Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study

<p>Abstract</p> <p>Background</p> <p>Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB) is associated with a strong T helper (Th) 1-type cytokine response in the cerebrospinal fluid (CSF) followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown.</p> <p>Methods</p> <p>To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker), CCL22 (Th2 marker), IL-17 (Th17 marker) and CXCL8 (general inflammation marker), in serum and in CSF from untreated patients with confirmed NB (n = 133), and non-NB patients (n = 96), and related the findings to clinical data. Samples from patients with possible early NB (n = 15) and possible late NB (n = 19) were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17), where CSF was obtained at spinal anaesthesia.</p> <p>Results</p> <p>The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p < 0.0001 for all comparisons). Patients in the early NB group, showing a short duration of symptoms, had lower CCL22 levels in CSF than did the confirmed NB group (p < 0.0001). Furthermore, patients within the confirmed NB group showing a duration of symptoms <2 weeks, tended to have lower CCL22 levels in CSF than did those with longer symptom duration (p = 0.023). Cytokine/chemokine levels were not correlated with clinical parameters or to levels of anti-<it>Borrelia</it>-antibodies.</p> <p>Conclusion</p> <p>Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.</p

Clinical performance and analytical accuracy of a C6 peptide-based point-of-care lateral flow immunoassay in Lyme borreliosis serology

We evaluated the analytical accuracy and the clinical performance of a ReaScan+ C6 LYME IgG point-of-care immunoassay (Reagena; index test). Analytical accuracy was evaluated in comparison to a C6 Lyme ELISA™ reference method (Oxford Immunotec) with retrospectively identified serum and CSF samples. The clinical performance was evaluated by using Lyme borreliosis patient and control subject serum and CSF samples. The study was conducted by following the 2015 Standards for Reporting of Diagnostic Accuracy Studies procedure. The sensitivity and specificity of the index test with serum samples were 83% and 91.6%, respectively, when C6 Lyme ELISA™ was used as a reference. The clinical sensitivity of the index test was 97.2%/96.8% for identifying Borrelia specific antibodies in definite/possible Lyme neuroborreliosis. With CSF samples, the clinical sensitivity was 97.2% for definite and 87.1% for possible Lyme neuroborreliosis. The clinical specificity of the assay was 96.1% with serum and 100% with CSF samples.</p

Clinical, epidemiological and immunological aspects of Lyme borreliosis with special focus on the role of the complement system

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

with Special Focus on the Role of the Complement System

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The chemokine CXCL13 in cerebrospinal fluid in childrenwith Lyme neuroborreliosis

AbstractAnti-Borrelia antibodies in the cerebrospinal fluid (CSF) are required for definite diagnosis of Lyme neuroborreliosis (LNB).However, children often present with early LNB, and antibody production in the CSF may not be demonstrated. Recent studieshave suggested the chemokine CXCL13 to be an early marker for LNB. The aim of the study was to evaluate CXCL13 forlaboratory diagnosis in pediatric LNB patients and to evaluate the association with pleocytosis in CSF, clinical features, andrecovery. CSF samples were collected from LNB patients, classified as definite LNB (n = 44) or possible LNB (n = 22), andcontrols classified as non-LNB (n = 102) or other specific diagnoses (n = 23). CSF samples were analyzed with the recomBeadCXCL13 assay (Mikrogen Diagnostik, Germany), cut-off 160 pg/mL. CXCL13 was significantly higher in LNB patientscompared to controls (p < 0.001). Among LNB patients, 58/66 had elevated CXCL13, and among controls, 111/125 hadCXCL13 levels under cut-off (sensitivity 88%, specificity 89%). In LNB patients with pleocytosis but no detectable anti-Borrelia antibodies in CSF (possible LNB), CXCL13 was elevated in 16/22 (73%). A weak correlation between CXCL13 andpleocytosis in CSF was found in LNB patients (Rho = 0.46, p < 0.01), but no differences in CXCL13 levels in relation to specificclinical features. In conclusion, CXCL13 is elevated in CSF in children with LNB, showing acceptable sensitivity and specificity.In patients with possible LNB, CXCL13 was elevated in a majority of cases (73%) and is suggested as a complementarydiagnostic tool in pediatric LNB patients. CXCL13 was not associated with specific clinical features or recovery.Keywords CXCL13 . Chemokine . Lyme neuroborreliosis . Diagnostic test . Cerebrospinal fluid . Childre

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Neuroborreliosis-an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Swede

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Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective stud