Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. D4a iado L- n L- a endemonstrated. ligands. been their has TLR-9 by and stimulated TLR-4 be of to ligand RNA. proteins as additional CD14 lipopolysac- Poly(I:C)/double-stranded requires as and TLRs such that compounds CpG-DNA of microbial strated changes recognize endotoxins, including which VKC, (LPS), cells, 9. immune of charide and and pathogenesis 4 resident the by 2, in expressed (TLRs) immunity receptors receptors innate toll-like and the of of eosinophils expression cells role cells, conjunctival a mast T-helper demonstrated of a evidence infiltration by cent conjunctival characterized with is associated VKC lymphocytes. corneal reaction, in CD4 allergic inflammation with (Th2)-driven surface life. associated 2 ocular of type often quality that of demonstrated secretion, decrease studies and and Several function redness visual photophobia, of of impairment and symptoms involvement intense affecting by mostly conjunctiva, characterized and cornea the age. of pre-pubertal disease in allergic boys chronic, a is (VKC) keratoconjunctivitis Vernal studies. further Introduction requires VKC. it with although tear patients targets, in Conclusion: therapeutic reaction treatment. inflammatory potential surface expression corticosteroid represent ocular Conjunctival topical may during after TLRs decreased hyperemia. reduced and TLR-9 conjunctival significantly CD14 and and severity of was TLR4 the subjects severity TLR-9, CD14, with healthy conjunctival and with correlated and with CD14 significantly correlated sCD14, were sCD14, compared was TLR-9 not when sCD14 and but A lower TLR-4 TLR-4, TLR-9 group the CD14, of and in sCD14, while TLR-4, of decreased were reaction, CD14, expression significantly A papillary Lower expression of was R. group of and Results: TLR-9 and in tears treatment. Q and Patients in corticosteroid group TLR-4 after sCD14 VKC included. CD14, and with of groups were of Expression all and subjects in days. sCD14 healthy Blot 7 Western of 10 for by evaluated and daily were quiescent times N=4) epithelium the 4 conjunctival R, in VKC by drops N=9), (group with A, eye patients recovery (group the corticosteroid in inflammation after active expression with influence during and 9 treated VKC may and N=5) with aim TLR-4 patients and Q, The CD14, 18 conjunctival (TLR) (group investigated. Methods: and phase been receptors sCD14 phases. yet soluble quiescent toll-like not tear and has active via of (VKC) the changes keratoconjunctivitis in reaction evaluate vernal to immune in is CD14 study of of this role modulation of The the diseases. in allergic of involved development is CD14 Background: Abstract 2020 23, July 3 2 1 Zicari Maria Anna sacchetti marta mechanism? pathogenic patients novel in a epiphenomenon TLR-9 or inflammatory and an 4 TLR- keratoconjunctivitis: Vernal and with CD14 surface ocular of Changes oilnc met Roma 1 Umberto Policlinico I Umberto Policlinico Rome of Sapienza University 1 ,7 6, aclaNebbioso Marcella , 3 oee,teimnptoeei fVChsntbe opeeyunderstood. completely been not has VKC of immunopathogenesis the However, n lsadoLambiase Alessandro and , ,2 1, ainswt K xeinercretflr-p foua ufc inflammation, surface ocular of flare-ups recurrent experience VKC with Patients 2 ac segatto marco , 1 1 13 1 8-10 rn abicca irene , D4i utfntoa eetrexpressed receptor multifunctional a is CD14 Lsaeafml fpattern-recognition of family a are TLRs 1 11 ,3-5 1, lc Bruscolini Alice , 12 ieetfidnsdemon- findings Different mn hm h oeof role the them, Among 1 , 2 Re- Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. rtisfo ersmlsadcnucia mrsinctlg eeotie ysncto n centrifu- and sonication by obtained were cytology impression conjunctival and samples tear from Proteins epithe- conjunctival and analysis sCD14 blot tear Western evaluate -20 to 9. at samples and stored biological TLR-4 then 0.4 on CD14, and (Millicell-CM, conjunctiva, performed lium insert bulbar was collected culture analysis temporal cell were blot and sterile Tears Western nasal a the applying -20 seconds. to by at 30 eyes Millipore) stored both after mm, period and Worth, in removed 12 minutes Fort treatment collection and 3 Inc., tear of for fornix after Lab. end rpm conjunctival performed (Alcon 13000 the inferior Microsponges at At the centrifugation Sharp-tip healthy at by sterile days. and collected. placed of 7 were imbibition gently VKC for samples by TX) conjunctival collected daily of and were times tear eyes samples and 4 Tear above both drops described eye mild, in as evaluated Italy) 1= collected were Catania, (0=absence, patients were S.r.l., 3 Medivis samples to drop, 0 tear from and scored subjects. cytology were impression Symptoms Conjunctival photophobia. and 3=severe). tearing and itching, 2=moderate scale. scored as Oxford 3=severe). by and such and scored examination 2=moderate hyperemia of and lamp conjunctival mild, staining slit by vital 1= of evaluated fluorescein severity (0=absence, was by 3 and reaction to presence papillary signs 0 tarsal the ocular upper from Specifically, of presence and the investigated. limbal and days. secretion, was collected 7 and was VKC results least of test at prick symptoms from skin year. and including treatments 1 history least systemic clinical at and visit, from baseline topical inflammation At antiallergic of (iii) signs involvement; use and corneal not symptoms or of did of absence and absence patients with hyperemia group: All VKC conjunctival quiescent of of history (ii) absence involvement; group: severe symptoms, recovery corneal to ocular moderate of intermittent with presence associated and and symptoms mild ocular secretion persistent and of hyperemia presence conjunctival group: presentation. Active University clinical (i) and of history groups: Committee clinical different on Ethic based the was was VKC by of consent approved Diagnosis Informed was study Helsinky. the of (ii) and Declaration Rome. Pediatrics caregiver, the of of A), Department and of included Sapienza and (group participants tenants were Organs the all inflammation subjects Sense following by of healthy active Department Ten Rome, signed the during R). of at University (group (i) performed VKC Sapienza was of at study study: recovery The after this group. and control in Q) as (group included phase were ocular quiescent VKC during of with flare-ups patients during conjunc- Eighteen and in phase TLR9 quiescent and Methods in the TLR4 and CD14 treatment. in CD14, Material conjunctival corticosteroid VKC of topical and with and after sCD14 patients and tears tear in before in of involvement inflammation assessed sCD14 the was of investigate epithelium expression to diseases. tival Specifically, allergic is VKC. in study with not of this but patients development of subjects, the aim healthy the in of Therefore, CD14 tears LPS in and by sCD14 stimulation TLR-4 and TLR-4 of cells that role epithelial demonstrated a conjunctivitis suggesting conjunctivitis. allergic response, allergic of allergic model Th2-associated a suppressed in study TNF- IL-12, experimental IL-1, An T-helper as immune such cytokines adaptive of activates described. release compounds and (sCD14). microbial production form inducing with soluble IL-8. by a binding response, as TLRs (Th1) exists and also 1 it type CD14 and that form membrane-bound shown a been in cells immune and resident by 1 2 15-17 12, 11, 2 23 22, 17 h oeo Lsi h ahgnsso clrsraedsae a enetnieystudied. extensively been has diseases surface ocular of pathogenesis the in TLRs of role The ainsicue ngopAwihrcie ramn ihHdootsn Crii eye (Cortivis Hydrocortisone with treatment received which A group in included Patients leain fsD4adC1 nalri odtossc satm,hsbe previously been has asthma, as such conditions allergic in CD14 and sCD14 of Alterations 18 nhmn,tepeec fC1 a endsrbdi onaadconjunctival and cornea in described been has CD14 of presence the humans, In 2 21 ainswr se o h rsneo symptoms of presence the for asked were Patients ,4 3, ° C. ona pteildmg a evaluated was damage epithelial Corneal 22 ojntvlipeso yooywas cytology impression Conjunctival 4 ainswt K eeicue in included were VKC with Patients 19 ° C. 24 α, L6and IL-6 14 μ thas It ,Ø m, ,20 4, 8 Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. infiatdces fbt L- n L- hncmae ihhatycnrl TR4 0.17 (TLR-4: controls healthy with compared when 1.3 TLR-9 TLR-9: 0.54 and TLR-9: TLR-4 p=0.028; both a.u., of decrease (0.82 significant changes a compa- significant when show VKC not with patients did (0.4 in controls. controls decreased healthy healthy significantly with was with red TLR-4 compared of when expression epithelium CD14, Conjunctival of expression conjunctival B) (1.02 in 1 Q (Figure group difference both significant in show VKC not with (1.18 and (0.49 (p=0.001) R CD14 conjunctival subjects and (0.7 of healthy decrease subjects with significant healthy showed compared A with when group compared VKC when with was Patients VKC expression p=0.013). CD14 with a.u., conjunctival patients fact, In in results. decreased similar significantly showed CD14 of expression epithelium Conjunctival 1A). (0.45 (Figure sCD14 controls. healthy tear of decrease p significant (p con- healthy a subjects with showed thy compared phase when active expression sCD14 the are tear of study (0.58 decrease this trols significant in showed included VKC patients with Patients of characteristics clinical 1. Table and in Demographic summarized aeroallergens. for test prick 8.5 22 age 9 age mean mean 8 female, females, age 1 2 10.7 mean males, age females, (7 mean 4 VKC females, with males, 3 (6 and subjects males healthy Ten (15 VKC with patients Eighteen TLR-9 values and P TLR-4 Inc). CD14, SPSS Results Chicago: topical with IBM, after to correlated 18, and used were (SPSS before was test. significant. parameters expression rho statistically T-test Clinical conjunctival Sperman sample by TLR-9 A. Paired levels and group expression subjects. TLR-4 in healthy CD14, treatment and and corticosteroid VKC levels, conjunctival TLR-9 with tear and patients sCD14 TLR-4 CD14, compare of and levels, groups tear between sCD14 compare (a.u.). expression to units used was arbitrary T-test as sample from Independent expressed sCD14 are Values whereas staining. cytology, Red analysis impression Ponceau conjunctival Statistical was inte- using in actin of by Notably, loading normalized protein calculated. protein was the was samples between normalize staining tear ratio to Red the from reference protein/Ponceau and derived as housekeeping Windows, Images chosen correspondent for Italy). software the Milan, ImageJ and Laboratories, with rest Italy) (Biorad analyzed Milan, System were Laboratories, Imaging blots (Biorad byWestern Chemidoc substrates visualized through ECL were Western detected antibodies Clarity and anti-rabbit protein-bound with secondary Italy), reaction (sc- with Milan, chemiluminescence incubation anti-actin following Laboratories, following using and the (Biorad after, USA), day with antibodies Cruz The overnight CA, anti-mouse Santa USA). Biotechnology, and probed CA, (sc-52962, Cruz Biotechnology, and anti-TLR4 Cruz Santa temperature, Santa USA), (sc-58951, room 47778, CA, anti-CD14 at Biotechnology, USA), hour Cruz CA, no 1 Biotechnology, Santa with for blocked (sc-25468, PBS-tween) then anti-TLR9 in were antibodies: membranes (5% Italy), milk Milan, dry Laboratories, fat (Biorad system transfer turbo Trans-blot described. previously as gation p < < ± .0) K ru n ru (1.1 R group and Q group VKC 0.001). .0) Fgr ,B) A, 2 (Figure 0.001). er)wr nlddi h eoeygop() lvn(1)oto 8ptet hwdpstv skin positive showed patients 18 of out (61%) Eleven (R). group recovery the in included were years) 5 ± ± .7au s1 vs a.u. 0.27 ± .2au,p a.u., 0.12 .2au,p a.u., 0.02 < .0)adwt ohVCgopQ(0.87 Q group VKC both with and 0.001) ± < . er)wr nteqisetpae(ru )ad4ptet 4mls enage mean males, (4 patients 4 and Q) (group phase quiescent the in were years) 4.4 < ± 01 n K ru TR4 0.5 (TLR-4: R group VKC and 0001) ± .0) ainswt K nteqisetpaeadatrVCrcvr did recovery VKC after and phase quiescent the in VKC with Patients 0.001). .4au,p a.u., 0.14 .8au,p001 n ihVCgopQ(L-:0.65 (TLR-4: Q group VKC with and p=0.011) a.u., 0.08 ± 4 25 24, .7au s1.06 vs a.u. 0.27 rey rtiswr rnfre nontoells ebaeb using by membrane nitrocellulose onto transferred were proteins Briefly, ± < . ..v 1 vs a.u. 0.4 .0) ycmaigtedffrn rus ainswt K in VKC with patients groups, different the comparing By 0.001). ± . er)wr nteatv hs gopA fVC 4males, (4 5 VKC, of A) (group phase active the in were years) 2.3 ± .6 i o hwsgicn hne hncmae with compared when changes significant show not did 0.16) ± .7au,p a.u., 0.07 ± ± 3 yas eeicue scnrlgop iepatients Nine group. control as included were 3years) .2au) K ainsi h ciepaeshowed phase active the in patients VKC a.u.). 0.12 < ± .0) hl ojntvlepeso fTLR-9 of expression conjunctival while 0.001), .6au,p005 n ru (1.1 R group and p=0.005) a.u., 0.16 ± .8au =.3;TR9 1.1 TLR-9: p=0.035; a.u, 0.18 ± ± . er)wr nlddi h study. the in included were years) 5.7 . .. hncmae ihheal- with compared when a.u.) 0.2 < ± ± .5wr considered were 0.05 ± .8au,p a.u., 0.58 .2au,p=0.004; a.u., 0.12 .9au s1 vs a.u. 0.29 ± ± .8a.u., 0.08 .4a.u.) 0.14 < ± 0.001) ± 0.13, ± 0.03 0.1 Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. s0.38 vs u eut losoe htcnucia pteimepeso fTR4adTR9dcesddrn active during healthy decreased TLR-9 to and TLR-4 similar of levels expression epithelium expression conjunctival CD14 that CD14 showed surface also showed results the ocular phase Our by hand, suggested quiescent as other the treatments, the in corticosteroid with On topical patients subjects. associated after inflammation. VKC is normalize VKC that CD14 to of result time surface observation inflammatory This longer recrudescence ocular CD14. ocular require of develop conjunctival may expression the to and expression lower sCD14 of risk the tear that resolution higher of hypothesis expression the and sCD14. alternative of treatment tear the changes be of significant support corticosteroid by find decrease may may topical not the supported patients did of and be VKC we hyperaemia may days reaction, in conjunctival hypothesis seven of observed This severity after VKC. expression the active However, CD14 between during correlation surface reaction significant cultures. inflammatory ocular the the macrophage of IL-13. of and decrease epiphenomenon release and monocyte, the an the TNF-alpha in that by release and IL10, hypothesize cells sCD14 may IL-5, mast inhibit IL-4, and IL-13 eosinophils including cells, and cytokines Th2 circulating of attacks. of Th2 infiltration asthma expression of by of the characterized development is that the VKC in suggesting Accordingly, effect severity, protective asthma a with have correlated could sCD14 inversely were switch levels a sCD14 induce production. may IgE and and balance reported. Th1/Th2 been influence has suppression. de- may response Th2 and pathway consequent signalling, CD14 and atopy. TLRs’ the response toward susceptibility. through in Th1 atopy alterations release a toward in consequence, cytokine involved reaction a stimulates immune is LPS adaptive CD14 with the that viates binding hypothesized CD14 been that has demonstrated response immune it modulates understood, CD14 development tely that the demonstrated on clearly role reaction. protective been potential has products inflammatory were a it microbial surface expression plays fact, to ocular CD14 CD14 In epithelium that in reaction. conjunctival involved suggesting inflammatory and VKC are of sCD14 with TLR-9 tear patients and Specifically, in TLR4 VKC. decreased with CD14, patients that in demonstrated flare-ups we study, this In Discussion 0.18 (TLR4: baseline sCD14 with 3) tear compared (Figure when of 0.09 values except conjunc- significant vs With reached of a.u symptoms. TLR-4 absence were ocular only with and absent however, symptoms, daily expression to and times mild 4 signs and Hydrocortisone of involvement topical (0.48 improvement corneal with showed and treated patients were hyperemia All group tival days. active 7 the in after patients evaluated sCD14: nine (tear of out diseases Six allergic other without vs with patients between found 0.63 were difference significant (p=0.015, No correlated R=-0.767). TLR-4 significantly (p=0.044, R=-0.668), also expression were (p=0.049, expres- sCD14 scores lower CD14 hyperemia tear the conjunctival Conjunctival with with of R=-0.891). correlated (p=0.001, and significantly TLR-9 R=-0.779), was and (p=0.005, significant score R=-0.850) sCD14 reaction show tear papillary not of higher did sion the significant TLR-9 VKC, showed with while patients R subjects In group healthy VKC with compared (p=0.025). healthy when increased with changes. (p=0.005) compared significantly TLR-4 when was TLR-4 of conjunctival TLR-9 decrease of while decrease significant (p=0.010) showed controls phase quiescent the in VKC ± ± .9auv 0.75 vs a.u 0.29 .7auv 0.51 vs a.u 0.17 ± 5 26 15, .2au L-:0.88 TLR-9: a.u, 0.22 38 ± .3au =.3;C1:0.46 CD14: p=0.035; a.u, 0.03 29 lhuhterl fC1 nteptoeei falri iesshsntytbe comple- been yet not has diseases allergic of pathogenesis the in CD14 of role the Although napeiti ouain nascainbtencruaigsD4lvl n o IL-4 low and levels sCD14 circulating between association an population, paediatric a In 32 ± via thsbe lodmntae htdrn ct shaatcsi hlrn plasma children, in attacks asthma acute during that demonstrated also been has It ± .6au ojntvlC1:0.75 CD14: conjunctival a.u; 0.36 .6au,altebooia aaee vlae hwddces fconjunctival of decrease showed evaluated parameter biological the all a.u), 0.16 Ls n eeteiec xeddisrl ntedvlpeto h allergic the of development the in role its extended evidence recent and TLRs, 0 31 30, ± .2auv 0.82 vs a.u 0.42 oevr C1 a ensont neatwt el yihbtn IL-6 inhibiting by cells B with interact to shown been has sCD14 Moreover, ± . . s0.29 vs a.u 0.1 ± .5au respectively) a.u; 0.35 4 ± .4auv 0.79 vs a.u 0.34 ± .7au L-:0.5 TLR-9: a.u, 0.17 35 nvtosuissoe htIL-4 that showed studies vitro In 6 37 36, ± 3 34 33, .7au L-:0.43 TLR-4: a.u, 0.37 ae nti vdne we evidence, this on Based ± .6auv 0.31 vs a.u 0.06 26 eea studies Several 2 3 7 28 27, 13, 12, ± .0a.u 0.30 ± ± 0.13). 0.11 As Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. 0 oiiS ieaA oin ,Lmis ,Bnn .Epeso fTl-iercposi elh and healthy in receptors Toll-like of Expression S. Bonini 48-9. A, discussion Lambiase 112:1528; A, 2005; Iovieno Ophthalmology factor conjunctiva. A, growth allergic Micera cells. Nerve epithelial S, S. conjunctival Bonini VKC Bonini 10. primary S, cultured in Bonini 15:2037-44. expression A, 2009; 9 Lambiase diseases: Vis and Mol 4 surface EM, (TLR) ocular Normando receptor in B, toll-like receptors Stampachiacchiere modulates Toll-like 120:441-50. A, S. 2011; Micera Bonini (Lond) Th-2-like 9. F, Sci 146:1169-74. of Mantelli Clin 1991; Accumulation M, findings. Immunol al. Sacchetti new J et and A, conjunctivitis. C, overview vernal Micera Simonelli with A, D, patients Lambiase Macchia of P, 8. conjunctiva Parronchi the G, in Prete cells Del vernal T P, in helper surface Biswas ocular E, 3:381-7. the Maggi 2007; of 2003; 7. inflammation Ophthalmol Immunol chronic Clin Allergic J Allergy S. Am Bonini Opin R, Curr questionnaire. Sgrulletta keratoconjunctivitis. A, keratoconjunctivitis testing Lambiase vernal S, and Development Bonini with 6. al. children et C, in Gramiccioni life O, Fassio of S, 144:557-63. quality Aronni A, the Lambiase Opin the I, of Curr Baiardini to keratoconjunctivitis. M, vernal approach Sacchetti of 5. Tailored grading Clinical S. 7:436-41. A. 2007; Bonini Lambiase Immunol F, A, Clin Mantelli Allergy M, Leonardi Sacchetti V, S, Bonini Deligianni 117:1294-9. 4. 2010; F, Ophthalmology Mantelli keratoconjunctivitis. vernal A, 32:49-60. of 2018; Lambiase treatment Agents M, current Homeost conjunctivitis: Regul Sacchetti Allergic Biol A. 3. keratoconjunctivitis J Lambiase M, Vernal management. Nebbioso and al. 107:1157-63. C, pathogenesis Cavaliere et 2000; A, on Ophthalmology O, Bruscolini concepts followup. I, Zuccaro long-term Abicca P, M, with Pasqualetti Sacchetti patients 2. S, 195 Marchi of A, series Lambiase case a S, revisited: Bonini S, agents Bonini of 1. role therapeutic potential foster may the 9 tevaluate References and suggesting TLR-4 VKC, ligands its in receptors. and these reaction CD14 targeting allergic of expression of decreased development surface the ocular inhibition that significant showed induced study VKC This in treatment expression. expression. steroid conjunctival conjunctival topical TLR-4 interaction TLR-4 of that of ocular LPS decrease demonstrated with of that results associated development signalling. was that our improvement the TLR-4 Accordingly, showing clinical in through the study that TLR-4 response and experimental and topical patients Th2 an of CD14 decrease of administration of to that results role showed able the conditions. protective was atopic by a TLR-4 to supported of with predispose is hypothesis induce may reaction the may which influence hand, by allergic hormonal demonstrated. TLRs other or been of agents the has microbial expression On reaction VKC. including epithelium allergic in factors, conjunctival environmental of reaction of that development allergic changes known the of is in development it epithelium the fact, conjunctival In showed in of patients cells role VKC immune active of infiltrating The conjunctiva was the the expression and infiltrating TLR-4 epithelium) cells TLR-4. epithelium (conjunctival immune conjunctival of that that reported expression showed been results increased has Our it clarified. phase. while further active decreased reduced the be in were should patients TLR-9 VKC VKC of and in biopsies TLR-4 conjunctival in studies. rhinitis. that decreased several showed allergic was by which allergic in supported the studies, cells is of previous development inflammatory inflammation with of and line inhibition epithelial the in to in is contribute finding may This TLRs that reaction. suggesting VKC, of inflammation 10 hs nig ugs osbedffrn oepae yrsdn cells resident by played role different possible a suggest findings These Lactobacillus 0 41 40, nadto,i a enrpre htTR9expression TLR-9 that reported been has it addition, In a ffciei euigiflmaoyrato nVKC in reaction inflammatory reducing in effective was 5 9 40 39, h rtcierl fTR9aantallergic against TLR-9 of role protective The ,10 9, 8 44 18, ovrey h oeo TLR-4 of role the Conversely, nadto,Iveoe al. et Iovieno addition, In 42-44 45 24 Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. 0 e oe E essa ,Vt ,SetrF ra A oe ,e l oul D4at sanegative a 29:265-76. as acts 1999; CD14 Immunol Soluble J al. Eur et M, function. Jones and MA, activation Arias 2007; cell F, T Stelter Soc N, human Thorac Vita of Am A, regulator Bensussan Proc JE, interactions. Nores and Rey 30. actions risk: asthma and endotoxin, 4:221-5. CD14, FD. 154:5071-9. Martinez 1995; Annu 29. endotoxin. produce Immunol bacterial cells J by 13:437-57. cells. stimulation Dendritic cell 1995; T al. of Immunol CD4+ et mechanisms Rev naive Receptor-dependent JA, PS. from Tobias Culpepper cells RJ, CS, Ulevitch Th1 28. Hsieh of P, development Vieira the M, direct including Litton and infections, NA, IL-12 recurrent Hosken and SE, 7:436-43. disease Macatonia 2007; atopic 27. Rep in role Asthma CD14: Allergy diphenyl Soluble Curr 20:4426-34. of B. media. 2013; effects Granum Molecular otitis Chem KC, al. Med et Carlsen Curr G, Lodrup Zeni metabolism. 26. CW, cell Nogueira in glucose P, pathway Rosa and La NGF cholesterol M, of on Segatto cytological Changes L, diselenide 74:605-7. Trapani A. and JT, 2019; Lambiase Rocha Clinical Allergy C, da study. Cavaliere 25. al. challenge I, et allergen Abicca conjunctival D, 243:870-6. A, A 2005; Merlo Bruscolini rhinoconjunctivitis: Ophthalmol M, S, allergic Exp Segatto Bonini Clin M, Arch R, Sacchetti Graefes 24. Sgrulletta deficiency. M, cell stem Cortes 17:47-52. limbal A, in 2011; Lambiase findings Vis neuropeptides Mol M, of levels conjunctivitis. Tear Sacchetti al. allergic 23. et in G, challenge Petrachi F, allergen Mantelli specific S, Speranza after A, increase Lambiase Diagnostic A, II Micera DEWS M, TFOS Sacchetti al. 22. 15:539-74. et K, 2017; Keratoconjuncti- Dumbleton Surf 45:64. Vernal M, Dogru Ocul 2019; al. A, Pediatr report. et Djalilian R, J L, Methodology Chalmers Ital Leonardi R, Arita system. F, JS, grading Midulla Wolffsohn glands 21. clinical G, lacrimal Castro on 46:4235-44. the De focused 2005; by M, update Sci tears Nebbioso an Vis in G, vitis: Ophthalmol secreted Capata Invest CD14 AM, cells. and Zicari epithelial LBP 20. corneal allergic I. of experimental Altosaar response attenuates M, LPS Griffith signalling the SG, 4 modulate Vascotto receptor DR, Toll-like Blais CK. 19. 164:275-81. Joo 2011; KJ, 4:169-75. Immunol 2005; Cho Exp Allergy genetic SH, Clin of Inflamm conjunctivitis. Choi Targets contribution SH, Drug potential receptors: Curr Chung allergy. toll-like allergic 18. and and in CD14 inflammation interaction TF. to Fok environment mechanisms GW, by and Wong factors gene NL, Tang innate of TF, between example Leung an bridge 17. CD14: a FD. 57:188-92. CD14: 2002; Martinez F. Allergy D, Martinez disease. Vercelli 7:45-8. 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. Mean (years) Age Female Male (N) Gender study. the in included patients of characteristics Clin clinical Arch and Graefes Demographic of keratoconjunctivitis. 1. evidence vernal Table Preliminary with S. patients Bonini 246:435-41. in A, 2008; treatment Micera Ophthalmol eye-drop B, Exp probiotic Stampachiacchiere of M, 168:4524-30. efficacy Sacchetti 2002; A, the Immunol development Lambiase J optimal A, Bacterial for cells. Iovieno required dendritic al. is 45. of 4 et role receptor Toll-like responses: J, DB. immune Lewis Lefort P, Th2 oxide Stepick-Biek of FQ, ME, nitric Dahl Cunha via K, Dabbagh responses MS, 171:1001-8. 44. asthma-like 2003; Macedo Immunol suppresses de J 4 activity. EL, receptor 2 Faquim-Mauro Toll-like synthase CpG commensal through AC, 118:229-41. of of signaling Keller 2004; Recognition doses lipopolysaccharide Cell D, R. High homeostasis. Medzhitov Rodriguez intestinal al. S, for 43. et required Edberg is ML, F, receptors Eslami-Varzaneh Belladonna toll-like J, by C, Paglino microflora Vacca 4:1852. S, 2013; R, Rakoff-Nahoum Commun Bianchi 42. Nat pathway. MT, TLR9-TRIF Pallotta tolerogenic a F, J stimulate Fallarino Organ oligodeoxynucleotides Allergy C, World Volpi donors. immunological and allergic 41. Physical and al. non-allergic et from D, cells Bock 13:100109. epithelial S, Eisenbart nasal 2020; Different R, primary in Riepl human Expression E, of TLR9 Hummer barrier and DC, asthma Dittlein TLR4 C, 2012:925164. allergic S. Bergougnan Bonini 2012; alleviates 40. L, Otolaryngol Dexamethasone Businco J 22:184-9. al. Rienzo Int 2018; Di et Rhinitis. P, Sci of J, Muzi Pharmacol Fan Phenotypes A, Med Micera FJ, Rev M, Eur CD14 Jia Lauriello 4. ZL, 39. down-regulates receptor Zhang IL-13 like Y, Toll D. through 155:3145-51. Sui Vercelli rat 1995; Q, G, immature Immunol Wang J Viale ZR, monocytes. AG, Wang human 38. Siccardi normal CP, in secretion Thienes TNF-alpha E, and 52:323-30. Soprana expression 1992; Biol G, Leukoc Cosentino J CD14 37. macrophages. soluble down-regulate and 64:710-7. interleukin-4 monocytes 2009; and human Allergy Interferon-gamma JP. with in patients. Obrecht level release keratoconjunctivitis AE, vernal CD14 Fisscher and and R, soluble angiogenic Landmann subjects metalloproteases, plasma 36. matrix normal of Cytokines, of 20:19. R. Association Sack tears 2019; al. A, in Res Beaton et factors M, Respir L, Bortolotti growth China. S, Xiao in Sathe Y, A, study Leonardi Liu control 35. Y, case 2006; Relati- Zhou a children: Med J, adults: in Care in Ma asthma Crit severity X, Acute Respir asthma Huang al. J T, et Am Zhou severity. L, 34. and Teoh levels, K, plasma Rueter genotypes, G, CC16 Zhang B J 173:617-22. and SK, human production. CD14 edge: Khoo IgE among Cutting IA, and onships al. IgG1 Laing on et AC, P, effects Martin Ferrara opposite 33. LK, CD14: Borysiewicz soluble serum F, with total 164:3480-6. Stelter interaction 2000; with by N, Immunol and regulated Vita 5’ levels is JE, the function CD14 Nores in cell 20:976-83. Rey soluble Polymorphism* 1999; MA, circulating A Biol Arias with FD. Mol 32. Martinez associated Cell Respir PG, is J Holt gene Am RP, CD14 E. Erickson the immunoglobulin M, of Halonen region IC, flanking Lohman M, Baldini 31. ± SD 53724140 4 1 4 2 7 3 15 (N=18) VKC with patients All 10.7 ± . 9 5.7 (N=9) A group VKC ± . 8.5 2.3 7 (N=5) Q group VOC ± . 22 4.4 (N=4) R group VKC ± 5 Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. K nteatv hs,7dy fe oia ramn ihHdootsn y rp.*=statistical = * drops. eye Hydrocortisone with treatment topical after days 7 baseline. phase, vs active significant the = * in controls. VKC healthy with 3 R). compared Figure (group (R) recovery recovery VKC VKC vs after significant statistical and group; C¸ = disease healthy the vs significant of statistical phases (Q) quiescent and recovery group; VKC healthy 2 vs significant vs Figure statistical C¸ significant = Q); statistical (group = phase the * quiescent in R). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. 10 Posted on Authorea 23 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159551292.25822092 — This a preprint and has not been peer reviewed. Data may be preliminary. 11