Article

Suppression of complement regulatory proteins (CRPs) exacerbates experimental autoimmune anterior uveitis (EAAU)

Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
The Journal of Immunology (Impact Factor: 5.36). 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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    • "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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    ABSTRACT: This study was initiated to explore the effect of recombinant rat Crry linked to the Fc portion of rat IgG2a (Crry-Ig) on the induction of experimental autoimmune anterior uveitis (EAAU) and on established disease. EAAU was induced in Lewis rats by immunization with bovine melanin-associated antigen (MAA). MAA sensitized animals received Crry-Ig, rat IgG2a (isotype control) or PBS separately before the onset of EAAU or after the onset of clinical disease. Administration of Crry-Ig suppressed the induction of EAAU while all animals injected with IgG2a or PBS developed the normal course of EAAU. Treatment with Crry-Ig resulted in the suppression of ocular complement activation as well as the functional activity of complement in the peripheral blood. At the peak of EAAU, levels of IFN-γ, IP-10, ICAM-1 and LECAM-1 were significantly reduced within the eyes of Crry-Ig treated Lewis rats. Importantly, administration of Crry-Ig even after the onset of EAAU resulted in a sharp decline in the disease activity and early resolution of EAAU. Collectively, the evidence presented here demonstrate that inhibition of complement by Crry-Ig results in low levels of inflammatory molecules-C3 activation products, MAC, cytokines, chemokines and adhesion molecules in the eye. Down-regulation of these molecules affects the infiltration and recruitment of inflammatory cells to the eye resulting in the inhibition of EAAU.
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    • "These results demonstrated that the suppression of Crry and CD59 leads to increased intraocular complement activation as evidenced by the increased deposition of C3 activation products and MAC. Taken together, our data demonstrated that the direct interference with the function and/or cell surface expression of Crry and CD59 in vivo resulted in a significant reduction in Crry and CD59, increased complement activation and the exacerbation of EAAU (Jha et al., 2006b). "
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    ABSTRACT: In the normal eye, the complement system is continuously activated at low levels and both membrane-bound and soluble intraocular complement regulatory proteins tightly regulate this spontaneous complement activation. This allows protection against pathogens without causing any damage to self-tissue and vision loss. The complement system and complement regulatory proteins control the intraocular inflammation in autoimmune uveitis and play an important role in the development of corneal inflammation, age-related macular degeneration and diabetic retinopathy. The evidence derived from both animal models and patient studies support the concept that complement inhibition is a relevant therapeutic target in the treatment of various ocular diseases. Currently, several clinical trials using complement inhibitors are going on. It is possible that, in the near future, complement inhibitors might be used as therapeutic agents in eye clinics.
    Molecular Immunology 10/2007; 44(16):3901-8. DOI:10.1016/j.molimm.2007.06.145 · 3.00 Impact Factor
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