NEW ORLEANS—Intrathecal levels of T and B cells are comparable in progressive multiple sclerosis (MS), compared with relapsing-remitting MS, according to research described at the ACTRIMS 2016 Forum. The major difference between the two forms of the disease, according to the researchers, is that although the immune cells are mobile in relapsing-remitting MS, they are predominantly embedded in CNS tissue in progressive MS. “This compartmentalization of the immune responses is likely the major reason for the failure of current immunomodulatory treatments in both subtypes of progressive MS,” said Mika Komori, MD, PhD, of the Neuroimmunological Unit at the National Institute of Neurological Disorders and Stroke.
Neurologists have interpreted immunomodulatory therapies’ lack of efficacy in progressive MS as evidence that neurodegeneration, rather than immunopathology, stimulates CNS tissue destruction. Dr. Komori and colleagues sought to develop a methodology that reliably quantifies immune-cell infiltration of CNS tissue by combining CSF immunophenotyping with analysis of immune-cell specific soluble markers.
The researchers collected CSF from 198 subjects, including patients with relapsing-remitting MS, secondary progressive MS, primary progressive MS, noninflammatory neurologic disorders, and other inflammatory neurologic disorders, as well as from healthy donors, and processed the samples in a blinded fashion. They optimized electroluminescent assays to quantify 19 soluble biomarkers in the CSF. Cell-specific secretion was assessed in supernatants from sorted primary immune cells. The investigators quantified absolute numbers of CSF immune cells by flow cytometry in 50-fold concentrated CSF and used them to define three ratios between the concentrations of cell-specific soluble CSF biomarkers and absolute numbers of corresponding CSF cells per milliliter of CSF (ie, sCD14:monocyte, sCD21:B-cell, and CD27:T-cell).
The sCD14:monocyte ratio did not differ among diagnostic groups, but the sCD21:B-cell and especially sCD27:T-cell ratios were significantly higher in progressive MS, compared with all other diagnostic groups. The sCD21:B-cell and sCD27:T-cell ratios differentiated patients with progressive MS from those with relapsing-remitting MS with an area under reviewer operator characteristic curve (AUC) comparable to that of current clinically used tests (AUC, 0.76–0.77). An excess of the soluble biomarkers in comparison with the number of CSF cells that produce it implies presence of the second, nonmobile pool of secreting immune cells embedded in CNS tissue. Dr. Komori and colleagues validated the interpretation that higher biomarker ratios parallel infiltration of CNS tissue by corresponding immune cells in patients with available CNS autopsy or biopsy results with 100% concordance.