J Neuropathol Exp Neurol. 2016 Jul 13. pii: nlw063. [Epub ahead of print]
RORγt Expression and Lymphoid Neogenesis in the Brain of Patients with Secondary Progressive Multiple Sclerosis.
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.
Figure: Initial priming of naive CD4+ T lymphocyte cells by dendritic cells (DC) induces expression of Bcl-6. However, their commitment to specific effector lineages is governed by transcription factors: T-bet (Th1), GATA3 (Th2), RORγt (Th17). Regardless of their origin, Th cells drive the differentiation of B cells into memory
and plasma cells, which is necessary for long-lived protective Ab responses.
B cell activity has long since been recognized in MS; whether it be relapsing MS or progressive MS. Oligoclonal bands in the spinal fluid account for over 90% of MS cases, with the pattern II demyelinating lesion (with a prominent deposition of antibodies and complement) being the most common lesion subtype, cements their importance. To set up shop anywhere in the body, B cells build a community (scientific name = ectopic lymphoid-like structures/ELS). By achieving their community they can sustain immune responses locally – pretty simple really (“the general who wins the battle makes many calculations in his temple before the battle is fought” – Art of War). Such a requirement is fundamental when fighting infections or curtailing tumor spread, but bad news if you’re going to develop an autoimmune disorder.
In MS, there is prominent inflammation in the brain meninges (the covering of the brain), and is hallmarked by the formation of ELS which aggravate the pathology in the adjacent brain tissue. The formation of these sites is the same as the pathways involved in the neogenesis of lymphoid tissue during development (see Figure above). Recently, experimental work have linked Th17 cells (a subset of CD4+ T lymphocytes involved in host defense) with lymphoid tissue neogenesis in the meninges of mice with EAE (Pikor NB et al. Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell re-modeling to propagate neuroinflammation. Immunity 2015;43:1160–73). An effector marker of these Th17 cells is the expression of the transcriptional regulator retinoic acid receptor-related orphan receptor-γt (RORγt). It is not known whether RORγt-expressing cells may be involved in lymphoid neogenesis in the CNS of MS cases. And this is what Serafini et al. were looking at, specifically in SPMS. Why? Because there is extensive (~40%) inflammation in meninges of SPMS cases associated with the formation of ELS. And, not surprisingly they demonstrate that the frequency of RORγt-expressing Th17 cells are higher inside and in proximity to meningeal ELS.
Since meningeal ELS have been associated with more severe cortical damage in MS, understanding their formation will be important in developing new treatment targets in MS. Whatever is developed it may need to be delivered intrathecally to avoid the systemic complications and to improve efficacy.