Immune response in optic nerve and retina in a multiple sclerosis model
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), which is characterized by an inflammatory demyelination. Frequently, the disease is accompanied by an inflammation of the optic nerve, which could lead to a visual impairment [1]. These alterations of the vision are often early symptoms of MS.
In previous studies, the optic nerve and retinal structures were analyzed in an experimental autoimmune encephalomyelitis model (EAE) [2]. Our institute could show a strong correlation between the immune cell infiltration level (R2=0.83) or the demyelination score (R2=0.98) and the clinical symptoms. As soon as the optic nerve degenerated, the retina was also affected. Therefore, the retina was analyzed. Examinations of the retina proved that an increase of apoptotic retinal ganglion cells (RGC; p=0.02) and a RGC decline (p=0.02) occurred (Figure 1). Thus, structural alterations of the retinae were observed.
Retinal ganglion cell decline
The RGCs were stained on flatmounts and cross-sections of the retina. A) Cells of the flatmounts were labeled with an unspecific Nissel dye. B) A significantly decrease of the RGCs was noted (p<0.001). C) To verify the result, RGCs were visualized with a specific marker, Brn-3a (red), on cross-sections of the retina (white arrows). D) Also with the specific marker, a cell loss was detected (p=0.02). Scale bar: 25 µm. *: p<0.05; ***: p<0.001. CO=control, EAE=treated; GCL=ganglion cell layer, IPL=inner plexiform layer, INL=inner nuclear layer (Horstmann et al., 2013)
Multiple sclerosis is also associated with autoimmune mechanisms [3]. Therefore, microglia and macrophages were examined in the EAE model. An increase of both, microglia (p<0.001) and macrophage population (p=0.002) was measured (Abb. 2). An enhanced interleukin 6 production was also noted (p=0.007) [2]. These mechanisms are hallmarks for inflammatory processes. Similar infiltration mechanisms of microglia and macrophages as in the retina are also know to occur in the CNS [4]. This strengthens the theory that an examination of the optic nerve and retina allows us to get insights into the pathomechanisms in the brain. As a next step, the possible effect of certain therapeutic agents on retinal structures and immune cell infiltrates should be analyzed.
Response of microglia and macrophages
A) The microglia (Iba1) and macrophages (F4/80) were stained on cross-sections of the retina. B) Not only the microglia increased significantly (p<0.001), even the macrophage number was doubled (p=0.002). Scale bar: 25 µm. *: p<0.05; ***: p<0.001. CO=control, EAE=treated; GCL=ganglion cell layer, IPL=inner plexiform layer, INL=inner nuclear layer (Horstmann et al., 2013)
Peer reviewed publication
Horstmann L, Schmid H, Heinen AP, Kurschus FC, Dick HB, Joachim SC. Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of an experimental autoimmune encephalomyelitis model. Journal of Neuroinflammation, 2013;10:120.
Conference contributions
Horstmann L, Pedreiturria X, Kuehn S, Kühl L, Haak K, Schmid H et al. Activation of glial cells in retina and optic nerve of an experimental autoimmune encephalomyelitis model. Invest Ophthalmol Vis Sci, 2015.
Horstmann L, Schmid H, Kurschus F, Waisman A, Dick B, Joachim S. Retinal ganglion cell loss and inflammatory demyelination in an experimental autoimmune encephalomyelitis model. Invest Ophthalmol Vis Sci, 2013;54:1417.
Schmid H, Horstmann L, Kurschus F, Waisman A, Dick B, Joachim S. Glia alterations in the retina of a multiple sclerosis animal model. Invest Ophthalmol Vis Sci, 2013;54:5588.
References
[1] Shindler KS, Revere K, Dutt M, Ying GS, Chung DC. In vivo detection of experimental optic neuritis by pupillometry. Exp Eye Res, 2012;100:1-6.
[2] Horstmann L, Schmid H, Heinen AP, Kurschus FC, Dick HB, Joachim SC. Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of an experimental autoimmune encephalomyelitis model. Journal of Neuroinflammation, 2013;10:120.
[3] Hendrickx DA, Schuurman KG, van Draanen M, Hamann J, Huitinga I. Enhanced uptake of multiple sclerosis-derived myelin by THP-1 macrophages and primary human microglia. Journal of Neuroinflammation, 2014;11:64.
[4] Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci, 2011;14:1142-9.