Article

Suppression of Complement Regulatory Proteins (CRPs) Exacerbates Experimental Autoimmune Anterior Uveitis (EAAU)

Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky, United States
The Journal of Immunology (Impact Factor: 4.92). 07/2006; 176(12):7221-31. DOI: 10.4049/jimmunol.176.12.7221
Source: PubMed

ABSTRACT

This study was undertaken to explore the role of complement regulatory proteins (CRPs) in experimental autoimmune anterior uveitis (EAAU). We observed that the levels of CRPs, Crry and CD59, in the eyes of Lewis rats increased during EAAU and remained elevated when the disease resolved. The in vivo role of these CRPs in EAAU was explored using neutralizing mAbs, antisense oligodeoxynucleotides (AS-ODNs), and small interfering RNAs against rat Crry and CD59. Suppression of Crry in vivo at days 9, 14, or 19 by neutralizing mAb or AS-ODNs resulted in the early onset of disease, the exacerbation of intraocular inflammation, and delayed resolution. Suppression of CD59 was only effective when the Abs and ODNs were given before the onset of disease. The most profound effect on the disease was observed when a mixture of Crry and CD59 mAbs or AS-ODNs was administered. A similar effect was observed with a combination of Crry and CD59 small interfering RNA. There was no permanent histologic damage to ocular tissue after the inflammation cleared in these animals. Increased complement activation as determined by increased deposition of C3, C3 activation fragments, and membrane attack complex was observed in the eyes of Lewis rats when the function and/or expression of Crry and CD59 was suppressed. Thus, our results suggest that various ocular tissues up-regulate the expression of Crry and CD59 to avoid self-injury during autoimmune uveitis and that these CRPs play an active role in the resolution of EAAU by down-regulating complement activation in vivo.

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Available from: Puran Bora, May 14, 2014
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    • "Under normal conditions, the complement system is active at a low level and is tightly regulated by various complement regulatory proteins (CRegs), such as complement factor H (CFH), decay-accelerating factor, and S-protein [11]. Disruption in the balance of complement activation and CRegs will result in harmful effects and lead to several immune-related diseases including uveitis [12,13]. CFH is one of the most important regulators in the alternative complement pathway and is involved in the pathogenesis of immunological diseases [14-16]. "
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    • "Under normal conditions, complement system is continuously active at a low level and is tightly regulated by intraocular complement regulatory proteins (CRegs) such as complement factor H (CFH), decay-accelerating factor and S-protein. Studies have shown that suppression of CRegs can exacerbate EAAU due to unregulated complement activation [30,31]. CFH acts as a key regulator in the complement alternative pathway and is involved in the pathogenesis of many immunological diseases [32-34]. "
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    • "Animals were examined daily between days 7 and 30 post immunization for the clinical signs of uveitis using slit lamp biomicroscopy. EAAU was scored by an observer unaware of the experimental design using the criteria previously reported (Bora et al., 1995, 1997, 2004; Jha et al., 2006a, 2006b, 2007, 2009; Kim et al., 1995; Matta et al., 2008, 2010). Eyes were also harvested at various time points for histological analysis to assess the course and the severity of inflammation using the criteria previously described by us (Bora et al., 1995, 1997, 2004; Jha et al., 2006a, 2006b, 2007, 2009; Kim et al., 1995; Matta et al., 2008, 2010). "
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