Search

Background: Natalizumab, a treatment used in multiple sclerosis (MS), is associated with cases of progressive multifocal leukoencephalopathy (PML). Objective: We describe two cases of PML in related but not genetically apparented natalizumab-treated MS patients who are stepsisters. Reported cases/outcomes: While Patient 1 developed PML, Patient 2 was on natalizumab and had contacts with Patient 1. Patient 2 was diagnosed with PML 5 months after Patient 1. Conclusion: The clinical and temporal data highly suggest that there was JC virus (JCV) transmission from one patient to the other with development of PML as primo-infection in Patient 2.

Background: Multiple sclerosis (MS) is thought to be T cell mediated but the mechanisms eliciting such a dysregulated adaptative immune response remain enigmatic. Objective: To examine the activation profile of antigen-presenting cells (APCs) in MS. Methods: A total of 98 study subjects were enrolled including patients suffering from relapsing–remitting, secondary- and primary-progressive (PP) MS, other inflammatory neurological diseases, and healthy controls. Blood monocytes and B cells were stimulated using specific ligands of toll-like receptors (TLRs) or inflammasomes or Epstein–Barr virus (EBV) particles. Their activation profile was determined before or after stimulation by flow cytometry (CD40, CD80, CD83, CD86, and human leukocyte antigen–antigen D related (HLA-DR)) and Luminex assay, measuring the concentration of eight cytokines in culture supernatants. Differences among groups were assessed in a linear model framework. Results: We demonstrate that relapsing MS patients exhibit an increased expression of HLA-DR and CD40 ex vivo, mostly at the surface of B cells. Specific stimulations of TLR or inflammasomes enhance the expression of components of the immunological synapse and the cytokine secretion but without differences between categories of study subjects. Conclusion: These data suggest that the activation profile of B cells is increased in MS. However, the perception of the danger signal by B lymphocytes and monocytes does not seem to be different in MS patients as compared to control subjects.

Background/objectives: Neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients correlate with the degree of neuronal injury. To date, little is known about NfL concentrations in the serum of relapsing remitting multiple sclerosis (RRMS) patients and their relationship with CSF levels and magnetic resonance imaging (MRI) measures of disease severity. We aimed to validate the quantification of NfL in serum samples of RRMS, as a biofluid source easily accessible for longitudinal studies. Methods: A total of 31 RRMS patients underwent CSF and serum sampling. After a median time of 3.6 years, 19 of these RRMS patients, 10 newly recruited RRMS patients and 18 healthy controls had a 3T MRI and serum sampling. NfL concentrations were determined by electrochemiluminescence immunoassay. Results: NfL levels in serum were highly correlated to levels in CSF ( r = 0.62, p = 0.0002). Concentrations in serum were higher in patients than in controls at baseline ( p = 0.004) and follow-up ( p = 0.0009) and did not change over time ( p = 0.56). Serum NfL levels correlated with white matter (WM) lesion volume ( r = 0.68, p Conclusion: CSF and serum NfL levels were highly correlated, and serum concentrations were increased in RRMS. Serum NfL levels correlated with MRI markers of WM disease severity. Our findings further support longitudinal studies of serum NfL as a potential biomarker of on-going disease progression and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.

A phase I/II clinical trial has been performed in 12 amyotrophic lateral sclerosis (ALS) patients to evaluate the safety and tolerability of intrathecal implants of encapsulated genetically engineered baby hamster kidney (BHK) cells releasing human ciliary neurotrophic factor (CNTF). These patients have been assessed for a possible intrathecal or systemic immune response against the implanted xenogeneic cells. Hundreds of pg CNTF/ml could be detected for several weeks in the cerebrospinal fluid (CSF) of 9 out of 12 patients, in 2 patients up to 20 weeks after capsule implantation. Slightly elevated leukocyte counts were observed in 6 patients. Clear evidence for a delayed humoral immune response was found in the CSF of only 3 patients out of 12 (patients #4, #6, and #10). Characterization of the antigen(s) recognized by the antibodies present in these CSF samples allowed to identify bovine fetuin as the main antigenic component. The defined medium used for maintaining the capsules in vitro before implantation contains bovine fetuin. Fetuin may therefore still be adsorbed to the surface of the cells and/or the polymer membrane, or be present in the medium surrounding the encapsulated cells at the time of implantation. Because of the insufficient availability of CSF samples, as well as the relatively poor sensitivity of the assays used, a weak humoral immune response against components of the implanted cells themselves cannot be excluded. However, the present study demonstrates that encapsulated xenogeneic cells implanted intrathecally can survive for up to 20 weeks in the absence of immunosuppression and that neither CNTF nor the presence of antibodies against bovine fetuin elicit any adverse side effects in the implanted patients.