By Jai Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Perumal is on the speakers bureau for Biogen Idec, Teva Pharmaceuticals, Genzyme Corp., and Acorda Therapeutics.
SYNOPSIS: A study of intrathecal immune markers in neuro-immunological diseases revealed increased numbers of activated T and B cells in both relapsing and progressive multiple sclerosis (MS), but they were preferentially embedded in the brain tissue in progressive MS.
SOURCE: Kimori M, et al. Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol 2015;78:3-20.
In the current management of neuro-inflammatory diseases, including multiple sclerosis (MS), assessment of intrathecal inflammation in clinical practice is limited to evidence of contrast-enhancing lesions on magnetic resonance imaging (MRI) and elevated IgG index and oligoclonal bands in cerebrospinal fluid (CSF), apart from elevated cell count and protein. These markers are non-specific and do not provide further details on the underlying inflammatory processes. While elevated IgG index and presence of oligoclonal bands might help in making a diagnosis of MS, since they are static in nature, they are not helpful in monitoring response to therapy. There are little data regarding cell-specific immune markers and dynamic biomarkers of intrathecal inflammation. Knowledge of the specific immune mechanisms leading to injury in a particular disease or disease subtype, such as progressive MS, and biomarkers that allow us to monitor treatment response would ultimately lead to better treatment strategies and outcomes. They would also serve as useful tools to evaluate the efficacy of potential treatments in clinical trials, especially in early, short-duration therapeutic feasibility studies. With these goals in mind, Kimori et al sought to evaluate several CSF biomarkers and to identify and quantify cell-specific biomarkers and their primary immune-cell source. They attempted to confirm the validity of the measured biomarkers in independent cohorts of patients with neuroimmunological disorders and integrate the data to establish a biomarker profile, rather than one individual marker that would identify a disease or categorize specific disease subtypes.
This study included two cohorts of patients and eight embedded healthy controls. Each cohort included 193 patients. Cohort A was enrolled between January 2008 and 2011 and cohort B between February 2011 and January 2014, after implementation of the immunophenotyping protocol that was used to compute a biomarker profile. Subjects included patients with all types of MS (relapsing-remitting, secondary progressive, and primary progressive) and non-MS patients. Non-MS patients were categorized into either other inflammatory neurological disease (OIND) or non-inflammatory neurological diseases (NIND). OIND category included patients with cryptococcal meningoencephalitis, paraneoplastic syndrome, cyclic meningitis, Aicardi–Goutieres syndrome with central nervous system (CNS) involvement, Susac syndrome, neonatal-onset multisystem inflammatory disease with CNS involvement, Lyme disease with CNS involvement, human T-cell lymphotropic virus type 1–associated myelopathy, sarcoidosis with CNS involvement, CNS lupus erythematosus, CNS vasculitis, autoimmune lymphoproliferative syndrome with CNS involvement, and encephalitis/ventriculitis of unknown origin. The NIND group included patients with systemic Lyme disease without CNS involvement, systemic cryptococcosis without CNS involvement, epilepsy, amyotrophic lateral sclerosis, compressive myelopathy, leukodystrophy, mitochondrial disease, hydromyelia, headache/dizziness without any CNS abnormality and ischemic/gliotic white matter lesions. CSF samples were collected and subjects underwent MRI examinations. Apart from routine tests on CSF, including cell count, protein level, and electrophoresis, an electrochemiluminescent assay was developed to detect and quantify several specific immune biomarkers. Assays for immune cells, which were the sources of the biomarkers, were undertaken as well.
CD27 secreted by activated T cells significantly and reproducibly differentiated all neuroimmunological patients (MS and OIND groups) from NIND patients and healthy controls. Ratios of specific biomarkers to their cell of origin in the CSF were calculated. When compared to healthy controls, a higher ratio would suggest that the secreted biomarker marker was not from immune cells measured in the CSF but from immune cells embedded in the CNS tissue. On comparing three pairs of biomarker/immune cell of origin ratios, sCD27/T cell was significantly higher in progressive MS patients than any other group. sCD27/T cell and sCD21/B cell ratios also differentiated progressive MS from relapsing-remitting MS. These results appear to indicate that inflammation in progressive MS comes from immune cells within CNS tissue rather than active passage from systemic circulation to the CSF, as in relapsing-remitting MS. Based on the authors’ model, a biomarker profile that could predict specific diagnostic categories with an accuracy > 60% could not be identified, but sCD27 was the single best predictive biomarker of active intrathecal inflammation.
Commentary
In the management of neuroimmunological diseases, it would be invaluable to have a biomarker that can identify a specific diagnostic entity accurately and help monitor clinical course and response to treatment. Though far from perfect, contrast-enhancing lesions on MRI and elevated IgG index and oligoclonal bands are still used in confirming a diagnosis of MS, and contrast-enhancing lesions are used to monitor response to treatment. This study examined several specific CSF biomarkers with the aim of detecting a biomarker profile that would accurately predict a specific diagnosis and dynamic biomarkers that could be used to monitor therapeutic response in clinical practice or clinical trials. Although the authors could not identify a biomarker profile that could predict disease entities with high accuracy, T cell-mediated inflammation, as measured by sCD27, seemed to be the most consistent marker of intrathecal inflammation. With regard to MS, the findings suggest that there still appears to be a significant inflammatory component in progressive MS, but it is predominantly due to embedded CNS immune cells rather than infiltration of immune cells into the CSF through a breach in the blood-brain-barrier, as seen in relapsing-remitting MS. This adds to previously published data about the different nature of inflammation in progressive MS and relative lack of efficacy of current MS therapies in this form of MS. Continued further research into potential biomarkers will hopefully provide immunological clues to better address treatment in progressive MS.
A study of intrathecal immune markers in neuro-immunological diseases revealed increased numbers of activated T and B cells in both relapsing and progressive multiple sclerosis, but they were preferentially embedded in the brain tissue in progressive multiple sclerosis.
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