� 140 KD, 4 domains, conserved � Unique to eye � Functions in retinoid transport
Quantitation of disease:
Scored on a scale of 0 – 4, according to number and size of lesions.
Strain dependence of susceptibility
B10.RIII, B10.A - susceptible
AKR, BALB/c - resistant
Normal EAU 2–3 + Fundoscopy Histology Induction: Immunize with IRBP or adoptively transfer primed T cells (Th1) Onset: d 4-6 (cell transfer) or d 9-12 (immunization)
day 14 (cell transfer) or
day 21 (immunization)
Assess EAU & responses
// 2 4 6 19 0 21
Murine EAU vs. uveitis - clinical and histology EAU in mouse Ocular Sarcoidosis Normal mouse retina Human: Normal fundus Ocular Sarcoidosis Mouse : Normal fundus Uveitic fundus
Cellular mechanisms in EAU
T cell dependent: Transferred from immunized donors to normal recipients by T cells, but not by serum (although antibodies when present can modify the course of disease)
Pathogenic T cell has a Th1-like phenotype
Susceptible individuals are genetically predisposed to a Th1 response
Long-term T cell lines specific to retinal antigen transfer disease without formation of detectable serum antibodies
Disease suppressed or reversed by pharmacological T cell-targeting agents, e.g., CsA, rapamycin, anti-IL-2R Ab
Amenable to regulation by Ag-specific genetic therapies through induction of peripheral tolerance
IL-10 has a negative regulatory role
EAU vs human uveitis: similarities and differences
Triggering event induced “spontaneous”
Reactivity to retinal Ag immunizing Ag S-Ag, IRBP, recoverin
Clinical course acute or chronic usually chronic
chororoiditis yes Yes retinitis Yes yes subretinal neovasc some some iridocyclitis yes yes
Genetic control MHC & background MHC (background?)
MHC genes involved class II class I and class II
Central role for T cells Yes (lines, clones) Yes (efficacy of T ce ll targeting treatments)
Role of antibodies Modifying Suspected
Caspi, R.R. Immune mechanisms in uveitis. Springer Sem. Immunopathol . 21:113-124, 1999.
Caspi, Rachel R. The Role of Cytokines in Induction and Regulation of Autoimmune Uveitis. In: Cytokines and Autoimmune Diseases , (V.K. Kuchroo, N. Sarvetnick, D.A. Hafler and L.G. Nicholson, Eds.). pp. 227-245, Humana Press, NJ, 2001
Gery, I., R.B. Nussenblatt, C.C. Chan and R.R. Caspi. Autoimmune diseases of the eye. in: The Molecular Pathology of Autoimmune Diseases , 2 nd Edition, (A.N. Theophilopoulos and C.A. Bona,, editors). Taylor and Francis, New York, NY pp. 978-998, 2002
Caspi, RR. Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis. International Reviews of Immunology 21:197-208, 2002.
Pennesi, G and R.R. Caspi. Genetic control of susceptibility in clinical and experimental uveitis. International Reviews of Immunology 21:67-88, 2002.
Caspi RR. Regulation, counter-regulation, and immunotherapy of autoimmune responses to immunologically privileged retinal antigens. Immunol Res. 2-3):149-60 (2003).