CXCL16 contributes to neutrophil recruitment to cerebrospinal fluid in pneumococcal meningitis.

In this study, we analyzed the expression and function of CXCL16 in pneumococcal meningitis. CXCL16 was found to be up‐regulated in RAW264.7 macrophages (but not in neutrophils and endothelial cells) upon pneumococcal stimulation, in the cerebrospinal fluid of patients, and in the brains as well as the cerebrospinal fluid of mice with pneumococcal meningitis. CXCL16 up‐regulation in vivo was dependent on Toll‐like receptor (TLR) 2/TLR4 and MyD88 signaling. Neutralization of CXCL16 in animals before intracisternal pneumococcal infection (using anti‐CXCL16 antibodies) resulted in reduced cerebrospinal fluid pleocytosis. In vitro, murine neutrophils expressed the CXCL16 receptor CXCR6 and showed dose‐dependant migration toward a CXCL16 gradient. Thus, this study implicates CXCL16 as an additional neutrophil chemoattractant in cerebrospinal fluid in early pneumococcal meningitis.

The chemokine CXCL13 in acute neuroborreliosis.

OBJECTIVE: Recent studies have suggested an important role of the B cell chemoattractant CXCL13 in acute neuroborreliosis (NB). Our aim was to confirm the diagnostic role of CXCL13 and to evaluate its relevance as a therapy response and disease activity marker in NB. METHODS: CXCL13 was measured in cerebrospinal fluid (CSF) and serum of patients with NB (n=28), systemic borreliosis (SB, n=9), Guillain-Barré syndrome (GBS, n=11), Bell's palsy (BP, n=19), other cranial nerve palsies (CNP, n=5), cephalgia (C, n=20), bacterial CNS infections (B-CNS-I, n=16) and viral CNS infections (V-CNS-I, n=18). For follow-up studies, serial sample pairs were evaluated from 25 patients with NB (n=56), 11 with B-CNS-I (n=25) and 14 with V-CNS-I (n=36). RESULTS: CSF-CXCL13 was significantly elevated in NB compared with other neurological diseases (p<0.001). Using receiver operating characteristic analysis, 337 ng/g was determined as a cut-off with a sensitivity of 96.4% and a specificity of 96.9%. Of all the parameters investigated, CSF CXCL13 showed the fastest response to antibiotic therapy, decreasing significantly (p=0.008) within 1 week. In untreated patients, CSF CXCL13 was elevated in patients with a short duration of disease. Borrelia burgdorferi antibody index showed no significant (p=0.356) change over follow-up. CONCLUSIONS: The study confirms the relevance of CXCL13 as a diagnostic biomarker of NB and suggests that CSF CXCL13 in NB is linked to duration of disease and could be a marker of disease activity and response to antibiotic therapy.

Clonally expanded plasma cells in the cerebrospinal fluid of patients with central nervous system autoimmune demyelination produce "oligoclonal bands".

Clonally expanded plasma cells (cePC) and oligoclonal IgG (oligoclonal bands, OCB) in the cerebrospinal fluid (CSF) suggest an involvement of B cell mechanisms in autoimmune CNS demyelination. Due to their CSF-restricted occurrence, OCB are commonly believed to be the products of B cells inside the borders of the blood brain barrier. A comparison of CSF cell Ig transcriptomes and CSF-Ig proteomes recently demonstrated, that in multiple sclerosis patients CSF cells are the origin of CSF immunoglobulins. We expand these findings by applying anti-idiotypic antibodies to detect specific heavy chain CDR3 idiotopes of cePC-produced antibodies amongst OCB in the CSF of a patient each with MS and acute disseminated encephalomyelitis.

What are the indications for lumbar puncture in patients with Lyme disease?

Lyme neuroborreliosis (LNB) is a tick-borne disease of the nervous system, caused by the spirochete Borrelia burgdorferi. Having entered the host at the site of the tick bite, the spirochetes can initially cause a local inflammatory reaction, called erythema migrans. If left untreated, the Borrelia can disseminate in the second stage of the disease and invade the central nervous system, causing LNB. The diagnosis of LNB is based on a compatible clinical picture (meningitis, cranial neuritis or radiculoneuritis), lymphocytic pleocytosis in the cerebrospinal fluid (CSF) and intrathecal Borrelia burgdorferi-specific antibody production. As the clinical picture of LNB may be unspecific, a lumbar puncture to analyze the CSF is usually mandatory for confirmation of the suspected diagnosis. The indications for a lumbar puncture and the limitations of the different diagnostic procedures are the main topics of this review. In addition, a short overview of the epidemiology and the therapeutic principles of LNB is given.

The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis.

BACKGROUND: The chemokine CXCL13 is known to dictate homing and motility of B cells in lymphoid tissue and has been implicated in the formation of ectopic lymphoid tissue in chronic inflammation. Whether it influences B cell trafficking during acute infection, is largely unclear. In previous studies, we showed that (I) CXCL13 levels are markedly increased in the B cell-rich cerebrospinal fluid (CSF) of patients with acute Lyme neuroborreliosis (LNB), and (II) CXCL13 is released by monocytes upon recognition of borrelial outer surface proteins by Toll-like receptor 2. Here, we assessed the role of CXCL13--in comparison to other chemokines--in the recruitment of B cells to the CSF of patients with acute LNB. METHODS: Measurement of chemokines was done by ELISA. B cells were isolated from whole blood using magnetic cell separation (MACS). For migration experiments, a modified Boyden chamber assay was used and the migrated B cells were further analysed by FACS. The migration was inhibited either by preincubation of the CSF samples with neutralizing antibodies, heating to 60 degrees C, removal of proteins >3 kDa, or by pre-treatment of the B cells with pertussis toxin. The principal statistical tests used were one-way analysis of variance and Bonferroni test (chemokine measurements) as well as paired Student's t-test (migration experiments). RESULTS: Measurements of chemokine levels revealed an increase in three of the four known major B cell chemoattractants CXCL13, CCL19 and CXCL12 in LNB CSF. The CXCL13 CSF:serum ratio, as a measure of the chemotactic gradient, was substantially higher than that of CCL19 and CXCL12. Moreover, the chemotactic activity of LNB CSF was reduced up to 56% after preincubation with a neutralizing CXCL13 antibody, while combined preincubation with antibodies against CXCL13, CCL19, and CXCL12 did not lead to further reduction. Since treatment with pertussis toxin, heating to 60 degrees C, and removal of proteins >3 kDa abrogated the chemotactic activity, further not yet identified chemokines seem to be involved in B cell recruitment to LNB CSF. CONCLUSION: Combined, our study suggests a key role of CXCL13 in B cell migration to sites of infection as shown here for the CSF of LNB patients.

Autoimmune-mediated polyneuropathy triggered by borrelial infection?

A patient with proven borrelial infection of the central nervous system (CNS) and progressive weakness of the arms was treated with antibiotics. Although the initially elevated CXCL13 concentration in the cerebrospinal fluid decreased, indicating effective treatment of the infection, weakness progressed. Investigation revealed multiple nerve conduction blocks and the presence of GM1 antibodies, suggesting a multifocal motor neuropathy; the patient improved on treatment with intravenous immunoglobulins. This report of an autoimmune-mediated polyneuropathy in a patient with borrelial CNS infection indicates that such patients might respond to immunomodulatory therapy if antibiotic treatment is not effective.

The pathogenesis of lyme neuroborreliosis: from infection to inflammation.

This review describes the current knowledge of the pathogenesis of acute Lyme neuroborreliosis (LNB), from invasion to inflammation of the central nervous system. Borrelia burgdorferi (B.b.) enters the host through a tick bite on the skin and may disseminate from there to secondary organs, including the central nervous system. To achieve this, B.b. first has to evade the hostile immune system. In a second step, the borrelia have to reach the central nervous system and cross the blood-brain barrier. Once in the cerebrospinal fluid (CSF), the spirochetes elicit an inflammatory response. We describe current knowledge about the infiltration of leukocytes into the CSF in LNB. In the final section, we discuss the mechanisms by which the spirochetal infection leads to the observed neural dysfunction. To conclude, we construct a stringent concept of the pathogenesis of LNB.

Borrelia garinii induces CXCL13 production in human monocytes through Toll-like receptor 2.

Recent studies have suggested an important role for the B-cell-attracting chemokine CXCL13 in the B-cell-dominated cerebrospinal fluid (CSF) infiltrate in patients with neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB patients. It has not been clear, however, whether high CSF CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well. Furthermore, the mechanisms leading to the observed CXCL13 expression have not been identified yet. Here we describe similarly elevated CSF CXCL13 levels in patients with neurosyphilis, while pneumococcal meningitis patient CSF do not have high CXCL13 levels. In parallel, challenge of human monocytes in vitro with two of the spirochetal causative organisms, Borrelia garinii (the Borrelia species most frequently found in NB patients) and Treponema pallidum, but not challenge with pneumococci, induced CXCL13 release. This finding implies that a common spirochetal motif is a CXCL13 inducer. Accordingly, we found that the lipid moiety N-palmitoyl-S-(bis[palmitoyloxy]propyl)cystein (Pam(3)C) (three palmitoyl residues bound to N-terminal cysteine) of the spirochetal lipoproteins is critical for the CXCL13 induction in monocytes. As the Pam(3)C motif is known to signal via Toll-like receptor 2 (TLR2) and an anti-TLR2 monoclonal antibody blocked CXCL13 production of human monocytes incubated with B. garinii, this suggests that TLR2 is a major mediator of Borrelia-induced secretion of CXCL13 from human monocytes.

Complement C1q and C3 are critical for the innate immune response to Streptococcus pneumoniae in the central nervous system.

Previous studies suggest that the complement system can contribute to limiting pneumococcal outgrowth within the CNS. In this study, we evaluated the role of the complement system in the activation of the innate immune response and the development of the prognosis-relevant intracranial complications in a murine model of pneumococcal meningitis. Thereby, we used mice deficient in C1q, lacking only the classical pathway, and C3, lacking all three complement activation pathways. At 24 h after intracisternal infection, bacterial titers in the CNS were almost 12- and 20-fold higher in C1q- and C3-deficient-mice, respectively, than in wild-type mice. Mean CSF leukocyte counts were reduced by 47 and 73% in C1q- and C3-deficient-mice, respectively. Intrathecal reconstitution with wild-type serum in C3-deficient mice restored both the ability of mice to combat pneumococcal infection of the CSF and the ability of leukocytes to egress into the CSF. The altered recruitment of leukocytes into the CSF of C3-deficient mice was paralleled by a strong reduction of the brain expression of cytokines and chemokines. The dampened immune response in C3-deficient mice was accompanied by a reduction of meningitis-induced intracranial complications, but, surprisingly, also with a worsening of short-term outcome. The latter seems to be due to more severe bacteremia (12- and 120-fold higher in C1q- and C3-deficient-mice, respectively) and, consecutively, more severe systemic complications. Thus, our study demonstrated for the first time that the complement system plays an integral role in mounting the intense host immune response to Streptococcus pneumoniae infection of the CNS.

Adhesion of Borrelia garinii to neuronal cells is mediated by the interaction of OspA with proteoglycans.

To study pathogenic mechanisms of Lyme meningoradiculitis, dorsal root ganglia (DRG) cells and two neuronal cell lines (B50, SH-SY5Y) were incubated with Borrelia garinii, the Borrelia species most frequently isolated from CSF of Lyme neuroborreliosis patients in Europe. We demonstrated that (I) OspA-positive B. garinii adhere to neuronal cells, (II) Borrelia adhesion can be blocked by a monoclonal antibody against OspA, (III) preincubation with proteoglycans interferes with the adhesion process and (IV) rOspA directly binds to the proteoglycans. This indicates that both OspA and the cell bound proteoglycans are involved in the attachment of B. garinii to neuronal cells.

Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients.

The diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production. Patients with neuroborreliosis are usually treated with intravenous ceftriaxone for 2-3 weeks. In case of allergy, doxycycline may be used. Treatment efficacy is detected by the improvement of the neurological symptoms and the normalization of the CSF pleocytosis. The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue. There is no formal definition of the PLD syndrome, and its pathogenesis is unclear. Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies.

Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir.

Human herpesvirus 6 (HHV-6), the causative agent of exanthema subitum in childhood, can also induce meningoencephalitis in immunocompromised individuals. In contrast, HHV-6 encephalitis in immunocompetent patients is rare, and the clinical syndrome not well defined. We report a case of meningoencephalitis caused by HHV-6 type B in an otherwise healthy woman.

CXCL11 is involved in leucocyte recruitment to the central nervous system in neuroborreliosis.

We investigated the role of the CXCR3 chemokine CXCL11 (I-TAC) for leukocyte recruitment to the CSF in neuroborreliosis (NB). CXCL11 levels in the CSF of 17 patients with acute NB were elevated compared with 20 non-inflammatory controls (100.1 vs. 54.1 pg/ml, p = 0.002). Using a modified Boyden chamber chemotaxis-assay, the CSF of patients with acute NB was more chemotactic than the control CSF-samples (p = 0.001). A strong correlation (p < 0.001) between CXCL11 levels, chemotactic activity and CSF-white cell count was detected. Though the chemotactic activity of CSF from NB patients was only partially reduced by a human recombinant CXCL11 antibody, these findings suggest that, among other chemotactic factors, CXCL11 may play a role in the chemotaxis of mononuclear cells in NB.

Successful cardic surgery 24 hours after craniotomy in a patient with infective endocarditis and embolic cerebellar infarction: case report.

Follow up management in a patient already treated with decompressive craniotomy for a space-occupying endocarditic stroke is difficult. While immediate valve replacement eliminates the focus and therefore the high risk of re-embolization, a neurosurgical intervention is considered a contraindication to early cardiosurgery. Herein, the first report is presented of a critically ill patient with bacterial endocarditis and a space-occupying cerebellar infarction with imminent herniation, who successfully underwent mitral valve replacement only 24 h after decompressive craniotomy. To prevent rebleeding, maximal hemostasis was ensured during the neurosurgical intervention. For cardiosurgery, the patient was cooled to 21 degrees C, mildly hyperventilated, and maintained at an adequate perfusion pressure during cardiopulmonary bypass. A bioprosthesis was used to reduce the time of anticoagulation. The patient did not develop new infarcts after either intervention, and there was only a very small hemorrhagic transformation without a relevant mass effect. At five months after surgery the patient had minimal neurological abnormalities and was able to conduct his daily life without help.