NEW ORLEANS—Meningeal B-cell infiltrates may be the main source of inflammatory or cytotoxic molecules that are released into the CSF to cause cortical tissue injury in progressive multiple sclerosis (MS), according to a study described at the ACTRIMS 2016 Forum. The proinflammatory CSF profile of patients with high levels of gray matter damage significantly differs from that of patients with low levels of gray matter damage, thus suggesting that measuring levels of meningeal B-cell infiltrates may be a useful approach for patient stratification at disease onset.
Gray matter damage is the best correlate of the accumulation of physical and cognitive deficits and one of the main substrates of disability progression in MS, according to the researchers. New advanced imaging techniques enable a more accurate estimation of the load of gray matter demyelination and brain atrophy, thus suggesting that increased levels of gray matter pathology play a crucial role in more rapid progressive outcome. Investigators have proposed meningeal B-cell infiltrates as the main source of the intrathecal inflammatory or cytotoxic milieu in the CSF that may mediate and exacerbate the gradient of tissue injury in the adjacent gray matter.
Roberta Magliozzi, PhD, of the University of Verona in Italy, and colleagues undertook a study to identify specific biomarkers and imaging tools to predict and monitor gray matter pathology and its association with MS progression. The investigators performed advanced MRI imaging of gray matter damage and an extensive protein analysis of CSF for 70 patients with MS and 12 controls. Dr. Magliozzi’s group also analyzed molecular expression in paired meningeal and CSF samples from 20 postmortem cases of secondary progressive MS and 10 control cases to verify whether inflammatory mediators expressed by the meningeal infiltrates are released into the CSF.
The researchers observed that a pronounced proinflammatory CSF profile, including overexpression of CXCL13, CXCL12, CCL19, CCL21, IL6, IL10, APRIL, BAFF, TNF, TNFR1, LIGHT, IFN-γ, gray matter-CSF, and MMP2, was strictly associated with increased gray matter pathology and disease progression in patients with MS. The proinflammatory CSF profile suggested lymphoid-neogenesis, B-cell and plasmablast or plasma-cell involvement, and a TNF-mediated inflammatory response. A pattern of increased regulatory molecules, including IFNα, IFNβ, IFNλ, CCL22, and CCL25, was associated with a lower level of gray matter pathology. Consistent with this finding, the investigators detected increased expression of CXCL13, CXCL9, TNF, IFNγ, LTα, LTβ, IL10, IL16, and IL12p40 in the meninges and CSF samples of postmortem cases of secondary progressive MS with a higher level of meningeal inflammation and gray matter demyelination.