Parabiosis Reveals That Recruitment of Circulating Antigen Presenting Cells is Necessary for the Induction of Autoimmune Retinitis

Abstract

Purpose : Characterizing immune cells and conditions that govern their recruitment and function in autoimmune diseases of the nervous system or in neurodegenerative processes is an area of active investigation. We sought to analyze the origin of antigen presenting cells associated with the induction of retinal autoimmunity using a system that relies on spontaneous autoimmunity rather than experimentally induced autoimmunity, avoiding uncertainties associated with immunization with adjuvants at remotes sites or adoptive transfer of in-vitro activated T cells.

Methods : We used R161H TCR transgenic mice (Horai, et. al. J Autoimmunity 44:21, provided by Dr. R. Caspi, B10.R3 background), which spontaneously and rapidly develop severe autoimmune retinitis (AR), in conjunction with CD11c^DTR/GFP mice (B6/J background) that allow tracking of activated, antigen presenting microglia within the retina (GFP^hi cells). R161H^+/- x B6/J F₁ mice were used to analyze the influx/expansion of antigen presenting cells and T cells relative to the course of AR. Parabiosis using R161H^+/- x B6/J F₁ mice paired with B10.R3 x B6/J F₁ (wild type recipient) mice was done to explore the origin and phenotype of antigen presenting cells crucial for the induction of autoimmunity. Analysis was done by retinal imaging, flow cytometry, and histology.

Results : Onset of AR in R161H^+/- x B6/J F₁ mice was delayed relative to B10.R3-R161H^+/- mice revealing a distinct prophase of the disease prior to frank autoimmunity that was characterized by expansion of GFP^hi cells within the retina prior to any clinical or histological evidence of autoimmunity. Parabiosis between mice carrying the R161H and CD11c^DTR/GFP transgenes and wild type recipients showed that recruitment of circulating GFP^hicells to retinas was required for induction of AR. GFP^hi cells were found in 19/30 retinas from wild type recipients with 12 of those recipients developing AR. Conversely, none of the 11 recipients devoid of GFP^hicells developed AR (p = 0.0006).

Conclusions : Our results here contrast with our previous findings showing that retinal antigen presenting cells expanding in response to either sterile inflammatory injury or neurodegeneration were derived from myeloid cells within the retina or optic nerve thus highlighting a unique facet of retinal autoimmunity.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.