Dry eye disease and uveitis: a closer look at immune

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Jul 3, 2016 - immune mechanisms underlying both eye diseases reveals .... and in toxicological testing, feline, canine and porcine models are highly suitable ... Genetic associations with uveitis in humans have been described extensively.
    Dry eye disease and uveitis: a closer look at immune mechanisms in animal models of two ocular autoimmune diseases Tanima Bose, Maria Diedrichs-Moehring, Gerhild Wildner PII: DOI: Reference:

S1568-9972(16)30193-8 doi: 10.1016/j.autrev.2016.09.001 AUTREV 1912

To appear in:

Autoimmunity Reviews

Received date: Accepted date:

3 July 2016 8 July 2016

Please cite this article as: Bose Tanima, Diedrichs-Moehring Maria, Wildner Gerhild, Dry eye disease and uveitis: a closer look at immune mechanisms in animal models of two ocular autoimmune diseases, Autoimmunity Reviews (2016), doi: 10.1016/j.autrev.2016.09.001

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ACCEPTED MANUSCRIPT Dry eye disease and uveitis: a closer look at immune mechanisms in animal models of two ocular autoimmune diseases

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Running title: Animal models of dry eye disease and uveitis

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Authors: Tanima Bose1, Maria Diedrichs-Moehring2, Gerhild Wildner2*

Affiliation: 1Lee Kong Chian School of Medicine, Singapore, 59 Nanyang 636921 Singapore;

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Clinic of

the

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Drive,

LMU Munich, Section of

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Immunobiology, Department of Ophthalmology, Mathildenstr. 8, 80336 Munich, Germany

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Corresponding author: *Tel.: +49 89 4400 53888; fax: +49 89 4400 53045;

Keywords:

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E-mail address: [email protected]

Sjögren

syndrome,

EAU,

autoimmune

disease,

signaling

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pathways, therapies

Text Word counts: 5986 Abstract word count: 184 Number of Figure: 1, Number of Table: 1 Number of references: 232

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ACCEPTED MANUSCRIPT Abstract: Understanding the immunopathogenesis of autoimmune and inflammatory

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diseases is a prerequisite for specific and effective therapeutical intervention. This review focuses on animal models of two common ocular inflammatory

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diseases, dry eye disease (DED), affecting the ocular surface, and uveitis with inflammation of the inner eye. In both diseases autoimmunity plays an important role, in idiopathic uveitis immune reactivity to intraocular

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autoantigens is pivotal, while in dry eye disease autoimmunity seems to play a

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role in one subtype of disease, Sjögren’s syndrome (SjS). Comparing the immune mechanisms underlying both eye diseases reveals similarities, and

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significant differences. Studies have shown genetic predispositions, T and B cell involvement, cytokine and chemokine signatures and signaling pathways

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as well as environmental influences in both DED and uveitis. Uveitis and DED are heterogeneous diseases and there is no single animal model, which

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adequately represents both diseases. However, there is evidence to suggest

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that certain T cell-targeting therapies can be used to treat both, dry eye disease and uveitis. Animal models are essential to autoimmunity research, from the basic understanding of immune mechanisms to the pre-clinical testing of potential new therapies.

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ACCEPTED MANUSCRIPT Contents: 1. Introduction

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2. Role of animal models in ocular autoimmunity 2.1 Determination of clinical signatures

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2.2 Immunological signatures of different disease models 2.2.1 Immune cells: Chemokine signature 2.2.2 Immune cells: Cytokine signature

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2.3 Understanding signaling pathways

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2.4 The role of environmental stress in the initiation of ocular autoimmunity 2.5 Therapeutic perspective

Take-home messages

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Acknowledgement

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3. Conclusion

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References

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ACCEPTED MANUSCRIPT 1.

Introduction

Dry eye disease

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Dry eye disease (DED) or keratoconjunctivitis sicca (KCS) is an autoimmune disorder of the ocular surface, affecting up to 35% of the adult population [1,

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2]. It is characterized by inflammation of the ocular surface and involves conjunctiva, cornea, eyelids, meibomian glands, goblet cells and lacrimal glands. The symptoms of DED are burning, itchy eyes that may become

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painful with progressive disease, which can lead to corneal ulceration,

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reduced vision and in some cases even to blindness. DED is caused by insufficient tear production or increased evaporation of the tears due to decreased lipid production from the disturbed function of meibomian glands.

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KCS can be associated with Sjögren’s syndrome (SjS) [3]. This disease was

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first described by a Danish physician in 1933 in a series of patients with symptoms of primary (pSjS, associated with dry eye or mouth) or secondary

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sSjS, associated with other autoimmune diseases such as rheumatoid arthritis

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[4]. Although the symptoms of SjS had been described during the early 20th century, its immunopathogenesis, signaling pathways, underlying immune mechanisms and role of environmental stress have only recently been investigated using various animal models of DED. Such animal models include: autoimmune dacryoadenitis or sialadenitis, non-obese diabetic (NOD) mice, inhibitor of DNA-binding 3 (Id3)-knockout (ko) mice, desiccating stress/low humidity- or cevimeline-induced SjS model etc. [5, 6]. The animal species used for DED research include rodents (mice, rats) canine (dogs), porcine (pigs), sheep, feline (cats) and even non-human primate models [7, 8].

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Uveitis

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Autoimmune uveitis is defined as a non-infectious, T cell-mediated intraocular inflammatory disease comprising all parts of the eye. According to the

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affected anatomical sites of the eye, uveitis is classified as anterior uveitis (AU, iritis, ciliary body), intermediate uveitis (peripheral retina, inflammatory cells in the vitreous), posterior uveitis (retina, retinal pigment epithelium,

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choroid, vitreous, papilla) or pan uveitis affecting all intraocular tissues. The

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symptoms of the disease are blurred and decreased vision, which can even lead to blindness. The destruction of the retinal architecture is irreversible, but

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not painful, while in the often painful anterior type the inflammation can in some cases resolve without damage to the ocular tissue. Long-lasting and

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severe intraocular inflammation can lead to sequels like glaucoma, cataract or cystoid macular edema, chorioretinal neovascularizations or formation of

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epiretinal membranes. Glaucoma can result in the irreversible damage of

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retinal ganglion cells, while cataract and especially cystoid macular edema may compromise vision. To investigate the pathomechanisms underlying the complex and heterogenic human disease animal models of experimental autoimmune uveitis/uveoretinitis (EAU) have been established, which can be induced in genetically susceptible animals either by active immunization of retinal proteins and peptides thereof, and/or by adoptive transfer of activated T lymphocytes specific for retinal proteins or peptides. Uveitis models in guinea pigs [9-14], rats [15-19], mice [20-31], monkeys [32, 33] and horses [34, 35] have been established, the most commonly used models are in mice and rats.

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ACCEPTED MANUSCRIPT Susceptibility for uveitis in animals is strictly genetically controlled; only some strains of mice or rats [20, 21, 36] can be used for disease induction.

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With the development of these animal models it was possible to characterize and analyze different key points of this disease, namely the involvement of

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different immune cell types of the adaptive and innate immunity, the engagement of downstream signaling pathways of those immune cells, contribution of different cytokines and the role of environmental cues on the

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previously mentioned factors.

Role of animal models in ocular autoimmunity

2.1

Determination of clinical signatures

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2.

Dry eye disease

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The normal clinical tests performed to identify the clinical features of dry eye in animal models are phenol red thread test (PRT) or Schirmer paper strip test

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to measure the tear secretion, or fluorescein staining measured in a slit-lamp

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microscope to detect the abnormality of the tear film on the corneal surface. The other notable tests are counting the spontaneous blink rate or conjunctival impression cytology to measure the density of goblet cells in pig eyes [37]. One interesting study has been performed in rabbits to evaluate the tear film, the viscosity and the tear break area by a video recording system, where the insult in the eye was generated by hypochloric acid, and an artificial tear preparation with viscosity agents like hyaluronate, cellulose or chondroitin sulfate was used to evaluate the tear film instability and viscosity [38]. Most of the clinical tests were evaluated in rabbit and porcine models due to their similarity with the human eye.

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ACCEPTED MANUSCRIPT Uveitis In mice developing only posterior uveitis, the inflammation can be determined

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clinically by slit lamp investigation of the fundus. In Lewis rats infiltration of inflammatory cells into the anterior chamber can be easily observed by

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examination of the eye with an ophthalmoscope. In both, mice and rats, destruction of the retinal architecture is scored by histological sections of the posterior part of the eye. For EAU there are generally accepted scores for

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both inflammation as well as tissue destruction, measuring disease activity

Immunological signatures of different disease models

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2.2.

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and outcome in dry eye disease is more complex and less standardized.

Dry eye disease

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The choice of animal models in general depends on the questions the researchers would like to address. Since mice are generally preferred for

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genetic manipulation and rabbits are used for pharmacological experiments

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and in toxicological testing, feline, canine and porcine models are highly suitable for the proper detection of pathologic features like blinking rate and Schirmer tear test. Commonly used animal models are NOD mice and their derivative strain IQI/jic, the latter developing only SjS, but not type 1 diabetes; ko mice lacking the basic helix-loop-helix transcription factor "Inhibitor of DNA-binding 3" (Id3); mice defective in the phosphatidylinositol 3-kinase (PI3K)-ERK signaling pathway; mice transgenically overexpressing the B cell growth and survival factor BAFF and MRL/lpr mice lacking Fas, which are all spontaneously developing SjS; or induced models like (NZBxNZW)F1 mice after injection with either complete Freund’s adjuvant (CFA) or a viral mimic

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ACCEPTED MANUSCRIPT or mice immunized with autoantigens expressed in lacrimal glands like Rofactor peptides or kallikrein or treated with scopolamine or alum; or

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environmentally regulated models (mice exposed to desiccating stress in a controlled-environment chamber) [39-44]. All of the listed model animals are

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developing lymphocytic infiltration in salivary and lacrimal glands, resulting in loss of function and will be described and referred to in the following text.

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Uveitis

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Mouse: experimental uveitis

Uveitis can be induced in some mouse strains either by immunization with

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whole interphotoreceptor retinoid binding protein (IRBP) or peptides in CFA with additional concomitant injection of pertussis toxin (PTX), or by adoptive

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transfer of activated, antigen-specific T lymphocytes. The most susceptible

[45].

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mouse strain is B10.RIII, also the only one known so far not requiring PTX

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Genetic associations with uveitis in humans have been described extensively [46-57], and the role of human leukocyte antigen (HLA) molecules in uveitis has been studied in HLA class I (A29, B27, B51) and class II (DR3, DR4, DR2, DQ6, DQ8) transgenic (tg) mice. Whereas HLA-A29 tg mice develop spontaneous EAU [58], HLA-B27 and -B51 transgenic mice do not show signs of spontaneous ocular disease [59]. Immunized C57BL/6-HLA-B27 tg animals display less severe signs of inflammation than wild type mice [60]. Most HLA class II tg mice develop severe uveitis after immunization with IRBP, whereas HLA-DR3-transgenic mice are only susceptible to EAU induction with retinal S-antigen/arrestin (S-Ag) [61]. S-Ag is also immunogenic in HLA-DR4 and

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ACCEPTED MANUSCRIPT HLA-DQ8 tg mice, but not in mice with the HLA-DR4 transgene (DRB1*0401) [62].

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Wild type as well as genetically manipulated mice predominantly develop a monophasic disease affecting only the posterior part of the eye. A

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spontaneously occurring, late synchronized recurrence of posterior uveitis was published for IRBP-induced EAU in B10.A mice [63]. Rat: experimental uveitis

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The Lewis rat strain with the RT1l haplotype is most susceptible [36] and most

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commonly used to study EAU in rats. In addition to IRBP [36], which is the only uveitogenic protein in wild type and most of the transgenic mice, various

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ocular proteins and peptides can be used to induce EAU in rats (e.g. S-Ag [64], phosducin [65], rhodopsin [66], recoverin [67], myelin basic protein

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(MBP) [68], S100 [69], melanin-associated antigen [70], cellular retinaldehyde-binding protein (CRALBP) [71], tyrosinase-related protein 1

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(TrP1) [32] and retinal pigment epithelium-specific protein 65kDa (RPE65)

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[72]. Many of these autoantigens are also immunogenic in human patients [73-75].

In Lewis rats, the best-characterized autoantigens with respect to uveitogenic epitopes are IRBP [15-19, 76] and S-Ag [26-31]. Both proteins and their peptides induce pan-uveitis at an incidence of up to 100% in Lewis rats after immunization with CFA, without PTX. Adoptive transfer of activated, antigenspecific T cells will lead to uveitis as well. Two highly pathogenic peptides, one from S-Ag (PDSAg, aa 341-354) and the other from IRBP (R14, aa 1169-1191), cause both severe posterior as well as anterior inflammation but resulted in different types of uveitis. Peptide PDSAg

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ACCEPTED MANUSCRIPT induces a monophasic/chronic uveitis with chorioretinal neovascularization in affected eyes [77, 78], a late complication that is also observed in human

relapsing-remitting [76, 77].

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Horses: spontaneous and experimental uveitis

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uveitis patients. In contrast, peptide R14 mediated uveitis is spontaneously

Approximately 10-15% of warm-blooded horses develop spontaneous recurrent uveitis (equine recurrent uveitis, ERU). ERU shares many

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corresponding clinical and pathological features with chronic human

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(intermediate) uveitis [35]. Enhanced proliferative response of equine vitreal lymphocytes can be observed to a set of retinal autoantigens that are also

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immunogenic in human patients [74, 79] and pathogenic in Lewis rats [26, 80]. Elevated levels of antibodies specific for S-Ag and IRBP are detected in

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serum and vitreous of ERU horses compared to healthy animals [81]. IRBP was shown to be a very potent autoantigen in ERU, 100% of animals develop

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recurrent uveitis after immunization with IRBP in CFA [82]. In contrast, S-Ag

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failed to induce ERU in ponies [83], and only 1 of 8 horses developed uveitis after immunization with S-Ag [84], despite a strong T cell response to S-Ag and various S-Ag peptides. Recurrences could be induced only by reinjections of IRBP in CFA. Analyzing T cell responses to autoantigens in induced and spontaneous ERU revealed intermolecular as well as intramolecular epitope spreading and is regarded as a possible cause for recurrences [82, 85]. A novel autoantigen for uveitis, CRALBP, was detected in equine uveitis and confirmed to be pathogenic in rat EAU and immunogenic in human uveitis [71, 75].

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ACCEPTED MANUSCRIPT 2.2.1 Immune cells: Chemokine signature Dry eye disease

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In inflamed cornea, conjunctiva, lacrimal glands and/or meibomian glands increased levels of pro-inflammatory cytokines/chemokines were found, along

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with elevated levels of pro-inflammatory cytokines in tears that are accompanied by increased epithelial cell apoptosis, decreased tear production and diminished goblet cells. To start with the adaptive system, the

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pronounced effect of autoreactive CD4+ T helper (Th) cells expressing the

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Th1 cytokines interleukin (IL)-2 and interferon (IFN)-γ but not IL-4 was described [86]. IL-17 might also be involved in the pathogenesis, since

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administration of anti IL-17 antibody ameliorates DED-induced corneal epithelial barrier dysfunction [87]. It has been shown that CXC chemokine

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receptor 3 (CXCR3) and CCR6 are needed for the migration of CD4+ Th1 as well as Th17 cells to the ocular surface, which are subsequently mediating

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ocular surface diseases in a desiccating, stress-induced mouse model of dry

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eye disease [88]. For the maintenance and migration of Th17 cells CCR7 and CCR6/chemokine ligand 20 (CCL20) are important in a scopolamine-induced dry eye model [89]. The pivotal role of B cells was investigated in Id3-/- mice [90], suggesting a pathogenic role of IgG3 antibodies in this mouse strain. Moreover, the B cell repertoire and maturation were studied in a mouse model of SjS, called B6.Aec1/2, indicating that in these mice a diverse B cell repertoire is required for an efficient T-B cell interaction, resulting in autoreactive antibodies [91]. In recent years, it was found that autoantibodies play a major role in the disease pathogenesis due to their presence in the sera of patients with Sjögren-mediated DED and the successful induction of

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ACCEPTED MANUSCRIPT disease in recipient animals by passive transfer of IgG from patients with SjS. In addition, autoantibodies against kallikrein-13 were detected in a

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desiccating, stress-induced mouse model [92-94]. In addition to infiltrating lymphocytes, macrophages and dendritic cells are also detectable, and T cells

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preferentially expressing T cell receptor (TCR)V6 and TCRV8, as shown in the NOD mouse model [95-97].

Along the line of adaptive immunity, the role of innate immune pathways has

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also been investigated. Toll-like receptor (TLR) 4, 5 and 9 are detectable in

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patients with dysfunctional tear syndrome. Correlating with the human studies in experimental dry eye disease a higher surface expression of TLR4 on the

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corneal epithelium was observed, accompanied by infiltration of CD11c+ dendritic cell (DC) after treatment with scopolamine and placing the animals in

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controlled-environment chamber. In vitro co-culturing of DC with corneal extracts from DED-induced mice resulted in a higher expression of pro-

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inflammatory cytokines like IL-1, TNF-α and IL-6, indicating an activation of

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DC following TLR4 expression [98]. Enhanced expression of TLR2, 4 and 9 in the conjunctiva and contribution to inflammation have also been shown in several other animal models such as an autoimmune sialoadenitis model in NOD mice, DED induced in C57BL/6 and TLR9-/- mice after either inhibition of TLR expression or agonistic stimulation via TLR [99-101]. Uveitis In uveitis, TLRs seem to play no major role. Mice deficient in TLR2, 4 and 9 are fully susceptible for EAU induced by immunization with IRBP emulsified in mycobacteria containing CFA. No difference regarding the retinal destructions

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ACCEPTED MANUSCRIPT as well as the immune response have been observed in comparison to the wild type mice [102].

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In contrast, IL-1R- and MyD88-deficient mice are resistant to EAU. MyD88 ko mice shift their immune response to a Th2 type without developing a ‘Th2

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disease’. They lack intraocular invasion of eosinophils as observed in the mice deficient in IFN-γ [103]. IL-1R ko mice showed an impaired immune response with respect to both, Th1 and Th2 cytokines, indicating a

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redundancy in the adjuvant effect needed for EAU induction irrespective of the

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signaling through IL-1R and MyD88 [102].

In experimental autoimmune uveitis, trafficking and infiltration of monocytes to

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inflammatory sites is associated with the expression of chemokine receptors CCR2, CCR5 and CX3CR1 [104], and the levels of respective ligands for

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CCR2 (CCL2/MCP-1), CCR5 (CLL5/RANTES, CCL4/MIP-1β and CCL3/MIP1α) and CX3CR1 (CXCL10/IP-10) increase during the development of EAU in

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rats [105] and mice [106, 107]. Nevertheless, in CCR2-deficient mice EAU

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can be induced and monocyte recruitment is observed [108]. Absence of CX3CR1 exacerbates EAU and enhances the accumulation of macrophages accompanied by enhanced neuronal apoptosis [109]. After immunizing mice deficient in both of CCR2 and CX3CR1, infiltration of macrophages as well as retinal destruction and angiogenesis are reduced and predominantly neutrophil granulocytes and lymphocytes participate in the inflammatory processes [110]. This indicates that CCR2 as well as CX3CR1 are involved in macrophage recruitment across the blood-retinal barrier (BRB), and both could compensate each other depending on the animal model. For T cell trafficking in EAU, the expression of CCR5 on leukocytes [111] and the

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ACCEPTED MANUSCRIPT presence of CCL3 on retinal vessels are reported as a pre-requisite for the development of uveitis in mice [112]. However, antagonistic blockade of

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CCR5 by MET-RANTES, an N-terminally modified CCL5 binding to CCR5 and CCR1 in rodents only prevents EAU in rats induced by adoptive transfer of

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PDSAg-specific but not R14-specific T cells. This indicates that pathogenic T lymphocytes specific for different antigens recruit inflammatory cells to the

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eyes via the choroid or retinal/iris vessels, depending on the antigen [77, 113].

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2.2.2 Immune cells: Cytokine signature Dry eye disease

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Interestingly, cytokines from both innate and adaptive immune system are described to be involved in dry eye disease pathogenesis. IL-1, IL-6, and

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TNF- have been suggested to play a role in destruction of acinar cells in autoimmune sialoadenitis. In NOD (BALB/c mice), increase of IL-1 and

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decrease of IL-6 precede periductal lymphoid aggregates and cell destruction

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[113]. On the other hand, by inducing graft versus host disease (GvHD) in an IL-6 transgenic mouse model, sialoadenitis in salivary glands was observed indicating that high levels of IL-6 may contribute to the pathogenesis of dry eye disease [114]. In C57BL/6 mice, topical treatment with IL-1R-antagonist ameliorates disease, whereas in NOD mice the inhibition of TNF- in the salivary gland could have a negative effect on salivary gland function shown [115, 116]. In human patients with SjS, elevated levels of the pleiotropic cytokine IL-12 were found in affected organs. In IL-12 tg mice, over-expressing IL-12, showed strikingly similar signs as also found in dry eye disease and SjS, like

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ACCEPTED MANUSCRIPT reduced tear flow and acini, increase in lymphocytic foci accompanied by an increase in natural killer (NK) cells, indicating a role of IL-12 in the initiation of

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the disease [117, 118]. A predominant level of IL-12 mRNA was found in early disease in MRL/lpr

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mice with SjS, but IL-10 mRNA was also detected in salivary gland tissue before onset and was upregulated during the course of disease, suggesting involvement of both IL-10 and IL-12 in the pathogenesis [119]. IL-10 is

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normally regarded as an anti-inflammatory cytokine, counter-regulating pro-

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inflammatory cytokine release (reviewed in [120, 121]), but enhanced levels of IFN-γ, TNF-α, IL-6, IL-17 and interestingly also IL-10 were found in a chimeric

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human-mouse model of SjS [122]. In serum of patients with SjS elevated levels of IL-10 were observed, correlating with disease activity and suggesting

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a potentially pathogenic role of IL-10 as well, especially in the presence of IFN-γ [123]. On the other hand, successful topical anti-inflammatory treatment

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was accompanied by increased IL-10 in conjunctival fluid [124].

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Different functions of CD4+ Th1 and Th2 subtypes are delineated due to the presence of various cytokines. Detection of IL-2, IFN-γ, IL-4 and IL-5, associating with B cell accumulation, suggests a role of Th1 in disease induction and maintenance, and Th2 in disease progression. The Th1associated pro-inflammatory cytokine IFN-γ is regulating the conjunctival apoptosis in desiccating stress models [125-127], and IL-7 upregulates the expression of IFN-γ [128]. IL-13 as a Th2 cytokine is also proposed to be involved in disease pathology as shown in Id3-/- mice [129]. The role of Th17 cells was critically explored in SjS in a chronic dry eye mouse model. Chronic ocular surface damage is mainly mediated by a

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ACCEPTED MANUSCRIPT memory T cell population, the response of which is predominantly mediated by Th17 cells [87]. Depletion of CD8+ cells promoted the induction of IL-17A

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producing cells. Interestingly, adoptive transfer of CD4+ cells from CD8+depleted animals to nude mice can contribute to the more severe form of

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disease in the recipients. Co-transfer of CD8+CD103+ Treg had no effect indicating that CD8+ can suppress the initiation of pathogenic Th17 cells, but not the prolongation of disease [130].

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As shown in Fig. 1A, Foxp3+CD25+ T regulatory (Tregs) cells play a bystander

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role in controlling the disease progression. It is shown in one study that transfer of lymphocytes from scurfy mice, lacking CD4+CD25+ Treg cells, into

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an immunodeficient RAG-1 ko mouse can induce inflammation with a loss of functions in lacrimal glands [130, 131].

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Moreover, the importance of transforming growth factor (TGF-), which is

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released from T cells and macrophages, was studied in conditional TGF- RI ko mice. Interestingly it was found that impaired TGF- signaling had no effect

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in male animals, but resulted in inflammation and increase in pro-inflammatory cytokines in salivary glands along with the up-regulation of peripheral T cells in female animals underlining that female individuals are more susceptible to salivary inflammation. The atypical distribution of aquaporin-5 in these female ko mice also suggested a secretory impairment of their salivary glands [132]. An interesting study with pSjS and sSjS in IL-14 (B cell growth factor) transgenic mice demonstrated that they develop all clinical and immunological features of pSjS in the same time-frame as patients with pSjS, pointing out that auto-antibodies may be involved in early decreased gland function [133]. Additionally, the role of IL-14 and IL-21 (expressed on T, B and NK cells) was

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ACCEPTED MANUSCRIPT delineated in a local suppression in NOD and IL-14 transgenic mice, showing the different stages of local injury culminating into a systemic

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inflammation with an injury in parotid glands, lungs and kidney [134-136].

designing new drugs for dry eye disease. Uveitis

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Most importantly, the involvement of these cytokine pathways may help

While the development of EAU was initially considered to be mediated by

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activation of Th1 cells [137, 138], Th17 cells have meanwhile been identified

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and intensively described to play a role in the pathogenesis of EAU [139-143]. According to the animal models, human endogenous uveitis is also

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considered to be a Th1/Th17 cell-driven disease [139] with infiltration of granulocytes, macrophages and non-specific lymphocytes causing tissue

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damage. How both cytokines, IFN-γ and IL-17, are involved in autoimmune pathogenesis is not yet fully understood (Fig. 1B). IFN-γ ko as well as IL-17 ko

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mice can develop EAU [103, 141, 144, 145], and clinical trials targeting IL-17

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in uveitis have not been successful. Paradoxically, IFN-γ ko mice develop even more severe intraocular inflammation than wild type mice, caused by massive infiltration of eosinophils and enhanced levels of IL-5 and IL-13 [103]. These two Th2-type cytokines are protective in wild type mice [146] and IL-13 also ameliorates EAU in monkeys [147]. The immunization of IL-17 ko mice revealed a disease onset comparable to wild type mice, but a better recovery, indicating an importance for Th1 cells in initiating the disease and IL-17 producing cells in the late phase [141]. Both Th1 as well as Th17 cells can transfer disease to naïve mice, but which type dominates or/and how it contributes to the disease seemed to be dependent on the model and the

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ACCEPTED MANUSCRIPT induction of the disease. Using IRBP-pulsed DC, a more Th1-prone disease was observed, whereas immunization with autoantigen emulsified in CFA

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favors Th17/IL-17-driven EAU in mice [140]. In Lewis rats, the relapsing-remitting and the monophasic/chronic disease

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revealed dynamic changes of IFN-γ and IL-17-producing populations of intraocular T cells at different stages of disease [148], and increasing T cells co-expressing IFN-γ and IL-17 (Th1/Th17) and even IL-10 in monophasic

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EAU, while this population decreased after onset of ocular inflammation in

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relapsing disease. Cells producing multiple cytokines were only found within the eyes and not in the periphery. This suggests a regulatory role for these

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multiple cytokine-expressing ocular T lymphocytes [148, 149]. Comparative gene array analysis of rat T cell lines inducing relapsing-remitting or

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monophasic EAU revealed that IFN-γ is pivotal for relapses, which is

[148].

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supported by intraocular injection of IFN-γ, resulting in synchronized relapses

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Th17 cells are potently induced by IL-6 and TGF- and become proinflammatory in the presence of IL-23 (reviewed in [150]). Blockade of IL-6/ IL6 receptor can ameliorate EAU only in the initiation phase of the disease by inhibiting the induction of Th17 cells, but this was unsuccessful at a later time point [151-153]. IL-10 was shown to play a key role in regulating and controlling immune responses and tolerance (reviewed in [120] and [121]). Neutralization of IL-10 with antibody treatment deteriorates EAU, while over-expression of IL-10 in the eye can ameliorate EAU [154, 155]. Fisher344 rats have higher levels of IL-10 in the eyes, which may contribute to their resistance to EAU induction in

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ACCEPTED MANUSCRIPT the absence of PTX [156]. Induction of EAU in tg mice expressing IL-10, either constitutively in macrophages or inducible in activated T cells, revealed

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that IL-10 protects from EAU by inhibiting de novo priming of auto-reactive T cells, as well as suppressing recruitment and/or function of leukocytes

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involved in inflammation and tissue damage [157].

Like IL-10, the cytokine TGF- is also controlling inflammatory processes in the eye. This cytokine is constitutively expressed in the eye by many cell

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types and is engaged in the immune privilege of the eye [158]. Within the eye

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TGF- is converted from its latent to the active form driven by thrombospondin- [159], and in combination with alpha-melanocyte-

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stimulating hormone (α-MSH) the active TGF- is able to induce ocular antigen-specific Tregs. These Tregs can show bystander suppression of T

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lymphocytes specific for different ocular antigens, but not of non-ocular-

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specific T cells [160].

Tumor necrosis factor alpha (TNF-α) is a pleiotropic cytokine, secreted among

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others by T cells and macrophages during inflammatory responses. It initiates and orchestrates further infiltration of lymphocytes, like non-specific T cells, macrophages and dendritic cells into the eye by the upregulation of adhesion molecules, like ICAM-1, VCAM [161, 162], and chemokines as well as their receptors like CCR2 [163]. TNF-α drives maturation and survival of dendritic cells and macrophage activation, leading to enhanced production of nitric oxide (NO), which is thought to cause retinal damage. During the early course of EAU in rats, microglia generate NO and TNF-α [164, 165] and migrate within the retina before the influx of inflammatory mononuclear cells is observed [165]. Blockade of TNF-α with the TNF-receptor subunit p55 has

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ACCEPTED MANUSCRIPT been shown to be a potent therapy to ameliorate tissue damage shown in mice [166] and rats [167]. In rats it was shown that soluble TNF mediates cell

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trafficking into the eye. Once in the eye, this cytokine signaling via TNFR1, can lead to macrophage activation and subsequent tissue damage [167]. In

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mouse EAU the signaling via TNFR1 controlled macrophage activation with NO production and their trafficking to the site of inflammation [163, 168, 169]. TNFR2 is implicated in modulating migration of leukocytes, tissue repair and

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angiogenesis [170]. TNFR2 ko mice showed increased recruitment of

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inflammatory cells and choroidal neovascularization (CNV), while TNFR1 deficiency increased apoptosis and thus decreased the number of

Understanding signaling pathways

Dry eye disease

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2.3

ED

inflammatory cells at the site of tissue injury [171].

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The role of signaling pathways in dry eye disease is mostly explored with the

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help of genetic manipulation in mouse models. For example, the role of c-JUN kinase in corneal epithelial disease was explored with a Janus Kinase (JNK)2knockout model [172]. JNK2 ko, but not JNK1 ko mice show resistance to desiccation-induced corneal disease. The stress-activation of JNK increases metalloproteinase (MMP) production, which has a negative effect on the corneal epithelium. Especially the role of MMP-9 in disrupting the corneal barrier by degrading the tight junctions of the corneal epithelial cells was found to be crucial for dry eye pathogenesis [173]. In addition, inflammatory cytokines (IL-1, IL-1, TNF-) induce MAPK signaling pathways in lacrimal glands of BALB/c mice, and p38-MAPK pathway inhibition was shown to

20

ACCEPTED MANUSCRIPT ameliorate dry eye symptoms in MRL/lpr mice [174]. One isoform of the calcium-dependent, secretory phospholipase A2, sPLA2-IIA, which is

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upregulated in multiple inflammatory diseases in humans, seems to be important for the normal immune defense of the ocular surface since it is

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highly expressed in tears and conjunctiva. In a scopolamine-air-ventilationinduced mouse model of DED, the level of sPLA2-IIA even increased in the inflamed tissues [174, 175]. The role of B cells in SjS was investigated in

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protein kinase C (PKC)-knockout mice. PKC concurs to B cell tolerance,

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tissue-infiltration of lymphocytes and apoptosis. PKC ko mice have increased B cell infiltration and also enhanced levels of IFN-γ in salivary glands, leading

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to tissue damage and SjS-like disease [176]. Along the line, the increase of TLR9+ PBMC with increased phosphorylation of p38 MAPK was identified in

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submandibular glands during the early phase of pSjS in the NOD mouse model [177]. According to the role of B cells in SjS, IL-4/Signal Transducer

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and Activator of Transcription (STAT)6-expressing Th2 cells were found to be

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important for SjS. In NOD/STAT6 ko mice, there was no dysfunction of exocrine glands observed despite leukocyte infiltration [178]. The information about most of these pathways led to new strategies for therapeutic intervention (Table 1). Uveitis Autoreactive T cells inducing either monophasic/chronic or relapsing-remitting uveitis in rats were investigated for their gene expression profiles. T cells specific for PDSAg (monophasic EAU) and R14 (relapsing EAU) were compared and revealed upregulation of 26 genes belonging to signaling pathways of Wnt, Hedgehog, MAP-kinase, JAK-STAT, and antigen-

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ACCEPTED MANUSCRIPT presentation, only in R14-specific T cells. The role of Wnt signaling in uveitis, as shown by the upregulation of proteins belonging to the WNT-PCP, the

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canonical WNT, and hedgehog pathways (Jak2, Jnk2, Nqo1, Wnt5b, Casp3, Cnksr3/Magi1, Ecad, Gli1, Jag1, and Tgm2) in rat T cells that induce

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relapsing uveitis [149, 179] was later indirectly confirmed by the finding of decreased secreted WNT inhibitors Dickkopf-3 (DKK3) and secreted Frizzledrelated proteins (SFRP)2 in the vitreous of equine recurrent uveitis [180]. The

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upregulated genes in autoreactive rat T cells are all upstream or downstream

MA

of IFN-γ signaling, which is thought to play a pivotal role in relapsing uveitis [149, 179].

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In vitreous and retinal lesions of equine uveitis up-regulation of vascular endothelial growth factor (VEGF) and concomitant down-regulation of pigment

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epithelium-derived factor (PEDF) was observed [181]. VEGF promotes and PEDF protects from neovascularization. The monophasic rat EAU induced

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with S-Ag peptide-specific T cells revealed that these T lymphocytes produce

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VEGF and thus can induce neovascularization in rat eyes after resolution of clinically visible uveitis [78]. Talin-1, a protein linking cytoplasmic domains of integrin- to actin filaments is down-regulated in granulocytes after they had migrated to the eye during inflammation of equine uveitis [182]. Expression of TIMP2, a tissue inhibitor of MMP and as well the angiogenesis and neuroprotective factor, was diminished in ERU eyes, which allows altered expression of several MMPs in the eyes during inflammation [183]. Suppressors of cytokine signaling (SOCS) were up-regulated in the eye during uveitis, where their expression was correlated with the course of the disease [184]. Mice with STAT3-deficient

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ACCEPTED MANUSCRIPT CD4+ T cells were resistant to EAU. Also, they had a defective Th17 differentiation, while T cells expressed an increase of Foxp3, IL-10, IL-4 and

The role of environmental stress in the initiation of ocular

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2.4

PT

IFN-γ [185].

autoimmunity Dry eye disease

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The role of the environment is quite crucial in DED, since ambient dehydrating

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environment can lead to the changes in the phenotypical features and disease progression. That is why there are a number of animal models generated

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using the controlled-environment chamber or desiccating stress- or scopolamine-induced models. An interesting study with a porcine model

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shows how the viability of corneal epithelial cells is affected by exposure to the ambient air [186, 187]. Oxidative damage is involved in dry eye disease,

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along with many ocular disorders, like cataract and age-related macular

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degeneration. There is one study, which simulated the ‘office dry eye symptom’ by exposing rats to low-humidity airflow and placing the animals on a swing [188]. As a mechanistic pathway induced by reactive oxygen species, shown in an environment-induced murine dry eye model, the involvement of NLRP3 inflammasome activation and increasing IL-1 secretion through the activation of caspase-1 is described [189]. As a potential entity to be responsible in oxidative-stress-induced dry eye, selenoprotein P (SeP) is shown as a key target molecule in rat and human dry eye conditions [190]. Uveitis

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ACCEPTED MANUSCRIPT Environmental factors in uveitis are less obvious. Retinal auto-antigens like IRBP or S-Ag are sequestered proteins and usually not accessible to the

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immune system. Therefore, antigenic mimicry is a proposed pathomechanism to explain the activation of cross-reactive lymphocytes in the periphery. For S-

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Ag, sequence homologies have been found with epitopes/peptides from viruses, bacteria, yeast and even food proteins. T lymphocytes from Lewis rats specific for retinal S-Ag peptides cross-react with several peptides of

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pathogens and bovine milk casein and these cross-reacting peptides caused

MA

EAU following immunization in Lewis rats [30, 191-195]. Another mimotope of retinal S-Ag peptide PDSAg, a peptide of HLA-B alleles, which is cross-

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reactive on the T cell level in rats and humans failed to induce a severe inflammation in Lewis rats, but was highly efficient in inducing oral tolerance

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to retinal autoantigens [196, 197]. This indicates that antigenic mimicry is a mechanism acting not only on the effector side but also for regulatory

2.5

AC

CE

lymphocytes [198-200].

Therapeutic perspective

Dry eye disease Therapeutic approaches are based on the understanding of the immune mechanisms. There are drugs targeting some of the pathways (IL-1R, JAK inhibitors) mentioned above that are in phase 2/3 human trials. For testing the drugs, it is utterly important to have human disease condition-simulated animal models. We have schematically described the different kinds of potential drugs for dry eye disease in Table 1. Uveitis

24

ACCEPTED MANUSCRIPT The first drug approved for uveitis with the help of animal models was cyclosporine A [201-203]. Pharmacologic drugs like sirolimus and biologicals

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like anti-IL-2R, anti- TNF- and anti-IL-17 were tested in EAU animal models [204]. Sirolimus and anti- TNF- are in the phase of clinical approval, while

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anti-IL-17 therapies have failed in clinical trials for uveitis (Table 1). A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), PP-001, can suppress rat EAU by systemic treatment and will now be tested

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for intraocular application, with the aim of avoiding a generalized

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immunosuppression by only targeting pathogenic T cells in the eye [78]. The reconstitution of immune tolerance by oral application of autoantigen or a non-

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pathogenic mimotope (oral tolerance) like peptide B27PD of HLA-B molecules mimicking S-Ag peptide PDSAg is also of high interest for the treatment of

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uveitis without side-effects [196, 198, 199]. Respective adjuvants are needed

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to improve the effect of oral tolerance induction.

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3. Conclusion

The fact that so many different animal models for the two diseases, dry eye and uveitis, were developed, points out that there is no single animal model that displays symptoms of both diseases and that fully represents either dry eye disease or uveitis in patients. Genetic predispositions, neither species/strain-related nor genetically modified, only promote either the one or the other disease. The innate (Freund's adjuvant, PTX) initiation of an inflammatory response requires an autoantigen-specific T cell response (adaptive immunity) to develop into the organ-specific disease uveitis, followed by the recruitment of destructive (innate) inflammatory cells to the

25

ACCEPTED MANUSCRIPT inner eye. Autoantibodies play only a minor or no role in the pathogenesis of uveitis, in contrast to dry eye disease, where the involvement of TLR is

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needed and autoantibodies can transfer the disease. In the pathogenesis of dry eye disease Th1, Th2 and Th17 cells as well as B

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cells play important roles. The function of the different cells and their cytokines and other products in inflammation, destruction and regulation is not yet clear and somehow controversial. In uveitis the predominant role of

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antigen-specific Th1 and Th17 cells in initiating the inflammation and/or

MA

maintaining the disease is shown in both rat and mouse EAU. They recruit non-specific lympho- and leukocytes, resulting in severe inflammation of the

ED

inner eye and destruction of the retinal architecture. IL-10 and TGF- are both involved in the induction of Treg that are controlling uveitis.

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Different signaling pathways were identified to be involved in the diseases of the ‘outer’ and ‘inner’ eye. In DED models, JNK2, p38-MAPK and PKC as

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well as STAT6 were found to be important signaling molecules, while signal

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transduction pathways in uveitogenic T cells in the rat model include WNTPCP, canonical WNT, hedgehog and MAPK as well as Jak/STAT pathways. Members of the WNT pathways were also found upregulated in eyes with equine uveitis, and SOCS expression correlating with disease activity was found in mouse eyes during EAU. Environmental factors causing either dry eye disease or uveitis are very different. While increased air flow together with low humidity can easily initiate dry eye disease in experimental animal models, the role of the environment in the induction of uveitis is less obvious. The (infectious?) trigger of pattern recognition receptors can be imitated by adjuvants, and for some retinal

26

ACCEPTED MANUSCRIPT autoantigens antigenic mimicry of proteins from pathogens or even a

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nutritional protein (milk) was described in the rat model.

Take-home messages

Expression of several autoimmune diseases in the same animal model

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is rare, thus DED and EAU need different models, although targeting the same organ at distinct sites.

Understanding the mechanisms mediated by both, adaptive and innate

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MA

immunity, leading to, maintaining and controlling the respective disease in animal models will allow to find new targets for pharmacological



ED

interventions.

Ideally, new therapeutic approaches should be tested in more than just

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one model to prove that they are not only effective for a certain type of

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disease/disease entity.

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Acknowledgement

We thank Stephan Thurau and Denis Wakefield for critically reading the manuscript.

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ACCEPTED MANUSCRIPT Table 1: Different animal models used for testing the drugs of dry eye disease and autoimmune uveitis Drug Human study phase 2/3 Acts primarily to preserve the ocular surface epithelial barrier of the eye.

Mouse [205], rat [206], rabbit [207]

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Ribamipide, PPAR agonist (rivoglitazone), TrkA agonist (MIM-D3) IL1RA (EBI-005)

Animal model tested

PT

Dry Eye Disease Mechanism of action

Mouse [208]

Alters the function of lymphocytes, dendritic cell and neutrophils Immunosuppressant, Calcineurin inhibitor

Mouse [210]

Dendrobium polysaccharide, FK506, FTY720, PES_103, Green tea, DA-0634, LFA-ICAM inhibitor

Altering the function of signaling pathways like TNF, NFB, MAPK, sphingosine receptor, MMP-9 inhibitor and adhesion molecules like LFA-ICAM and modulating oxidative stress

Mouse [212-216], rat [217, 218], rabbit [219]

Drug

Mechanism of action

Tofacitinib JAK inhibitor (CP-690560) Resolvin E analog (RX10045) Cyclosporin A cationic emulsion (Cyclokat)

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Stops IL-1 signaling by binding to the IL1 receptor (IL1R) Inhibits JAK signaling

ED

MA

Animal study

Mouse [209]

Rabbit [211]

Uveitis

Cyclosporine A

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Human study phase 1-3

AC

CE

Sirolimus (Rapamycin) Mycophenolate mofetil Cellcept DHODH-inhibitor PP001 Anti-TNF Adalimumab

Anti-IL-2R Basiliximab, Daclizumab Anti-IL-6R Tocilizumab Denufosol (INS37217), P2Y2 receptor agonist (chloride channel inhibitor)

Calcineurin inhibitor, targets activating T cells mTor-inhibitor, targets T cells Inhibits de novo synthesis of purine bases, preferentially T cells Inhibits de novo synthesis of pyrimidines, preferentially T cells Blocking TNF-a Blocking T cells

Animal model tested Rats [220, 221] Mice [222] Mice [223] Rats [78] Mice [224], Rats [225] Mice [226-228]

Indirect suppression of Th17 cells Treating cystoid macular edema, intravitreal application

Mice [151, 153, 229] Mice [230]

Inhibits PI3K, PKA, PKB/Akt, IKK and NF-кB and thus cytokine production Inhibits T cell activation

ko Mice [231]

Induction of oral tolerance

Rats [196]

Animal study CF101, A3 adenosine receptor agonist AEB017, Protein kinase C inhibitor HLA-peptide B27PD (Optiquel)

Mice [232]

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ACCEPTED MANUSCRIPT Fig. 1 Environmental insult

Chronic dry eye disease

Damage

Desiccating stress Pathogens

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OCULAR SURFACE

A

IFN-γ

Activation of toll-like receptors

IL-17, TNF-α

Treg Th17

Th17

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Th1

TGF-β

IL-1, IL-6, TNF-α

Autoreactive Th1 and Th17

IL-6,TGF-β,?

Activation of dendritic cells

APC

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IL-12

APC

Interaction of APC and autoreactive T cells

Naive T cell

APC

MA

DRAINING LYMPH NODE

PERIPHERY

APC

Th17

IL-6, IL-23

ation

of T

cells

AC APC

Peripheral lymph node: activation of naive T cells with an antigen crossreactive with ocular autoantigen „antigenic mimicry“

Th17/ Th1

cytokine, chemokine secretion

IFN-γ, TNF-α

IL-12

Reactivation of T cells: recognition of cross-reactive ocular autoantigen

Th1/ Th17

Th1 Th17 ?

PT

Naive T cell Th1

Activ

CE

B

IL-17 TNF-α

Healthy eye

APC APC

ED

Danger signal Infection?

EYE

Blood-retina barrier

Break-down of the ocular immune privilege: Recruitment of inflammatory cells followed by destruction of the blood-retina barrier and intraocular tissue

G MΦ

MΦ APC

G

APC

MΦ APC

G



MΦ G G

G MΦ

Inflammation

29

ACCEPTED MANUSCRIPT Figure Legend Figure 1: (A) The role of innate and adaptive immune system in the

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initiation and progression of dry eye disease. Environmental stress to ocular surface leads to the activation of toll-like receptors, followed by the

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activation of cytokines (IL-1, -6), which contribute to the activation of antigenpresenting cell (APC). They can activate naïve T cell and initiate their differentiation to Th1 and Th17 cells, which mediate chronic ocular surface

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damage that progresses into dry eye disease.

MA

(B) The initiation of intraocular inflammation (uveitis). Danger signals (i.e. from pathogens with antigens mimicking ocular autoantigens) activate APC

ED

via TLR. APC present antigen (mimotopes) to naïve T cells in peripheral lymph nodes and promote their differentiation into Th1 or Th17 cells. Once

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activated, the T cells can enter the eye by passing the blood-retina-barrier and will get reactivated by crossreactive ocular autoantigen. After reactivation, T

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cells secret cytokines and chemokines and attract inflammatory cells

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(monocytes/macrophages, granulocytes) from the circulation, with the consequence of vascular permeability and the break down of the ocular immune privilege. The invading mono- and granulocytes cause inflammation and have the ability to destroy the ocular tissues.

30

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