Lymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells

Abstract

In gray matter pathology of multiple sclerosis, neurodegeneration associates with a high degree of meningeal inflammatory activity. Importantly, ectopic lymphoid follicles (eLFs) were identified at the inflamed meninges of patients with progressive multiple sclerosis. Besides T lymphocytes, they comprise B cells and might elicit germinal center (GC)-like reactions. GC reactions are controlled by FOXP3 + T-follicular regulatory cells (T FR), but it is unknown if they participate in autoantibody production in eLFs. Receiving human post-mortem material, gathered from autopsies of progressive multiple sclerosis patients, indeed, distinct inflammatory infiltrates enriched with B cells could be detected in perivascular areas and deep sulci. CD35 + cells, parafollicular CD138 + plasma cells, and abundant expression of the homing receptor for GCs, CXCR5, on lymphocytes defined some of them as eLFs. However, they resembled GCs only in varying extent, as T cells did not express PD-1, only few cells were positive for the key transcriptional regulator BCL-6 and ongoing proliferation, whereas a substantial number of T cells expressed high NFATc1 like GC-follicular T cells. Then again, predominant cytoplasmic NFATc1 and an enrichment with CD3 + CD27 + memory and CD4 + CD69 + tissue-resident cells implied a chronic state, very much in line with PD-1 and BCL-6 downregulation. Intriguingly, FOXP3 + cells were almost absent in the whole brain sections and CD3 + FOXP3 + T FR s were never found in the lymphoid aggregates. This also points to less controlled humoral immune responses in those lymphoid aggregates possibly enabling the occurrence of CNS-specific autoantibodies in multiple sclerosis patients.

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

“…It may only comprise disordered mixtures of dendritic cell (DC)/B/T cells [ 60 ], but not a well-organized GC-like structure. The presence of Tregs in the ELS may also vary, and the ELS in patients with progressive MS does not have Tregs in the brain [ 61 ]. The converted Blimp1-deficient Tregs that express T H 17 cytokines may promote ELS formation [ 4 , 15 , 62 ].…”

B cell depletion therapies in autoimmune disease: advances and mechanistic insights

“…One of the earliest diagnostics for MS was the presence of IgG oligoclonal bands in the CSF, implying the presence of intrathecal antibody-producing cells 141 , 142 . Evidence of B cell accumulation in CNS lesions 143 and ectopic B cell follicles in the meninges of patients with SPMS (and, to a lesser extent, those with PPMS) 137 , 144 further implicated B cells in the aetiopathology of the disease. Deposition of complexes containing antibodies and complement components in MS plaques also suggests that B cells are important in MS pathogenesis 145 , 146 , although in a separate study these complexes were not found to be a specific feature of lesions, nor a hallmark of MS in particular 147 .…”

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

“…This also fits with the finding that the amount of B cells in meninges and B-cell related cytokines in the CSF associate with disease progression 17,28,33 . Furthermore, the extent of meningeal inflammation in MS patients, and more specifically the amount of meningeal B cells, has been strongly linked to the presence of tertiary lymphoid-like follicles 15,28 . Unfortunately, we could identify too few of these lymphocyte clusters in the meninges of our tissue cohort to test whether they indeed are found predominantly in the MS2 cluster, as one would expect.…”

“…Meningeal inflammation in SPMS is characterized by accumulation of immune cells like B-, T-and myeloid cells, either diffusely present or in aggregates resembling tertiary lymphoid follicles 14,15 . The degree of inflammation and the presence of follicles both associate with the severity of cortical pathology, possibly by production and subsequent diffusion of pro-inflammatory cytokines into the cortex 16,17 .…”