Visual dysfunction in experimental autoimmune encephalomyelitis: A review

Taekyun Shin 한국실험동물학회 2023 한국실험동물학회 학술발표대회 논문집 Vol.2023 No.2

Erythropoietin and autoimmune neuroinflammation: lessons from experimental autoimmune encephalomyelitis and experimental autoimmune neuritis

Taekyun Shin,Meejung Ahn,Changjong Moon,Seungjoon Kim 대한해부학회 2012 Anatomy & Cell Biology Vol.45 No.4

Erythropoietin (EPO) is known to have numerous biological functions. While its primary function is during haematopoiesis, recent studies have shown that EPO plays important role in cytoprotection, immunomodulation, and anti-apoptosis. These secondary functions of EPO are integral to tissue protection following hypoxic injury, ischemia-reperfusion injury, and spinal cord injury in the central nervous system. This review focuses on experimental evidence documenting the neuroprotective effects of EPO in organ-specific autoimmune nervous system disorders such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). In addition, the immunomodulatory role of EPO in the pathogenesis of EAE and EAN animal models of human multiple sclerosis and Guillain-Barré syndrome, respectively, will be discussed.

Pertussis toxin-induced hyperacute autoimmune encephalomyelitis in Lewis rats is correlated with increased expression of inducible nitric oxide synthase and tumor necrosis factor alpha

Ahn, Meejung,Kang, Jongchul,Lee, Yongduk,Riu, Keyzung,Kim, Yong-sik,Jee, Youngheun,Matsumoto, Yoh,Shin, Taekyun 제주대학교 방사능이용연구소 2001 연구보고 Vol.15 No.-

자기면역성 뇌척수염(experimental autoimmune encephalomyelitis, EAE)은 뇌조직항원을 면역한 후 야기되는 염증성 질병으로 사람 다발성결화증의 한 모델로 연구되고 있다. 자기면역성 뇌염의 시작은 뇌조직항원에 반응하는 림프구가 중추신경계에 침윤되면서 마비를 나타내는데 이 과정 중에는 여러 종류의 pro-inflammatory mediator (tumor necrosis factor-alpha (TNF-α)와 inducible nitric oxide synthase (iNOS)등)가 관여하는 것으로 알려지고 있다. 이 연구에서는 염증의 진행 단계에 따라 염증 유도 또는 염증 억제의 상반된 기능을 갖는 것으로 알려진 TNF-α와 iNOS가 심급성 뇌척수염 진행에 어떠한 영향을 미치는지를 조사하였다. 뇌염을 유도하기 위한 항원으로는 랫트 척수 조직 유제를 complete Freund adjuvant와 혼합하여 뒷 발바닥에 주사하였으며 심한 뇌척수염을 유도하기 위하여 pertussis toxin(500ng/ea)을 면역하는 날 복강내로 주사하고 매일 체중과 마비 정도를 확인하였다. 독소를 주사한 실험군에서는 대조군(11일)에 비해 마비의 시작이 빨랐으며(9일), 대조군은 자연 회복하는 반면 독소룰 주사한 실험군에서는 모두 폐사하였다. 척수 조직 내 TNF-α 와 iNOS의 양적인 변화를 조사하기 위하여 Competitive PCR과 Western blot를 이용하였으며, 세포형을 구분하기 위하여 면역염색을 이용하였다. Competitive PCR결과 TNF-α는 PT를 투여한 자기면역성뇌척수염의 심한 마비기(EAE,G3)에서 PT를 투여하지 않은 대조군보다 약 5배가 증가하였으며(p<0.01), Western blot결과 iNOS는 PT를 투여한 군에서 정상조직에 비해 약 6배가 증가하였고, PT를 투여하지 않은 군에 비해서는 약 3개바 증가하였다(p<0.01). 면역염색결과 PT를 투여하지 않은 랫트보다 투여한 랫트의 척수조직에서 iNOS 양성 세포가 약 15배가 증가하였으며(p<0.01), 또한 연속절편에서 이들 세포가 큰포식세포임을 확인하였다. 이상의 결과를 종합해 볼 때, 자기면역성 뇌척수염의 초기 유도과정에서는 TNF-α와 iNOS는 염증의 약화에 관여됨을 알 수 있었다. The involvement of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α), which have diverse roles in the progression of autoimmune disease models, was studied in pertussis toxin (PT-induced hyperacute experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The expression of TNF-α mRNA(increased 5 fold, p<0.01) and iNOS protein (3 fold, p<0.01) was much greater in the spinal cords with PT(+) EAE at the peak stage of EAE than in those with PT(-) EAE, as shown by competitive PCR and Western blot analysis, respectively. Immunohistochemistry showed that the majority of EDI-positive macrophages in EAE lesions contained iNOS, and that three were many more iNOS-positive cells in the CNS lesions of PT(+) rats than in those of PT(-) rats. These findings suggest that PT-induced hyperacute EAE is partly mediated by the enhanced expression of iNOS and TNF-α in the early stages of rat EAE.

Erythropoietin and autoimmune neuroinflammation: lessons from experimental autoimmune encephalomyelitis and experimental autoimmune neuritis

신태균,안미정,문창종,김승준 대한해부학회 2013 Anatomy & Cell Biology Vol.45 No.4

Erythropoietin (EPO) is known to have numerous biological functions. While its primary function is during haematopoiesis, recent studies have shown that EPO plays important role in cytoprotection, immunomodulation, and antiapoptosis. These secondary functions of EPO are integral to tissue protection following hypoxic injury, ischemia-reperfusion injury, and spinal cord injury in the central nervous system. This review focuses on experimental evidence documenting the neuroprotective effects of EPO in organ-specific autoimmune nervous system disorders such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). In addition, the immunomodulatory role of EPO in the pathogenesis of EAE and EAN animal models of human multiple sclerosis and Guillain-Barré syndrome, respectively, will be discussed.

<i>Bacillus</i>‐derived poly‐γ‐glutamic acid reciprocally regulates the differentiation of T helper 17 and regulatory T cells and attenuates experimental autoimmune encephalomyelitis

Lee, K.,Hwang, S.,Paik, D. J.,Kim, W. K.,Kim, J. M.,Youn, J. Blackwell Publishing Ltd 2012 Clinical and experimental immunology Vol.170 No.1

<P><B>Summary</B></P><P>Forkhead box protein 3 (FoxP3<SUP>+</SUP>) regulatory T (T<SUB>reg</SUB>) cells and interleukin (IL)‐17‐producing T helper 17 (Th17) cells have opposing effects on autoimmunity, as the former are crucial for maintaining self‐tolerance while the latter play a key role in precipitating inflammatory autoimmune diseases. Here we report that <I>Bacillus</I>‐derived poly‐γ‐glutamic acid (γ‐PGA) signals naive CD4<SUP>+</SUP> T cells to promote the selective differentiation of T<SUB>reg </SUB>cells and to suppress the differentiation of Th17 cells. The γ‐PGA inducibility of FoxP3 expression was due partially to transforming growth factor (TGF)‐β induction through a Toll‐like receptor (TLR)‐4/myeloid differentiating factor 88 (MyD88)‐dependent pathway. However, this pathway was dispensable for γ‐PGA suppression of Th17 differentiation. γ‐PGA inhibited IL‐6‐driven induction of Th17‐specific factors including signal transducer and activator of transcription‐3 (STAT‐3) and retinoic acid‐related orphan receptor γt (RORγt) while up‐regulating the STAT‐3 inhibitor suppressor of cytokine signalling 3 (SOCS3). Importantly, <I>in vivo</I> administration of γ‐PGA attenuated the symptoms of experimental autoimmune encephalomyelitis and at the same time reduced Th17 cell infiltrates in the central nervous system. Thus, we have identified the microbe‐associated molecular pattern, γ‐PGA, as a novel regulator of autoimmune responses, capable of promoting the differentiation of anti‐inflammatory T<SUB>reg</SUB> cells and suppressing the differentiation of proinflammatory Th17 cells. These findings draw attention to the potential of γ‐PGA for treating Th17 cell‐mediated autoimmune diseases.</P>

The Anti-Inflammatory Effects of Oral-Formulated Tacrolimus in Mice with Experimental Autoimmune Encephalomyelitis

김명진,성정준,김승현,김정민,전계선,문석균,안석원 대한의학회 2017 Journal of Korean medical science Vol.32 No.9

Multiple sclerosis (MS) is a T-lymphocyte-mediated autoimmune disease that is characterized by inflammation in the central nervous system (CNS). Although many disease-modifying therapies (DMTs) are presumed effective in patients with MS, studies on the efficacy and safety of DMTs for preventing MS relapse are limited. Therefore, we tested the immunosuppressive anti-inflammatory effects of oral-formulated tacrolimus (FK506) on MS in a mouse model of experimental autoimmune encephalomyelitis (EAE). The mice were randomly divided into 3 experimental groups: an untreated EAE group, a low-dose tacrolimus-treated EAE group, and a high-dose tacrolimus-treated EAE group. After autoimmunization of the EAE mice with myelin oligodendrocyte glycoprotein, symptom severity scores, immunohistochemistry of the myelination of the spinal cord, and western blotting were used to evaluate the EAE mice. After the autoimmunization, the symptom scores of each EAE group significantly differed at times. The group treated with the larger tacrolimus dose had the lowest symptom scores. The tacrolimus-treated EAE groups exhibited less demyelination and inflammation and weak immunoreactivity for all of the immunization biomarkers. Our results revealed that oral-formulated tacrolimus inhibited the autoimmunization in MS pathogenesis by inactivating inflammatory cells.

Amelioration of experimental autoimmune encephalomyelitis by Ishige okamurae

안미정,김정태,양원준,최유나,Poornima Ekanayake,고현주,지영훈,신태균 대한해부학회 2018 Anatomy & Cell Biology Vol.51 No.4

Experimental autoimmune encephalomyelitis (EAE) is a T-cell‒mediated autoimmune central nervous system disease characterized by inflammation with oxidative stress. The aim of this study was to evaluate an anti-inflammatory effect of Ishige okamurae on EAE-induced paralysis in rats. An ethanolic extract of I. okamurae significantly delayed the first onset and reduced the duration and severity of hind-limb paralysis. The neuropathological and immunohistochemical findings in the spinal cord were in agreement with these clinical results. T-cell proliferation assay revealed that the ethyl-acetate fraction of I. okamurae suppressed the proliferation of myelin basic protein reactive T cells from EAE affected rats. Flow cytometric analysis showed TCRαβ+ T cells was significantly reduced in the spleen of EAE rats with I. okamurae treatment with concurrent decrease of inflammatory mediators including tumor necrosis factor-α and cyclooxygenase-2. Collectively, it is postulated that I. okamurae ameliorates EAE paralysis with suppression of T-cell proliferation as well as decrease of pro-inflammatory mediators as far as rat EAE is concerned.

Potential involvement of glycogen synthase kinase (GSK)-3β in a rat model of multiple sclerosis:

Mee jung Ahn,Jeong tae Kim,Chang nam Park,Jin hee Cho,Young heun Jee,Kyung sook Jung,Chang jong Moon,Tae kyun Shin 대한해부학회 2017 Anatomy & Cell Biology Vol.50 No.1

Glycogen synthase kinase (GSK)-3β has been known as a pro-inflammatory molecule in neuroinflammation. The involvement of GSK-3β remains unsolved in acute monophasic rat experimental autoimmune encephalomyelitis (EAE). The aim of this study was to evaluate a potential role of GSK-3β in central nervous system (CNS) autoimmunity through its inhibition by lithium. Lithium treatment significantly delayed the onset of EAE paralysis and ameliorated its severity. Lithium treatment reduced the serum level of pro-inflammatory tumor necrosis factor a but not that of interleukin 10. Western blot analysis showed that the phosphorylation of GSK-3β (p-GSK-3β) and its upstream factor Akt was significantly increased in the lithium-treated group. Immunohistochemical examination revealed that lithium treatment also suppressed the activation of ionized calcium binding protein-1–positive microglial cells and vascular cell adhesion molecule-1 expression in the spinal cords of lithium-treated EAE rats. These results demonstrate that lithium ameliorates clinical symptom of acute monophasic rat EAE, and GSK-3 is a target for the suppression of acute neuroinflammation as far as rat model of human CNS disease is involved.

Mechanism of experimental autoimmune encephalomyelitis in Lewis rats

Taekyun Shin,Meejung Ahn,Yoh Matsumoto 대한해부학회 2012 Anatomy & Cell Biology Vol.45 No.3

Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic paralytic central nervous system disease, in which most rats spontaneously recover from paralysis. EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein. EAE is mediated by CD4⁺ Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells. Recently, it was established that classically activated macrophages (M1 phenotype) play an important role in the initiation of EAE, while alternatively activated macrophages (M2 phenotype) contribute to spontaneous recovery from rat EAE. This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages.

Gene Expression Profile of Olfactory Transduction Signaling in an Animal Model of Human Multiple Sclerosis

김정태,안미정,최유나,Poornima Ekanayake,박철민,문창종,정경숙,Akane Tanaka,Hiroshi Matsuda,신태균 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.1

Olfactory dysfunction occurs in multiple sclerosis in humans, as well as in an animal model of experimental autoimmune encephalomyelitis (EAE). The aim of this study was to analyze differentially expressed genes (DEGs) in olfactory bulb of EAE-affected mice by next generation sequencing, with a particular focus on changes in olfaction-related signals. EAE was induced in C57BL/6 mice following immunization with myelin oligodendrocyte glycoprotein and adjuvant. Inflammatory lesions were identified in the olfactory bulbs as well as in the spinal cord of immunized mice. Analysis of DEGs in the olfactory bulb of EAE-affected mice revealed that 44 genes were upregulated (and which were primarily related to inflammatory mediators), while 519 genes were downregulated; among the latter, olfactory marker protein and stomatin-like 3, which have been linked to olfactory signal transduction, were significantly downregulated (log2 [fold change] >1 and p-value <0.05). These findings suggest that inflammation in the olfactory bulb of EAE-affected mice is associated with the downregulation of some olfactory signal transduction genes, particularly olfactory marker protein and stomatin-like 3, which may lead to olfactory dysfunction in an animal model of human multiple sclerosis.