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Anatomy of human eye and retinal layers. Diagram of the eye and the organization of retinal layers and cells showing H&E staining of representative section of human retina. Abbreviations: OS, outer segments; IS, inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer.
Source publication
Autoantibodies (AAbs) against glycolytic enzymes: aldolase, α-enolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase are prevalent in sera of patients with blinding retinal diseases, such as paraneoplastic [cancer-associated retinopathy (CAR)] and non-paraneoplastic autoimmune retinopathies, as well as in many other autoimmune disea...
Citations
... These AABs, however, may also be present in various uveitic diseases, cataracts, and normal individuals without ocular diseases. Therefore, it remains controversial to diagnose AIR based solely on AAB positivity [5][6][7][8][9]. ...
Background: To describe longitudinal changes in patients with non-paraneoplastic autoimmune retinopathy (npAIR) by utilizing different diagnostic modalities/tests. Methods: The index study is a retrospective longitudinal review of sixteen eyes of eight patients from a tertiary care eye hospital diagnosed with npAIR. Multiple diagnostic modalities such as wide-angle fundus photography (WAFP), WA fundus autofluorescence (WAFAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann visual field (GVF) perimetry, microperimetry (MP), electrophysiologic testing, and adaptive optics scanning laser ophthalmoscopy (AOSLO) were reviewed and analyzed. Results: At the baseline visits, anomalies were detected by multimodal diagnostic tests on all patients. Subjects were followed up for a median duration of 11.5 [3.0–18.7] months. Structural changes at the baseline were detected in 14 of 16 (87.5%) eyes on WAFP and WAFAF and 13 of 16 (81.2%) eyes on SD-OCT. Eight of the ten (80%) eyes that underwent AOSLO imaging depicted structural changes. Functional changes were detected in 14 of 16 (87.5%) eyes on GVF, 15 of 16 (93.7%) eyes on MP, and 11 of 16 (68.7%) eyes on full-field electroretinogram (ff-ERG). Multifocal electroretinogram (mf-ERG) and visual evoked potential (VEP) tests were performed in 14 eyes, of which 12 (85.7%) and 14 (100%) of the eyes demonstrated functional abnormalities, respectively, at baseline. Compared to all the other structural diagnostic tools, AOSLO had a better ability to demonstrate deterioration in retinal microstructures occurring at follow-ups. Functional deterioration at follow-up was detected on GVF in 8 of 10 (80%) eyes, mf-ERG in 4 of 8 (50%) eyes, and MP in 7 of 16 (43.7%) eyes. The ff-ERG and VEP were stable in the majority of cases at follow-up. Conclusions: The utilization of multimodal imaging/tests in the diagnosing and monitoring of npAIR patients can aid in identifying anomalous changes over time. Analysis of both the anatomical and functional aspects by these devices can be supportive of detecting the changes early in such patients. AOSLO shows promise as it enables the capture of high-resolution images demonstrating quantifiable changes to retinal microstructure.
... We use this boundary line to screen for proteomic markers that might define this 'level of CNV control' axis (by regarding Euclidian distance between the UMAP coordinate and the SVM boundary). Interestingly, with Aldolase C-a key enzyme for glycolysis [43]-we find a biomarker that is significantly overrepresented on the ECC pole (compare Figure 2d-f, Table S8). We rate the finding of Aldolase C supportive for this model, as it has previously been associated with AMD [44]. ...
... In Figure 2, we can provide some significant marker correlations of morphological and functional nAMD features (Prefoldin Subunit 2 for SRF; Peroxiredoxin-6 for SHRM, both features determined on OCT scan) with Aldolase C being associated with effective control of CNV activity (Figure 2, compare CAC and ECC criteria in methods). The identified molecules have already been weakly associated with the given conditions but need to undergo further confirmation [40,41,43,44]. Interestingly, anti-retinal auto-antibodies against Aldolase C have been identified as potential disease drivers in nAMD [44]. ...
There is early evidence of extraocular systemic signals effecting function and morphology in neovascular age-related macular degeneration (nAMD). The prospective, cross-sectional BIOMAC study is an explorative investigation of peripheral blood proteome profiles and matched clinical features to uncover systemic determinacy in nAMD under anti-vascular endothelial growth factor intravitreal therapy (anti-VEGF IVT). It includes 46 nAMD patients stratified by the level of disease control under ongoing anti-VEGF treatment. Proteomic profiles in peripheral blood samples of every patient were detected with LC-MS/MS mass spectrometry. The patients underwent extensive clinical examination with a focus on macular function and morphology. In silico analysis includes unbiased dimensionality reduction and clustering, a subsequent annotation of clinical features, and non-linear models for recognition of underlying patterns. The model assessment was performed using leave-one-out cross validation. The findings provide an exploratory demonstration of the link between systemic proteomic signals and macular disease pattern using and validating non-linear classification models. Three main results were obtained: (1) Proteome-based clustering identifies two distinct patient subclusters with the smaller one (n = 10) exhibiting a strong signature for oxidative stress response. Matching the relevant meta-features on the individual patient's level identifies pulmonary dysfunction as an underlying health condition in these patients. (2) We identify biomarkers for nAMD disease features with Aldolase C as a putative factor associated with superior disease control under ongoing anti-VEGF treatment. (3) Apart from this, isolated protein markers are only weakly correlated with nAMD disease expression. In contrast, applying a non-linear classification model identifies complex molecular patterns hidden in a high number of proteomic dimensions determining macular disease expression. In conclusion, so far unconsidered systemic signals in the peripheral blood proteome contribute to the clinically observed phenotype of nAMD, which should be examined in future translational research on AMD.
... All PrEST antigens with hits in both JIA plasma pools on the planar array were included in the bead array, as well as PrEST antigens from the majority of the proteins captured by both pools in the immunoprecipitations. Antigens from proteins detected by immunoprecipitation, but unlikely to be produced by the cell type used for protein extract were not included in the bead array. The remaining PrEST antigens were chosen to represent all subcellular locations and protein families identified in planar array and immunoprecipitations, together with antigens from proteins recognized as autoantigens in JIA or autoimmune uveitis in the literature (4,(18)(19)(20)(22)(23)(24)(25)(26)(27). ...
Background
Many children with juvenile idiopathic arthritis (JIA) have autoantibodies, targeting nuclear components (anti-nuclear antibodies, ANA). ANA in JIA is associated with uveitis, an eye inflammation which may cause permanent vision impairment if not detected and treated. However, ANA-testing is neither specific nor sensitive enough to be a clinically reliable predictor of uveitis risk, and the precise autoantigens targeted by ANA in JIA are largely unknown. If identified, specific autoantibodies highly associated with uveitis could be used as biomarkers to facilitate identification of JIA patients at risk.
Methods
Antibodies from six ANA-positive, oligoarticular JIA patients, with and without uveitis, were explored by two large-scale methods: (1) screening against 42,100 peptides on an autoimmunity profiling planar array, and (2) immunoprecipitations from cell lysates with antigen identification by mass spectrometry. Three hundred thirty-five peptide antigens, selected from proteins identified in the large-scale methods and the scientific literature were investigated using a bead-based array in a cohort of 56 patients with oligoarticular- or RF-negative polyarticular JIA, eight of which were having current or previous uveitis.
Results
In the planar array, reactivity was detected against 332 peptide antigens. The immunoprecipitations identified reactivity towards 131 proteins. Only two proteins were identified by both methods. In the bead-based array of selected peptide antigens, patients with uveitis had a generally higher autoreactivity, seen as higher median fluorescence intensity (MFI) across all antigens, compared to patients without uveitis. Reactivity towards 17 specific antigens was significantly higher in patients with uveitis compared to patients without uveitis. Hierarchical clustering revealed that patients with uveitis clustered together.
Conclusion
This study investigated autoantigens in JIA and uveitis, by combining two exploratory methods and confirmation in a targeted array. JIA patients with current or a history of uveitis had significantly higher reactivity towards 17 autoantigens and a generally higher autoreactivity compared to JIA patients without uveitis. Hierarchical clustering suggests that a combination of certain autoantibodies, rather than reactivity towards one specific antigen, is associated with uveitis. Our analysis of autoantibodies associated with uveitis in JIA could be a starting point for identification of prognostic biomarkers useful in JIA clinical care.
... Enolase-α is an important catalyzing enzyme in the glycolytic pathway. It is widely distributed in the retina and mainly distribute in photoreceptor cells and Müller cells 30 . Enolase-α antibody may penetrate retinal tissue and inhibit the catalytic function of enolase-α, resulting in the dysfunction of glycolysis and ATP depletion in retina cells. ...
This study aimed to investigate the correlation between the severity of photoreceptor damage and the level of anti-retina antibodies (ARAs) in aqueous humor, including recoverin, CA II and enolase-α IgG antibody of macular edema patients. Aqueous humor samples were collected from macular edema patients and from cataract patients. Patients were divided into three groups according to the severity of discontinuity of ellipsoid zone (EZ) shown on optical coherence tomography (OCT) imaging: cataract patients with intact EZ, macular edema patients with mild EZ damage, and macular edema patients with severe EZ damage. The level of ARAs was determined with enzyme-linked immunosorbent assay (ELISA). The correlation between the level of ARAs and the degree of photoreceptor damage was analyzed. The level of ARAs of the intact EZ group was significantly lower than that in the severely damaged group ( P < 0.05). The level of recoverin IgG of the intact EZ group was significantly lower than mildly damaged group ( P = 0.030). In a subgroup analysis, the level of recoverin IgG of DME patients was correlated with their central retinal thickness (CRT) ( r = 0.462, P = 0.035). The level of ARAs in aqueous humor of patients with DME and RVO-ME was correlated with the degree of photoreceptor damage.
... In addition to its catalytic function, enolase has many other functions related to different biological processes. Human enolase has been reported to play roles in many diseases, such as cancers (Wang et al., 2020;Yang et al., 2020), autoimmune disorders (Adamus, 2017), infections (Bergmann et al., 2013), and ischemia (Haupt et al., 2016). Enolase acts as a moonlighting protein in various pathogens. ...
Mycoplasmas are a group of prokaryotes without cell walls that have evolved through several rounds of degenerative evolution. With a low cell DNA G + C content and definitively long genetic lineages, mycoplasmas are thought to be in a state of rapid evolution. However, little associated evidence has been provided. Enolase is a key enzyme in glycolysis that is widely found in all species from the three domains, and it is evolutionarily conserved. In our previous studies, enolase acted as a virulence factor and participated in cell-surface adhesion in Mycoplasma hyopneumoniae . Furthermore, unique loop regions were first found in the crystal structure of Mhp Eno. Here, enolase structures from Mycoplasma pneumoniae and Mycoplasma bovis were determined. An extra helix 7 is specific and conservatively found in almost all mycoplasma enolases, as confirmed by crystal structures and sequence alignment. Particular motifs for helix 7, which is composed of F-K/G-K-L/F-K-X-A-I, have been proposed and could be regarded as molecular markers. To our surprise, the genetic distances between any two mycoplasma enolases were obviously longer than those between the two corresponding species themselves, indicating divergent evolution of mycoplasma enolases, whereas no horizontal gene transfer was detected in mycoplasma enolase genens. Furthermore, different evolutionary patterns were adopted by different loop regions of mycoplasma enolase. Enolases from different Mycoplasma species also showed different affinities for PLG and fibronectin. Our results indicate the rapid and divergent evolution of mycoplasma enolase and mycoplasmas. This study will also aid understanding the independent evolution of Mycoplasma species after separation from their common ancestor.
... Aldolase has been described as an autoantigen in patients with some autoimmune disorders including Alzheimer's disease (Mor et al., 2005), atypical movement disorders (Privitera et al., 2013), and autoimmune retinopathies (Adamus 2017). Antibodies in serum from Alzheimer's patients, as well as some patients with multiple sclerosis and healthy controls, bind to aldolase A (ALDOA) (Mor et al., 2005). ...
Fructose 1,6-bisphosphate aldolase is a ubiquitous cytosolic enzyme that catalyzes the fourth step of glycolysis. Aldolases are classified into three groups: Class-I, Class-IA, and Class-II; all classes share similar structural features but low amino acid identity. Apart from their conserved role in carbohydrate metabolism, aldolases have been reported to perform numerous non-enzymatic functions. Here we review the myriad “moonlighting” functions of this classical enzyme, many of which are centered on its ability to bind to an array of partner proteins that impact cellular scaffolding, signaling, transcription, and motility. In addition to the cytosolic location, aldolase has been found the extracellular surface of several pathogenic bacteria, fungi, protozoans, and metazoans. In the extracellular space, the enzyme has been reported to perform virulence-enhancing moonlighting functions e.g., plasminogen binding, host cell adhesion, and immunomodulation. Aldolase’s importance has made it both a drug target and vaccine candidate. In this review, we note the several inhibitors that have been synthesized with high specificity for the aldolases of pathogens and cancer cells and have been shown to inhibit classical enzyme activity and moonlighting functions. We also review the many trials in which recombinant aldolases have been used as vaccine targets against a wide variety of pathogenic organisms including bacteria, fungi, and metazoan parasites. Most of such trials generated significant protection from challenge infection, correlated with antigen-specific cellular and humoral immune responses. We argue that refinement of aldolase antigen preparations and expansion of immunization trials should be encouraged to promote the advancement of promising, protective aldolase vaccines.
... Reported to be related to various types of cancers, anti-Rab6 autoantibody could be found in both npAIR and pAIR patients 2,9 . The autoantibody against Rab6 is not detected in the normal population, thus making it a potentially specific biomarker for AIR, although the prevalence is low 10 . On the contrary, anti-HSP60 represents a natural antibody developed toward common pathogen invasions 36 www.nature.com/scientificreports/ ...
Autoimmune retinopathy (AIR) is a rare immune-mediated inflammation of the retina. The autoantibodies against retinal proteins and glycolytic enzymes were reported to be involved in the pathogenesis. This retrospective cohort study assessed the antiretinal autoantibody profiles and their association with clinical outcomes of AIR patients in Thailand. We included 44 patients, 75% were females, with the overall median age of onset of 48 (17–74, IQR 40–55.5) years. Common clinical presentations were nyctalopia (65.9%), blurred vision (52.3%), constricted visual field (43.2%), and nonrecordable electroretinography (65.9%). Underlying malignancy and autoimmune diseases were found in 2 and 12 female patients, respectively. We found 41 autoantibodies, with anti-α-enolase (65.9%) showing the highest prevalence, followed by anti-CAII (43.2%), anti-aldolase (40.9%), and anti-GAPDH (36.4%). Anti-aldolase was associated with male gender (P = 0.012, OR 7.11, 95% CI 1.54–32.91). Anti-CAII showed significant association with age of onset (P = 0.025, 95% CI − 17.28 to − 1.24), while anti-α-enolase (P = 0.002, OR 4.37, 95% CI 1.83–10.37) and anti-GAPDH (P = 0.001, OR 1.87, 95% CI 1.32–2.64) were significantly associated with nonrecordable electroretinography. Association between the antibody profiles and clinical outcomes may be used to direct and adjust the treatment plans and provide insights in the pathogenesis of AIR.
... Antibodies against TPI (Vermeulen et al., 2011), ALDO (Magrys et al., 2007;Goëb et al., 2009;Vermeulen et al., 2011), GAPDH (Adamus et al., 2011), PGK (Goëb et al., 2009, PGM (Kimura et al., 2010;Vermeulen et al., 2011) and ENO (Terrier et al., 2007;Goëb et al., 2009;Adamus et al., 2011;Vermeulen et al., 2011;Maccallini et al., 2018) are linked to the development of retinopathy, rheumatoid arthritis, autoimmune hepatitis, inflammatory bowel disease and Lyme disease. The high expression of the glycolytic proteins in the diseases mentioned before, together with frequent infections and chronic inflammation, and the high extracellular exposure of some of these protein may promote the production of autoantibodies (Adamus, 2017), suggest that "mimicking" glycolytic enzymes in order to establish on a host, might not be the best mechanism. HEXOKINASE Hexokinase was first described by Otto Meyerhof who demonstrated the stimulatory effect of a baker's yeast extract on the fermentation of hexoses (Meyerhof, 1927). ...
Moonlighting proteins are defined as proteins with two or more functions that are unrelated and independent to each other, so that inactivation of one of them should not affect the second one and vice versa. Intriguingly, all the glycolytic enzymes are described as moonlighting proteins in some organisms. Hexokinase (HXK) is a critical enzyme in the glycolytic pathway and displays a wide range of functions in different organisms such as fungi, parasites, mammals, and plants. This review discusses HXKs moonlighting functions in depth since they have a profound impact on the responses to nutritional, environmental, and disease challenges. HXKs’ activities can be as diverse as performing metabolic activities, as a gene repressor complexing with other proteins, as protein kinase, as immune receptor and regulating processes like autophagy, programmed cell death or immune system responses. However, most of those functions are particular for some organisms while the most common moonlighting HXK function in several kingdoms is being a glucose sensor. In this review, we also analyze how different regulation mechanisms cause HXK to change its subcellular localization, oligomeric or conformational state, the response to substrate and product concentration, and its interactions with membrane, proteins, or RNA, all of which might impact the HXK moonlighting functions.
... The upregulation of enolase during metabolic processes as well as the release from dying cells may lead to its uptake by antigen-presenting cells. The subsequent B cell activation triggers an excessive production of anti-enolase antibodies (AAbs) that can potentially initiate tissue injury, e.g., as a result of immune complex deposition [23]. In fact, circulating anti-alpha-enolase antibodies (anti-ENO1 Ab) were identified in numerous autoimmune diseases like autoimmune retinopathy and cancer-associated retinopathy [24,25], ANCA positive vasculitis [26], systemic and multiple sclerosis [27,28], Behçet's disease [29], rheumatoid arthritis patients [30], ulcerative colitis and Crohn's disease [31], lupus nephritis, mixed cryoglobulinemia and primary membranous nephropathy [32,33]. ...
Celiac disease is a life-long intestinal autoimmune disease, characterized by the gluten intolerance and chronic enteric inflammation. Traditionally presented by intestinal manifestations, however, a shift toward extra intestinal presentation is taking place. One of the affected organs is the nervous systems presented by neuropsychiatric manifestations, hence the mechanism and pathways are not clear. The presence of neuronal and alpha-enolases and their corresponding antibodies were noticed in the mucosa and serum of celiac disease patients, as well as in other various autoimmune diseases with psycho-neurological manifestations. The aims of the present review are to screen the literature on different isoforms of enolase, mainly alpha enolase, and their specific antibodies and to suggest their potential pathophysiological mechanisms relaying the enolases to intestinal or extraintestinal celiac disease manifestations. The shared aspects between the enolases and celiac disease and the cross-talks between alpha-enolase and tissue transglutaminase suggest new potential pathophysiological mechanisms that might drive celiac disease evolvement.
... The presence of anti-ENO1 autoantibodies is well documented in autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune retinopathy (Adamus, 2017). In RA, these autoantibodies recognize an immunodominant citrullinated peptide within the ENO1 N-terminus (Lundberg et al., 2008), and are clinical diagnostic biomarkers. ...
... Alpha-enolase autoantibodies are also present in cancer patients, often associated with cancer-associated retinopathy (CAR) (Adamus, 2017). Unlike in RA, ENO1 autoantibodies from CAR patients do not specifically target citrullinated peptides but rather recognize several epitopes, including an immunodominant N-terminal domain peptide, 56 RYMGKGVS 63 , and a C-terminal peptide implicated in plasminogen binding, 421 AKFAGRNF 428 (Adamus et al., 1998). ...
Alpha-enolase, also known as enolase-1 (ENO1), is a glycolytic enzyme that “moonlights” as a plasminogen receptor in the cell surface, particularly in tumors, contributing to cancer cell proliferation, migration, invasion, and metastasis. ENO1 also promotes other oncogenic events, including protein-protein interactions that regulate glycolysis, activation of signaling pathways, and resistance to chemotherapy. ENO1 overexpression has been established in a broad range of human cancers and is often associated with poor prognosis. This increased expression is usually accompanied by the generation of anti-ENO1 autoantibodies in some cancer patients, making this protein a tumor associated antigen. These autoantibodies are common in patients with cancer associated retinopathy, where they exert pathogenic effects, and may be triggered by immunodominant peptides within the ENO1 sequence or by posttranslational modifications. ENO1 overexpression in multiple cancer types, localization in the tumor cell surface, and demonstrated targetability make this protein a promising cancer biomarker and therapeutic target. This mini-review summarizes our current knowledge of ENO1 functions in cancer and its growing potential as a cancer biomarker and guide for the development of novel anti-tumor treatments.
