Follicle on the Roof: Tertiary Lymphoid Structures in Central Nervous System Autoimmunity

Abstract

Leptomeningeal tertiary lymphoid structures (TLS) have emerged as a relatively common pathological feature of autoimmune disease, including multiple sclerosis (MS) and particularly in people with progressive and nonremitting MS. These ectopic lymphoid aggregates, observed in the leptomeninges adjacent to so-called "Type 3" sub-pial cortical lesions, are associated with more severe gray matter damage and worse clinical outcomes. Mouse models of MS that recapitulate TLS formation in the central nervous system (CNS) have provided critical insights into the mechanisms driving their development and maintenance. In these models of experimental autoimmune encephalomyelitis (EAE) initiation of TLS is facilitated by Th17 cells, which promote chronic inflammation via cytokines such as IL-17 and GM-CSF. The cell surface expression of lymphotoxin-α and lymphotoxin-β heterotrimers (LTαβ) on lymphocytes, including Th17 cells, elaborates the organization of ectopic lymphoid tissues via LTβR signaling on radio-resistant stromal cells and resident fibroblasts. Ultimately a pro-inflammatory environment characterized by cytokines such as IL-17 and GM-CSF promotes the recruitment of neutrophils which produce proteases and chemokines that sustain a pro-inflammatory milieu. Emerging EAE data suggest that disrupting TLS organization or targeting key pathways involved in their maintenance could represent promising strategies for modulating chronic CNS inflammation in MS. Understanding the cellular and molecular mechanisms regulating TLS dynamics is therefore critical for the development of therapies aimed at halting or reversing nonremitting MS disease.

Keywords: B cells; Th17; autoimmunity; experimental autoimmune encephalomyelitis; lymphotoxin; multiple sclerosis; neutrophils.

FIGURE 1

Structure of the steady‐state and inflamed meninges and brain. (Left) Homeostatic CNS and meninges: Reservoir of immune cells in the dura are continually supplied by the skull bone marrow, while leptomeninges remain relatively clear of immune cells and toxic factors. Lymphatic vessels in the leptomeninges drain solutes from CSF into dural sinuses. Underlying glia limitans maintained by tight junctions between astrocyte end feet are intact, and gray and white matter are healthy and myelinated. Microglia remain in resting state. (Right) Pathogenic T cells induce elaboration of fibroblast niche, recruitment of neutrophils and B cells from the periphery, and production of toxic factors that disrupt the glia limitans. A combination of noxious solutes from the leptomeninges and activated microglia leads to subpial gray matter damage (lesion). Persistent gray matter damage eventually results in neuronal death and cortical atrophy (not shown).

FIGURE 2

Elaboration of a leptomeningeal immune cell niche. (Left) Invasion of the leptomeninges by pathogenic Th17 cells. Engagement of LTβR on fibroblasts and secretion of inflammatory factors such as IL‐17 and IL‐22 induces fibroblast remodeling and activation. Glia limitans remains intact and gray matter is undisturbed. (Middle) Activated fibroblasts produce factors that induce granulopoiesis in the periphery (G‐CSF), as well as chemokines for neutrophil (in red), B cell (in blue), and T cell (in green) recruitment to the inflammatory milieu. Secretion of IL‐17 and TNFα by Th17 cells disrupts the subpial glia limitans. (Right) Prolonged inflammation and immune cell recruitment result in an elaborated lymphoid niche supported by activated fibroblasts (TLS). Inflammatory factors secreted by immune cells in the TLS further disrupt glia limitans (MMPs) and cause activation of glial cells (IL‐1β, TNFα, C3, C1q), resulting in damage to gray matter.