Immunology

of

Uveitis
(Autoimmune Uveitis)

Dr S.H. Zarkesh
Department Of Immunology, Medical School, Isfahan University
Of Medical Sciences, Isfahan,

I.R.IRAN

email: s.h.zarkesh@sheffield.ac.uk
Website: www.shef.ac.uk/hamid

Autoimmune Disease
Definition

Ehrlich

referred to this phenomenon as horror

autotoxicus

Specific

adaptive immune response directed

against self antigen(s) with loss of tolerance,
usually peripheral, not central

Trigger(s)

is usually unknown.

Immune response involves both environmental

and genetic factors

female

predominance

Autoimmune Disease
Characteristics
remissions
organ

specific or organ non-specific

persistence
tissue

and exacerbations

of antigen due to lack of clearance

damage is produced by:

antigen specific cytotoxic T cells (CD8+)
antigen-non-specific NK cells and
macrophages
immune complexes
autoantibodies , and/or
granulocytes

Possible Pathogenic Defects

Human Autoimmunity

Multiple genes are involved in human autoimmune disease e.g.

IDDM (type I), especially involving the MHC

Defects in several of these genes may:

disrupt multiple tolerance pathways and
contribute in an additive or synergistic way to these polygenic
diseases
Important individual roles for:
Fas-FasL
IL-2/IL-2RAICD)
BCTLA-4 interaction
This suggests that each role may be involved in different pathways
of tolerance, perhaps for distinct types of self antigens

Human Autoimmune Diseases

Organ Non-Specific Diseases
SLE (systemic lupus erythematosus)
RA (rheumatoid arthritis)

Autoimmune uveitis

can be
part of a systemic autoimmune syndrome involving
multiple tissues, such as Behcets disease, systemic
sarcoidosis.
In other diseases the eye may be the only target,
such as in idiopathic uveitis, birdshot
retinochoroidopathy, and sympathetic ophthalmia

Uveitic diseases are believed to have an

autoimmune component supported by:

1) lack of a known infectious trigger

2) and by frequent presence of immunological
responses to retinal proteins.
3) Many uveitic diseases show strong
associations with particular human leukocyte
antigen (HLA) haplotypes.

The model of experimental autoimmune

uveitis/uveoretinitis
(EAU)
In rodents is used as an animal model for
human uveitis.
The classical model of EAU is induced by
active immunization with a retinal antigen (Ag) emulsified in
complete Freunds adjuvant (CFA), a mineral oil
supplemented
with heat-killed mycobacteria.
In all but the most
susceptible mouse and rat strains, an injection of pertussis
toxin must be given as an additional inflammatory stimulus

uveitogenic stimulus that is thought to trigger uveitis in

humans, which is believed to involve

1) an exposure to a retinal or cross reactive Ag, combined
with an infectious event that
provides innate inflammatory danger signals.
2) Uveitogenic retinal proteins include
retinal arrestin (soluble Ag),
interphotoreceptor
retinoid-binding protein (IRBP),
rhodopsin,
recoverin,
phosducin,
and retinal pigment epitheliumderived RPE-65.

Of the available models,

the mouse model of EAU induced with retinoid-binding protein

(IRBP) is the best characterized and the most widely used.
The typical histological appearance of EAU resembles that of
human uveitis, with inflammatory infiltrates in the vitreous,
retina,
and choroid and damage to the photoreceptor cell layer. You can
see the details of this phenomenon in next slide.

Adaptive/effector T cells from EAUinduced animals can pass the disease to

nave, genetically compatible recipient
animals by adoptive transfer.
The donor T cells are activated with the
immunizing Ag in vitro and are infused into
recipient animals.
The recipients develop a destructive disease
rapidly, usually within a week.

Recently, an alternative model to IRBP/CFA-induced uveitis

have been developed .
Dendritic cells (DC) are professional
Ag-presenting cells capable of stimulating nave T
cells, and are likely to be the main Ag-presenting cells in the
early stages of EAU induction.
A model of EAU was developed
by injection of matured splenic DC loaded with the
major uveitogenic peptide of IRBP into nave wild-type
mice.

Compared with the classical EAU model induced by active

immunization with IRBP or its peptide in CFA,
1) duration of the disease is shorter, the pathology
appears to be less severe,
2) and the inflammatory infiltrate has a predominantly
granulocytic rather than mononuclear cell composition.
Importantly,
3) EAU elicited with Ag-pulsed DC is not only clinically
distinct from CFA induced EAU, but also is driven by unique
effector mechanisms
. This model may offer new insights into the heterogenous
nature of human uveitis.

Cytokines play an important role in maintaining lymphocyte

homeostasis under conditions of health and disease.
Intraocular expression of cytokines has been studied in patients
with uveitis, with reports of increased levels of inflammatory
cytokines and decreased levels of regulatory
Cytokines.
The roles of various cytokines and how they affect the
critical checkpoints of uveitis, as studied in animal models
and to a lesser extent in patients, are shown in Table 1 and
discussed in the following slides.

Th1 Cells and Cytokines in Uveitis

(IFN-gamma and IL-12)
IL-12, composed of 2 heterodimeric subunits, p35 and p40
is produced by DC and macrophages, is a key Th1-inducing
cytokine.
The roles of IL-12 and of IFN-g, the main signature
cytokine of the Th1 lineage, have been intensively studied in
EAU models in the 1990s.
At that time, the Th17 subset
(discussed ahead) had not yet been described, and the Th1
subset was thought to be the major pathogenic effector T cell
subset in uveitis.
An IRBP-specific uveitogenic T cell line
polarized to the Th1 phenotype in the presence of IL-12 and
producing massive amounts of IFN-g was highly uveitogenic
in nave recipient animals.

Emerging Treatments of Clinical Uveitis

Targeting Cytokines and Their Receptors

Established therapies for uveitis are based largely

on
nonspecific immunosuppression (corticosteroids,
antimetabolites,and alkylating agents).
However, because of the severe side effects of
these treatments, it is important to develop new
approaches based on increased understanding
of basic disease mechanisms, so as to intervene
more specifically in the pathogenic processes

 Although

involvement
of many cytokines has been demonstrated
in experimental
Uveitis as shown in the next slide.

One of the hazards involves the pleiotropic

nature of some cytokines and the possibility to elicit
unexpected reactions. As an example, a clinical trial to treat
multiple sclerosis that was undertaken on the basis of early
data in mice showing that IFN-g can have protective effects
in EAE (similarly to EAU) resulted in exacerbation of the
disease and had to be stopped

 CsA was

first shown to have a therapeutic

effect in the rat EAU model before going to
clinical trials.
The macrolides FK-506 (tacrolimus) and
rapamycin (sirolimus) also target the IL-2
signaling pathway and are effective for
some types of uveitis

 More

recent studies have examined IL-2

receptor-directed therapy with monoclonal
antibodies (daclizumab) as an approach
to target activated T cells.
This therapy has shown efficacy in
advanced clinical trials.

 Interestingly,the

possibility that such

treatment might actually aggravate
T cell-mediated autoimmunity because IL-2
is necessary for the maintenance and
activity of Treg cells (at least in mice)
was not fulfilled.

 The

mechanism behind the therapeutic

effects
of daclizumab is complex and incompletely
understood,
but includes an enhancement in CD56bright NK cells with inhibitory function

Since the eye is a small and relatively closed

organ, local therapies in the eye are an attractive
approach that can obviate systemic side effects.
Intravitreal injections or implants are already in
use for such local therapies, and biological
products can also be delivered into the eye.
Locally produced IL-10 has been shown to be
beneficial in animal models

This
opens the possibility for intraocular injection of
other antiinflammatory
molecules, such as IL-27 and IL-35, or even
in vitro generated Treg cells. For this purpose, it
will be important
to develop minimally invasive and highly efficient
local drug delivery approaches

Approach to Treatment
Anterior

Uveitis

Topical:

Steroid drops
Cycloplegics

Systemic:
Corticosteroids
Steroid sparing agents

Posterior

Uveitis

Local:
Periocular steroid

injections
Systemic:
Corticosteroids
Steroid sparing agents

Treatment of Refractory Uveitis:

Conventional Therapies
Drug

Dosage and
route

Monitoring

Methotrexate

10-25
mg/week
Oral or
parenera

Monitor as in RA

Cyclosporine

5 mg/kg/day,
oral

Monitor
creatinine, Mg+
+ and lytes

Azathioprine

1-1.5
mg/kg/day, oral

Montor CBC and

LFTs

Cyclophosphami
de

1-1.5
mg/kg/day, oral

Monitor CBC
and Urinalysis