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I would like to to applaud the editorial by Peter J. McDonnell, MD, on the “Ocular effects of autoimmunity” (Ophthalmology Times, June 15, 2018). Not only did this editorial broaden the playing field in trying to take away the sting of the “mystery of unknown etiology” of diagnosis but it also suggested alternate mechanisms for ophthalmic pathophysiology, say from the standpoint of latent Epstein-Barr (EB) virus infection, early and later transcription factor and immune response.
This type of thinking and research in ophthalmology has begun and may be achieving more comprehensive discussion. For example, in 20031 to understand the role of oxidative damage in agerelated macular degeneration (AMD), Gu et al. found carboxyethylpyrrole protein adducts from free radical oxidation of docosahexaenoic acid lipids, also found in drusen, to be more abundant in AMD patients than normal human donors.
Given the progressive oxidative stress damage to the cone membranes and retinal pigment epithelium (RPE) with AMD perhaps yet additional lipoprotein breakdown products that produce adducts and immune deposits under or above Bruch’s membrane, these breakdown products with autoimmune potential could possibly be a source for antibody removal in the form of vaccines or more specific antiinflammatory drugs.
Others2,3,4,5 more recently have raised similar issues about drusen composition with immunoreactivities to apolipoprotein E, amyloid beta, Complement component C5, vitronectin, and others from chronic inflammation that may prompt retinal antibody and autoantibody and autoimmune reactions, in addition to chronic Complement and inflammatory mediator response in AMD.
In a similar vein to the EB virus infection that is discussed, there is also recent evidence in Alzheimer’s disease6 and AMD7 that human herpes virus 6A perhaps by downregulating CD46 after it docks with it on astrocytes surfaces, can lead to complement activation (as it does with MS leading to oligoclonal antibodies).
The loss or reduction of CD46 is one of the earliest retinal RPE changes on the way to geographic atrophy.7 As you point out, generations from now people will say: “Autoimmunity, of course..."
Joseph W. Eichenbaum, MD, MPH is an adjunct associate professor ophthalmology atMt. Sinai School of Medicine New York, NY.
1. Gu X, Meer SG, Miyagi M, Rayborn ME, Hollyfield JG et al. Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem. 2003;278:42027-42035.
2. Umeda S, Suzuki MT, Okamoto H, Ono F, Mizota A, Terao K, Yoshikawa Y, Tanaka Y, Iwata T. Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis) FASEB J. 2005b;19:1683–1685.
3. Morohoshi K, Goodwin AM, Ohbayashi M, Ono SJ. Autoimmunity in retinal degeneration: autoimmune retinopathy and age-related macular degeneration. J Autoimmun. 2009;33:247-254.
4. Adamus G. Are anti-retinal autoantibodies a cause or a consequence of retinal degeneration in autoimmune retinopathies? Front Immunol. 2018;9:765. doi: 10.3389/ fimmu.2018.00765.
5. Lashkari K, Teague G, Chen H, Lin YQ, Kumar S, McLaughlin MM, LÃ³pez FJ. A monoclonal antibody targeting amyloid beta restores complement factor I bioactivity: Potential implications in age-related macular degeneration and Alzheimer’s disease. PLoS One. 2018;13:e0195751.
6. Readhead B et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpes virus. Neuron. 2018;99:64-82
7. Fierz W. Age-related macular degeneration: A connection between human herpes virus-6A-induced CD46 downregulation and complement activation? Front Immunol. 2017;17;1314. Epub 2017 Oct 17.