Reduced Levels of Tear Lacritin Are Associated With Corneal Neuropathy in Patients With the Ocular Component of Sjögren's Syndrome

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2016 Oct 7

PMID 27711909

Citations 19

Authors

Nancy A McNamara

Shaokui Ge

Salena M Lee

Alison M Enghauser

Lindsey Kuehl

Feeling Y-T Chen

Marianne Gallup

Robert L McKown

Affiliations

Soon will be listed here.

Abstract

Purpose: To determine whether levels of endogenous tear protein, lacritin, are linked to altered corneal innervation and dry eye severity in patients with Sjögren's syndrome (SS).

Methods: Clinical data were obtained from 10 SS and 10 age-matched controls. Enzyme-linked immunosorbent assay was used to assess total tear lacritin extracted from Schirmer strips. Western blot was used to detect active lacritin monomer (∼25 kDa), active lacritin fragment (∼12-15 kDa), and inactive tissue transglutaminase-generated lacritin (≥40 kDa). In vivo confocal microscopy was used to assess nerve fiber density (NFD) and length (NFL). Relationships between nerve morphology and tear lacritin were examined by Spearman correlation. Diagnostic performance of tear lacritin was analyzed using receiver operating characteristic.

Results: Active tear lacritin was significantly reduced in SS patients (3.72 ± 5.62 [SS] versus 18.17 ± 4.57 ng/100 ng total tear protein [controls]; P < 0.001), while inactive lacritin was increased (84.99% ± 11.15% [SS] versus 51.04% ± 12.03% [controls]; P < 0.001). Nerve fiber density (21.70 ± 18.93 vs. 31.80 ± 9.35; P = 0.03) and NFL (4.18 ± 3.44 vs. 6.54 ± 2.47; P < 0.05) were significantly decreased in SS patients compared to controls. Reduced NFL (r = 0.74, P < 0.01) and NFD (r = 0.70, P < 0.01) were highly correlated with reduced tear lacritin. Similarly, total tear lacritin was highly correlated with Schirmers (r = 0.77, P < 0.01), ocular staining (r = -0.80, P < 0.01), and corneal sensitivity (r = 0.81, P < 0.01). Tear lacritin showed equivalent or better diagnostic performance compared to traditional clinical measures for SS (100.00% sensitivity, 85.71% specificity, cutoff = 14.50 ng/100 ng tear protein).

Conclusions: Reduced tear lacritin levels in SS patients are highly correlated with clinical signs of dry eye, as well as decreased NFD and NFL. Lacritin and its components provide excellent diagnostic sensitivity and specificity in SS.

Citing Articles

Dry Eye Disease: An Update on Changing Perspectives on Causes, Diagnosis, and Management.

Dash N, Choudhury D Cureus. 2024; 16(5):e59985.

PMID: 38854318 PMC: 11162257. DOI: 10.7759/cureus.59985.

Corneal Sub-Basal Nerve Plexus in Non-Diabetic Small Fiber Polyneuropathies and the Diagnostic Role of In Vivo Corneal Confocal Microscopy.

Roszkowska A, Wylegala A, Gargiulo L, Inferrera L, Russo M, Mencucci R J Clin Med. 2023; 12(2).

PMID: 36675593 PMC: 9862881. DOI: 10.3390/jcm12020664.

Moxibustion with Walnut Shell Spectacles Could Improve the Objective Symptoms and Tear Film Stability of Patients with Dry Eye Disease: A Randomized Controlled Trial.

Zhang G, Fu W, Xu J, Hu P, Zhang Y, Sang Z Evid Based Complement Alternat Med. 2022; 2022:1773444.

PMID: 36506807 PMC: 9729042. DOI: 10.1155/2022/1773444.

A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration.

Efraim Y, Chen F, Cheong K, Gaylord E, McNamara N, Knox S Cell Rep. 2022; 40(9):111307.

PMID: 36044852 PMC: 9549932. DOI: 10.1016/j.celrep.2022.111307.

Trigeminal Nerve Affection in Patients with Neuro-Sjögren Detected by Corneal Confocal Microscopy.

Seeliger T, Gehlhaar M, Oluwatoba-Popoola I, Konen F, Haar M, Donicova E J Clin Med. 2022; 11(15).

PMID: 35956101 PMC: 9369441. DOI: 10.3390/jcm11154484.

References

Villani E, Galimberti D, Viola F, Mapelli C, Ratiglia R . The cornea in Sjogren's syndrome: an in vivo confocal study. Invest Ophthalmol Vis Sci. 2007; 48(5):2017-22. DOI: 10.1167/iovs.06-1129. View

Rhiner C, Gysi S, Frohli E, Hengartner M, Hajnal A . Syndecan regulates cell migration and axon guidance in C. elegans. Development. 2005; 132(20):4621-33. DOI: 10.1242/dev.02042. View

Cruzat A, Pavan-Langston D, Hamrah P . In vivo confocal microscopy of corneal nerves: analysis and clinical correlation. Semin Ophthalmol. 2010; 25(5-6):171-7. PMC: 3148212. DOI: 10.3109/08820538.2010.518133. View

McKown R, Coleman Frazier E, Zadrozny K, Deleault A, Raab R, Ryan D . A cleavage-potentiated fragment of tear lacritin is bactericidal. J Biol Chem. 2014; 289(32):22172-82. PMC: 4139230. DOI: 10.1074/jbc.M114.570143. View

Knox S, Lombaert I, Haddox C, Abrams S, Cotrim A, Wilson A . Parasympathetic stimulation improves epithelial organ regeneration. Nat Commun. 2013; 4:1494. PMC: 3582394. DOI: 10.1038/ncomms2493. View

Benitez Del Castillo J, Wasfy M, Fernandez C, Garcia-Sanchez J . An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci. 2004; 45(9):3030-5. DOI: 10.1167/iovs.04-0251. View

Tavakoli M, Quattrini C, Abbott C, Kallinikos P, Marshall A, Finnigan J . Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 2010; 33(8):1792-7. PMC: 2909064. DOI: 10.2337/dc10-0253. View

Olofsson P, Rosas-Ballina M, Levine Y, Tracey K . Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev. 2012; 248(1):188-204. PMC: 4536565. DOI: 10.1111/j.1600-065X.2012.01138.x. View

Whitcher J, Shiboski C, Shiboski S, Heidenreich A, Kitagawa K, Zhang S . A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's Syndrome International Registry. Am J Ophthalmol. 2009; 149(3):405-15. PMC: 3459675. DOI: 10.1016/j.ajo.2009.09.013. View

10.

Dartt D . Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases. Prog Retin Eye Res. 2009; 28(3):155-77. PMC: 3652637. DOI: 10.1016/j.preteyeres.2009.04.003. View

11.

Shiboski S, Shiboski C, Criswell L, Baer A, Challacombe S, Lanfranchi H . American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012; 64(4):475-87. PMC: 3349440. DOI: 10.1002/acr.21591. View

12.

Zhang M, Chen J, Luo L, Xiao Q, Sun M, Liu Z . Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy. Cornea. 2005; 24(7):818-24. DOI: 10.1097/01.ico.0000154402.01710.95. View

13.

Tuisku I, Konttinen Y, Konttinen L, Tervo T . Alterations in corneal sensitivity and nerve morphology in patients with primary Sjögren's syndrome. Exp Eye Res. 2008; 86(6):879-85. DOI: 10.1016/j.exer.2008.03.002. View

14.

McKown R, Wang N, Raab R, Karnati R, Zhang Y, Williams P . Lacritin and other new proteins of the lacrimal functional unit. Exp Eye Res. 2008; 88(5):848-58. PMC: 2712882. DOI: 10.1016/j.exer.2008.09.002. View

15.

Patel S, McLaren J, Hodge D, Bourne W . Confocal microscopy in vivo in corneas of long-term contact lens wearers. Invest Ophthalmol Vis Sci. 2002; 43(4):995-1003. View

16.

Nichols J, Green-Church K . Mass spectrometry-based proteomic analyses in contact lens-related dry eye. Cornea. 2009; 28(10):1109-17. DOI: 10.1097/ICO.0b013e3181a2ad81. View

17.

Samudre S, Lattanzio Jr F, Lossen V, Hosseini A, Sheppard Jr J, McKown R . Lacritin, a novel human tear glycoprotein, promotes sustained basal tearing and is well tolerated. Invest Ophthalmol Vis Sci. 2010; 52(9):6265-70. PMC: 3176019. DOI: 10.1167/iovs.10-6220. View

18.

Aluru S, Agarwal S, Srinivasan B, Iyer G, Rajappa S, Tatu U . Lacrimal proline rich 4 (LPRR4) protein in the tear fluid is a potential biomarker of dry eye syndrome. PLoS One. 2012; 7(12):e51979. PMC: 3525644. DOI: 10.1371/journal.pone.0051979. View

19.

Vijmasi T, Chen F, Balasubbu S, Gallup M, McKown R, Laurie G . Topical administration of lacritin is a novel therapy for aqueous-deficient dry eye disease. Invest Ophthalmol Vis Sci. 2014; 55(8):5401-9. PMC: 4148924. DOI: 10.1167/iovs.14-13924. View

20.

Patel D, Tavakoli M, Craig J, Efron N, McGhee C . Corneal sensitivity and slit scanning in vivo confocal microscopy of the subbasal nerve plexus of the normal central and peripheral human cornea. Cornea. 2009; 28(7):735-40. DOI: 10.1097/ICO.0b013e318193e0e3. View