Degeneration of Retinal ON Bipolar Cells Induced by Serum Including Autoantibody against TRPM1 in Mouse Model of Paraneoplastic Retinopathy

Abstract

The paraneoplastic retinopathies (PRs) are a group of eye diseases characterized by a sudden and progressive dysfunction of the retina caused by an antibody against a protein in a neoplasm. Evidence has been obtained that the transient receptor potential melastatin 1 (TRPM1) protein was one of the antigens for the autoantibody against the ON bipolar cells in PR patients. However, it has not been determined how the autoantibody causes the dysfunction of the ON bipolar cells. We hypothesized that the antibody against TRPM1 in the serum of patients with PR causes a degeneration of retinal ON bipolar cells. To test this hypothesis, we injected the serum from the PR patient, previously shown to contain anti-TRPM1 antibodies by westerblot, intravitreally into mice and examined the effects on the retina. We found that the electroretinograms (ERGs) of the mice were altered acutely after the injection, and the shape of the ERGs resembled that of the patient with PR. Immunohistochemical analysis of the eyes injected with the serum showed immunoreactivity against bipolar cells only in wild-type animals and not in TRPM1 knockout mice,consistent with the serum containing anti-TRPM1 antibodies. Histology also showed that some of the bipolar cells were apoptotic by 5 hours after the injection in wild type mice, but no bipolar cell death was found in TRPM1 knockout mice, . At 3 months, the inner nuclear layer was thinner and the amplitudes of the ERGs were still reduced. These results indicate that the serum of a patient with PR contained an antibody against TRPM1 caused an acute death of retinal ON bipolar cells of mice.

The role of transient receptor potential channels in joint diseases

“…Although DDD does not always correlate with the presence and severity of LBP, an IVD-related problem is generally accepted to be the most common cause of LBP (Schwarzer et al, 1995), as degenerated IVDs are frequently invaded by newlyformed nociceptive nerves (Sivan et al, 2014;Urban et al, 2004). Discogenic nociceptive pain is caused by a neuronal sensitisation, due to internal IVD disruption (Roberts et al, 2006), while neuropathic pain arises from neuronal damage and inflammation caused by IVD-related compression of nerve roots (Cramer and Darby, 1997;Ito and Creemers, 2013).…”

“…TRPV1 is activated by acidic pH (Dhaka et al, 2009), which is an important factor in chondrocyte and IVD homeostasis. Lactic acid accumulates in degenerative joints and IVDs as a result of impaired fluid transport (Roberts et al, 2006;Urban et al, 2004), altering the cellular repair capacity and promoting pain (Le Maitre et al, 2007). As a putative sensor for acidic pH, over-stimulated or up-regulated TRPV1 can be possibly involved in the responses of chondrocytes and IVD cells to acidity.…”

“…TRPV5/6 are highly Ca 2+ selective and tightly regulated by intracellular Ca 2+ concentration (van Abel et al, 2005). TRPV6 knockout mice suffer from severe osteoarthritis and loss of proteoglycans in articular cartilage .…”

Alternative methods to detect anti‐TRPM1 antibodies

“…Without these processes, it was difficult to differentiate the patients’ serum samples from the few control serum samples assessed in parallel. In fact, we experienced similar difficulties in obtaining reliable staining images of the bipolar cells when using other serum samples from TRPM1‐associated autoimmune retinopathy in a previous study . The technician in our lab found that performing the required optimization was not trivial, unlike Western blotting, which requires minimal effort.…”

Electrically Evoked Potentials Are Reduced Compared to Axon Numbers in Rhodopsin P347L Transgenic Rabbits With Severe Photoreceptor Degeneration

“…The retinas were used for histologic analyses, as previously described in detail. 22 The optic nerves were approximately 1 to 5 mm posterior to the sclera. They were fixed in 1% osmium tetroxide in phosphate-buffered saline.…”