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Updated: Jun 14, 2026
Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues
Published on: May 8, 2016
Differential ICAM-1 isoform expression regulates the development and progression of experimental autoimmune
Xianzhen Hu1, Scott R Barnum1, Jillian E Wohler1
1Department of Microbiology University of Alabama at Birmingham, Birmingham, AL, USA 35294.
Insights
Alternative splicing of Intercellular adhesion molecule-1 (ICAM-1) produces functional isoforms. These isoforms significantly impact experimental autoimmune encephalomyelitis (EAE) severity and T cell responses, suggesting roles in multiple sclerosis.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Intercellular adhesion molecule-1 (ICAM-1) is crucial for leukocyte function and immune responses.
- ICAM-1, part of the immunoglobulin superfamily, exhibits alternative splicing, generating diverse protein isoforms.
- Limited functional data exists for ICAM-1 isoforms, particularly their expression and ligand interactions.
Purpose of the Study:
- To investigate the functional significance of alternatively spliced ICAM-1 isoforms in vivo.
- To determine the impact of specific ICAM-1 isoforms on the disease course of experimental autoimmune encephalomyelitis (EAE).
- To explore the role of ICAM-1 isoforms in T cell activation and cytokine production.
Main Methods:
- Utilized two distinct lines of mutant mice (Icam1(tm1Jcgr) and Icam1(tm1Bay)) with altered ICAM-1 isoform expression.
- Assessed disease severity and progression in models of EAE.
- Analyzed T cell proliferation kinetics and interferon-gamma (IFN-gamma) production.
Main Results:
- Mutant mice lacking Mac-1 binding isoforms (Icam1(tm1Jcgr)) exhibited significantly attenuated EAE.
- Mice expressing specific isoforms (Icam1(tm1Bay)) showed severe EAE, increased T cell proliferation, and higher IFN-gamma levels compared to wild-type and Icam1(tm1Jcgr) mice.
- Demonstrated that alternatively spliced ICAM-1 isoforms are functional and influence EAE pathogenesis.
Conclusions:
- Alternatively spliced ICAM-1 isoforms play critical roles in central nervous system (CNS) inflammation and demyelination during EAE.
- These findings suggest ICAM-1 isoforms may be therapeutic targets for inflammatory diseases like multiple sclerosis.
- Differential engagement of ICAM-1 ligands, such as Mac-1, by specific isoforms likely mediates their functional effects.
Abstract:
Intercellular adhesion molecule-1 (ICAM-1) functions in leukocyte trafficking, activation, and the formation of the immunological synapse. ICAM-1 is a member of the immunoglobulin superfamily of adhesion proteins, which share a similar structure of repeating Ig-like domains. Many genes in this family, including ICAM-1, show alternative splicing leading to the production of different protein isoforms, although little functional information is available regarding the expression patterns, ligand interactions, and functions of these isoforms, especially those arising from the ICAM-1 gene. In this study, we show using different lines of mutant mice (Icam1(tm1Jcgr) and Icam1(tm1Bay)) that alterations in the expression of the alternatively spliced ICAM-1 isoforms can significantly influence the disease course during the development of EAE. Icam1(tm1Jcgr) mutant mice, unlike Icam1(tm1Bay) mutants, do not express isoforms containing the Mac-1 binding domain and had significantly attenuated of EAE. In contrast, Icam1(tm1Bay) mice developed severe EAE in both active and adoptive transfer models compared to both Icam1(tm1Jcgr) and wild type mice. We also observed that T cells from Icam1(tm1Bay) mice displayed increased proliferation kinetics and produced higher levels of IFN-gamma compared to Icam1(tm1Jcgr) and wild type mice. Thus, our investigations show that the alternatively spliced ICAM-1 isoforms are functional, and play key roles during the progression of CNS inflammation and demyelination in EAE. Furthermore, our findings suggest that these isoforms may also play key roles in controlling the development of inflammatory diseases such as multiple sclerosis, possibly through differential engagement with ICAM-1 ligands such as Mac-1.
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