Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease

Abstract

Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study we used C3 -/-mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3 +/-mice (with serum C3 levels 50% that of wild type mice) developed EAE with a severity intermediate between wild type and C3 -/-mice. Importantly transfer of wild type encephalitogenic T cells to C3 -/-mice resulted in attenuated EAE. C3 -/-mice with EAE had fewer CD4 + and CD8 + T cells in the CNS and 50% fewer of these cells produced IFN-γ compared to wild type mice. When treated with anti-CD3 antibody, CD4 + T cell from wild type and C3 -/-mice had similar activation profiles as judged by IFN-γ production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3 -/-mice. T cells from primed C3 -/-mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease.

C3-dependent mechanism of microglial priming relevant to multiple sclerosis

“…To test this possibility in the Crry −/− model, EAE was induced. Disease was markedly accelerated and exacerbated in Crry −/− mice, despite the fact that C3 levels were very low (12), and C3 deficiency was reportedly protective in EAE in some but not all studies (35)(36)(37). Microglial activation is well recognized as an early pathogenic feature of EAE, and, indeed, inhibitors of microglial activation suppress disease (38).…”

Suppression of Cytokine-Mediated Complement Factor Gene Expression through Selective Activation of the Ah Receptor with 3′,4′-Dimethoxy-α-naphthoflavone

“…C3 expression has been demonstrated to be pivotal in inflammatory diseases, including rheumatoid arthritis, as exemplified by C3(Ϫ/Ϫ) mouse models, which are resistant to experimentally induced arthritis (Ji et al, 2001). Likewise, the development and severity of experimental autoimmune encephalitis (EAE), a model for multiple sclerosis, has been shown to be dependent on an intact C3-mediated complement system (Szalai et al, 2007). Interestingly, C3(Ϫ/ϩ) mice have serum C3 concentrations 50% of their wild-type counterparts and exhibit diminished EAE severity through a mechanism likely to involve reduced migration and activation of T-cells within the spinal cord (Szalai et al, 2007).…”

“…Likewise, the development and severity of experimental autoimmune encephalitis (EAE), a model for multiple sclerosis, has been shown to be dependent on an intact C3-mediated complement system (Szalai et al, 2007). Interestingly, C3(Ϫ/ϩ) mice have serum C3 concentrations 50% of their wild-type counterparts and exhibit diminished EAE severity through a mechanism likely to involve reduced migration and activation of T-cells within the spinal cord (Szalai et al, 2007). Here, we reveal that DiMNF, acting as an SAhRM, has the capacity to suppress C3 levels by 40% in vitro, suggesting that DiMNF may be effective therapeutically.…”

Autoimmunity and Apoptosis - Therapeutic Implications

“…Polymorphisms in peptidylarginine deaminase (PADI) and insulin genes (INS) are associated with RA and IDDM respectively [53,54] whereas variants of PDCD1 (encoding programmed cell death 1), SLC22A4 (within cytokine gene cluster), FCRL3 (encoding receptors with homology to the Fc-receptors of Ig), SUMO4 (small ubiquitin-like modifier 4), and CD25 (encoding a subunit of the IL-2 receptor complex) have been shown to be associated with several autoimmune conditions including SLE, RA, IDDM, Crohn's disease and autoimmune thyroid disorders [3,4,6,7,41,55,56]. Also, genetic lesions including point mutations in AIRE as well as complement deficiency have been vastly shown to be associated with an increased chance of autoimmunity [57][58][59][60][61][62][63][64][65][66]. This list is still being updated by an abundance of information that emerges from genotype susceptibility studies using animal models, genomewide mapping, and array technologies that investigate the gene expression profile during a particular immune response.…”