Figure 4 - uploaded by Robert F Mullins
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Goldmann visual field of the left eye showing a near normal V4e isopter (magenta) and I4e isopter (blue) and moderate symmetrical constriction of the I2e isopter (red).
Source publication
To describe the clinical, molecular, and serologic findings of a case in which autoimmune retinopathy and early-onset heritable retinal degeneration were both considered in the differential diagnosis.
A 3-year-old girl had clinical findings suggestive of a childhood-onset retinal degeneration. Samples of DNA and serum were collected. The coding reg...
Context in source publication
Context 1
... visual acuity and fundus findings on this visit were unchanged from her initial examination. Goldmann perimetry revealed no detectable peripheral vision OD but quite well preserved peripheral vision OS (Figure 4). At this point, the asymmetry of the pupil responses, acuity, visual field and fundus examination caused the authors to consider the possibility of an inflammatory or autoimmune retinal insult as an explanation for her retinal findings. ...
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Citations
... For the most part, it is an adultonset problem, and it has been reported that patients with pAIR (CAR) tend to be significantly older than npAIR ones [17,91]. Childhood-onset cases have been reported [95]. We have confirmed repeatedly both findings in our personal experience. ...
This chapter summarizes the application of electroretinogram, electrooculogram, and/or visual evoked potential in patients with acute zonal occult outer retinopathy, multiple evanescent white dot syndrome, acute posterior multifocal placoid pigment epitheliopathy, birdshot chorioretinopathy, autoimmune retinopathy, and neuroretinopathy.
... 6 Typically, however, screening for anti-retinal autoantibodies results in multiple bands that range in size and intensity, and it is extremely rare to observe a single pathogenic autoantibody. 7 In this case, multiple circulating anti-retinal antibodies were identified, suggesting a humoral component of immune activation. However, we also identified a strong T-cell response, demonstrating that both arms of the immune system are involved in the retinal injury seen in AIR. ...
Purpose:
1) To describe a case of autoimmune retinopathy mimicking heritable photoreceptor degeneration in a patient with common variable immune deficiency and 2) to investigate the humoral and cell-mediated branches of the immune system in this patient to better understand the mechanism of immune-mediated photoreceptor damage in this disease.
Methods:
Retrospective chart review with evaluation of multimodal imaging, genotype analysis, and investigation of circulating autoantibodies and T-cell response to retinal antigens.
Results:
A 40-year-old woman with bilateral, progressive vision loss was referred for evaluation of a possible inherited retinal degeneration. She was found to have asymmetric peripheral visual field constriction, cystoid macular edema, vitreous cells, and bone spicule-like pigmentary changes in both eyes. An extensive workup for underlying infectious or inflammatory causes was unrevealing, and molecular analysis for heritable retinal degeneration failed to identify a plausible disease-causing genotype. Screening for antiretinal antibodies showed the presence of multiple antiretinal antibodies, consistent with a diagnosis of autoimmune retinopathy. Immunologic workup demonstrated markedly decreased levels of serum IgA and IgG, consistent with common variable immune deficiency. T-cells isolated from the patient showed increased proliferation when stimulated with human retinal proteins, supporting a role for both cell- and humoral-mediated autoimmunity. Treatment with mycophenolate mofetil and intravenous immunoglobin therapy slowed the progression of disease and resulted in preservation of her central vision.
Conclusion:
Autoimmune retinopathy can be seen in common variable immune deficiency and has clinical findings similar to heritable photoreceptor degeneration. Both the humoral and cellular immune responses are involved in the pathophysiology. Immune modulatory therapy has stabilized the disease course in this patient and may play an important role in the management of autoimmune retinopathy.
... Multiple reports have shown the association of both alpha- enolase and gamma-enolase antibodies in serum to autoimmune re- tinopathy. 2,3 Serum anti-enolase antibodies can be found in other in- flammatory conditions and their presence does not prove causality in the context of autoimmune retinopathy. 4,5 However, in this case, an extensive workup for autoimmune retinopathy was negative except for the large renal oncocytoma, which was positive for alpha-enolase throughout the biopsy sample on immunohistochemistry. Hence, we postulate in this case that the large burden of alpha-enolase expressed by the tumor was the inciting antigen for the autoimmune retinopathy and optic neuropathy. ...
Purpose
To report a case of autoimmune retinopathy and optic neuropathy associated with an enolase-positive renal oncocytoma.
Observations
A 41-year-old man presented with subacute, painless, bilateral vision loss. On initial examination, visual acuity measured 20/125 OD and 20/1250 OS, and telangiectatic vessels were noted on the optic nerves and in the maculae. Goldmann perimetry showed bilateral, cecocentral scotomas, and electroretinography demonstrated reduced photopic and scotopic signals, concerning for autoimmune retinopathy. Serum testing showed multiple positive anti-optic nerve and anti-retinal antibodies, including to alpha-enolase. Extensive systemic workup was negative except for a large, exophytic, right renal mass. Biopsy was consistent with a benign oncocytoma, and immunohistochemical staining showed diffusely positive alpha-enolase staining. The patient was treated with a five-day course of intravenous methylprednisolone and plasmapheresis with minimal improvement. Surgical excision of the oncocytoma was performed. At 9-months post-operatively, visual acuity had improved to 20/40 OU, with corresponding improvement on visual field and electroretinography testing.
Conclusions and importance
To our knowledge, this is the first report of autoimmune retinopathy and optic neuropathy associated with a renal oncocytoma. The case highlights the importance of a thorough systemic workup in cases of suspected autoimmune retinopathy and reminds clinicians that even tumors considered benign can have distal effects on other organs.
... Further, increased oxidation of alpha-enolase also occurs in other models of AD [57, 67]. Several pathologies are linked to enolase-dependent pathways [68, 69]. Another protein that is involved in energy metabolism, i.e., ATP synthase α-chain, a component of Complex V of the mitochondrial electron transport chain, is also found to be oxidatively modified in these knock in mice. ...
Alzheimer disease (AD) is the most common type of dementia and is characterized pathologically by the presence of neurofibrillary tangles (NFTs), senile plaques (SPs), and loss of synapses. The main component of SP is amyloid-beta peptide (Aβ), a 39 to 43 amino acid peptide, generated by the proteolytic cleavage of amyloid precursor protein (APP) by the action of beta- and gamma-secretases. The presenilins (PS) are components of the γ-secretase, which contains the protease active center. Mutations in PS enhance the production of the Aβ42 peptide. To date, more than 160 mutations in PS1 have been identified. Many PS mutations increase the production of the β-secretase-mediated C-terminal (CT) 99 amino acid-long fragment (CT99), which is subsequently cleaved by γ-secretase to yield Aβ peptides. Aβ has been proposed to induce oxidative stress and neurotoxicity. Previous studies from our laboratory and others showed an age-dependent increase in oxidative stress markers, loss of lipid asymmetry, and Aβ production and amyloid deposition in the brain of APP/PS1 mice. In the present study, we used APP (NLh)/APP(NLh) × PS-1(P246L)/PS-1(P246L) human double mutant knock-in APP/PS-1 mice to identify specific targets of brain protein carbonylation in an age-dependent manner. We found a number of proteins that are oxidatively modified in APP/PS1 mice compared to age-matched controls. The relevance of the identified proteins to the progression and pathogenesis of AD is discussed.
... Membrane strips that were only probed with secondary antibody served as negative controls; membrane strips that were probed with a serum sample that had previously demonstrated antienolase antibody activity served as a positive control. 13 The number of bands on Western blot was counted in a masked fashion for each patient sample. Bands corresponding to the reduced IgG heavy-chain band were not included in analysis; visualized bands were omitted if the band signal intensity was less than 1.5 times that of the background for that sample as quantified using Adobe Photoshop (version 10.0; Adobe Systems Inc, San Jose, California). ...
... In addition, autoimmune retinopathy may mimic inherited retinal disease in some cases, as we noted recently in a patient with anti-enolase activity. 13 The role of circulating antibodies reactive to retinal proteins in the pathogenesis of other retinal diseases is still unclear and was discussed in a recent letter and a response to that letter in this journal. [17][18][19] Previous studies looking at healthy populations have reported varying levels of antiretinal antibody activity. ...
... However there is good evidence that antibodies to enolase and especially to recoverin cause retinal degeneration. 7,11,13,20 Further studies are needed to determine the identity of pathogenic autoantibodies as well as the significance of reactivity against aqueous-and detergent-soluble retinal proteins. Patients with additional typesofposterioruveitisshouldbetested,andserumsamples should also be assessed during different stages of disease to correlate autoantibody activity with appearance of retinal inflammation. ...
To characterize the seroreactivity against retinal proteins in patients with posterior uveitis, retinal disease of noninflammatory origin, and healthy controls.
Patients with posterior uveitis (n = 47), molecularly confirmed photoreceptor degenerations (n = 11), and healthy controls (n = 33) received dilated fundus examinations at the University of Iowa. Aqueous-soluble and detergent-soluble fractions of human retina were separated by gel electrophoresis and transferred to polyvinylidene fluoride membranes. Membranes were probed with patient serum samples to detect IgG, IgA, and IgM human antibodies that react with retinal antigens. The number of bands detected by Western blot was counted, and their molecular weights were determined.
Antibodies recognizing retinal proteins were found in healthy controls, in patients with posterior uveitis, and in patients with molecularly confirmed heritable retinal degenerations. In healthy controls, 42% of individuals had circulating autoantibodies that recognized retinal proteins. Healthy controls had a low odds ratio of serum reactivity to soluble antigens (0.7; 95% confidence interval [CI], 0.4-1.2). Patients with inflammatory retinal diseases and inherited retinal diseases had 4.89 (95% CI, 2.25-10.64; P < .001) and 2.71 (95% CI, 1.19-6.16; P = .02) times more activity against soluble retinal antigens compared with controls.
Healthy control patients exhibited a significantly higher level of background autoantibody activity against retinal proteins than previously reported. Antibody activity in healthy controls was primarily directed against membrane-bound retinal proteins, whereas in patients with pathologic retinal conditions, antibodies targeting nonmembrane-bound retinal proteins predominate.
Purpose:
Our aim was to use molecular biological methods to study evidence of autoimmune disease in five patients with acute zonal occult outer retinopathy (AZOOR).
Methods:
Ophthalmologic data and sera were collected from all patients, who underwent visual field (VF) examination, optical coherence tomography (OCT), and multifocal electroretinogram (mfERG) recording. Serum was prepared from each patient's blood and analyzed for antiretinal antibody activity using immunohistochemistry and Western blot analysis on mouse and human retinas. We also searched for antigen proteins using mass spectrometry.
Results:
Symptoms were blurred vision in three patients and VF defects in two; all had enlargement of the Mariotte blind spot by VF testing. OCT findings in areas corresponding to the scotoma revealed disruptions of junction borders between inner and outer segment lines. mfERGs amplitudes were reduced in each corresponding scotoma area. Immunohistochemical serum staining revealed the target antigen was present in all photoreceptors of the mouse sensory retina. Western blot analysis using patient serum samples revealed some possible candidate antigens. Mass spectrometry could not determine the causative antigen; however, a list of candidates was discovered.
Conclusion:
We determined that AZOOR could be an autoimmune disease. All AZOOR patients tested using molecular biological methods had antiretinal antigens.
