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Immunology ofUveitis

(Autoimmune Uveitis)

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

 I..I!"

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

mailto:s.h.zarkesh@sheffield.ac.ukmailto:s.h.zarkesh@sheffield.ac.uk

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Autoimmune Disease

DefinitionEhrlich referred to this phenomenon as horrorautotoxicus

Specific adaptive immune response directedagainst self antigen(s) with loss of tolerance,usually peripheral, not central

Trigger(s) is usually unknown.

 Immune response involves both environmentaland genetic factors

female predominance

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Autoimmune Disease

Characteristics

remissions and eacerbations

organ specific or organ non!specific

persistence of antigen due to lack of clearance

tissue damage is produced by" antigen specific cytotoic T cells (#$%&)

 antigen!non!specific ' cells andmacrophagesimmune compleesautoantibodies , andor

granulocytes

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Possible Pathogenic Defects

Human Autoimmunity *ultiple genes are involved in human autoimmune disease e.g.

I$$* (type I), especially involving the *+#

$efects 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"

as!as- I-!I-!/   0I#$)

17−

#T-0!2 interaction

This suggests that each role may be involved in different pathways

of tolerance, perhaps for distinct types of self antigens

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Human Autoimmune Diseases

  3rgan 'on!Specific $iseases

• S-E (systemic lupus erythematosus)

• /0 (rheumatoid arthritis)

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# Autoimmune uveitis

# can be#  "art of a systemic autoimmune syndrome involving

multi"le tissues# such as $ehc%et&s disease# systemic

sarcoidosis.

#  In other diseases the eye may be the only target#

such as in idio"athic uveitis# birdshot

retinochoroido"athy# and sym"athetic o"hthalmia

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# Uveitic diseases are believed to have an

# autoimmune com"onent su""orted by:

#  

# ') lack of a knon infectious trigger

# ) and by freuent "resence of immunological

res"onses to retinal "roteins.

# *) +any uveitic diseases sho strong

# associations ith "articular human leukocyte

antigen (,-A) ha"loty"es.

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# he model of e/"erimental autoimmune

uveitis!uveoretinitis

# (0AU) # In rodents is used as an animal model for 

# human uveitis.

# he classical model of 0AU is induced by

# active immunization ith a retinal antigen (Ag) emulsified in

# com"lete 1reund&s ad2uvant (31A)# a mineral oil

su""lemented

# ith heat4killed mycobacteria.

# In all but the most

# susce"tible mouse and rat strains# an in2ection of "ertussis

# to/in must be given as an additional inflammatory stimulus

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# uveitogenic stimulus that is thought to trigger uveitis in# humans# hich is believed to involve

# ') an e/"osure to a retinal or cross reactive Ag# combined

ith an infectious event that

#  "rovides innate inflammatory danger signals.

# ) Uveitogenic retinal "roteins include

#

 retinal arrestin (soluble Ag)## inter"hotorece"tor 

# retinoid4binding "rotein (I5$6)#

# rhodo"sin#

# recoverin##  "hosducin#

# and retinal "igment e"itheliumderived 560478.

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# 9f the available models#

# the mouse model of 0AU induced ith retinoid4binding "rotein

(I5$6) is the best characterized and the most idely used.

# he ty"ical histological a""earance of 0AU resembles that of

human uveitis# ith inflammatory infiltrates in the vitreous#

retina#

# and choroid and damage to the "hotorece"tor cell layer. ou can

see the details of this "henomenon in ne/t slide.

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#

Ada"tive!effector cells from 0AU4induced animals can "ass the disease to

na;

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# 5ecently# an alternative model to I5$6!31A4induced uveitis

have been develo"ed .

# =endritic cells (=3) are "rofessional

# Ag4"resenting cells ca"able of stimulating na;

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# 3om"ared ith the classical 0AU model induced by active

immunization ith I5$6 or its "e"tide in 31A#

# ') duration of the disease is shorter# the "athology

# a""ears to be less severe#

# ) and the inflammatory infiltrate has a "redominantly

granulocytic rather than mononuclear cell com"osition.

Im"ortantly#

# *) 0AU elicited ith Ag4"ulsed =3 is not only clinically

distinct from 31A induced 0AU# but also is driven by uniue

effector mechanisms

# . his model may offer ne insights into the heterogenous

nature of human uveitis.

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# 3ytokines "lay an im"ortant role in maintaining lym"hocyte

# homeostasis under conditions of health and disease.

# Intraocular e/"ression of cytokines has been studied in "atients# ith uveitis# ith re"orts of increased levels of inflammatory

# cytokines and decreased levels of regulatory

# 3ytokines.

# he roles of various cytokines and ho they affect the# critical check"oints of uveitis# as studied in animal models

# and to a lesser e/tent in "atients# are shon in able ' and

# discussed in the folloing slides.

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$h% &ells and &ytokines in Uveitis

'I(")gamma and I*)%+# I-4'# com"osed of heterodimeric subunits# "*8 and ">?

# is "roduced by =3 and macro"hages# is a key h'4inducing

# cytokine.

#  he roles of I-4' and of I14g# the main signature# cytokine of the h' lineage# have been intensively studied in

# 0AU models in the '?s.

# At that time# the h'B subset

# (discussed ahead) had not yet been described# and the h'

# subset as thought to be the ma2or "athogenic effector cell# subset in uveitis.

#  An I5$64s"ecific uveitogenic cell line

# "olarized to the h' "henoty"e in the "resence of I-4' and

# "roducing massive amounts of I14g as highly uveitogenic

# in na;

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-merging $reatments of &linical Uveitis

$argeting &ytokines and $heir eceptors# 0stablished thera"ies for uveitis are based largely

on

# nons"ecific immunosu""ression (corticosteroids#antimetabolites#and alkylating agents).

#  ,oever# because of the severe side effects of

these treatments# it is im"ortant to develo" ne

a""roaches based on increased understanding# of basic disease mechanisms# so as to intervene

more s"ecifically in the "athogenic "rocesses

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Although involvement

of many cytokines has been demonstrated

in e/"erimentalUveitis as shon in the ne/t slide.

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# 9ne of the hazards involves the "leiotro"ic

# nature of some cytokines and the "ossibility to elicit

# une/"ected reactions. As an e/am"le# a clinical trial to treat

# multi"le sclerosis that as undertaken on the basis of early

# data in mice shoing that I14g can have "rotective effects

# in 0A0 (similarly to 0AU) resulted in e/acerbation of the

#

disease and had to be sto""ed

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3sA as first shon to have a thera"eutic

effect in the rat 0AU model before going to

clinical trials.he macrolides 1C48?7 (tacrolimus) and

ra"amycin (sirolimus) also target the I-4

signaling "athay and are effective forsome ty"es of uveitis

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+ore recent studies have e/amined I-4

rece"tor4directed thera"y ith monoclonal

antibodies (daclizumab) as an a""roachto target activated cells.

his thera"y has shon efficacy in

advanced clinical trials.

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Interestingly#the "ossibility that such

treatment might actually aggravate

cell4mediated autoimmunity because I-4is necessary for the maintenance and

activity of reg cells (at least in mice)

as not fulfilled.

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he mechanism behind the thera"eutic

effects

of daclizumab is com"le/ and incom"letelyunderstood#

 but includes an enhancement in 3=874

 bright C cells ith inhibitory function

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# Dince the eye is a small and relatively closed

organ# local thera"ies in the eye are an attractive

a""roach that can obviate systemic side effects.#  Intravitreal in2ections or im"lants are already in

use for such local thera"ies# and biological

#  "roducts can also be delivered into the eye.

# -ocally "roduced I-4'? has been shon to be

 beneficial in animal models

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# his

# o"ens the "ossibility for intraocular in2ection of

other antiinflammatory# molecules# such as I-4B and I-4*8# or even

# in vitro generated reg cells. 1or this "ur"ose# it

ill be im"ortant

# to develo" minimally invasive and highly efficient

# local drug delivery a""roaches

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 !pproach to $reatment

Anterior Uveitiso"ical:

Dteroid dro"s 3yclo"legics

Dystemic:

3orticosteroids Dteroid s"aring agents

6osterior Uveitis-ocal:

6eriocular steroid

in2ections

Dystemic: 3orticosteroids Dteroid s"aring agents

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$reatment of efractory Uveitis&onventional $herapies

Drug Dosage androute

Monitoring

Methotrexate 10-25mg/week

Oral orparenera

Monitor as in RA

Cyclosporine 5 mg/kg/dayoral Monitorcreatinine Mg!! and lytes

A"athioprine 1-1#5mg/kg/day oral

Montor C$C and%&'s

Cyclophosphamide

1-1#5mg/kg/day oral

Monitor C$Cand (rinalysis

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