{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:51:57Z","timestamp":1782989517086,"version":"3.54.5"},"reference-count":104,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,22]],"date-time":"2023-10-22T00:00:00Z","timestamp":1697932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed at analyzing the corneal neural regeneration in ankylosing spondylitis patients using in vivo corneal confocal microscopy in correlation with Langerhans cell density, morphology, and dry eye parameters. Approximately 24 ankylosing spondylitis subjects and 35 age- and gender-matched control subjects were enrolled. Data analysis showed that all corneal nerve-fiber descriptives were lower in the ankylosing spondylitis group, implicating disrupted neural regeneration. Peripheral Langerhans cell density showed a negative correlation with nerve fiber descriptions. A negative correlation between tear film break-up time and corneal nerve fiber total branch density was detected. The potential role of somatosensory terminal Piezo2 channelopathy in the pathogenesis of dry eye disease and ankylosing spondylitis is highlighted in our study, exposing the neuroimmunological link between these diseases. We hypothesized earlier that spinal neuroimmune-induced sensitization due to this somatosensory terminal primary damage could lead to Langerhans cell activation in the cornea, in association with downregulated Piezo1 channels on these cells. This activation could lead to a Th17\/Treg imbalance in dry eye secondary to ankylosing spondylitis. Hence, the corneal Piezo2 channelopathy-induced impaired Piezo2-Piezo1 crosstalk could explain the disrupted neural regeneration. Moreover, the translation of our findings highlights the link between Piezo2 channelopathy-induced gateway to pathophysiology and the gateway reflex, not to mention the potential role of spinal wide dynamic range neurons in the evolution of neuropathic pain and the flare-ups in ankylosing spondylitis and dry eye disease.<\/jats:p>","DOI":"10.3390\/ijms242015455","type":"journal-article","created":{"date-parts":[[2023,10,22]],"date-time":"2023-10-22T07:02:53Z","timestamp":1697958173000},"page":"15455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Disrupted Neural Regeneration in Dry Eye Secondary to Ankylosing Spondylitis\u2014With a Theoretical Link between Piezo2 Channelopathy and Gateway Reflex, WDR Neurons, and Flare-Ups"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-1306","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Sonkodi","sequence":"first","affiliation":[{"name":"Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1123 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"Marsovszky","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Csorba","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Balog","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bence","family":"Kopper","sequence":"additional","affiliation":[{"name":"Faculty of Kinesiology, Hungarian University of Sports Science, 1123 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-8458","authenticated-orcid":false,"given":"Anik\u00f3","family":"Keller-Pint\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n Zsolt","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8285-1153","authenticated-orcid":false,"given":"Mikl\u00f3s D.","family":"Resch","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/S0140-6736(07)60635-7","article-title":"Ankylosing spondylitis","volume":"369","author":"Braun","year":"2007","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Berkes, I., and Koltai, E. (2020). Have We Looked in the Wrong Direction for More Than 100 Years? Delayed Onset Muscle Soreness Is, in Fact, Neural Microdamage Rather Than Muscle Damage. Antioxidants, 9.","DOI":"10.3390\/antiox9030212"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sonkodi, B. (2021). Delayed Onset Muscle Soreness (DOMS): The Repeated Bout Effect and Chemotherapy-Induced Axonopathy May Help Explain the Dying-Back Mechanism in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases. Brain Sci., 11.","DOI":"10.3390\/brainsci11010108"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"738316","DOI":"10.3389\/fphar.2021.738316","article-title":"Dynamics of Adaptive Immune Cell and NK Cell Subsets in Patients with Ankylosing Spondylitis After IL-17A Inhibition by Secukinumab","volume":"12","author":"Jiang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"(2007). The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul. Surf., 5, 93\u2013107.","DOI":"10.1016\/S1542-0124(12)70082-4"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jtos.2017.10.001","article-title":"Neuropathic pain and dry eye","volume":"16","author":"Galor","year":"2018","journal-title":"Ocul. Surf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"DES7","DOI":"10.1167\/iovs.17-23475","article-title":"Definition and Diagnostic Criteria of Dry Eye Disease: Historical Overview and Future Directions","volume":"59","author":"Shimazaki","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"744396","DOI":"10.3389\/fimmu.2021.744396","article-title":"Epidemiology of Ocular Manifestations in Autoimmune Disease","volume":"12","author":"Glover","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lee, C.Y., Chen, H.C., Huang, J.Y., Yen, C.H., Hwang, Y.S., Chang, C.K., and Yang, S.F. (2022). The Presence of Ankylosing Spondylitis and the Incidence of Subsequent External Eye Diseases: A Population-Based Cohort Study. Int. J. Environ. Res. Public. Health, 19.","DOI":"10.3390\/ijerph192316296"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1007\/s12031-022-02015-9","article-title":"Is the Sex Difference a Clue to the Pathomechanism of Dry Eye Disease? Watch out for the NGF-TrkA-Piezo2 Signaling Axis and the Piezo2 Channelopathy","volume":"72","author":"Sonkodi","year":"2022","journal-title":"J. Mol. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1038\/nn.4162","article-title":"Piezo2 is the principal mechanotransduction channel for proprioception","volume":"18","author":"Woo","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sonkodi, B. (2023). Miswired Proprioception in Amyotrophic Lateral Sclerosis in Relation to Pain Sensation (and in Delayed Onset Muscle Soreness)-Is Piezo2 Channelopathy a Principal Transcription Activator in Proprioceptive Terminals Besides Being the Potential Primary Damage?. Life, 13.","DOI":"10.3390\/life13030657"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Bardoni, R., and Po\u00f3r, G. (2022). Osteoporosis in Light of a New Mechanism Theory of Delayed Onset Muscle Soreness and Non-Contact Anterior Cruciate Ligament Injury. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169046"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sonkodi, B. (2022). Psoriasis, Is It a Microdamage of Our \u201cSixth Sense\u201d? A Neurocentric View. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911940"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/S1474-4422(17)30336-8","article-title":"Vladimir Mikhailovich Bekhterev","volume":"17","author":"Bozhkova","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Hegedus, A., Kopper, B., and Berkes, I. (2022). Significantly Delayed Medium-Latency Response of the Stretch Reflex in Delayed-Onset Muscle Soreness of the Quadriceps Femoris Muscles Is Indicative of Sensory Neuronal Microdamage. J. Funct. Morphol. Kinesiol., 7.","DOI":"10.3390\/jfmk7020043"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Kopa, Z., and Nyirady, P. (2021). Post Orgasmic Illness Syndrome (POIS) and Delayed Onset Muscle Soreness (DOMS): Do They Have Anything in Common?. Cells, 10.","DOI":"10.3390\/cells10081867"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nagy, Z.F., Sonkodi, B., Pal, M., Klivenyi, P., and Szell, M. (2023). Likely Pathogenic Variants of Ca(v)1.3 and Na(v)1.1 Encoding Genes in Amyotrophic Lateral Sclerosis Could Elucidate the Dysregulated Pain Pathways. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030933"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Bardoni, R., Hangody, L., Radak, Z., and Berkes, I. (2021). Does Compression Sensory Axonopathy in the Proximal Tibia Contribute to Noncontact Anterior Cruciate Ligament Injury in a Causative Way?\u2014A New Theory for the Injury Mechanism. Life, 11.","DOI":"10.3390\/life11050443"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sonkodi, B. (2022). Delayed Onset Muscle Soreness and Critical Neural Microdamage-Derived Neuroinflammation. Biomolecules, 12.","DOI":"10.3390\/biom12091207"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e001480","DOI":"10.1136\/rmdopen-2020-001480","article-title":"To move or not to move: The paradoxical effect of physical exercise in axial spondyloarthritis","volume":"7","author":"Perrotta","year":"2021","journal-title":"RMD Open"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R108","DOI":"10.1186\/ar3833","article-title":"Osteoporosis in ankylosing spondylitis\u2014Prevalence, risk factors and methods of assessment","volume":"14","author":"Klingberg","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102304","DOI":"10.1016\/j.msksp.2020.102304","article-title":"Cervical proprioception accuracy is impaired in patients with axial spondyloarthritis","volume":"51","author":"Ozen","year":"2021","journal-title":"Musculoskelet. Sci. Pract."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1007\/s00296-019-04419-0","article-title":"Cervical proprioceptive impairment in patients with rheumatoid arthritis","volume":"39","author":"Ulutatar","year":"2019","journal-title":"Rheumatol. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1126\/science.add3598","article-title":"Excessive mechanotransduction in sensory neurons causes joint contractures","volume":"379","author":"Ma","year":"2023","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.pbiomolbio.2017.07.011","article-title":"Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology","volume":"130","author":"Suchyna","year":"2017","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaat9892","DOI":"10.1126\/scitranslmed.aat9892","article-title":"PIEZO2 mediates injury-induced tactile pain in mice and humans","volume":"10","author":"Szczot","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1038\/ncomms2673","article-title":"A role for Piezo2 in EPAC1-dependent mechanical allodynia","volume":"4","author":"Eijkelkamp","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"644929","DOI":"10.3389\/fphys.2021.644929","article-title":"Piezo2 Knockdown Inhibits Noxious Mechanical Stimulation and NGF-Induced Sensitization in A-Delta Bone Afferent Neurons","volume":"12","author":"Nencini","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1177\/10738584221088575","article-title":"Mechanosensitive Ion Channels, Axonal Growth, and Regeneration","volume":"29","author":"Miles","year":"2023","journal-title":"Neuroscientist"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ejpb.2022.02.016","article-title":"Emerging approaches of neural regeneration using physical stimulations solely or coupled with smart piezoelectric nano-biomaterials","volume":"173","author":"De","year":"2022","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17663","DOI":"10.1021\/acsami.7b04323","article-title":"Piezoelectric Effects of Materials on Bio-Interfaces","volume":"9","author":"Marino","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s00296-020-04781-4","article-title":"The structural, functional and electrophysiological assessment of paraspinal musculature of patients with ankylosing spondylitis and non-radiographic axial spondyloarthropathy","volume":"41","author":"Ozturk","year":"2021","journal-title":"Rheumatol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00296-009-0841-7","article-title":"Neurological complications of ankylosing spondylitis: Neurophysiological assessment","volume":"29","author":"Khedr","year":"2009","journal-title":"Rheumatol. Int."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Marsovszky, L., Csorba, A., Balog, A., Kopper, B., Nagy, Z.Z., and Resch, M.D. (2023). Neural Regeneration in Dry Eye Secondary to Systemic Lupus Erythematosus Is Also Disrupted like in Rheumatoid Arthritis, but in a Progressive Fashion. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310680"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Csorba, A., Marsovszky, L., Balog, A., Kopper, B., Nagy, Z.Z., and Resch, M.D. (2023). Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087514"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., P\u00e1llinger, \u00c9., Radovits, T., Csulak, E., Shenker-Horv\u00e1th, K., Kopper, B., Buz\u00e1s, E.I., Syd\u00f3, N., and Merkely, B. (2022). CD3+\/CD56+ NKT-like Cells Show Imbalanced Control Immediately after Exercise in Delayed-Onset Muscle Soreness. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911117"},{"key":"ref_38","first-page":"469","article-title":"Immune cells and bone formation in ankylosing spondylitis","volume":"30","author":"Kim","year":"2012","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4239\/wjd.v9.i12.220","article-title":"Unexpected alliance between syndecan-1 and innate-like T cells to protect host from autoimmune effects of interleukin-17","volume":"9","author":"Jaiswal","year":"2018","journal-title":"World J. Diabetes"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.4049\/jimmunol.171.4.2057","article-title":"Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8\/heparan sulfate\/syndecan-1 complexes","volume":"171","author":"Marshall","year":"2003","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.bbamcr.2015.01.023","article-title":"Syndecan-1 regulates the biological activities of interleukin-34","volume":"1853","author":"Segaliny","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1002\/art.33507","article-title":"Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive gamma\/delta T cells in patients with active ankylosing spondylitis","volume":"64","author":"Kenna","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bernal-Alferes, B., Gomez-Mosqueira, R., Ortega-Tapia, G.T., Burgos-Vargas, R., Garcia-Latorre, E., Dominguez-Lopez, M.L., and Romero-Lopez, J.P. (2023). The role of gammadelta T cells in the immunopathogenesis of inflammatory diseases: From basic biology to therapeutic targeting. J. Leukoc. Biol.","DOI":"10.1093\/jleuko\/qiad046"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1136\/ard-2022-223428","article-title":"Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis","volume":"82","author":"Chen","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s10875-012-9774-0","article-title":"Levels of circulating Th17 cells and regulatory T cells in ankylosing spondylitis patients with an inadequate response to anti-TNF-alpha therapy","volume":"33","author":"Xueyi","year":"2013","journal-title":"J. Clin. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Fasching, P., Stradner, M., Graninger, W., Dejaco, C., and Fessler, J. (2017). Therapeutic Potential of Targeting the Th17\/Treg Axis in Autoimmune Disorders. Molecules, 22.","DOI":"10.3390\/molecules22010134"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"102933","DOI":"10.1016\/j.autrev.2021.102933","article-title":"Autoimmunity in dry eye disease\u2014An updated review of evidence on effector and memory Th17 cells in disease pathogenicity","volume":"20","author":"Chen","year":"2021","journal-title":"Autoimmun. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/art.22290","article-title":"Microdamage and altered vascularity at the enthesis-bone interface provides an anatomic explanation for bone involvement in the HLA-B27-associated spondylarthritides and allied disorders","volume":"56","author":"Benjamin","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e47454","DOI":"10.7554\/eLife.47454","article-title":"The mechanosensitive Piezo1 channel is required for bone formation","volume":"8","author":"Sun","year":"2019","journal-title":"Elife"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17696","DOI":"10.1038\/s41598-017-18089-0","article-title":"Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells","volume":"7","author":"Sugimoto","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1177\/1753425912461677","article-title":"In vivo confocal microscopic evaluation of corneal Langerhans cell density, and distribution and evaluation of dry eye in rheumatoid arthritis","volume":"19","author":"Marsovszky","year":"2013","journal-title":"Innate Immun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"543835","DOI":"10.1155\/2015\/543835","article-title":"Dry eye and corneal langerhans cells in systemic lupus erythematosus","volume":"2015","author":"Resch","year":"2015","journal-title":"J. Ophthalmol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1177\/1753425913498912","article-title":"Corneal Langerhans cell and dry eye examinations in ankylosing spondylitis","volume":"20","author":"Marsovszky","year":"2014","journal-title":"Innate Immun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.neuron.2019.01.050","article-title":"The Mechanosensitive Ion Channel Piezo Inhibits Axon Regeneration","volume":"102","author":"Song","year":"2019","journal-title":"Neuron"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1001\/archopht.124.4.462","article-title":"Altered expression of neurotransmitter receptors and neuromediators in vernal keratoconjunctivitis","volume":"124","author":"Motterle","year":"2006","journal-title":"Arch. Ophthalmol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.preteyeres.2012.02.003","article-title":"Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease","volume":"31","author":"Barabino","year":"2012","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1042\/BJ20040585","article-title":"Heparan sulphate proteoglycans interact with neurocan and promote neurite outgrowth from cerebellar granule cells","volume":"383","author":"Akita","year":"2004","journal-title":"Biochem. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.celrep.2014.06.008","article-title":"Syndecan promotes axon regeneration by stabilizing growth cone migration","volume":"8","author":"Edwards","year":"2014","journal-title":"Cell Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101784","DOI":"10.1016\/j.isci.2020.101784","article-title":"Syndecan-1 Stimulates Adult Neurogenesis in the Mouse Ventricular-Subventricular Zone after Injury","volume":"23","author":"Mouthon","year":"2020","journal-title":"iScience"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2156529","DOI":"10.1080\/10641963.2022.2156529","article-title":"Syndecan 1 may slow the progression of subclinical atherosclerosis in patients with ankylosing spondylitis","volume":"45","author":"Yilmaz","year":"2023","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"40764","DOI":"10.1074\/jbc.M306736200","article-title":"Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration","volume":"278","author":"Endo","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"C92","DOI":"10.1152\/ajpcell.00346.2018","article-title":"Piezo1 mediates angiogenesis through activation of MT1-MMP signaling","volume":"316","author":"Kang","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nri2785","article-title":"FOXP3+ regulatory T cells in the human immune system","volume":"10","author":"Sakaguchi","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1167\/iovs.08-2536","article-title":"Human corneal endothelial cells expressing programmed death-ligand 1 (PD-L1) suppress PD-1+ T helper 1 cells by a contact-dependent mechanism","volume":"50","author":"Sugita","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1167\/iovs.05-1281","article-title":"Apical corneal barrier disruption in experimental murine dry eye is abrogated by methylprednisolone and doxycycline","volume":"47","author":"Corrales","year":"2006","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Canadas, P., Alberquilla Garcia-Velasco, M., Hernandez Verdejo, J.L., and Teus, M.A. (2022). Update on Corneal Confocal Microscopy Imaging. Diagnostics, 13.","DOI":"10.3390\/diagnostics13010046"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"891575","DOI":"10.3389\/fendo.2022.891575","article-title":"Implementation of corneal confocal microscopy for screening and early detection of diabetic neuropathy in primary care alongside retinopathy screening: Results from a feasibility study","volume":"13","author":"Carmichael","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1002\/mds.27025","article-title":"Peripheral neuropathy as marker of severe Parkinson\u2019s disease phenotype","volume":"32","author":"Merola","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1097\/ICO.0000000000003018","article-title":"Corneal Cellular and Neuroinflammatory Changes After SARS-CoV-2 Infection","volume":"41","author":"Kolkedi","year":"2022","journal-title":"Cornea"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1097\/ICO.0000000000002060","article-title":"Corneal Subbasal Nerve Analysis Using In Vivo Confocal Microscopy in Patients with Dry Eye: Analysis and Clinical Correlations","volume":"38","author":"Liu","year":"2019","journal-title":"Cornea"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5525","DOI":"10.1167\/iovs.18-25321","article-title":"No Relation Between the Severity of Corneal Nerve, Epithelial, and Keratocyte Cell Morphology with Measures of Dry Eye Disease in Type 1 Diabetes","volume":"59","author":"Ferdousi","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.2337\/dc12-2075","article-title":"Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes","volume":"36","author":"Sivaskandarajah","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.clinthera.2021.04.003","article-title":"Corneal Confocal Microscopy: A Biomarker for Diabetic Peripheral Neuropathy","volume":"43","author":"Petropoulos","year":"2021","journal-title":"Clin. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neulet.2015.01.048","article-title":"Mechanisms of distal axonal degeneration in peripheral neuropathies","volume":"596","author":"Cashman","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1167\/iovs.62.1.2","article-title":"Sodium Channel Blockers Modulate Abnormal Activity of Regenerating Nociceptive Corneal Nerves After Surgical Lesion","volume":"62","author":"Luna","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"8976","DOI":"10.1523\/JNEUROSCI.0247-20.2020","article-title":"Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea","volume":"40","author":"Gonzalez","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jtos.2021.08.004","article-title":"Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study","volume":"22","author":"Cox","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"297","DOI":"10.5114\/reum.2020.100112","article-title":"Calcium physiology, metabolism and supplementation: A glance at patients with ankylosing spondylitis","volume":"58","author":"Talotta","year":"2020","journal-title":"Reumatologia"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1093\/intimm\/dxab022","article-title":"Gateway reflexes, neuronal circuits that regulate the autoreactive T cells in organs having blood barriers","volume":"34","author":"Uchida","year":"2022","journal-title":"Int. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.cell.2012.01.022","article-title":"Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier","volume":"148","author":"Arima","year":"2012","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Sonkodi, B. (2022). Should We Void Lactate in the Pathophysiology of Delayed Onset Muscle Soreness? Not So Fast! Let\u2019s See a Neurocentric View!. Metabolites, 12.","DOI":"10.3390\/metabo12090857"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/ics.12864","article-title":"Modulation of Piezo1 influences human skin architecture and oxytocin expression","volume":"45","author":"Labarrade","year":"2023","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e79917","DOI":"10.7554\/eLife.79917","article-title":"Na(V)1.1 is essential for proprioceptive signaling and motor behaviors","volume":"11","author":"Espino","year":"2022","journal-title":"Elife"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Varga, E., Hangody, L., Poor, G., and Berkes, I. (2021). Finishing stationary cycling too early after anterior cruciate ligament reconstruction is likely to lead to higher failure. BMC Sports Sci. Med. Rehabil., 13.","DOI":"10.1186\/s13102-021-00377-y"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/S0140-6736(73)91360-3","article-title":"Ankylosing spondylitis and HL-A 27","volume":"1","author":"Brewerton","year":"1973","journal-title":"Lancet"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/imm.13242","article-title":"New developments in our understanding of ankylosing spondylitis pathogenesis","volume":"161","author":"Voruganti","year":"2020","journal-title":"Immunology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1003999","DOI":"10.3389\/fphys.2022.1003999","article-title":"Piezo buffers mechanical stress via modulation of intracellular Ca(2+) handling in the Drosophila heart","volume":"13","author":"Zechini","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/ng.873","article-title":"Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility","volume":"43","author":"Evans","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1007\/s10067-018-4125-z","article-title":"Association of neuropathic-like pain characteristics with clinical and radiographic features in patients with ankylosing spondylitis","volume":"37","author":"Choi","year":"2018","journal-title":"Clin. Rheumatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1093\/pm\/pnab319","article-title":"Can Central Sensitization After Injury Persist as an Autonomous Pain Generator? A Comprehensive Search for Evidence","volume":"23","author":"Brazenor","year":"2022","journal-title":"Pain. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/S1474-4422(22)00485-9","article-title":"Pain research in 2022: Nociceptors and central sensitisation","volume":"22","author":"Treede","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1038\/s41467-023-38241-x","article-title":"Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis","volume":"14","author":"Obeidat","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"ra15","DOI":"10.1126\/scisignal.2005667","article-title":"Activation of TRPV1 channels inhibits mechanosensitive Piezo channel activity by depleting membrane phosphoinositides","volume":"8","author":"Borbiro","year":"2015","journal-title":"Sci. Signal"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"764396","DOI":"10.3389\/fphar.2021.764396","article-title":"Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain","volume":"12","author":"Puja","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1126\/science.150.3699.971","article-title":"Pain mechanisms: A new theory","volume":"150","author":"Melzack","year":"1965","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"266","DOI":"10.4103\/ijabmr.IJABMR_72_17","article-title":"A Curious Case of Ankylosing Spondylosis and Motor Neuron Disease: A Mere Coincidence or Correlation?","volume":"8","author":"Roy","year":"2018","journal-title":"Int. J. Appl. Basic. Med. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/art.1780270401","article-title":"Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria","volume":"27","author":"Valkenburg","year":"1984","journal-title":"Arthritis Rheum."},{"key":"ref_99","first-page":"2286","article-title":"A new approach to defining disease status in ankylosing spondylitis: The Bath Ankylosing Spondylitis Disease Activity Index","volume":"21","author":"Garrett","year":"1994","journal-title":"J. Rheumatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1136\/ard.61.6.554","article-title":"Classification criteria for Sjogren\u2019s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group","volume":"61","author":"Vitali","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"108851","DOI":"10.1016\/j.exer.2021.108851","article-title":"Change patterns in the corneal sub-basal nerve and corneal aberrations in patients with dry eye disease: An artificial intelligence analysis","volume":"215","author":"Jing","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1001\/archopht.118.5.615","article-title":"Reliability and validity of the Ocular Surface Disease Index","volume":"118","author":"Schiffman","year":"2000","journal-title":"Arch. Ophthalmol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/eye.2010.228","article-title":"The relationship between clinical signs and dry eye symptoms","volume":"25","author":"Pult","year":"2011","journal-title":"Eye"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1007\/s00417-004-1075-8","article-title":"In vivo confocal microscopic evaluation of Langerhans cell density and distribution in the normal human corneal epithelium","volume":"243","author":"Zhivov","year":"2005","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15455\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:57Z","timestamp":1760130597000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,22]]},"references-count":104,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015455"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015455","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,22]]}}}