The immunopathology of advanced multiple sclerosis
We recently analyzed a large cohort of multiple sclerosis (MS) autopsy cases of the Netherlands Brain Bank (NBB) and showed that 57% of the lesion in advanced MS is active (containing activated microglia/macrophages). These active lesions correlated with disease severity and differed between males and female MS patients.1 Already in normal appearing white matter microglia show early signs of demyelination.5 T cells are also frequently present in advanced stages of MS and have a tissue resident memory (Trm) phenotype, are more frequently CD8+ then CD4+, are located perivascular, enriched in active and mixed active/inactive MS lesions and correlated with lesion activity, lesion load and disease severity.2-4 Like Trm cells, B cells are located perivascular and were also enriched in active MS lesions but in lower numbers and a proportion of the MS patients had almost no detectable B cells in the regions analyzed. MS patients with limited presence of B cells had less severe MS, and less active and mixed active /inactive lesions. We conclude that advanced MS is characterize by a high innate and adaptive immune activity which is heterogeneous and relates to the clinical disease course.
Meningeal lymphatics and peripheral immunity in brain function and dysfunction
Immune cells and their derived molecules have major impact on brain function. Mice deficient in adaptive immunity have impaired cognitive and social function compared to that of wild-type mice. Importantly, replenishment of the T cell compartment in immune deficient mice restored proper brain function. Despite the robust influence on brain function, T cells are not found within the brain parenchyma, a fact that only adds more mystery into these enigmatic interactions between T cells and the brain. Our results suggest that meningeal space, surrounding the brain, is the site where CNS-associated immune activity takes place. We have recently discovered a presence of meningeal lymphatic vessels that drain CNS molecules and immune cells to the deep cervical lymph nodes. This communication between the CNS and the peripheral immunity is playing a key role in neurophysiology and in several CNS disorders. Interestingly, meningeal lymphatics are impaired in aging and their dysfunction may be related to age-related cognitive decline as well as to Alzheimer’s pathology. In addition to providing new insights into age-related disorders, meningeal lymphatics may also serve as a novel therapeutic target for these diseases and are worth of in-depth mechanistic exploration.