consistent with LB, as well as 255 control subjects, were studied. The diagnostic panel included the following new LB tests: Immunetics Quick ELISA C6 Borrelia assay kit (C6), invariable region 6 peptide antibody assays (IR6), Liaison Borrelia CLIA (Li) and the chemokine CXCL13. Results were compared with the older Virotech Borrelia burgdorferi ELISA (VT) and with a Western blot method, the Virotech Borrelia Ecoline IgG/IgM Line Immunoblot (WB EL), when appropriate.In general, no significant differences were noted between the C6, VT and Li tests regarding serosensitivity in various LB manifestations. However, the seropositivity rate was lower for the C6 test compared with the VT and Li tests 2–3 and 6 months after diagnosis of erythema migrans (EM), indicating normalization of antibody levels. In addition, EM patients reporting a previous LB episode had a C6 seropositivity rate similar to that of patients without a previous LB episode, and seroprevalence in healthy blood donors was lower in the C6 test than the VT and Li tests. Taken together, these results support the recommendation of the serum C6 test as a Borrelia serological test due to its ability to reflect ongoing or recent infection.Although the majority of EM patients at presentation showed concordant serological responses to IR6 peptides representing the three main Borrelia species and the C6 peptide, there were also clinical EM cases that were C6-negative and could be detected mainly by a seroresponse to a B. burgdorferi sensu stricto-derived IR6 peptide. Thus, an antibody test combining antigens could be of value in the serodiagnosis of LB in Europe.The serosensitivity of the C6 test in cases of Lyme neuroborreliosis (LNB) was shown to be associated with symptom duration. A serosensitivity rate of 93% was found in LNB patients ³ 12 years of age with a symptom duration of more than 30 days. Therefore, a negative C6 test in serum in such a patient argues against an LNB diagnosis.The presence of chemokine CXCL13 in cerebrospinal fluid was confirmed to be a reliable marker of LNB. CXCL13 differentiated LNB from other conditions and also indicated a high probability of LNB in children with short symptom duration where anti-Borrelia antibodies were still lacking in the cerebrospinal fluid.A two-tiered approach (C6 test in combination with WB EL) showed no significant improvement in specificity over the C6 test alone. However, WB EL may be useful in diagnosing suspected cases of acrodermatitis chronicum atrophicans and Lyme arthritis, usually displaying multiple IgG bands.In conclusion, although the serodiagnosis of LB remains to be settled, this thesis provides some practical tools regarding the use and interpretation of Borrelia serology including proposed diagnostic routines.
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| 7. |
- Irander, Kristina, 1943-
(författare)
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An 18 year Follow-up of Allergy Development : Findings of Nasal Markers of Allergic Inflammation
- 2008
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In addition to the family history of allergy (FH), there is a need o find objective markers of allergy development as early in life as possible in order to focus preventive measurements on high risk infants. Rhinitis problems are common causes to morbidity in adults due to allergic as well as non-allergic mechanisms. Accurate diagnoses are essential for decisions of optimal management of the patients, but in non-allergic rhinitis groups there are no objective tests to verify the diagnosis, if this is needed.Aims: The primary aim was to evaluate the occurrence of nasal metacromatic (MC) cells during infancy as predictors for allergy development in a group of high risk subjects from birth up to 18 years of age. Additional aims were to find and evaluate nasal markers with ability to differentiate between allergic rhinitis with and without current allergen exposure from normal controls.Subjects and methods: New-borns (n = 67) with and without family histories of allergy were included, and during the first 18 months of life occurrence of nasal MC could be evaluated in 64 infants (33 positive/31 negative MC findings). The cohort was followed up for allergy development at the ages of 18 months, 6 years and 18 years. Nasal markers as MC, nasal NO, nitrite/nitrate in nasal lavage and acoustic rhinometry at the 18-years follow-up were related to the allergic manifestations at this age.Results: Positive nasal MC findings during infancy predicted allergy development up to 18 years of age in 31/33 subjects (94 %), as compared to 37/44 with positive FH (84 %). Negative MC findings during infancy did not exclude the risk, as 15/31 developed allergy (48 %). At the 18-years follow-up the numbers of individuals with demonstrable MC were significantly higher (p = 0.01) in the group of individuals with allergy symptoms (16/30) compared to the group of individuals with no allergy (1/12). Nasal NO levels, nitrite/nitrate concentrations in nasal lavages and acoustic rhinometry did not differentiate the allergic groups from the normal group.Conclusions: Positive nasal MC findings during infancy predicted allergy development up to 18 years of age, and the cell findings often preceded the allergic symptoms. The marker can not be used as a single predictor of allergy development due to negative MC findings in a high proportion of allergic subjects. Positive MC findings combined with positive FH resulted in the best the risk evaluation. Differences between groups with and without current allergen exposure and healthy controls were not found by means of acoustic rhinometry, nasal MC, nasal NO or nitrites/nitrates levels. Further research to find reliable nasal markers is needed.
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| 8. |
- Nordberg, Marika
(författare)
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Tick-Borne Infections in Humans : Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 9. |
- Sjöwall, Johanna
(författare)
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Clinical and Immunological Aspects of Lyme borreliosis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme borreliosis (LB) is a tick-borne infection caused by spirochetes of the Borrelia (B.) burgdorferi sensu lato complex. The infection is associated with several clinical features, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common in Europe. The prognosis after antibiotic therapy is generally good. However, some patients may have residual symptoms post-treatment. The cause of the delayed convalescence is unclear. There are several factors that may affect the clinical outcome of LB, for example, the early interaction between the host’s immune response and B. burgdorferi, the spirochete genotype, antibiotic therapy, as well as the host’s vulnerability.This thesis aimed to explore the type of early immune response that is generated to B. burgdorferi and its importance for the clinical outcome of LB, and to study the condition of persistent symptoms post-NB from clinical, immunological and diagnostic perspectives. In total, 125 adult patients with different clinical features and outcomes of LB and 23 healthy controls were included.In a prospective follow-up study of EM, we confirmed that the prognosis of EM is good after antibiotic therapy, and that B. afzelii is the most common B. burgdorferi genotype associated with EM in the Nordic countries. Seven patients (8%) reported persistent symptoms more than six months post-treatment. These patients had also a decreased early expression of inflammatory, Th1-type cytokines in the EM lesions, suggesting an importance of early, local Th1-type immunity to B. burgdorferi for a successful clinical outcome of LB. No correlation between clinical characteristics, allergic predisposition, B. burgdorferi genotype or serology and the development of symptoms post-treatment was found.Asymptomatic B. burgdorferi-seropositive individuals are interesting from clinical and immunological points of view, since they apparently have encountered B. burgdorferi without developing symptoms of LB. In this thesis, asymptomatic individuals were shown to display an enhanced innate inflammatory immune response to live B. garinii spirochetes, induced by dendritic cells and whole blood cells, in comparison with patients with a history of subacute NB and healthy controls. Whether this is the optimal immune response to B. burgdorferi remains to be determined.A randomized, placebo-controlled cross-over study showed that three weeks of doxycycline therapy did not significantly improve objective neurological signs, subjective symptoms or quality of life in NB patients with persistent symptoms post-treatment. Nor could any doxycycline-mediated effects on systemic cytokine responses be demonstrated.Brain magnetic resonance imaging (MRI) findings in NB patients with persistent symptoms post-treatment were shown to be nonspecific and to correlate with age, but not with the duration of symptoms.In conclusion, this thesis shows that there is an association between the early immune response to B. burgdorferi sensu lato and the clinical outcome of LB. The cause of prolonged convalescence post-treatment remains unknown and needs further investigation. However, repeated treatment with doxycycline does not lead to improvement of the persistent symptoms; nor does brain MRI facilitate diagnosis of, or provide an explanation for the post-treatment symptoms.
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| 10. |
- Jarefors, Sara, 1975-
(författare)
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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
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 11. |
- Stjernberg, Louise
(författare)
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Epidemiological aspects of tick borne diseases with focus on risk and prevention
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The incidence and variety of diseases associated with ticks have increased world-wide and ticks are currently considered to be second only to mosquitoes as vectors of human infectious diseases in the world. In the northern hemisphere, Ixodes ricinus, the most common tick, transmits diseases caused by several infectious pathogens, including different types of bacteria, virus and protozoa. In Sweden, Lyme borreliosis, tick-borne encephalitis and erlichiosis are established, and more than 10.000 people are infected each year. This thesis focuses on aspects of risks associated with tick bites, the risk of contracting tick borne diseases including long-term outcome, and preventive measures and behaviour among people living in tick endemic areas. The first study describes the long-term outcome in patients treated with antibiotics due to neuroborreliosis. At the follow up, 75% of the patients had recovered completely and 25% (95% confidence interval; 17% - 33%) suffered from residual neurological symptoms such as facial palsy, concentration disorder, paresthesia and/or neuropathy. In order to avoid sequelae, early diagnosis and treatment are of great importance. The second study investigated the exposure and contraction of tick-bites with the risk of developing Lyme borreliosis from these tick-bites. Results showed that among people well aware of tick-borne diseases and who inspect their skin daily for ticks, the monthly rate of being tick bitten was 0.04 (95% confidence interval; 0.02-0.06) per 10 hours spent out of doors. Within six months, 3% had contracted Lyme borreliosis, i.e. the risk of developing this disease was 0.5% (95% confidence interval; 0.44-0.56) per tick-bite. The third (experimental) study was aimed at determining whether light-coloured or dark-coloured clothing had the least attractive effect on Ixodes ricinus. The overall found ticks between the both colours differed significantly, with 62% (95% confidence interval; 59% - 65%) of the ticks found on light-coloured clothing. Dark-coloured clothing seems to attract fewer ticks. The fourth study describes tick preventive measures, and their predictors, taken among highly exposed people. In total, 69% of the participants regularly took preventive measures, personally and/or in the environment. When analysing gender and preventive measure solely, women took more preventive measures compared to men. When analysing all risk variables together, spending less time in tick endemic area and being tick bitten the same tick season significantly increased the probability of taking any preventive measures. After being tick bitten, men increased their performance of preventive measures more than women.
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