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Glycomics, Extracellular Matrix, and Anti-glycan Antibodies in Exfoliation Syndrome

Huflejt, Margaret E. PhD*; Preiss, Jordan S. BA*; Thomson, Jennifer E. BSc*; Gils, Ingrid M. BA*; Vuskovic, Marko I. DSci

doi: 10.1097/IJG.0000000000000118
The Extracellular Matrix
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Exfoliation syndrome (XFS) is considered to be a disease of extracellular matrix. Here we review key experimental evidence of aberrations in structure, expression, and function of glycoproteins, complex carbohydrates, and glycosaminoglycans found in extracellular matrix components forming exfoliation material in patients presenting with XFS. We hypothesize that certain components of the accumulating exfoliation material can become immunogenic, and multiple natural antibodies or autoantibodies are generated. Anti-glycan antibodies (AGAs) can be captured on Printed Glycan Array. Our preliminary results show robust immunoprofiles of AGAs in sera of patients with XFS, and the significant presence of AGAs in aqueous humor of these patients. These findings offer insight into the dynamics of AGAs during the development of XFS that could lead to the identification of the AGA-based XFS immuno-signature.

*Tumor Glycome Laboratory, Department of Cardiothoracic Surgery, Division of Thoracic Surgery and Thoracic Oncology, NYU School of Medicine, New York, NY

Computer Science Department, San Diego State University, San Diego, CA

Disclosure: The authors declare no conflict of interest.

Reprints: Margaret E. Huflejt, PhD, Department of Cardiothoracic Surgery, NYU Langone Medical Center, School of Medicine, 530 First Avenue, New York, NY 10016. (e-mail: margaret.huflejt@nyumc.org).

Received August 4, 2014

Accepted August 11, 2014

A dense coat of complex structural glycans attached to membrane proteins and lipids covers the surface of every cell. Most human cells also produce and secrete cell-type specific extracellular matrix (ECM) components. The interactions of cells with other cells and with the environment in which they function depend largely on the structure and organization of this cell membrane-attached glycan coat and the ECM in which cells are embedded. The ECM is composed of 3 major classes of macromolecules: (i) proteins, which are usually fibrous and heavily glycosylated such as laminins, fibronectin, vitronectin, integrins, collagens, and fibrillin-1 among others; (ii) proteoglycans, which are proteins with covalently attached carbohydrate polymers glycosaminoglycans (GAGs) chondroitin sulfate, keratan sulfate, heparin sulfate; and (iii) hyaluronan (hyaluronic acid), the only high molecular mass, polymeric GAGs which is not sulfated and is not covalently attached to proteins. Figure 1 illustrates the glycosylation network covering the surface of a human cancer cell, and also the polarity of glycosylation types defined here by the presence of glycans specifically recognized by the 2 human galactose-binding lectins, Galectin-3, and Galectin-4.1

FIGURE 1

FIGURE 1

Glycobiology is the study of structure, composition, synthesis, cellular and tissue distribution, and function of carbohydrate molecules. Glycomics is a subset of glycobiology, and includes a comprehensive study of (i) structure and function of glycomes, which contain all structural complex glycans (carbohydrates) of a given organism, a tissue or a cell type; and (ii) the extensive genetic machinery composed of “glycogenes” responsible for the glycan synthesis, processing, and distribution. Glycotranscriptomics investigates expression patterns of hundreds of “glycogenes”-coding enzymes involved in the synthesis, processing, and degradation of complex glycans, and of the genes products of which are responsible for the distribution of glycosylated molecules and structural polysaccharides to their proper destination in the cellular membrane or to the extracellular environment. Among the glycogenes, there are also genes coding the proteins-components of ECM, which in most cases are heavily glycosylated, and genes coding enzymes involved in the ECM processing, such as for example, glycosidases, hyaluronidases, collagenases, and Lysyl oxidase-like-1 (LOXL1). LOXL1 is an enzyme that is essential to the biogenesis of connective tissue, catalyzing the first step in the formation of cross-links in collagens and elastin. Because of a large number of glycogenes and a highly sophisticated regulation of their expression, glycomes are highly dynamic and cell-type specific, and their glycan-components reflect the cellular activity and the cell cycle status.

One of the disorders associated with abnormalities within the ECM is exfoliation syndrome (XFS), the most common identifiable cause of open-angle glaucoma worldwide.2 Diagnosis of XFS is based on the biomicroscopical detection of small deposits of white fibrillar material on the anterior lens surface.3–5 However, characterization of XFM is challenging due to insufficient quantity and resistance of the material to chemical and biochemical analytical processing methods. Initial analyses of XFM revealed its resistance to degradation by most proteolytic enzymes including collagenase, trypsin, pepsin, and papain.6,7 Further studies established the presence of multiple protein components of ECM/basement membrane including laminin, nidogen/entactin, and fibronectin,8–10 epitopes of the elastic fiber system, such as α-elastin, tropoelastin, fibrillin-1, amyloid P, vitronectin, the elastin-associated glycoprotein gp115/emilin,11–15 and the latent TGF-binding proteins, LTBP-1 and LTBP-2.16

Development of novel XFM solubilization strategies combined with the sensitive and elaborate direct proteomic analytical approach using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) allowed confirmation of the presence of proteins earlier found in XFM, identification of the multifunctional protein clusterin and tissue inhibitor of metalloprotease-3 (TIMP-3), as well as novel molecules, among them fibulin-2, desmocollin-2, syndecan-3, the proteoglycan versican, membrane metalloproteases of the ADAM family (a disintegrin and metalloprotease), and the initiation component of the classic complement activation pathway C1q. Identity and location of these proteins in XFM were then confirmed using classic immunohistochemistry.17

A key genetic factor linking ECM with XFS is a polymorphism of the LOXL1 gene coding lysyl oxidase-like-1, an enzyme essential to the biogenesis and function of ECM. Three common sequence variants or single-nucleotide polymorphisms in the LOXL1 gene on chromosome 15q24.1 were found to be strongly associated with both XFS syndrome and XFS glaucoma in Scandinavian populations from Iceland and Sweden, and accounted for virtually all XFS cases within the populations studied.18 It appears also that the LOXL1 gene is a major genetic risk factor for XFS worldwide.19 Lysyl oxidase-like-1 enzyme is apparently a powerful, multifunctional modulator of ECM structure and composition, and alteration of its activity is expected to be reflected in the function of ECM,20 and in the biology of cells expressing an aberrant gene, and residing in an environment of altered ECM. Moreover, aberrations within the molecular structure of the LOXL1 gene may also contribute to the pathology of XFS.19

The presence in XFM of various glycoconjugate-containing components of the ECM has been well documented. The first indirect histochemical and immunohistochemical approaches provided evidence of a complex glycoprotein/proteoglycan-structure composed of a protein core surrounded by glycoconjugates including GAGs, also forming the amorphous ground substance and present on the surface of the exfoliation fibrils in the interfibrillar matrix.21–26 Hyaluronan has been found in both XFM,27–31 and in aqueous humor.32 Because of their abundance suggesting overproduction and abnormal metabolism, GAGs have been suggested as one of the key changes in XFS.25,30

The multiple complex N-glycosylated glycans containing mannosyl, galactosyl, N-acetyl-D-galactosaminyl, N-acetyl-D-glucosaminyl, and terminal sialic acid residues have been identified by lectins.33–38 The HNK-1 epitope, a 3-sulpho-glucuronic acid-containing glycan was demonstrated in intraocular XFM.29,39–42 Moreover, Kivelä et al43 found HNK-1-positive deposits in the periphery of iris blood vessels of involved and fellow eyes in clinically unilateral XFS, but not in normal control eyes, and suggested an asymmetric rather than a unilateral involvement, in agreement with previous electron microscopic findings in conjunctival biopsy studies.44,45 The presence of HNK-1 epitope in intraocular XFM and its absence in extraocular XFM41,42 indicates a difference in composition of XFM likely reflecting the differences in the microenvironment of ECM produced and secreted by the cell types residing in the given tissues.

The HNK-1 carbohydrate epitope was first described as an antigen of human natural killer cells,46 and later found on other glycoconjugates in myelin, such as P0 and the HNK-1 glycolipids.47,48 The HNK-1 carbohydrate epitope is highly immunogenic; high levels of anti-HNK-1 IgM autoantibodies in the circulation have been associated with peripheral neuropathies,49 and the correlation between the HNK-1 autoantibodies and the damage to nervous tissue was confirmed by the observation that antibodies from human patients cause demyelination in chicken.50

In addition to its involvement in neuropathies, HNK-1 carbohydrate is expressed by recognition molecules of the immunoglobulin superfamily, and by multiple components of ECM including members of the tenascin family, integrins, and proteoglycans,51 and there are also indications that the HNK-1 carbohydrate is involved in the maintenance of the blood-brain barrier.52

Production and progressive accumulation of exfoliation material has been found in the proximity of practically all cell types in the eye,30,53–56 and the contributions of ECM components by many cell types likely explain the heterogeneity of the XFM. There is also extensive evidence for the systemic nature of XFS as the deposits of exfoliation material have been found throughout the body.57–61 It is therefore highly likely that the test developed for XFS based on sera of patients with and without XFS will detect a risk of XFS before its manifestation in the environment of the eye, and before the tissue damage is at the advanced stage. Such test would allow the early XFS-preventive management and monitoring of the effectiveness of the anti-XFS treatments.

Because of their amorphous nature, molecular heterogeneity and the high content of structural glycans, and various GAGs out of their functional context, certain components of the accumulating XFM can become immunogenic, and multiple natural antibodies or autoantibodies are generated. Autoantibodies against GAGs have already been found in patients with glaucoma.62 It is also very likely that such XFM-derived natural antibodies can then recognize various glycan-containing molecules either because of molecular mimicry,63–65 or as a direct result of the original antigens containing glycoconjugates. If infections contribute to XFS pathophysiology, the probability of the appearance of the XFS-associated or of the XFS-specific anti-glycan antibodies (AGAs) increases, due to the immunogenic contribution of the pathogen-associated molecular patterns.66,67

Sera of patients with various forms of glaucoma have been tested for the presence of autoantibodies using Western blots of retinal antigens,68 Western blots of optic nerve antigens,69 or protein macroarray,70 and in each case, a complex pattern of antibodies was found, showing significant differences between antibody profiles in patients and the healthy study subjects. Using Western blots of bovine retinal antigens, significant differences between the IgG antibody profiles in aqueous humor of the glaucoma groups (XFS and POAG) and control subjects has also been demonstrated.71

Serum AGAs are under intensive investigation in our laboratory72 as diagnostic and prognostic biomarkers, as indicators of responses to clinical interventions, and as indicators of overall immune health status. Here we hypothesize that (i) serum AGAs indicate early appearance of XFS and identify abnormal proteoglycans and aberrant glycosylation associated with XFM; (ii) these AGAs can be identified using Printed Glycan Array (PGA); and (iii) the differences between AGA immunoprofiles in patients with and without XFS will lead to the identification of an AGA-based immunosignature of XFS.

PGA is a glycomics tool that provides insight into the functional interactions between glycans and the carbohydrate-binding proteins, for example, selectins and galectins. PGA also provides information about the immune recognition of glycans by AGAs and other components of the immune system, for example, complement components. The PGA in our research is a “glycochip,” which is generated using standard robotic nanoprinting technology that allows printing of a large range of amine-functionalized glycans using amine-reactive N-hydroxysuccinimide-activated glass slides with a surface modified for rapid covalent coupling.73 Our current “NYU-PGA-400” glycochip is a microarray composed of 382 synthetic glycans, most of which can be found in nature on normal human cells, pathogen-infected cells and cancer cells, stimulated immune cells, and on pathogenic microorganisms. Human serum contains a vast selection of AGA that then bind to the glycan probes on a PGA to form a distinct, patient-specific “immunoprofile.” The combinations of AGAs within immunoprofiles of healthy individuals are relatively stable over time, but may become quite dynamic during the development of a pathologic process. The dynamics of the AGAs is captured on PGA and resolved using our PGA-dedicated bioinformatics and the classifier “ImmunoRuler” software. In case-control studies, classifier ImmunoRuler algorithm generates individual AGA-based “risk scores” for every study subject what allows discrimination between the study groups and identification of the “signature glycans.”74,75 Signal intensities of individual antibodies binding to the “signature glycans” can be either lower or higher in the “case” as compared with the “control” study group.

Using our NYU-PGA-400 platform, we have evaluated immunoprofiles of matched pairs of serum and aqueous humor of 3 XFS patients from the New York Eye and Ear Infirmary. The human subject protocol for this study was approved by the Institutional Review Board of the New York Eye and Ear Infirmary, and written informed consent was obtained from all participating subjects. The principal goal was to determine whether our method allows visualization of the presence of AGAs in the small volume of about 100 μL of aqueous humor collected during a surgical procedure. Figure 2 shows that indeed, we can detect AGAs in aqueous humor, although the observed AGA-binding intensities were quite low, and in fact much lower that the bindings of AGAs in the matched sera of these patients to the same glycans. So far, we had not observed aqueous humor AGAs binding to any other glycan probe than to the glycans bound also by serum AGAs of same patient.

FIGURE 2

FIGURE 2

The bar graph plot in the Figure 3 shows a composite result of visualization of both serum and aqueous humor AGAs of all 3 patients. The entire plot is quite long, and therefore for better clarity of presentation, the number of glycans/AGA bindings in the plot has been reduced to only these bindings that demonstrate a specific significance, such as the presence of aqueous humor AGAs (red bars, red arrows), and the predominant bindings of AGAs in sera of XFS patients (blue bars, blue arrows), or in our “control pooled” serum (orange bars, orange arrows) collected from healthy individuals.

FIGURE 3

FIGURE 3

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FUTURE PLANS

We intend to determine the putative immunosignature of XFS, and validate it in a large population, masked to case status. Once validated, this serum AGA-based test is expected to facilitate early detection, diagnosis, and staging of patients with XFS, and monitoring of the responses to therapeutic procedures. Individual glycans-components of the immunosignature are also expected to reveal at least a subset of aberrant glycans-products of genetic glycan-synthetic/processing machinery in XFS patients. The large library of the individual serum AGA immunoprofiles could also be used as a source of immunoinformation in search for the biomarkers of environmental/infectious factors that contribute to the increased risk for the XFS.

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Keywords:

exfoliation syndrome; anti-glycan antibodies; printed glycan array; exfoliation material; extracellular matrix; glycosylation

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