title: Deletion of both ICAM-1 and C3 enhances severity of experimental autoimmune encephalomyelitis compared to C3-deficient mice.
abstract: Multiple sclerosis (MS) is an autoimmune disease characterized by central nervous system (CNS) inflammation and leukocyte infiltration, demyelination of neurons, and blood-brain barrier breakdown. The development of experimental autoimmune encephalomyelitis (EAE), the animal model for MS is dependent on a number of components of the immune system including complement and adhesion molecules. Previous studies in our lab have examined the role of C3, the central complement component, and intercellular adhesion molecule-1 (ICAM-1) a key cell adhesion molecule involved in leukocyte trafficking to sites of inflammation including the CNS. In these studies we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-induced EAE is markedly attenuated in both ICAM-1(-/-) and C3(-/-) mice. Given the pivotal role that these proteins play in EAE, we hypothesized that EAE in ICAM-1(-/-) and C3(-/-) double mutant mice would likely fail to develop. Unexpectedly, EAE in ICAM-1(-/-)xC3(-/-) mice was only modestly attenuated compared to wild type mice and significantly worse than C3(-/-) mice. Leukocyte infiltration was commensurate with disease severity between the three groups of mice. Spinal cord T cells from ICAM-1(-/-)xC3(-/-) mice produced the highest levels of IFN-gamma and TNF-alpha, despite reduced disease severity compared to wild type mice. The mechanisms behind the elevated EAE severity in ICAM-1(-/-)xC3(-/-) mice may relate to altered homing of leukocytes or processing of self-antigens in the double mutant background.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Sherry S
authors.initials: SS
authors.lastname: Smith
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Jillian E
authors.initials: JE
authors.lastname: Wohler
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bullard
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Szalai
authors.forename: Scott R
authors.initials: SR
authors.lastname: Barnum
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000009:adverse effects; D063308:Myelin-Oligodendrocyte Glycoprotein; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D003176:Complement C3; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D018799:Intercellular Adhesion Molecule-1