Tick-borne diseases and the central nervous system : clinical and immunological aspects

Sammanfattning: 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.