[14] In the Aire knockout mouse model of dry eye (considered similar to human Sjogren's syndrome), topical lacritin restores pilocarpine-induced tearing, largely eliminates lissamine green staining and reduces the size of inflammatory foci in the lacrimal gland.

[7] Lacritin consists of 119 amino acids after cleavage of the N-terminal signal peptide and displays several predicted alpha helices, mostly in the C-terminal half.

[17] PONDR (Predictor of Naturally Disordered Regions)[19] predicts that the C-terminal and N-terminal halves are respectively 'ordered' and 'disordered'.

With a predicted protein core molecular weight of 12.3 kDa, it is possible that mobility is partially retarded by lacritin's amphipathic alpha helices.

[21] The ~0.6 micro molar level of tissue transglutaminase estimated in human tears is sufficient to promote crosslinking.

[21] Glutamine 106 resides within the amphipathic alpha helix near the C-terminus responsible for binding the N-terminus of syndecan-1.

Lacritin-c (10.7 kDa; pI 4.6) displays a novel C-terminus that should be incapable of binding syndecan-1, and lacks cell survival activity.

Top down mass spec sequencing revealed that human tears contain five N- and forty-two different C-terminal lacritin-a proteoforms.

Protease inhibitor studies suggest that processing of lacritin into C-terminal proteoforms requires a variety of tear proteases including cathepsin B, calpain, alanyl amino peptidase, arginyl aminopeptidase, MMP9, MMP10, cathepsin G, plasma kallikrein, plasmin, thrombin and trypsin.

Lacritin is a glycoprotein of the human tear film, and to a lesser extent of saliva, lung lavage[27] and plasma.

[18] Lacritin also promotes secretion[4] (including that of lipocalin-1 and lactoferrin[6]), cell survival and regeneration of the corneal epithelium after wounding.

[8] Three times daily topical treatment with C-terminal lacritin synthetic peptide 'Lacripep' (also known as 'N-94/C-6') at a 4 μM concentration regenerated corneal nerves and the ocular surface epithelium in the mouse Aire-/- dry eye model.

Recent studies suggest that lacritin monomer is differentially down regulated in not only in dry eye,[31] but also in blepharitis.

[18] Higher human lacritin concentrations are optimal on rat or mouse cells[4] or on rabbit eyes.

[14] In a recent phase I/II clinical trial, a 22 μM topical dose of 'Lacripep' applied three times daily was effective at two weeks in primary Sjogren's Syndrome patients with an eye dryness score greater than 60, a score indicative of moderate to severe dry eye.

[25] In both cases, stability is largely restored by spiking in synthetic lacritin peptides N-94 or N-94/C-6 as proxy C-terminal proteoforms.

[25] Each peptide inserts rapidly into (O-acyl)-omega-hydroxy fatty acid (OAHFA)[25] thought to reside at the aqueous lipid boundary in tears.

Lacritin mitogenic signaling[18] follows two pathways: Rapid dephosphorylation of PKCα causes it to transiently move from the cytoplasm to the area of the Golgi apparatus and peripheral nucleus.

[7] Lacritin stimulated secretion of tear proteins lipocalin and lactoferrin from monkey lacrimal acinar cells does not appear to be mediated by Ca2+, unlike the agonist carbachol.

[6] When monkey lacrimal acinar cells are stressed with inflammatory cytokines (as occurs in dry eye), carbachol loses its capacity to promote the secretion of lipocalin.

[6] Genomic sequencing assembled by Ensembl reveals the existence of putative lacritin orthologues in other species.

[37] Antibodies directed to the C-, but not N-, terminus of human lacritin are most effective[37] - in keeping with the predicted conservation of the C-terminal amphipathic alpha helix[37] necessary for cell targeting.

[4][29][38][39] The salivary gland expression appears to be attributable to a discrete group of unidentified ductal-like cells.

Viewed collectively, the LFU is the primary source of lacritin in the body, and the eye the main target.

Only a small fraction of the estimated 1543 proteins[44] in tears are differentially deficient or upregulated in dry eye.

[48] Tear lacritin monomer is barely detectable in the initial stage of infection by Fusarium solani in fungal keratitis.

[49] Also down regulated are tear lipocalin-1 and cystatin S.[49] Fungal keratitis accounts for half of all corneal ulcers in Africa and India[50][51][52] - the primary source of blindness in these countries.

[53] Phase II clinical trial of 'Lacripep™ in Subjects With Dry Eye Associated With Primary Sjögren's Syndrome' (NCT03226444)[54] is complete.