Meningeal Infiltration of the Spinal Cord by Non-Classically Activated B Cells is Associated with Chronic Disease Course in a Spontaneous B Cell-Dependent Model of CNS Autoimmune Disease

Abstract

We characterized B cell infiltration of the spinal cord in a B cell-dependent spontaneous model of central nervous system (CNS) autoimmunity that develops in a proportion of mice with mutant T and B cell receptors specific for myelin oligodendrocyte glycoprotein. We found that, while males are more likely to develop disease, females are more likely to have a chronic rather than monophasic disease course. B cell infiltration of the spinal cord was investigated by histology and FACs. CD4+ T cell infiltration was pervasive throughout the white and in some cases gray matter. B cells were almost exclusively restricted to the meninges, often in clusters reminiscent of those described in human multiple sclerosis. These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course. Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35+ follicular dendritic cells, or germinal centers. The majority of cluster B cells were IgD+ with little evidence of class switch. Consistent with this, B cells isolated from the spinal cord were of the naïve/memory CD38hi CD95lo phenotype. Nevertheless, they were CD62Llo and CD80hi compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen. Therefore, if meningeal B cells contribute to CNS pathology in autoimmunity, follicular differentiation is not necessary for the pathogenic mechanism.

Tertiary Lymphoid Organs in Central Nervous System Autoimmunity

“…Although these data support the hypothesis that GC reactions may happen in CNS TLOs, one has to keep in mind that it is extremely difficult to exclude that lymphocytes acquired the observed phenotype in the periphery and then migrated to the CNS. In contrast to these data, CNS B cells in the spontaneous OSE model showed no GC phenotype nor isotype switch, but appeared to be rather activated naïve B cells (74), confirming the notion that across the different models CNS TLOs are quite heterogeneous in their stage of development (Figure 1). Together the data from the different models suggest that definitely not all, but maybe the most organized and mature TLOs are also functional in supporting generation of differentiated T effector cells and affinity-matured B cells specific to CNS antigens.…”

“…HEV, which express adhesion molecules like PNAd or MadCAM to specifically attract naïve lymphocytes into SLOs and which have also been described in TLOs in other organs, were detected within TLOs in the MP4-immunization model (72). However, no evidence for HEVs was found in the spontaneous OSE model nor in the Th17 transfer model (C57Bl/6 background) (74, 75), while presence of HEVs was not determined in the SJL immunization and SJL Th17 transfer models. Since HEVs develop in response to cytokines like LT, their formation may require some time and occur only in the most mature TLOs.…”

“…In the opticospinal EAE (OSE)-mouse, which features both a transgenic MOG-specific TCR as well as a MOG-specific BCR and spontaneously develops EAE, TLO-like structures were found in the CNS (73, 74). …”

“…Similarly, in the MP4 immunization model TLOs form in the cerebral periventricular space, but also in the cerebellum and in association with spinal meninges (72). Upon transfer of Th17 cells in the C57Bl/6 background the majority of TLOs are located in the spinal meninges (75), and in the spontaneous OSE model TLOs are exclusively found in the spinal meninges (74). Whether TLOs form in the brain or spinal cord is most likely a consequence of the main route of infiltration, which differs between models.…”

“…Studies in the MP4-immunization model, the spontaneous OSE model, and the SJL Th17 adoptive transfer model revealed T cell proliferation in TLOs (72, 74, 76). However, since T cells can also proliferate in the CNS in the absence of TLOs these data alone do not prove functionality of CNS TLOs.…”