AUTREV-01793; No of Pages 14

Autoimmunity Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews

journal homepage: www.elsevier.com/locate/autrev

Review

The autoimmune diseases of the eyes

Francisco Assis de Andrade a,⁎, Savio Henrique Serafini Fiorot b, Eliezer Israel Benchimol c,
Jacqueline Provenzano b, Vanessa Jandre Martins a, Roger Abramino Levy d
a
Ophthalmology Department, Centro Oftalmológico Botafogo — COB, Rio de Janeiro, Brazil
b
Ophthalmolgy Discipline, Centro de Estudos e Pesquisas Oculistas Associados — CEPOA, Rio de Janeiro, Brazil
c
Ophthalmolgy department, Instituto de Pesquisas Evandro Chagas — FIOCRUZ, Rio de Janeiro, Brazil
d
Rheumatology Discipline, Universidade do Estado do Rio de Janeiro — UERJ, Rio de Janeiro, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: The eye is divided anatomically in three layers: an outer or fibrous layer (cornea/sclera), middle or vascular layer
Received 5 November 2015 (uvea — iris, ciliary body, and choroid) and an inner or sensorineural layer (retina). They compose the several an-
Accepted 27 November 2015 atomic and functional layers that enable the immune protection of the eye. The first layer involves an intact an-
Available online xxxx
atomic border with the blood–ocular barrier and immunosuppressive neuropeptides in the native aqueous
humor. The second layer trusts on the capability of the eye to reestablish an immunosuppressive micro-
Keywords:
Blood ocular barrier
environment by activating latent TGF-β and reestablishing the anterior chamber-associated immune deviation.
Pigmented epithelial cells The third layer involves a mechanism that is not yet completely recognized, but that has the ability to overcome
Retinal imaging a predominantly Th1 intraocular immune response and to reestablish anterior chamber-associated immune de-
Ocular immune privilege viation. Understanding the comprehensive mechanisms of these pathways, will lead to the development of new
Anterior chamber-associated immune treatments strategies in order to prevent damage to the eye from persistent or exacerbated inflammation, direct-
deviation (ACAID) ed at first to pathogens, but that may develop an autoimmune reaction.
© 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.1. Eye anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.2. Fibrous layer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.3. Cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.4. Limbus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.5. Sclera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.6. Vascular layer (uvea) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.7. Choroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.8. Ciliary body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.9. Iris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.10. Sensorineural layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.11. Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.12. Basic immunology of the eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Regional defense system in the eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Anterior segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Uveal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Posterior segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Disclosure of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author at: Avenida Vieira Souto 86/104, 22420-002 Rio de Janeiro, Brazil.
E-mail address: f.a.andrade@uol.com.br (F.A. de Andrade).

http://dx.doi.org/10.1016/j.autrev.2015.12.001
1568-9972/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
2 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

1. Introduction

1.1. Eye anatomy

The eye is divided anatomically in three distinguished layers: an

outer or fibrous layer (cornea/sclera), middle or vascular layer (uvea, a
continuous structure comprising iris, ciliary body, and choroid) and an
inner or sensorineural layer (retina). The human eye maintains a pres-
sure between 10 and 20 mm Hg, which is generated by the unidirection-
al flow of fluid (aqueous humor secreted by the ciliary body) from the
posterior chamber into the anterior chamber, leaving the eye via the tra-
becular meshwork, to drain into the episcleral veins [1]. (See Table 1.)

1.2. Fibrous layer

As seen in Fig. 1, the fibrous layer of eye is composed of three

structures: cornea, sclera and limbus. This layer is a dense tissue, poorly
vascularized, and homologous to the dura mater of the central nervous
system (CNS). This layer is opaque in 5/6 of its length (sclera) and it is
Fig. 1. Schematic view of a coronal session of a normal eye depicting the fibrous layer (cor-
transparent in the anterior portion (cornea), for optical purposes [2]. nea, limbus and sclera), the vascular layer (iris, ciliary body and choroid) and the sensori-
neural layer (retina).
1.3. Cornea

The cornea consists primarily of three layers: an outer layer contain-
ing an epithelium, a middle stromal layer consisting of a collagen-rich
extracellular matrix interspersed with keratocytes and an inner layer
of endothelial cells. The cornea is an avascular and transparent tissue;
which ensures two-thirds of refractive power of the eye, being the
steepest region of the fibrous tunic [3,4]. It has an elliptical shape with
the long axis and the meniscus with a more pronounced curvature
than the other parts [5,6]. The tear film covers the convex anterior sur-
face and the concave posterior surface is circular and is in direct contact
with the aqueous humor.
The cornea constitutes an anatomical and physiological protective
barrier of the ocular internal structures and its strength comes from its
own substance (stroma) [7]. The stroma represents 90% of the corneal
structural thickness [8]. It is composed of collagen fibrils (types I, III, V,
VI and XII, of which collagen type I is the predominant) that are
arranged in crystalline structures as seen in Fig. 2, separated by proteo-
glycans, being renewed and synthesized by keratocytes that are orga-
nized in a network of interconnected cells [9–12].
The spatial organization of the collagen fibrils and their diameter
uniformity avoid the diffraction the rays of light and allow the passage
to the aqueous humor of the incident visible light [13,14]. The transmis-
sion of light, refraction and reflection are the optical properties of the
cornea and these functions are dependable on the maintenance of its
transparency, which means that its own substance is kept in a condition
of relative dehydration [15].
1.4. Limbus
The limbus is a translucent area consisting of elements that are part
of the cornea and the sclera. The contribution of each tissue to the for-
mation of the limbus varies from its surface to its deepest part, as well
as in various sectors around the circumference of the limb [16,17]. It is
not only important as a translucent surgical landmark, but also due to
the unusual cell composition and the presence of steam cells in the con-
junctival and episcleral tissues strongly adhered above it.
A new corneal epithelium derives from this region and due to the
high antigen concentration present in the cells of this tissue; it is of
major importance in the immunological changes that occur in the sclera
and the cornea during the inflammatory process [18].
The conjunctiva is a mucosal membrane lining that begins at the lim-
bus and covers the anterior portion of the eye (Fig. 3). It allows indepen-
dent movements of the eyelids and the eyeball, provides mucus for
lubrication and contains lymphoid cells that participate in its

Table 1
Layers, structures and physiologic functions of the different parts of the eye.

Layers Structures Main components Function Related diseases

External or fibrous layer Cornea Collagen fibrils (type I) Protective barrier Mooren's ulcer, rheumatoid arthritis, juvenile idiopathic
Limbus Optical properties arthritis, relapsing polychondritis, scleritis, episcleritis
Sclera Steam cells New corneal epithelium
Immunological changes/
inflammatory process
Collagen lamellae Visual integrity of the eye
Conjunctiva Mucosal membrane Lubrication, Sjögren's syndrome
Immunologic protection Pemphigus vulgaris
Median or vascular Iris Blood ocular barrier Controls light entering the eye. Spondyloarthritis, juvenile idiopathic arthritis, sarcoidosis,
layer (uvea) Ciliary body • Pigmented — epithelial cells Production of aqueous humor. granulomatosis with polyangiitis, Behçet's, Blau's syndrome,
Choroid • Highly vascularized Supply oxygen and temperature intermediate uveitis, sympathetic ophthalmia
control of the retina
Collagen fibers, various cell
types and melanocytes
Internal or sensorineural Retina Blood ocular barrier Collecting and carrying the Systemic lupus erythematosus, VKH, antiphospholipid
layer • Macula • Pigmented-epithelial cells light and images syndrome, sarcoidosis, Behçet's, vitiligo, birdshot
• Optic nerve • Vascular-endothelial cells retinochoroidopathy, autoimmune neuropathies
• Vitreous humor

Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
Fig. 2. Ultrastructural session of the corneal stroma (arrow), depicting the collagen lamel-
lae arranged parallel to each other (Gomori trichrome × 100 — thanks to Andrea Monte
Alto Costa, Department of Embryology and Histology, UERJ).
immunological protection. The conjunctiva plays a key role in ocular
surface defense and maintenance the tear film [19].
1.5. Sclera
The human sclera is a remarkable structure that performs several
important functions for the visual integrity of the eye. In principle, the
sclera produces a firm substrate for the delicate intraocular contents,
protecting them from injury [20]. Its opacity ensures that the internal
scattering of light does not affect the retina image. The structural
shape of the eye is partly maintained by the presence of intraocular
pressure and its contents, which generates its optical stability [21].
Microscopically, the sclera can be divided into: episclera, scleral own
substance (stroma) and lamina fusca sclerae, in which is a thin layer of
pigmented connective tissue on the inner surface of the sclera of the
eye, connecting it with the choroid [22]. As seen in Fig. 4, the scleral stro-
ma is similar to the corneal stroma, but with a loss of organization of the
collagen lamellae [23].
The episclera is more vascularized with fine fiber layer of conjuncti-
val tissue and bulk density blending imperceptibly with the own sub-
stance of the sclera itself and unlike the fascia of the eye, the collagen
bundles are circumferentially arranged to the blood vessels walls [24].
A
B E
D
E
C
Fig. 3. Slit-lamp imaging of right eye showing the pupil (A), the iris (B), the limbus (C), the
conjunctiva (D) and the sclera (E).
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
3
B D
A
C
Fig. 4. Ultrastructural session depicting episclera (A), scleral stroma (B) showing the
collagen lamellae, the lamina fusca sclerae (C) and the choroid (D) (hematoxylin
and eosin × 500 — thanks to Andrea Monte Alto Costa, Department of Embryology and
Histology, UERJ).
1.6. Vascular layer (uvea)
The vascular layer of the eye or the uvea corresponds of three struc-
tures that, for didactic purposes, will be reviewed here separately: cho-
roid, ciliary body and iris.
1.7. Choroid
The uvea corresponds to the middle layer of the eye, of which the
choroid composes the posterior portion. It is constituted by a pigmented
vascular tissue, which is related externally with the lamina fusca sclerae
and internally with the retinal pigmented epithelium. Its anterior por-
tion is limited to the ciliary body, the inner face to the ora serrata and
further extends without interruption until the scleral optic nerve
(Fig. 5) . The choroid has the highest blood flow and densest packing
of vessels of any tissue in the body and has the lowest oxygen extraction
I
J
H
G
C
F B
A
Fig. 5. Ultrastructural coronal session of human eye showing the eyelid (A), conjunctiva
(B), limbus (C), cornea (D), anterior chamber (E), iris (F), ciliary body (G), pars plana
(H), choroid (I) and peripheral retina (J) (Gomori trichrome × 1000 — thanks to Andrea
Monte Alto Costa, Department of Embryology and Histology, UERJ).
4 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
[25]. Other tissues in the body extract much of the oxygen carried by he-
moglobin, and those tissues seem to do just fine. Although only 1% of the
oxygen is extracted from the blood, there is an enormous flux of oxygen
delivered to the outer retina [26]. The oxygen delivered by the choroid is
used by the mitochondria in the inner segments to generate energy for
the photoreceptors. In the dark the oxygen tension of the outer retina
falls to zero [27].
The choroid provides oxygen and nutrients to the outer third of the
retina and histologically consists of the following three vascular layers:
the suprachoroidal blade, the vascular layer, the choriocapillaris and the
basal lamina. The suprachoroidal blade is the outer layer, related to the
transition from choroid to the sclera and is composed of collagen fibers,
fibroblasts and melanocytes [28].
The vascular layer is embedded in a connective tissue composed of
disorganized collagen bundles, elastic fibers and various cell types
such as fibroblasts, mast cells, macrophages, lymphocytes, plasma cells
and melanocytes [29]. Physiologically, the main function of the uvea is
to supply oxygen to the retinal-pigmented epithelium and photorecep-
tors, but the temperature control of the retina is another role of key im-
portance [30].
1.8. Ciliary body
The ciliary body is a continuation of previous choroid and retina,
consisting essentially of smooth muscle (ciliary muscle) and ciliary pro-
cess. The ciliary body has a rear portion that is a flat zone prior to the ret-
ina and is called pars plana (Fig. 6). It is of utmost importance, since it is
responsible for the production of aqueous humor, accommodation and
contraction of the ciliary muscle and its repercussions in the refractive
power of the lens [31].
1.9. Iris
As seen in Fig. 7, the iris is the anterior portion of the uvea, highly
vascularized; it is of a round and slender shaper with an opening in
the center that is the pupil. It is responsible for controlling the amount
of light rays that will stimulate the retina photoreceptors [32,33].
C the images of different visits [39]. Nevertheless, fundus photography
A documenting the lesions at baseline and follow-up. Stereo photogra-
B disc edema, and macular and choroidal neovascularization.
Fig. 6. Ultra-wide field retinal imaging of left eye showing the optic disc (A), the pars plana
(B) and the macula (C).
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
B
A
C
Fig. 7. Slit-lamp imaging of the right eye showing the cornea (A), the lens (B) and the iris
(C).
1.10. Sensorineural layer
Sensorineural tunic, the innermost, has a nervous tissue nature,
being primarily composed of two layers: retinal-pigmented epithelium,
attached to choroid, and the retina [34].
1.11. Retina
The retina is a layer whose main elements are the visual cells or pho-
toreceptors (rods and cones), bipolar cells, and ganglion cells [35,36].
The synapses between these three elements give rise to the optic
nerve. The posterior two thirds of the optic part of the retina can be dis-
tinguished as the optic nerve and the macula, while the anterior first
third is related to the ciliary body and the lens is to the pars plana.
More internally the vitreous humor is located, it is composed of a hydro-
gel constituted primarily of collagen fibers, hyaluronic acid and water.
Externally the epithelial retinal pigment is found to be responsible for
the photoreceptors renewal and for the transport of retinol that is the
essential for the physiology of vision [37].
Retinal imaging is very useful in diagnosing and monitoring inflam-
matory diseases of the posterior segment. The most commonly used ret-
inal imaging techniques in uveitis include fundus photography, fundus
fluorescein angiography (FFA — Fig. 8), fundus auto fluorescence
(FAF), optical coherence tomography (OCT) and ultrasonography for
posterior segment inflammatory conditions [38].
Color fundus photographies help in documenting the retinal and/or
choroidal lesions and serves as a useful permanent document for mon-
itoring the progression and regression of the disease by thumb nailing
is routinely useful in most of the cases of posterior uveitides for
phies may be useful in cases with exudative retinal detachment, optic
The documentation by color photography is particularly useful in
monitoring retinitis, choroiditis, macular edema, retinal vasculitis
(Fig. 9), and also for assessing media clarity in eyes with vitritis [40].
FFA is useful in differentiating active from inactive uveitis and
also confirming the diagnosis of co-existent entities, such as cystoid
macular edema, choroidal neovascularization, subtle retinal vasculitis,
to monitor response therapy, and identifying the areas of capillary
non-perfusion as well as retinal neovascularization. The small mole-
cules of free unbound fluorescein dye leak out even from minimally
 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx 5

Fig. 8. Right and left imaging showing fundus fluorescein angiography (FFA) of the right eye without activity autoimmune disease.

inflamed retinal vessels including capillaries, thus making it an investi-
gation tool of choice for retinitis and retinal vasculitis [41].
Although FFA is not an ideal investigative tool for evaluating the cho-
roid, one can get some information on choriocapillaris perfusion mani-
fested as early choroidal hypofluorescence or non-perfusion in several
choroiditis entities, including Vogt–Koyanagi–Harada syndrome [42].
The fluorescence in angiographic pattern is characteristic in Vogt–
Koyanagi–Harada syndrome and sympathetic ophthalmia where it
shows initial pinpoint hyperfluorescent dots or areas of delayed choroi-
dal filling with late pooling of dye in the subretinal space that may be as-
sociated with optic disc hyperfluorescence [43–46]. FAF using confocal
scanning laser ophthalmoscope (cSLO) allows detection of low intensity
autofluorescence produced by fluorosphores such as lipofuscin present
in the retinal-pigmented epithelial (RPE) cells [47,48].
These fluorosphores (mainly lipofuscin) originate from the photore-
ceptor outer segments and accumulate in the RPE cell lysosomes and
their excessive presence in the RPE layer is an indicator of the quality
of the RPE cell metabolism. Since RPE is involved in most of the posterior
segment inflammation, FAF imaging provides useful information of the
metabolic state of RPE that may be indicative of disease activity [49].
In Vogt–Koyanagi–Harada disease, hypoautofluorescent signals are
seen in the areas of peripapillary atrophy, atrophic and pigmented
scars, and cystoid macular edema while serous detachment shows
hyperautofluorescence.
Sunset glow fundus in chronic Vogt–Koyanagi–Harada disease
per se is not associated with any significant autofluorescent changes
[50–52]. Wide-field FAF has recently been reported to correspond to vi-
sual field defect-related to alterations of the retinal pigment epithelium

3 2

2
3

Fig. 9. Right and left eyes showing fundus fluorescein angiography (FFA) with vasculitis [1], optic neuritis [2] and macular edema [3].

Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
6 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
B
A
C
D
Fig. 10. Retinal optical coherence tomography (OCT) showing the macula (A), nerve fiber
layer (B) retinal pigmented epithelial (C) and choroid (D).
in uveitis cases. Thus, overall autofluorescent imaging provides clinical-
ly useful information in posterior uveitis [53].
The retinal-pigmented epithelium is observed using some ophthal-
mic imaging techniques such as the OCT, which is one of the greatest ad-
vances in the diagnosis and monitoring of treatment of eye diseases in
recent years. The OCT is an excellent tool for imaging of various retinal
diseases, as it allows the visualization of optical sections of high resolu-
tion (Fig. 10). Examining the macula by OCT is feasible with non-dilated
pupils, of approximately 3 mm diameter by an experimented examiner
[54].
This makes OCT an extremely useful test in situations where one
cannot get a satisfactory mydriasis (posterior synechiae of the iris post
uveitis). The greater pupil dilation makes the examination easier. The
discomfort caused to the patient in OCT is minimal, unlike FFA requiring
intravenous dye injection [55]. Another advantage is that the wave-
length used, near infrared, causes little discomfort and is very fast.
OCT has been found to be useful in the imaging of posterior uveitis
both for establishing the diagnosis, as well as, monitoring response to
therapy. It helps in the localization of the disease by delineating its ex-
tent, depth and thickness and is very useful in quantifying macular
edema including cystoid macular edema (CME) [56]. When compared
to fundus FFA, OCT was found to have 89% sensitivity for diagnosing
CME (Fig. 11). FFA is still the most commonly used investigation method
in the evaluation of retinal ischemia, associated macroaneurysms, cen-
tral retinal vein or artery occlusion (Fig. 12) in eyes with vasculitis [57]
and in retinitis, as in Behçet's disease [58]. OCT is also useful in studying
the vitreoretinal interface and identifying vitreo-foveal traction in
uveitic eyes. In patients with Vogt–Koyanagi–Harada and sympathetic
ophthalmia, OCT is very useful in monitoring serous retinal detachments
[59]. During the early stage of Vogt–Koyanagi–Harada disease, the RPE
may be elevated because of underlying granulomas, thus producing cho-
roidal striations [60]. The retina inner to external limiting membrane did
not show any remarkable structural alteration in Vogt–Koyanagi–
Harada and sympathetic ophthalmia patients and the changes seen in
outer retina segment in sympathetic ophthalmia were reversible [61].
Ultrasonography may be useful in the evaluation of intraocular in-
flammatory conditions (Fig. 13), especially when visualization of the
fundus is poor due to media haze. Ultrasonography is useful in assessing
the location, extent, and density of vitritis (Fig. 14) and the 20-MHz fre-
quency probes can detect the typical snow-bank in intermediate uveitis
[62].
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
Fig. 11. Optical coherence tomography (OCT) displaying a cystoid macular edema (CME).
Ultrasound is also useful in the detection of posterior vitreous de-
tachment, a common finding in eyes with vitreous inflammation [63].
Ultrasound can be useful to monitor serous detachments in Vogt–
Koyanagi–Harada disease and sympathetic ophthalmia. However cur-
rently, OCT is a preferred modality for monitoring serous detachment.
The diagnostic ultrasound still has a role in acute Vogt–Koyanagi–
Harada disease where it typically shows diffuse, low-to-medium reflec-
tive choroidal thickening most evident in the posterior scleritis where it
shows high-reflective sclero-choroidal thickening. Scleral edema associ-
ated with fluid within Tenon's space results in an echolucent region just
posterior to the sclera results in the classic “T” sign [64].
There are some techniques to document retinal imaging and the
most used is FFA, but a newest one is the ultra-wide field fluorescein an-
giography (Fig. 15). Since posterior uveitis is associated with changes in
the peripheral retina, these findings are likely to be missed by conven-
tional fluorescein angiograms but can be visualized using ultra wide
field fluorescein angiography that has been reported to be more useful
than traditional fluorescein angiography and was especially useful in
following up patients with intermediate uveitis [65–67]. In recent
study, Campbell et al. [68] studied the disease activity and management
decisions based on examination plus simulated 30 or 60 degree FFA ver-
sus examination plus ultra-wide field FFA. Based on examination and
limited FFA the disease activity was detected in 51% of patients and
16% had management change based on examination with ultra-wide
field FFA, the disease activity was documented in 63% of patients and
management changed in 48% of patients; thus indicating the superiority
of wide-field over traditional FFA [69].
1.12. Basic immunology of the eye
Due to its embryonic origin, its peculiar anatomy and the presence of
physiological factors that modulate the immune response, the eye pre-
sents unique immunological characteristics. The control of the immune
responses in the eye is an example of a general phenomenon that is the
inflammatory response regulation by local conditions and factors that
modulate the expression of immunity. These factors range from the ex-
pression of adhesion molecules on specific quantity or quality for a par-
ticular organ to the local production of immunomodulatory substances.
In the eye, these molecules are synthesized locally; they regulate the ex-
pression and induction of immunity [70].
The eye is protected from invasive pathogens by two systems, an an-
atomical barrier and an immunological barrier [71]. The blood–ocular
barrier anatomically blocks harmful pathogens from invading the eye
from peripheral bloodstream and protects sight-related cells and tissues.
Pigmented-epithelial cells of the iris, ciliary body, and retina, vascular
 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx 7

Fig. 12. Right and left imaging showing fundus fluorescein angiography (FFA) with central vein occlusion.

endothelial cells of the retina, and corneal endothelial cells are impor-
tant components of the blood–ocular barrier Table 2. Once the blood–oc-
ular barrier is disrupted, another defense system, the regional immune
system of the eye, suppresses pathogenic T cells and protects the eye. Be-
cause of this unique feature, the eye is also considered to be an immune-
privileged site like the brain and the testes [72–74]. Streilein and col-
leagues provided the first evidence of ocular immune privilege [71].
They demonstrated that a typical example of ocular immune privilege
is the anterior chamber-associated immune deviation (ACAID) proposed
by these authors. In ACAID, ocular resident cells at the inner surface of
the blood–ocular barrier, such pigmented-epithelial cells of the iris, cili-
ary body pigmented-epithelial cells, retinal pigmented-epithelial cells,
and corneal endothelial cells, can suppress the activation of by stander
CD4+ T cells. Thus, a balance between activated CD4+ T cells in the
eye and ocular resident cells maintains the homeostasis of the eye [86].
2. Regional defense system in the eye
Under conditions of intraocular inflammation in experimental ani-
mals and humans, activated CD4+ T cells infiltrate the eye and cause
immune responses and inflammation, which damage vision-related
cells and tissues.
However, the eye has a unique immune system to protect important
cells and tissues from activated effector CD4+ T cells. When Streilein
and colleagues described ACAID, they provided the first evidence that
ocular parenchymal cells participate in the so-called ocular immune
privilege. They demonstrated that cells inoculated in the anterior
chamber of the eye induce antigen-specific suppression of the cellular
immune response, but not of the humoral immune response. The im-
mune deviation arises when antigens are placed not only in the anterior
chamber, but also in the vitreous cavity or subretinal space. ACAID arises
because intraocular antigen-presenting cells (APC) capture eye-derived
antigen, migrate directly into the bloodstream through the trabecular
meshwork, and traffic to spleen [75].
Tissue-based ocular mechanisms of immune privilege that contrib-
ute to the ocular defense systems have been identified. An important
molecule contributing to immune privilege in the eye is the Fas ligand
(FasL). An abundance of FasL is constitutively expressed throughout
the eye. FasL induces apoptosis of any activated Fas+ cells that enter
the eye, and FasL-induced cell death can lead to tolerance and blocks
the further growth of blood vessels that can damage the eye. TNF-
related apoptosis-inducing ligand is also expressed on ocular tissues
and participates in the ocular immune privileged environment condi-
tion. Additionally, immune regulation provided by ocular resistant
cells is a critical component of the ocular defense system [76].
ACAID is an eye-derived antigen specific immune regulation. In ad-
dition to this, ocular resident cells (pigmented-epithelial cells of iris, cil-
iary body and retina, corneal endothelial cells) contribute to the

Fig. 13. Right eye ultrasonography showing vitritis. Fig. 14. Left eye ultrasonography without autoimmune inflammatory disease involvement.

Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
8 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
A They recognize antigens displayed by APC, along with HLA molecules of
B class I or II, classified as αβ and γδ. Dendritic cells detected in different
Fig. 15. Ultra-wide field retinal imaging showing optic disc (A) and macula (B).
immune privilege of the eye by another immune regulation, which is
not specific to eye-derived antigen. The ocular resident cells are capable
of directly suppressing T cells activated by anti-CD3 antibody, but not by
eye-derived antigens [77–80]. Since then, this concept has evolved and
other mechanisms of immune regulation have been show to play a crit-
ical role in ocular disorders.
3. Anterior segment
The lid margin, conjunctiva and the cornea define the ocular surface;
which combined with the lacrimal system accounts for a functional en-
tity and is constantly exposed to external physical, inflammatory, or in-
fectious challenges [81]. The normal human conjunctiva, with the
presence of blood and lymph vessels, actively participates in the im-
mune defense of the ocular surface against these exogenous aggres-
sions. T- and B-lymphocytes, scattered plasma cells in the conjunctiva
and lacrimal gland are the conjunctival associated lymphoid system
(CALT) [82,83], being part of mucosal associated lymphoid tissue
(MALT) [84].
MALT has many features that enable it to act as a surface barrier:
ability to preferentially induce rather than raise, the presence of intra-
epithelial lymphocytes characterized by the expression of CD8 antigen
molecules and the human mucosal lymphocyte antigen (HML-1) and
specific cells, specialized in capturing and processing antigens (M
cells) [85].
The involvement of the conjunctiva and the lacrimal gland, as part of
MALT, are characterized by the presence of:
1 — Induction of tolerance to antigens exposed in the conjunctival
mucosa;
2 — intra-epithelial lymphocytes, corresponding to the suppressor/
cytotoxic subtype expressing HML-1 in the conjunctival
Table 2
Anatomical and immunological barriers of the eye.
Anatomical and immunological barriers of the eye
Physiological factors
Pigmented-epithelial cells Iris
Ciliary body
Retina
Blood–ocular barrier Corneal endothelial cells
Vascular endothelial cells of the retina
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
epithelium and participating in the immunopathogenesis of ocular
surface diseases;
3 — presence of E-cadherin adhesion molecule for intra-epithelial lym-
phocytes HML-1+ in the conjunctival epithelium;
4 — presence of defensins found in cornea, conjunctiva and lacrimal
gland.
T-lymphocytes, the predominant subpopulation of lymphocytes in
the conjunctiva, are present in the epithelium and in the own substance.
regions of the conjunctiva, process and present antigens to T cells in
conjunction with HLA class II. B-lymphocytes are rare in the conjunctiva,
being located in the own substance in the fornix region [86].
The plasma cells secreting antibodies are detected mainly in the ac-
cessory lacrimal glands of Krause in the lower group. Plasma cells, T-
and B-lymphocytes are also located between the main lacrimal acinar
glands. Plasma cells secrete immunoglobulin A (IgA), being the most
abundant in the tear film and may present as secretory IgA. It consists
of two IgA molecules which are joined by a transport fragment, respon-
sible for maintaining a stable antibody on a medium rich in proteolytic
enzymes [87]. Its role is to protect the mucosa, because although no bac-
terial or bacteriostatic activity, blocks the receptors of ocular surface
that could become capable of infection by virus or bacteria [88].
Innate and adaptive immune responses are part of an integrated sys-
tem [89,90]. The innate system consists of non-specific protecting fac-
tors such as eyelid, tear film, corneal epithelium, macrophages,
polymorphonuclear leukocytes and certain cytokines. These elements
are the first line of defense against external agents with the elementary
characteristic of occurring without previous experience of antigen rec-
ognition and consequently also not providing an immunological mem-
ory [91,92].
The adaptive immune system can recognize and kill microorganisms
and molecules selectively in a specific manner [93]. It performs the fol-
lowing functions: antigenic specificity, diversity, memory and immune
recognition of self and non-self. Each antibody and/or lymphocytes
can recognize only one antigen, but all these form a complex immune
system, that as a whole, is capable of recognizing thousands of antigenic
patterns. Thus, immunoglobulins and cytokines secreted by the
conjunctival lymphoid tissue, assist neutrophils and macrophages in
the destruction of antigens. Macrophages help lymphocytes, carrying
the eye antigen to the lymph node and recognizing, processing and
presenting to lymphocyte. Mast cells are located predominantly in the
limbus and also found in the bulbar conjunctiva. Their degranulation
is in response to an allergen or an injury, resulting in the release of
vasoactive substances (histamine, heparin, platelet activating factors,
leukotrienes), causing vasodilatation and increased vascular permeabil-
ity [94].
Tear film contains, in addition to IgA, a number of substances with
antimicrobial properties, such as lysozyme, lactoferrin and other immu-
noglobulins. Their effects are enhanced by the fixation components of
the complement system [95].
The tear film oxygenates, nourishes, lubricates and washes the ocu-
lar surface, contributing to the vitality of epithelial cells, protection
against microbial adhesion and invasion, as well as for maintaining
Ocular immune privilege
Anterior chamber-associated immune Activated effector CD4+ T cells
deviation (ACAID)
Auto-reactive cells Inflammatory cells and soluble products
 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx 9

the optical properties of the cornea. As seen in Fig. 16, the tear film
forms a concave meniscus which is composed of three layers: the
inner (mucin), the intermediate (aqueous) and the outer (lipid).
Mucin adheres to the glycocalyx of epithelial cells and is produced
by the conjunctiva goblet cells. The aqueous layer is thicker containing
electrolytes, enzymes, antimicrobial substances and mucin. It is secreted
both by the main and the accessory lacrimal glands. The lipid layer is the
most superficial and thinner layer. It is mainly derived from the
secretion of the meibomian glands and contains esters of fatty acids
and cholesterol [95].
Several investigative studies have been developed in order to evalu- A
ate patients complaining of ocular dryness and also to measure the tear
volume and its osmolarity [96–98].
Described in 1903, the Schirmer's test is one of the most used in
assessing the amount of tears produced (Fig. 17). Filter-paper strips
are inserted into the lower external conjunctival sac for 5 min, avoiding
contact with the cornea, without topical anesthesia (Schirmer's test I).
In 2002, the American–European Consensus Group (AECG) developed
the criteria setting an abnormal result as moistening of less than
5 mm of the strip after 5 min in at least one eye [99].
The tear osmolarity test may be carried out by various methods, with
a high osmolarity value usually found in all types of dry eye. There are
devices that can measure the tear osmolarity in 20 s, with a cut-off at Fig. 17. Right eye showing the Schirmer's test (A).
308 mOsm/ml but with variation of 8 mOsm/ml between two measure-
ments being suggestive of the diagnosis of Sjögren's syndrome [100].
Autoimmune diseases involving conjunctiva include cicatricial pem- The cornea, with its anatomical and physiological characteristics, ex-
phigoid, pemphigus vulgaris, erythema multiforme, vasculitis and press an autoimmune privilege that protects itself against damage
Sjögren's syndrome when lacrimal glands are affected leading to chang- caused by the immune system, but it also makes it vulnerable to various
es in the tear film [101,102]. inflammatory immune diseases. Peripheral cornea/limbus differs from
There are ocular surface staining procedures which test for the integ- central cornea in various aspects. The limbus is rich in blood and lym-
rity of the tear film and the presence of dry eye via staining with vital phatic vessels and presents itself as an arm for the afferent immune re-
dyes (Lissamine green and/or fluorescein). The Fluorescein test assesses sponse [106]. Blood vessels allow the diffusion into the peripheral
the cornea of the patient as well as flushing epithelial defects and/or cornea of immunoglobulins and proteins components of complement
punctate epithelial erosions. As seen in Fig. 18, the Lissamine green system. Therefore, in the central and peripheral cornea it is possible to
dye stains devitalized zones of corneal and/or conjunctival epithelium detect similar amounts of IgG and IgA, whereas IgM is detected only at
[103]. the periphery due to its high molecular weight. Thus, the presence of
The Sjögren's International Collaborative Clinical Alliance (SICCA) cellular and non-cellular components of the immune/inflammatory re-
included the Lissamine green test to evaluate severity of the involve- sponse to the peripheral cornea becomes more susceptible to being in-
ment of the conjunctiva with Fluorescein test for the corneal involve- volved in several autoimmune diseases and hypersensitivity, as
ment. Using both vital dyes, the SICCA group created a score for Mooren's ulcer and collagen diseases [107].
Sjögren's syndrome diagnosis called ocular staining scores (OSS) The central cornea already has constitutional characteristics that
[104]. The OSS is considered abnormal when it is greater than 3 out of promotes a state of immune privilege [108]:
12 for each eye [105].

Fig. 18. Left eye picture showing the keratoconjunctivitis SICCA stained by lissamine
Fig. 16. Schematic view of an anterior portion of the eye and tear film layers. green (A).

Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
10 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
1 — Reduced expression of both the class I and class II MHC antigens,
particularly in the endothelium.
2 — Absence of blood and lymphatic vessels makes it difficult to gener-
ate antigen information, as well as access of immune effector.
3 — A limited number of antigen presenting cells obstruct the transmis-
sion of antigen information for the immune system.
4 — It is constituted of cells that secrete molecules with immunosup-
pressive properties such as transforming growth factor β (TGF-β)
and interleukin-1 receptor antagonist (IL-1 RA-proinflammatory
cytokine), that modulate the action of antigen-presenting cells, T-
and B-cells, natural killers (NKs) and macrophages.
5 — The presence of molecules which inhibit the immune effectors,
such as DAF, CD59 and CD46, molecules that inhibit the action of
the complement system, and CD59L (FasL), leading to apoptosis ef-
fector T CD59+ cells.
6 — Influence of immune deviation induced by antigens in the ACAID,
wherein antigens that relapsed from the endothelium to aqueous
humor induce specific tolerance to donor antigens.
The sclera contains a very low number of inflammatory cells and is
composed mainly of collagen and proteoglycans, the first being the
main component and associated in developing ocular manifestation of
autoimmune diseases such as scleritis and episcleritis (Figs. 19 and
20). The ciliary vessels, nourished by a sparse vascular supply, cross
the sclera and its nutrition derives mainly from the episclera and the
choroid [24].
4. Uveal tract
The eye's privileged anatomic situation allows a unique phenomenon
of induction of systemic tolerance [109]. When antigens are first intro-
duced to the body via the anterior chamber, subsequent immunization
systemically with the same antigen does not cause a vigorous secondary
response, this phenomenon is know as the immunomodulation associat-
ed with anterior chamber of the eye. The presence of such a mechanism
adds to the possibility that a systemic response to the deleted ocular an-
tigens is mediated in this way [110].
Most of these mechanisms deal with the response generated
by resident inflammatory cells external of the eye tissues, however in-
flammation does not occur in these tissues only at the expense of cells
that migrate into eye, several local cells can initiate and propagate an in-
flammatory response. These cells are linked to the maintenance of ho-
meostasis in the eye by means of other phagocytic cells and cells
A without any systemic involvement, as in the case of sympathetic oph-
Fig. 19. Right eye picture showing episcleritis (A).
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
Fig. 20. Right eye picture showing scleritis.
debris, in addition to having an important role in local innate immunity
[111].
The uveal tract is particularly rich in such cells, including macro-
phages and dendritic cells expressing class II MHC receptors, and thus
function as APC. These cells appear to function as sentinel cells to cap-
ture and process antigens found within the eye. Mast cells are found
in large numbers in the choroid, but are absent in anterior uvea and
seem to play an important role in the induction of experimental autoim-
mune uveitis, suggesting that they can also participate in human disease
[112].
Despite all the local mechanisms that exist for the sole purpose of
protecting the eye against uncontrolled autoimmune reactions, some
of the systemic autoimmunity control processes do not work properly
in this organ. This is the case that takes place with negative selection.
This process is dependent on the presence of thymus in “self-antigens”
recognized by T-cells. Since not all endogenous antigens are present in
the thymus in sufficient to induce an efficient negative selection, cells
capable of recognizing self antigens concentrations reach the periphery
inevitably. The eye becomes a closed organ before the development of
the functional thymus; as a result, antigens expressed exclusively in
the eye are not shown therein, preventing the negative selection pro-
cess for these molecules [113]. Furthermore, it was demonstrated that
the expression of a unique antigen of the eye leads to the deletion of
cells recognizing this antigen and hampers the induction of autoim-
mune uveitis.
Autoimmune uveitis is in general divided into a wide spectrum of
autoimmune diseases [114]. There are syndromes in which uveitis is
associated, in these, it constitutes a component of a disease with other
systemic manifestations. Examples of these types of uveitis are the
ones associated with ankylosing spondylitis, juvenile idiopathic arthri-
tis, Vogt–Koyanagi–Harada's disease, Behçet's disease, vitiligo and
sarcoidosis [115].
There are also diseases characterized solely by eye inflammation
thalmia, intermediate uveitis and idiopathic uveitis [116].
Most of the knowledge on the mechanisms involved in the develop-
ment and control of uveitis has been obtained from experimental
animal models of the disease, of which the model of experimental auto-
immune uveitis in rodents and primates was undoubtedly the largest
contributor [117].
It has demonstrated that in Behçet's disease immunogenetic factors
are related or not to them [118]. Likewise, it has been described the in-
volvement or not in the development of experimental autoimmune
uveitis in mice. It was defined in experimental autoimmune uveitis,
that there are factors that allow the development of uveitis associated
with certain MHC molecules, while others seem to be protective. It has
 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
also been demonstrated that genes not associated with the MHC may
lead to autoimmunity, among them are genes which control the pro-
duction of cytokines and hormones [119].
When the protection mechanisms fail and the genetic and environ-
mental conditions are usually present, the development of the state of oc-
ular autoimmunity takes place. In experimental autoimmune uveitis, the
tolerance breakdown is easily noticeable due to the induction of the dis-
ease achieved by actively immunizing the model with an autoantigen
such as retinoid binding molecule or retinal S antigen (S-Ag) [120].
In the specific case of the eye, the breakdown of blood–retinal
barrier is usually the initiation of the autoimmune process
interphotoreceptors, and it is often recognized as a precipitating factor
in this process. The events leading up to the breakdown of the blood–
retinal barrier have been extensively studied in experimental autoim-
mune uveitis and the results obtained provide clues as to what may
occur with human patients [121]. It was been reported that the earliest
changes in cytokine expression in the retina occur seven days after the
experimental autoimmune uveitis induction by immunization with oc-
ular antigens and analyzed the expression of adhesion molecules in the
vascular endothelium of the retina confirms theses findings [122].
The CD4+ lymphocytes are cells found to be responsible for the dis-
ease induction. However, during disease progression, a significant num-
ber of CD8 + T-cells are also present in the eye. As demonstrated in
experimental studies, CD4+ T cells that cause eye injuries display a pat-
tern of type 1 cytokines, that is, secrete IL-2 and INF-γ when activated
[123].
However, it is important to note that these cells have an undifferen-
tiated pattern in the periphery during the sensitization phase of the dis-
ease, and only when they migrate to the eye, they assume the Th1
profile. Differentiation into Th1 cells can be influenced by the presence
of the macrophage migration factor inhibitor, secreted by the trabecular
cells.
This confirms the observation that granulomatous uveitis is caused
by T-cells that secrete pro-inflammatory cytokines [124].
5. Posterior segment
Lymphocytes reactive to retinal antigens have been demonstrated in
normal individuals as well as those with retinal disease. In the former
the presence of circulating auto-reactive cells suggests that immunoreg-
ulatory mechanisms must exist to prevent these cells from causing ret-
inal autoimmunity; in the latter it is tempting to contemplate the role of
these cells in the induction of retinal autoimmunity [125].
The major players in an immune response include a variety of in-
flammatory cells and the soluble products they secrete. Inflammatory
cells can be subdivided further into lymphocytes, phagocytes and auxil-
iary cells. In many cases, resident tissue cells are also having important
roles in immunity, especially in a local immune response in which the
final result is often an autoimmune attack towards the host tissue [126].
Despite the rather effective mechanisms of negative selection and
the processes that constitute the induction of peripheral tolerance,
mechanisms exist whereby a reaction against self is induced. This toler-
ance breakdown is the basis of autoimmunity. Non-resolving inflamma-
tory responses could potentially lead to tissue damage and subsequent
release of normally sequestered antigens. A reaction to these essentially
“foreign” self-antigens could initiate an autoimmune reaction and result
in further damage to the host tissue. Another mechanism by which an
autoimmune reaction can be triggered is through the phenomenon of
molecular mimicry. In this scenario there exists a similarity between
certain infectious agents and autoantigens [127].
A reaction against products of the invading organism may also
launch a reaction against self, and in predisposed individuals the ensu-
ing autoimmunity may be an unfortunate by-product of this response.
In the theory of molecular mimicry contributing to a breakdown of tol-
erance and causing autoimmunity, both cross reactive antibodies and T-
cell responses may be responsible [128,129].
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
11
The study of autoimmune diseases in animal models produced infor-
mation that helped investigators understand some of the complex path-
ways that may be involved in human autoimmune diseases as well
[130]. Both individuals with or without retinal inflammation are
thought to have circulating T-cells that react in vitro to retinal antigens.
To study the mechanisms by which these autoantigens may initiate ret-
inal autoimmunity in humans, many animal models have been pro-
posed in which retinal antigens are used to induce inflammation
[131]. These retinal autoantigens are S-antigen, interphotoreceptor
retinoid-binding protein (IRBP), rhodopsin, phosducin, and recoverin,
to name a few. Depending on the type and dose of antigen used, the in-
duced disease can be manifested as a retinal vasculitis, choroiditis, or a
chorioretinitis [132].
One of the most commonly used experimental models in
retinouveitis research involves the retinal-derived soluble protein
S-antigen. S-antigen, a 48 kD protein also referred to an arrestin, is high-
ly conserved protein found in the photoreceptor cells of the retina. The
experimental autoimmune uveitis can be induced in many animal
models, including non-human primates, guinea pigs, rats, and mice
and is a prototypic T-cell-mediated autoimmune response directed at
the neural retina. The inflammation is characterized by an initial retinal
vasculitis that extends into the photoreceptor layer, ultimately leading
to the total destruction of the latter. The disease process is mediated
by S-antigen-specific CD4 + T-cells and has been proven to be a type
IV hypersensitivity reaction [133].
As the name implies, IRBP is localized in the interphotoreceptor ma-
trix. This antigen also has been demonstrated to be highly uveitogenic in
many species, including mice, rats, rabbits, and non-human primates.
The disease induced in mice is very interesting because it displays fea-
tures such as retinal vasculitis, granuloma formation, retinal folds,
focal serous detachment and loss of photoreceptors [134].
To hypothesize a mechanism for retinal autoimmunity, it is clear
that there must exist a way in which retinal autoantigens can be locally
presented to peripherally activated T-cells. For cells present in the retina
to function potentially as APC, they must possess the markers necessary
for carrying out the presenting function. The most important of these is
the ability to express the MHC class II molecules. The retinal cells that
fall under this category include endothelial cells, retinal-pigmented ep-
ithelial cells, Müller cells, and microglial cells [135].
If retinal autoantigens can potentially cause such devastation in the
eye, it is equally evident that regulatory mechanisms are in place to pro-
tect the retina from such damage. It has been demonstrated that Müller
cells, the major form of glial cell in the neural retina, have an inhibitory
influence on in vivo lymphocyte proliferation despite expressing MHC
class II molecules. IL-2 production inhibition is thought to be the cause
of this downregulation. The retinal-pigmented epithelial cells, which
in vitro have been shown to display pro-inflammatory characteristics
in such a way to display pro-inflammatory characteristics like the in-
duction of lymphocyte proliferation in response to antigen presentation,
has also been demonstrated to produce TGF-β and retinal-pigmented
epithelial prospective peptide, both of which are immunosuppressive
factors. In addition to this, the presence of TGF-β in the vitreous cavity
also probably plays a role in the maintenance of balance in the retina.
Therefore the retina, while possessing the ability to mount an autoim-
mune response by virtue of its disease-causing autoantigens and pro-
inflammatory factors, also has a shield of immunomodulatory features
to protect itself against damage [136].
Since vision can potentially be impaired by any intraocular inflam-
mation, including immune-mediated inflammatory injury, it appears
that the eye has evolutionarily adapted itself to benefit from protection
against pathogens while simultaneously preventing blindness from im-
mune injury. Thus it is believed by many that the eye is a privileged site
in terms of immunity. This privilege depends upon the integrity of the
anatomical and biochemical structures of the eye such as lack of lym-
phatic drainage and the presence of blood–ocular barrier that sheltered
ocular antigens from the immune system [137]. In Takayasu's arteritis,
12 F.A. de Andrade et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
A
Fig. 21. Two examples of fundus fluorescein angiographies (FFA) showing optic neuritis (A).
the main pathological features are granulomatous inflammatory
panarteritis. Although the pathogenesis is unclear, an acute vascular in-
flammation is observed. This may be due to the activation of the MICA/
NKG2D pathway in response to unknown stimulus, resulting in activa-
tion of T and NK cells recruited to vascular wall [138].
Retinal autoimmunity is a subject that remains elusive. Despite the
fact that T cells reactive to retinal antigens and capable of causing dis-
ease are normally present, the immune system clearly is able to cope
with these autoreactive cells, since not every individual possesses reti-
nal autoimmunity [139].
To fully understand the complex mechanism of ocular immune sys-
tem and the immune response in general, the mechanism(s) by which
the threat of autoimmune disease is kept in check, as well as those
that play a role in the induction of autoimmunity, must be completely
elucidated.
As seen in Fig. 21, optic neuritis (ON) [140] is characterized by in-
flammation on the optic nerve [141], but the spectrum of autoimmune
optic neuropathies (AON) is expanding . The broad phenotypic spec-
trum includes single isolated optic neuritis (SION), relapsing inflamma-
tory optic neuritis (RION), chronic relapsing inflammatory optic
neuropathy (CRION) [142], the neuromyelitis optica (NMO) spectrum
disorder [143], multiple sclerosis associated optic neuritis (MSON)
[144] and unclassified optic neuritis (UCON) forms.
ON is one of the first clinical signs of multiple sclerosis and it can re-
sult in irreversible visual impairment due to the optic nerve axon de-
generation and apoptosis of retinal ganglion cells. It is also described
in NMO, an inflammatory disorder of the CNS that predominantly af-
fects the optic nerves and the spinal cord. Previously, it has been consid-
ered to be a severe variant of multiple sclerosis. However, the finding
that most NMO patients have autoantibodies against aquaporin-4
(AQP4) has improved the knowledge of its pathogenesis and led to
the concept that NMO is a distinct and isolated disorder. Testing for
serum anti-AQP4 autoantibodies is advised in all patients with severe,
atypical or recurrent ON because of the high diagnostic specificity that
this test represents [141]. The diagnostic specificity may be aided by
testing for glial biomarkers in the CSF, and prognostic accuracy by test-
ing for biomarkers for neuroaxonal degeneration [145–147].
6. Conclusion
It has been demonstrated that there are multiple anatomic and func-
tional layers that are necessary for the preservation of the privileged im-
mune protection of the eye. The first layer involves an intact anatomic
border with the blood–ocular barrier and immunosuppressive neuro-
peptides in the native aqueous humor. The second layer relies on the
ability of the eye to reestablish an immunosuppressive micro-environ-
ment by activating latent TGF-β and reestablishing ACAID. The third
Please cite this article as: de Andrade FA, et al, The autoimmune diseases of the eyes, Autoimmun Rev (2015), http://dx.doi.org/10.1016/
j.autrev.2015.12.001
A
layer involves a mechanism that is not yet fully identified, but that has
the ability to overcome a predominantly Th1 intraocular immune re-
sponse and to reestablish ACAID. Understanding the detailed mecha-
nisms of these pathways, will invariably lead to the development of
new treatments strategies in order to prevent damage to the eye from
a persistent or exaggerated inflammatory reaction, that is, at least ini-
tially, a protective response against pathogens that are threatening the
integrity of the eye and may trigger autoimmune reactions.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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