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

Abstract

Background: 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.

Methods: 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.

Results: 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-Borrelia-antibodies.

Conclusion: 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.

Figure 1

Cytokine/chemokine levels (pg/mL) in serum and in cerebrospinal fluid (CSF). Group 1: Confirmed neuroborreliosis (NB), patients with elevated Borrelia-specific antibody index or Borrelia-specific antibodies in CSF and pleocytosis. Group 2: Possible late NB, patients with elevated Borrelia-specific antibody index or Borrelia-specific antibodies in CSF but no pleocytosis. Group 3: Possible early NB, children with CSF pleocytosis but no detectable Borrelia-specific antibodies in CSF. Group 4: Non-NB, patients without pleocytosis and no detectable Borrelia-specific antibodies in CSF. Group 5: Control group, CSF was obtained at spinal anaesthesia from patients undergoing elective orthopaedic surgery. Bars represent the median cytokine/chemokine level in each group.

Figure 2

Cytokine/chemokine levels (pg/mL) in serum and in cerebrospinal fluid (CSF) in patients <15 years of age. Group 1: Confirmed neuroborreliosis (NB), patients with elevated Borrelia-specific antibody index or Borrelia-specific antibodies in CSF and pleocytosis. Group 3: Possible early NB, patients with CSF pleocytosis but no detectable Borrelia-specific antibodies in CSF. Group 4: Non-NB, patients without pleocytosis and no detectable Borrelia-specific antibodies in CSF. (There were no children in groups 2 and 5). Bars represent the median cytokine/chemokine level in each group.