Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Abstract

Misregulation of the innate immune response and other immune-related processes have been suggested to play a critical role in the pathogenesis of a number of different neurodegenerative diseases, including age related macular degeneration. In an animal model for photoreceptor degeneration, several genes of the innate and acquired immune system were found to be differentially regulated in the retina during the degenerative process. In addition to this differential regulation of individual genes, we found that in the rd1 retina a significantly higher number of genes involved in immune-related responses were expressed at any given time during the degenerative period. The peak of immune-related gene expression was at postnatal day 14, coinciding with the peak of photoreceptor apoptosis in the rd1 mouse. We directly tested the potential involvement of acquired and innate immune responses in initiation and progression of photoreceptor degeneration by analyzing double mutant animals. Retinal morphology and photoreceptor apoptosis of rd1 mice on a SCID genetic background (no mature T-and B-cells) or in combination with a RAG-1 (no functional B-and T-cells) or a C1qα (no functional classical complement activation pathway) knockout was followed during the degenerative process using light microscopy or TUNEL staining, respectively. Although complement factor C1qα was highly up-regulated in the rd1 retina concomitantly with the degenerative process, lack of this protein did not protect the rd1 retina. Similarly, retinal degeneration and photoreceptor apoptosis appeared to proceed normally in the rd1 mouse lacking functional Band T-cells. Our results suggest that both, the classical complement system of innate immunity and a functional acquired immune response are not essential for the degenerative process in the rd1 mouse retina.

Sialoadhesin Expression in Intact Degenerating Retinas and Following Transplantation

“…36 It has been shown in genetic studies that lack of functional B and T cells or of complement factor C1q␣ has no impact on the progression of photoreceptor cell loss in rd1 mice, suggesting that the classic complement system of innate immunity and acquired immune responses may not be implicated. 75 Yet, these observations and the fact that Sn is not expressed in retinal macrophages in the two models studied should not be taken as definitive indication that immune-related events do not contribute to photoreceptor cell loss.…”

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

“…In support of this hypothesis, we show that in the absence of C1q, cone photoreceptor viability and function are significantly compromised. It is of interest to note that in an elegant study, Rohrer et al 53 have recently reported that photoreceptor degeneration in the rd1 mouse, with a naturally occurring null mutation within the gene encoding the b-subunit of cyclic GMP phosphodiesterase, is unaffected in the absence of C1q. However, no ERG studies on cone cell function were reported in that study, and the rapidity of retinal degeneration in that model (complete photoreceptor loss within 3 weeks of birth) may have masked any more subtle effects in phenotype that may have been induced by the absence of C1q.…”

Analysis of Complement Expression in Light-Induced Retinal Degeneration: Synthesis and Deposition of C3 by Microglia/Macrophages Is Associated with Focal Photoreceptor Degeneration

“…57,58 However, the ablation of C1q␣ in rd1 mice did not appear to delay the removal of apoptotic cells, indicating that the classic pathway-or at least C1q␣-alone may not be sufficient to initiate their clearance. 59 We also showed differential expression of the carbohydrate recognition molecule ficolin B, which promotes the removal of late-stage apoptotic cells through binding to DNA, 60 mediated by the lectin pathway. Upregulation of these genes suggests that a role of complement activation in this model is the efficient removal of apoptotic cells after BCL.…”