RORγt Expression and Lymphoid Neogenesis in the Brain of Patients with Secondary Progressive Multiple Sclerosis

Abstract

Ectopic B-cell follicle-like structures (ELS) are found in the meninges of patients with secondary progressive multiple sclerosis (SPMS). Because cells expressing the transcriptional regulator retinoic acid receptor-related orphan receptor-γt (RORγt) and producing interleukin 17 (IL17), e.g. T helper 17 cells and lymphoid tissue inducer (LTi) cells, have been implicated in the formation of ELS, we studied RORγt and IL17 expression in brain tissue from patients with SPMS an assessed their relationships to immune infiltrates and meningeal ELS. By immunohistochemistry, small numbers of RORγt-positive cells were detected in the meninges of 6 of 12 SPMS cases analyzed. RORγt-positive cells were localized in B-cell follicles or aggregates and nearby diffuse meningeal infiltrates, and predominantly co-expressed CD3. Only a few RORγt-positive, CD3-negative cells were observed, suggesting the presence of group 3 innate lymphoid cells, which comprise the LTi cell subset. Some IL17-positive cells, co-expressing in part RORγt and predominantly CD3, were found in meningeal B-cell follicles from 4 SPMS cases. Rare RORγt-positive and IL17-positive cells were detected in white matter. Gene expression analysis of laser dissected meningeal infiltrates and white matter lesions confirmed low frequencies and virtual absence of RORγt and IL17 signals, respectively. Thus, there is selective migration or survival of RORγt-positive cells in MS patient meninges and an association of these cells with ELS.

Novel mechanism and biomarker of chronic progressive multiple sclerosis

“…Ectopic formation of FLS have been found in 40–70% of SP‐MS patients, especially in the subarachnoid space of the leptomeninges, close to inflamed bold vessels, but not in PP‐MS patients by post‐mortem brain dissection . Developmental stages of FLS are diverse, from newly‐formed and immature cellular aggregates, to highly‐organized cellular mass resembling tertiary lymphoid structures.…”

“…45 Another report showed that infiltration of plasma cells into the CNS is more frequent in SP-MS than RR-MS. 46 Ectopic formation of FLS and concealed immune responses behind the BBB Ectopic formation of FLS have been found in 40-70% of SP-MS patients, especially in the subarachnoid space of the leptomeninges, close to inflamed bold vessels, but not in PP-MS patients by post-mortem brain dissection. [47][48][49][50] Developmental stages of FLS are diverse, from newly-formed and immature cellular aggregates, to highly-organized cellular mass resembling tertiary lymphoid structures. FLS is composed of a variety of immune cells, including T lymphocytes, B lymphocytes and plasma cells with co-existing follicular dendritic cells.…”

Tertiary Lymphoid Organs in Central Nervous System Autoimmunity

“…Interestingly, untreated MS patients show elevated numbers of innate lymphoid cells in the peripheral blood and CSF (31, 32), and a recent study detected retinoic acid receptor-related orphan receptor γt (RORγt)-positive and CD3-negative cells in submeningeal B cell follicles (33). These cells may represent group 3 innate lymphoid cells, which comprise the LTi cell subset, and thus could potentially be involved in TLO formation.…”

Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis

“…Recent studies point to a pathogenic role for granulocyte-macrophage colony-stimulating factor (GM-CSF) producing T cells in MS via enhanced myeloid cell recruitment and activation [ 25 , 26 ], and GM-CSF producing CD4+ and CD8+ T cells have been identified in MS brain lesions [ 27 ]. Myeloid cells recruited to the CNS and the CNS resident microglia are implicated in MS pathogenesis as antigen-presenting cells, source of pro-inflammatory cytokines, and effectors of myelin destruction [ 11 , 26 , 28 ].The role of IL17- and IL17/IFNγ-producing CD4+ and CD8+ T cells in MS pathogenesis is debated, as conflicting data exist on the frequency of these cell subsets in the brain and cerebrospinal fluid [ 5 , 17 , 25 , 29 – 32 ]. It has been suggested that Th17 cells may be implicated in the formation of ectopic lymphoid-like tissue in the inflamed CNS [ 32 , 33 ].…”

“…Myeloid cells recruited to the CNS and the CNS resident microglia are implicated in MS pathogenesis as antigen-presenting cells, source of pro-inflammatory cytokines, and effectors of myelin destruction [ 11 , 26 , 28 ].The role of IL17- and IL17/IFNγ-producing CD4+ and CD8+ T cells in MS pathogenesis is debated, as conflicting data exist on the frequency of these cell subsets in the brain and cerebrospinal fluid [ 5 , 17 , 25 , 29 – 32 ]. It has been suggested that Th17 cells may be implicated in the formation of ectopic lymphoid-like tissue in the inflamed CNS [ 32 , 33 ]. Recently, clonally expanded CD4+ and CD8+ T cells with type 2 immunity functional features were identified in WM lesions characterized by complement and immunoglobulin deposition (pattern II brain lesions) [ 34 ].…”