scholarly journals IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition

2008 ◽  
Vol 205 (7) ◽  
pp. 1535-1541 ◽  
Author(s):  
Mark A. Kroenke ◽  
Thaddeus J. Carlson ◽  
Anuska V. Andjelkovic ◽  
Benjamin M. Segal
Keyword(s):  
T Cells ◽  
Critical Role ◽  
Polymerase Chain Reaction Analysis ◽  
Autoimmune Encephalomyelitis ◽  
Similar Clinical Outcome ◽  
Cytokine Inhibition ◽  
Polymerase Chain ◽  
Stimulating Factor ◽  
Pathogenic Process ◽  
Experimental Autoimmune

The interleukin (IL)-12p40 family of cytokines plays a critical role in the development of experimental autoimmune encephalomyelitis (EAE). However, the relative contributions of IL-12 and IL-23 to the pathogenic process remain to be elucidated. Here, we show that activation of uncommitted myelin-reactive T cells in the presence of either IL-12p70 or IL-23 confers encephalogenicity. Adoptive transfer of either IL-12p70– or IL-23–polarized T cells into naive syngeneic hosts resulted in an ascending paralysis that was clinically indistinguishable between the two groups. However, histological and reverse transcription–polymerase chain reaction analysis of central nervous system (CNS) tissues revealed distinct histopathological features and immune profiles. IL-12p70–driven disease was characterized by macrophage-rich infiltrates and prominent NOS2 up-regulation, whereas neutrophils and granulocyte–colony-stimulating factor (CSF) were prominent in IL-23–driven lesions. The monocyte-attracting chemokines CXCL9, 10, and 11 were preferentially expressed in the CNS of mice injected with IL-12p70–modulated T cells, whereas the neutrophil-attracting chemokines CXCL1 and CXCL2 were up-regulated in the CNS of mice given IL-23–modulated T cells. Treatment with anti–IL-17 or anti–granulocyte/macrophage-CSF inhibited EAE induced by transfer of IL-23–polarized, but not IL-12p70–polarized, cells. These findings indicate that autoimmunity can be mediated by distinct effector populations that use disparate immunological pathways to achieve a similar clinical outcome.

scholarly journals Protective Effect of Cytosolic Phospholipase A2 Inhibition against Inflammation and Degeneration by Promoting Regulatory T Cells in Rats with Experimental Autoimmune Encephalomyelitis

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Dan Yang ◽  
Hong-Fei Ji ◽  
Xue-Mei Zhang ◽  
Hui Yue ◽  
Lin Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Phospholipase A2 ◽  
Neuroprotective Effect ◽  
Critical Role ◽  
Cytosolic Phospholipase A2 ◽  
Autoimmune Encephalomyelitis ◽  
Cytosolic Phospholipase ◽  
Experimental Autoimmune

Cytosolic phospholipase A2 (cPLA2) is the rate-limiting enzyme that initiates the production of various inflammatory mediators. Previous studies have shown that inhibiting cPLA2exerts a neuroprotective effect on experimental autoimmune encephalomyelitis (EAE) by ameliorating the severity of the disease and influencing Th1 and Th17 responses. However, it remains unclear whether treatment with a cPLA2inhibitor will influence the regulatory T cells (Tregs) that play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. In this study, the cPLA2inhibitor AX059 reduced the onset and progression of EAE in Lewis rats. In addition, this effect was accompanied by activation of Tregs and alterations in the expression of their various cytokines. The study therefore demonstrated that Tregs are involved in the immunomodulatory effect mediated by cPLA2inhibition. These findings may have clinical application in the treatment of multiple sclerosis.

scholarly journals Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis

2003 ◽  
Vol 198 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Alan D. Salama ◽  
Tanuja Chitnis ◽  
Jaime Imitola ◽  
Mohammed Javeed I. Ansari ◽  
Hisaya Akiba ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Critical Role ◽  
Peripheral Tolerance ◽  
Delayed Type Hypersensitivity ◽  
Autoimmune Encephalomyelitis ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Deficient Mice ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

scholarly journals Regulatory T Cells Specific for the Same Framework 3 Region of the Vβ8.2 Chain Are Involved in the Control of Collagen II–induced Arthritis and Experimental Autoimmune Encephalomyelitis

1997 ◽  
Vol 185 (10) ◽  
pp. 1725-1733 ◽  
Author(s):  
Vipin Kumar ◽  
Fatema Aziz ◽  
Eli Sercarz ◽  
Alexander Miller
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Critical Role ◽  
Gene Segment ◽  
Joint Inflammation ◽  
Single Chain ◽  
Autoimmune Encephalomyelitis ◽  
Collagen Ii ◽  
Experimental Autoimmune

Recent evidence indicates that chronic autoimmune disease can result from breakdown of regulation and subsequent activation of self-reactive T cells. In many murine autoimmune disease systems and in the Lewis rat, antigen-specific T cells utilizing the T cell receptor (TCR) Vβ8.2 gene segment play a major role. In the myelin basic protein–induced experimental autoimmune encephalomyelitis (EAE) model in H-2u mice, we had shown that T cells recognizing a peptide determinant within the framework 3 region of the Vβ8.2 chain have a critical role in influencing the course of the disease. Here, we report experiments in another disease system, collagen II (CII)–induced arthritis (CIA) in DBA/1LacJ (H-2q) mice, indicating a remarkably parallel control circuit to that found for EAE. A critical role is played by CII-specific Vβ8.2bearing T cells in the CIA system, which we have confirmed. Animals treated with the superantigen SEB before CII administration are significantly protected from CIA. Next, we tested the ability of peptides encompassing the entire Vβ8.2 chain to induce proliferative responses. Only TCR peptide B5 (amino acids 76–101), a regulatory peptide in EAE, induced proliferation. B5 was then used to vaccinate DBA/1LacJ mice and was shown to reduce greatly the severity and incidence of CIA as measured by joint inflammation or histology. Furthermore, similar protection was found when B5 was administered after CII immunization. It was shown that there is physiological induction of a proliferative response to B5 during CIA and that the determinant within B5 is produced from a single chain TCR construct containing the entire Vβ8.2 chain. Finally, the regulation of CIA is discussed in the context of other experimental autoimmune diseases, especially EAE, with emphasis on what appear to be strikingly common mechanisms.

scholarly journals IL-23p19 and CD5 antigen-like form a possible novel heterodimeric cytokine and contribute to experimental autoimmune encephalomyelitis development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hideaki Hasegawa ◽  
Izuru Mizoguchi ◽  
Naoko Orii ◽  
Shinya Inoue ◽  
Yasuhiro Katahira ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Critical Role ◽  
Autoimmune Encephalomyelitis ◽  
Gm Csf ◽  
Reduced Frequency ◽  
Macrophage Colony ◽  
Deficient Mice ◽  
Experimental Autoimmune

AbstractAmong various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4+ T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4+ T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19/CD5L. This p19/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells. Both CD4+ T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF+CD4+ T cells. During the course of EAE, the serum level of p19/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.

scholarly journals Platelet Depletion is Effective in Ameliorating Anxiety-Like Behavior and Reducing the Pro-Inflammatory Environment in the Hippocampus in Murine Experimental Autoimmune Encephalomyelitis

2019 ◽  
Vol 8 (2) ◽  
pp. 162 ◽  
Author(s):  
Pece Kocovski ◽  
Xiangrui Jiang ◽  
Claretta D’Souza ◽  
Zhenjiang Li ◽  
Phuc Dang ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Neuropsychiatric Symptoms ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Lymphocytic Infiltration ◽  
Disease Stage ◽  
Autoimmune Encephalomyelitis ◽  
Significant Difference ◽  
Platelet Depletion ◽  
Experimental Autoimmune

The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet–neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS.

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