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Fig. 2 | Orphanet Journal of Rare Diseases

Fig. 2

From: Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Fig. 2

Hypothetical neuroimmune activation model leading to a vicious cycle of demyelination in metachromatic leukodystrophy (MLD). Sulfatide accumulation causes death of Schwann cells and phagocytes, and destruction of myelin in the peripheral nervous system (PNS) [2]. Destruction of myelin activates the third complement component (C3) by the alternative pathway [108, 110], possibly promoted by the disruption of Schwann cells and nerve environment [111] due to sulfatide accumulation. Myelin sheaths are subsequently opsonized by C3b and C3d molecules (hypothetical), which can induce a humoral immune response and act as ‘eat-me’ signals to trigger phagocytosis via the third complement / macrophage-1 receptor (CR3/MAC-1) [133], respectively. In addition, sulfatide accumulation induces the release of pro-inflammatory cytokines and activates endoneural macrophages [106, 107] by acting on the scavenger-receptor-AI/II (SRAI/II) [134]. The released pro-inflammatory cytokines act on the lipophilic receptors (eg. TLR) of endoneural macrophages to assist the phagocytosis of sulfatides and breakdown of myelin sheaths [112]. Macrophage cell death due to the accumulation of sulfatides (shown in purple) also results in presenting sulfatides on their HLD-DR receptors. This assists the activation of lymphocytes that are recruited and activated due to binding of sulfatides and pro-inflammatory cytokines on L-selectin [113]. The activation of lymphocytes in turn leads to cell death and a vicious cycle of demyelination

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