Suppression of complement regulatory proteins (CRPs) exacerbates experimental autoimmune anterior uveitis (EAAU).
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.
Jha
Purushottam
P
Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
Sohn
Jeong-Hyeon
JH
Xu
Qin
Q
Wang
Yali
Y
Kaplan
Henry J
HJ
Bora
Puran S
PS
Bora
Nalini S
NS
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000954:Antigens, Surface; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology; D018957:CD59 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology; D002417:Cattle; D003176:Complement C3 / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D008297:Male; D008543:Melanins / Q000276:immunology / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000138:chemical synthesis; D034741:RNA, Small Interfering / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D011956:Receptors, Cell Surface; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D014606:Uveitis, Anterior / Q000276:immunology* / Q000378:metabolism*
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D001324:Autoantigens; D018957:CD59 Antigens; D003176:Complement C3; D003169:Complement Inactivator Proteins; D015938:Complement Membrane Attack Complex; C513105:Cr1l protein, rat; D008543:Melanins; D020319:Oligodeoxyribonucleotides, Antisense; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; D050577:Complement C3-C5 Convertases