Formation and immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity

Abstract

Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic Multiple Sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of Multiple Sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T cell- and B cell-receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20 percent of B cells in organised meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in Multiple Sclerosis.

B cells in central nervous system disease: diversity, locations and pathophysiology

“…This gradient of damage emanating away from the meningeal B cell aggregates suggests that B cells are secreting factors that diffuse into the surrounding CNS parenchyma and either directly damage CNS cells or may indirectly injure them by promoting inflammatory polarization of microglia as iNOS + TNF + phagocytes are found in proximity to B cell aggregates 54 . Nonetheless, while prominent meningeal inflammation is associated with the upregulation of inflammatory cytokines locally and within CSF, it is also associated with increased expression of IL-10 in both MS 59 and EAE 60 . Thus, while B cell aggregates are associated with worse pathology, some components may also inhibit inflammation.…”

“…Moreover, in one EAE study, ~30% of B cells in meningeal B cell aggregates express mRNA for either IL-10 or IL-35 (ref. 60 ). In contrast, others have found that large numbers of IL-10-producing plasmablasts are seen in lymph nodes that drain the site of immunization in EAE but IL-10-expressing B-lineage cells are not seen in the CNS of EAE 111 , 117 .…”

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

“…Interestingly, after two months, the disease burden and mortality were higher in these animals compared to controls without ablation of ITGA4. This could be explained by the fact that one-third of the B cells in ectopic lymphoid follicles produce the anti-inflammatory cytokines IL-10 and IL-35 [ 127 ]. In contrast, in EAE mice with a selective B cell VLA-4 deficiency, the decrease of meningeal B cells also reduced EAE susceptibility.…”

“…The opticospinal encephalomyelitis mouse model also develops spontaneous EAE and both T and B cells express MOG-specific antigen receptors [ 127 ]. Treatment with anti-CD20 antibodies at the pre-symptomatic phase reduced disease severity [ 127 ], which, in comparison with the animal model 2D2xTh, suggests that B cells might have antigen-presenting functions before the onset of the disease. Interestingly, anti-CD20 antibodies did not abrogate the formation of meningeal lymphoid follicles, although they were smaller than the ones in untreated animals.…”

“…Interestingly, anti-CD20 antibodies did not abrogate the formation of meningeal lymphoid follicles, although they were smaller than the ones in untreated animals. B cell depletion after the onset of symptoms neither modulated disease progression nor reduced the area of meningeal lymphoid follicles [ 127 ], indicating that meningeal-resident B cells might be resistant to anti-CD20 therapies. Hence, once B cells have trafficked into the intrathecal compartment—leptomeningeal or CNS parenchymal—anti-CD20 therapies might be less effective.…”