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 −/− × C3 −/− 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 −/− × C3 −/− mice produced the highest levels of IFN-γ and TNF-α, despite reduced disease severity compared to wild type mice. The mechanisms behind the elevated EAE severity in ICAM-1 −/− × C3 −/− mice may relate to altered homing of leukocytes or processing of self-antigens in the double mutant background. Keywordsexperimental autoimmune encephalomyelitis; adhesion molecules; complement; neuroimmunology The role of complement and adhesion molecules in the development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis has been extensively studied [1,2,11]. In the course of these studies it has become clear that two ligands for members of the β 2 -integrin family of adhesion molecules, C3 and ICAM-1, play a critical Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. role in the onset and progression of EAE. Null mutations in either gene significantly delay the onset of, and reduce the severity of EAE [6,14]. Likewise, the deletion of the β 2 -integrin receptors that bind C3 and ICAM-1, namely Mac-1 and p150,95, also significantly attenuates EAE [4,5]. These studies indicate important and nonredundant functions for these proteins in the pathogenesis of demyelinating disease. Based on the significant, but incomplete protection from EAE observed when using mice deficient in either protein, we reasoned that a double mutant would develop...

Deletion of both the C3a and C5a receptors fails to protect against experimental autoimmune encephalomyelitis

“…Additional studies using C3aR/C5aR −/− mice need to be performed in other disease models to verify this possibility. Our results support previous observations in ICAM-1 −/− × C3 −/− mice [12] in that the protective features associated with one genotype in EAE can be overcome in the double mutant genotype. In this case the attenuated EAE reported for C3aR −/− mice [2] was lost in C3aR/C5aR −/− mice.…”

Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis

“…We also assessed whether the loss of C1q or C3 could protect against the EAE-induced motor impairment caused by spinal cord damage ( Figure 3). As previously reported [33,35,38], C3 knockout resulted in less severe EAE motor deficits with a significant decrease in the mean clinical score both at peak disease (14-15 days post immunization) and during the chronic phase (20-30 days post immunization). On the other hand, C1qa KO did not alter the EAE disease course in any way as the C1qa KO EAE mean clinical scores were virtually identical to WT EAE.…”

“…However, the alternative complement pathway plays a major role in driving pathology in EAE. Knockout of C3, Factor B, or receptors to C3 cleavage products (C3aR, CR3, and CR4) all reduce white matter lesion pathology and motor impairment measured by the EAE clinical score [33][34][35][36][37][38].…”

Role and mechanism of action of complement in regulating T cell immunity

“…However, studies with C3 −/− mice have produced conflicting data. In one study, C3 deficiency was found to attenuate murine EAE, a conclusion that was reaffirmed in a subsequent study by the same group (Nataf et al , 2000, Smith et al , 2008). In contrast, a study by a different group found no difference between WT and C3 −/− mice in the development of EAE (Calida et al , 2001).…”