Acute A nterior Uveitis and HLA-B27: 2 What's New?

Abstract

Acute anterior uveitis (AAU) is by far the most common form of uveitis [6]. It is characterized by a breakdown in the blood–aqueous barrier and acute inflammation of the iris and ciliary body. Immunopathologically, there is up-regulation of cell adhesion molecules on the uveal vasculature and aqueous humor expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and chemokines that selectively recruit and activate inflammatory cells (neutrophils, monocytes and lymphocytes) into the uvea and anterior chamber (AC). These cells are visible clinically on slit lamp biomicroscopy. The breakdown in the blood–ocular barrier results in leakage of serum proteins from the uveal vasculature into the AC, which is visible on biomicroscopy as aqueous flare and fibrin formation. Keratic precipitates (KPs) represent inflammatory cells that have precipitated on the corneal endothelium. Thus AAU is a prototypical inflammatory disease in which the clinician is uniquely able to visualize the inflammatory response in vivo and all of its sequelae using the slit lamp biomicroscope, and to correlate it with the immunopathological process.
About 50% of all cases of AAU are associated with the presence of HLA-B27, a class I major histocompatibility complex (MHC) [8]. HLA-B27-associated AAU represents a distinct clinical phenotype that may be associated with severe intraocular inflammation as well as systemic inflammatory diseases such as the seronegative spondyloarthropathies (SpA). There has been some recent progress in our understanding of the clinical features and the immunopathogenesis of this group of diseases. The aim of the present chapter is to highlight these advances for the clinician managing patients suffering from AAU.

Full text

Our kno wledge a nd under standing o f imm une-mediated
diseases has incr eased exp onentially o ver t he past f ew
years, especially in the areas of immunopathogenesis and
immunotherapeutics. U veitis is o ne o f t he most co m-
mon potentially blinding disorders, and one that is often
underestimated but is now considered a leading cause of
severe e ye da mage, pa rticularly in y ounger ag e gr oups.
Over the past few years, immune-mediated mechanisms—
both innate and adaptive—have also been implicated in
other disorders, such as diabetic retinopathy and macular
degeneration.
This t hird v olume o f U veitis a nd I mmunological
Disorders in t he Ess entials in Op hthalmology s eries
provides the ophthalmologist with practical information
on current diagnostic and therapeutic aspects of several
ocular disorders from the front to the back of the eye. In
addition, there are important discussions of the mecha-
nisms underl ying t hese co nditions, w hich inco rporate
the most recent research material available. The scope of
the chapters ranges from well-recognized immune disor-
ders such as cornea transplantation, uveitis and diabetic
retinopathy, to less w ell recognized but newly emerging
immunologically linked diseases, such as macular degen-
eration. This b ook co vers, in pa rticular, ne w asp ects of
HLA-B27-associated a nterior u veitis, k eratouveitis, a nd
steroid s ensitivity in u veitis pa tients. F urther em phasis
is placed on the nature of the intraocular inflammation
and systemic dis orders suc h as B ehçet’s vas culitis a nd
multiple sclerosis.
We are grateful to all of the authors that have contributed
to this edition of Uveitis and Immunological Disorders.
We are sure that this book will find its audience, and we
hope that it will serve in the interest of many patients.
Uwe Pleyer
John V. Forrester
Preface

Acute Anterior Uveitis and HLA-B27:
What’s New?
2
John H. Chang, Peter J. McCluskey, Denis Wakefield
Chapter 2
■ Acute anterior uveitis (AAU) accounts for 90% of all
uveitis cases seen by the general ophthalmologist.
■ About half o f all AA U cas es a re HL A-B27-
associated.
■ HLA-B27+ AA U r epresents a distinc t c linical
entity wi th im portant o cular a nd extrao cular
consequences.
■ The typical ocular phenotype of HLA-B27+ AAU
is that of acute onset, unilateral inflammation of
the iris and ciliary body, with a tendency towards
recurrent attacks and more severe inflammation,
including h ypopyon f ormation. M ales a re
affected more frequently than females.
■ All patients with AAU must have a dilated fun-
dus exa mination t o co nfirm t he diagnosis is
anterior uveitis, and careful clinical assessment
regarding p ossible associated systemic inf lam-
matory disease.
■ All pa tients wi th AA U sho uld b e in vestigated
with HL A-B27 typ ing, syp hilis s erology, a nd a
chest X-ray at a minimum.
■ 50% o f pa tients wi th HL A-B27+ AA U will
develop an associated seronegative sp ondyloar-
thropathy (S pA), w hilst a pproximately 25% o f
the patients initially diagnos ed with HLA-B27-
associated systemic disease will develop AAU.
■ HLA-B27 is t he str ongest kno wn g enetic r isk
factor for AAU. There are multiple subtypes of
HLA-B27, w hich ma y b e dif ferentially ass oci-
ated with disease.
■ In addition t o genetic fac tors, environmental
factors play a cr itical role in t he pathogenesis
of AAU.
■ Bacterial tr iggers ha ve b een str ongly im pli-
cated in the development of AAU and recurrent
episodes of ocular inflammation.
■ Human u veal a ntigen-presenting cells exp ress
TLR4, t he r eceptor f or LPS, a nd ma y p rovide
a cr itical mo lecular link b etween micr obial
triggers and the development of AAU.
■ Topical co rticosteroids a nd c ycloplegic ag ents
are the mainstay of treatment.
2.1 Introduction
Acute anterior uveitis (AAU) is by far the most common
form of uveitis [6]. It is characterized by a breakdown in
the blood–aqueous barrier and acute inflammation of the
iris and ciliary body. Immunopathologically, there is up-
regulation of cell adhesion molecules on the uveal vascula-
ture and aqueous humor expression of pro-inflammatory
cytokines such as tumor necrosis factor (TNF)-α, inter-
feron (IFN)-γ and chemokines that selectively recruit and
activate inflammatory cells (neutrophils, monocytes and
lymphocytes) into the uvea and anterior chamber (AC).
These cells a re visible clinically on slit lamp biomicros-
copy. The breakdown in the blood–ocular barrier results
in leakage of serum proteins from the uveal vasculature
into t he A C, w hich is visib le o n b iomicroscopy as
aqueous f lare an d f ibrin for mation. Keratic pre cipitates
(KPs) represent inflammatory cells that have precipitated
on the corneal endothelium. Thus AAU is a prototypical
inflammatory disease in w hich the clinician is uniq uely
able to visualize t he inflammatory response in vi vo and
all of its sequelae using the slit lamp biomicroscope, and
to correlate it with the immunopathological process.
About 50% of all cases of AAU are associated with the
presence of HLA-B27, a c lass I major histocompatibility
complex (MH C) [8]. HL A-B27-associated AA U r epre-
sents a distinct clinical phenotype that may be associated
with severe intraocular inflammation as well as systemic
inflammatory diseases such as the seronegative spond-
yloarthropathies (S pA). Ther e has b een s ome r ecent
Core Messages

10 2 Acute Anterior Uveitis and HLA-B27: What’s New?
2
progress in our understanding of the clinical features and
the immunopathogenesis of this group of diseases. The
aim of the present chapter is to highlight these advances
for the clinician managing patients suffering from AAU.
2.2 Epidemiology of Acute Anterior
Uveitis and HLA-B27
The annual incidence o f uveitis has b een reported to be
between 17 and 52 per 100,000 population, with a preva-
lence of between 38 and 714 per 100,000 population [6].
Anterior u veitis is t he p redominant f orm o f u veitis in
most populations studied, accounting for approximately
50–60% o f all cas es o f u veitis s een in t ertiary r eferral
centers. I n t he g eneral co mmunity, AA U acco unts f or
up t o 90% o f all u veitis cas es o nce r eferral st udy b ias
has b een r emoved [22]. I n o ne st udy, t he me an annual
incidence and p revalence rates o f anterior uveitis were,
respectively, 21 and 69 per 100,000 population, whilst the
total incidence and prevalence rates of all cases of uveitis
in that community were 23 a nd 75 p er 100,000 p opula-
tion, respectively [29].
HLA-B27-associated AAU is the most important form
of anterior uveitis (acute and chronic forms combined),
accounting f or 18–32% o f all cas es o f a nterior u veitis
(see Table 2.1 f or common causes of acute and chronic
anterior uveitis). As will be discussed later, HLA-B27 is the
strongest known genetic risk factor for AAU. The lifetime
cumulative incidence o f AAU in t he general population
has been reported to be about 0.2%, but this increases to
1% in the HLA-B27-positive population [19].
HLA-B27+ AAU demonstrates a clear gender prepon-
derance, with males being about 2.5 times more likely to
be a ffected t han f emales. The f irst attack of HL A-B27+
AAU occurs between 20 and 40 years of age in the great
majority of cases, and these patients are about a decade
younger than their HLA-B27 negative counterparts at the
time of disease onset [8].
2.2.1 Global Patterns of HLA-B27+
Acute Anterior Uveitis
In t he g eneral C aucasian p opulation, t he p revalence o f
HLA-B27 is a pproximately 8%, w hereas t he HL A-B27
antigen is p resent in a bout half o f the patients suffering
from AAU [8]. Ther e is a g lobal variation in t he preva-
lence of t he HL A-B27 gene, a nd d ue to t his, as w ell as
potential variations in o ther genetic and environmental
factors that are relevant to disease pathogenesis; there are
distinct g lobal pa tterns o f AAU. F or exa mple, t he rela-
tively lower frequency of HLA-B27+ AAU in Asia reflects
the lower prevalence of HLA-B27 in this area; it is as low
as 0.5% in Japan [6, 8].
2.3 HLA-B27 and Disease
HLA-B27 is a h uman leuk ocyte antigen (HLA) class I
molecule w hose strong ass ociations with dis ease s et it
apart from most HL A antigens, and so it has b een the
subject of much research over t he past 35 y ears. HL A
Table 2.1. Common causes of acute and chronic anterior uveitis
Acute anterior uveitis (AAU) Chronic anterior uveitis
HLA-B27+ AAU Juvenile idiopathic
arthritis (JIA)
Ocular involvement only
Ankylosing spondylitis
Reactive arthritis
Psoriatic arthropathy
Inflammatory bowel disease
Undifferentiated SpA
Idiopathic AAU (HLA-B27
negative)
Fuch’s heterochromic
iridocyclitis
Sarcoid uveitis Idiopathic
Behçet’s disease Sarcoid uveitis
Posner–Schlossman
Syndrome
Syphilitic uveitis
Lens-associated uveitis Herpetic (herpes
zoster/simplex)
Syphilitic uveitis
■ AAU is the most common form (90%) of uveitis
■ Approximately half of all patients with AAU are
positive for HLA-B27
■ There are global variations in t he prevalence of
HLA-B27 AAU
■ HLA-B27 AA U r epresents a distinc t c lini-
cal en tity wi th c linically im portant o cular a nd
extraocular implications
■ Males a re a ffected a bout 2.5 times mo re
frequently with HLA-B27 AAU than females
■ First a ttack o f HL A-B27 AA U usuall y o ccurs
between 20 and 40 years of age
Summary for the Clinician

2.3 HLA-B27 and Disease 11
molecules are encoded on the short arm of chromosome
6. HL A a ntigens a re vi tal t o no rmal immune sur veil-
lance and the generation of immune responses to foreign
antigens. Thes e mo lecules a re cr itically im portant in
various p hysiologic a nd pa thologic imm une p roc-
esses, inc luding a ntiviral r esponses, o rgan tra nsplan-
tation immunology a nd t umor immunology, and p lay
a key role in t he pa thogenesis o f a n expa nding list o f
immune-mediated inf lammatory dis eases. HL A a nti-
gens are divided into HLA class I and class II molecules,
which ha ve distinc t str uctural a nd f unctional c harac-
teristics (Table 2.2). HL A mo lecules p resent a ntigenic
peptides to T lymphocytes via distinct antigen processing
and HL A-restricted p resentation pa thways, wi th t he
common goal of initiating the antigen-specific adaptive
immune response.
The strong association between HLA-B27 and inflam-
matory dis eases, suc h as a nkylosing sp ondylitis (AS),
reactive a rthritis (inc luding Rei ter’s syndr ome) a nd
AAU has been known for over 30 years [2, 3, 8]. Within
this sp ectrum o f HL A-B27-associated inf lammatory
diseases, AS demo nstrates t he str ongest ass ociation,
with around 90% o f pa tients p ossessing t he HL A-B27
antigen. Nearly a t hird of these patients develop HLA-
B27+ AAU during the clinical course of their extraocular
inflammatory dis ease. D espite ext ensive r esearch f or
other g enes, HL A-B27 i s s till th e s trongest kn own
genetic risk factor for the development of AAU, but how
it predisposes to disease remains an enigma. Possession
of t he HL A-B27 a ntigen incr eases t he r elative r isk o f
AAU by 26 times [3]. Although 45–70% of patients with
AAU are HLA-B27 positive compared to only 4–8% o f
the general Caucasian population, it should be appreci-
ated that 99% o f subjects that have the HLA-B27 gene
are healthy and will not develop associated diseases dur-
ing their lifetime. This implies that other genetic factors
and en vironmental fac tors suc h as micr obial tr iggers
play an important role in t he development of AAU (as
discussed in Sect. 2.3.2).
X ra y cr ystallography has demo nstrated t he t hree-
dimensional structure of HLA-B27. It is a heterodimeric
membrane-bound g lycoprotein co nsisting o f a p oly-
morphic α chain, which is noncovalently linked to non-
polymorphic β-2-microglobulin. The α c hains co ntain
two p eptide-binding do mains (α1 and α2) w hich f orm
antigen-binding c lefts t hat b ind sho rt p eptides o f 8–12
amino acids [20].
2.3.1 New Developments
in the Immunogenetics of HLA-B27
Recent studies have shown that HLA-B27 is not a single
allele b ut a fa mily o f a t le ast 31 dif ferent alleles t hat
encode f or HL A-B27 sub types (na med HL A-B
*
2701
to H LA-B
*
2728) [17]. Ther e is a va ried distr ibution of
these HL A-B27 sub types in dif ferent p opulations, a nd
this may account for the varying strengths of HLA-B27-
disease association that are observed in dif ferent ethnic
groups. The mo re co mmon sub types, HL A-B
*
2705
(accounts f or a bout 90% o f HL A-B27+ indi viduals o f
northern European des cent), B
*
2702 a nd B
*
2704, ha ve
been shown to be strongly associated with AS [17]. Both
HLA-B
*
2705 a nd B
*
2702 w ere als o str ongly ass ociated
with AAU in a st udy of Dutch patients [11]. Ther e has
not b een a st udy of other HLA-B27 subtypes and their
association wi th AAU. However, at le ast tw o sub types,
HLA-B
*
2706 (co mmon in S outheast A sia) a nd B
*
2709
Table 2.2. HLA class I and class II molecules
HLA class I HLA class II
Subclass HLA-A, -B, -C
(classical)
HLA-DR,
-DQ, -DP
HLA-E, -F, -G (non-
classical)
Cellular
expression
Most human somatic
cells
Antigen-
presenting cells
No/minimal
expression on
uveal or corneal
endothelial cells
Dendritic cells
Macrophages
Monocytes
Antigen (Ag)
presented
Endogenous or
intracellular peptides
(self or viral origin)
Exogenous or
extracellular
peptides
T cell
presentation
Presents Ag to
CD8+ (cytotoxic)
T lymphocytes
Presents Ag to
CD4+ (helper)
T cells
Examples of well-
known disease
associations
HLA-B27 and AAU,
AS.
HLA-DR, -DQ
subtypes and
VKHD
HLA-29 and birdshot
retinochoroidopathy
HLA-DR15 and
pars planitis
HLA-B51 and
Behçet’s disease
HLA-DR4 and
sympathetic
ophthalmia
AAU, Acute anterior uveitis; AS, ankylosing spondylitis;
VKHD, Vogt–Koyanagi–Harada disease

12 2 Acute Anterior Uveitis and HLA-B27: What’s New?
2
(found in Sa rdinia) appear to lack a dis ease association
with AS [17]. Thes e HLA-B27 subtypes vary from each
other by only one or several amino acids, most ly at the
antigen-binding r egion o f t he mo lecule, a nd a re t hus
expected to alter the range of antigenic peptides bound
and p resented t o T cells b y HL A-B27. The f inding o f
differential HL A-B27 sub type dis ease ass ociation t hus
suggests that the antigen-presentation function of HLA-
B27 may play an important role in t he pathogenesis of
disease. Such observations support the “arthritogenic” or
“uveitogenic” p eptide hypothesis f or AS o r HL A-B27+
AAU pathogenesis, which proposes that disease is a con-
sequence o f s elf-reactive c ytotoxic T l ymphocytes (via
molecular mimicry) that are activated against a p eptide
found only in the joint or uvea [8, 17].
Recent st udies usin g a nimal mo dels o f HL A-B27-
associated inf lammatory dis eases ha ve c learly dem-
onstrated t he dir ect pa thogenic r ole o f HL A-B27.
HLA-B27 transgenic rats and mice that express human
HLA-B27 a ntigens w ere f ound t o sp ontaneously
develop a multisystemic inflammatory disease resem-
bling t he sp ectrum o f h uman HL A-B27-associated
spondyloarthropathies (SpA) [8, 18, 31]. Of pa rticular
interest, t hese tra nsgenic a nimals w ere he althy if
kept in a g erm-free environment, but once moved to
a no rmal en vironment a nd exp osed t o co mmensal
microbes, acute development of enterocolitis, ankylos-
ing arthritis, enthesitis, psoriasiform skin lesio ns and
inflammatory male genital lesions were triggered [32].
This provides further evidence to support not only the
importance of genetic factors but that of environmental
factors a nd in pa rticular, micr obial tr iggers, in t he
development of HLA-B27-associated diseases (see the
next s ection). Interestingly, however, AAU was no t a
prominent feature of the HLA-B27 transgenic animal
models.
2.3.2 Role of Microbial Triggers
in Immune-Mediated Inflammation
It is c lear t hat sp ecific en vironmental fac tors p lay a
critical role in t he development of HLA-B27 AAU, as
the great majority of HLA-B27-positive individuals do
not develop inflammatory diseases despite the strong
relative g enetic r isk o f de veloping AS o r AA U. I n
particular, there is ext ensive evidence from both clini-
cal and exp erimental studies t hat support t he role of
microbial triggers in the development of AAU. Reactive
arthritis and u veitis are prototypical exa mples o f t he
development o f no ninfectious imm une-mediated
inflammation following a tr iggering genitourinary or
gastrointestinal tract infection. Chlamydia trachomatis
and G ram-negative bac teria, suc h as cer tain sp ecies
of Salmonella, S higella, C ampylobacter, K lebsiella and
Yersinia, have been implicated in t he pathogenesis of
HLA-B27+ AAU [8]. The p recise pathogenic mecha-
nism r emains unc lear, b ut p utative “ uveitogenic”
peptides from these bacteria have been shown to have
the necess ary s equences t o b e a ble t o b e b ound a nd
presented by HLA-B27 to T cells. It has been proposed
that these microbe-derived antigens may trigger CD8+
T cell imm une r esponses t hat cr oss-react wi th s elf-
tissue antigens (molecular mimicry) that are uniquely
found in t he u vea o r jo int tissue , r esulting in a uto-
immune tissue inflammation [8].
Microbial tr iggers ha ve b een im plicated in t he
pathogenesis of recurrent attacks of HLA-B27+ AAU.
Raised a ntibody le vels aga inst Salmonella, C ampylo-
bacter jej uni, Klebsiella pneumonia and Yersinia we re
found to be associated with recurrent attacks of AAU
[15]. Furthermore, a close relation between the recur-
rences o f AAU a nd c hronic asym ptomatic ileo colitis
has b een obs erved, im plicating a pa thogenic r ole
for mucosal infection in t he development of anterior
uveitis [1].
It is also of interest that many animal models of ante-
rior uveitis involve the induction of ocular inflammation
with microbial cell wall components, such as endotoxin
or lipopolysaccharide (LPS) of Gram-negative bacteria,
and p eptidoglycan (PGN) o r li poteichoic acid (L TA)
of Gram-positive bacteria [8, 9]. The e ye appears to be
highly and selectively sensitive to the pro-inflammatory
effects of LPS in endotoxin-induced uveitis (EIU), with
no signif icant a bnormalities obs erved in o ther o rgans
in response to the uveitogenic dose of LPS. EIU is t he
most widel y us ed a nimal mo del f or AA U, a nd a lo w
dose of LPS given at a site remote from the eye induces
an acute breakdown in t he blood–aqueous barrier and
■ Although o ther g enes a re almost cer tainly
involved, HLA-B27 remains the strongest known
genetic risk factor for AAU.
■ HLA-B27 is no t a sin gle allele . I nstead, t here a re
multiple sub types o f HL A-B27, w hich a ppear t o
have dif ferential ass ociations wi th dis ease. The
more common subtypes, HLA-B
*
2705, B
*
2702 and
B
*
2704, are strongly associated with AS and AAU.
■ Transgenic a nimals exp ressing h uman HL A-
B27 sp ontaneously de velop a m ultisystemic
inflammatory disease.
Summary for the Clinician

2.5 Current Understanding of AAU Pathogenesis 13
the influx of acute inflammatory cells into the anterior
uvea and AC [8, 26]. S ome of the recent developments
in our understanding of innate immunity and the Toll-
like receptors (TLR) ha ve led t o ne w in sights into t he
potential mec hanisms b ehind t hese im portant obs er-
vations linking microbial triggers and inflammatory
disease, including AAU (see Sect. 2.5.2) [9].
2.3.3 HLA-B27-Associated
Inflammatory Disease
HLA-B27 is associated with not just AAU but a spectrum of
seronegative sp ondyloarthropathies (SpA). The str ongest
disease association of HLA-B27 is with ankylosing spond-
ylitis (AS), b ut t he o ther HL A-B27-associated inf lam-
matory dis eases inc lude r eactive a rthritis, inf lammatory
bowel disease (IBD) and its associated arthropathy, psori-
atic arthropathy, and undifferentiated SpA. From the avail-
able data, it is estimated that more than half of the patients
with HLA-B27+ AAU will develop AS or one of the other
SpA, w hilst a pproximately 25% o f t he pa tients ini tially
diagnosed with HLA-B27 associated systemic disease will
develop AAU during t heir lif etime [8]. The o phthalmolo-
gist must be aware of these systemic dis ease ass ociations
of HLA-B27 AAU, as he is uniq uely placed to recognize a
unifying syst emic HL A-B27-related diagnosis in pa tients
with AAU and symptoms of joint, skin or GIT dysfunction.
This r equires ca reful c linical ass essment, f ollow-up a nd
referral to the relevant internist for further investigation.
2.4 Other Genetic Risk Factors
for Acute Anterior Uveitis
Observations, inc luding t hose f rom twin co ncordance
studies and of familial ag gregation of AAU, indicate that
there are other non-HLA-B27 genes, both within and out-
side the MHC, that predispose to the development of AAU.
HLA-B27-positive f irst-degree r elatives o f pa tients wi th
HLA-B27 AA U ha ve a hig her r isk (13%) o f de veloping
AAU than HLA-B27-positive individuals without affected
relatives (1%) [12]. Recent genome-wide scans of families
with multiple affected members with AAU have identified
several chromosomal regions associated with AAU, includ-
ing regions on chromosomes 3, 5, 9, 13 and 15. Strong link-
age was obs erved a t a lo cus a t c hromosome 9p21–9p24
that uniquely associated with AAU but not with AS [21].
Chemokines play a pathogenic role in AAU by recruit-
ing inflammatory cells to the AC (see Sect. 2.5.1). A recent
study has reported a significantly increased frequency of
a functional polymorphism in the promoter region of the
gene for the chemokine C CL2/monocyte chemoattract-
ant p rotein (M CP)-1 in pa tients wi th HL A-B27+ AAU
compared to HLA-B27+ healthy controls [35].
Similarly, t here a re als o p robably as-y et-unidentified
genetic risk factors for idiopathic HLA-B27-negative AAU.
For example, MHC class I chain-associated gene A (MICA)
A4 allele was found to be at significantly higher frequency
in patients with HLA-B27-negative AAU compared to that
in ethnically matched HLA-B27-negative controls [14].
2.5 Current Understanding of AAU
Pathogenesis
There have been recent advances in our understanding of
the immunopathogenesis of AAU due to the existence of
several good animal models of AAU, as well as t he devel-
opment o f p owerful ne w r esearch t ools, suc h as in tra-
vital microscopy for studying leukocyte interactions with
the uveal vasculature in vi vo during the various stages of
experimental AAU, advances in mo lecular biology (such
as D NA micr oarrays t hat ca n ra pidly s creen f or t ens o f
thousands o f g enes), a nd ad vances in p roteomics. How-
ever, al though w e a re no w a ble t o diss ect t he m ultitude
of mo lecular st eps in t he e volution o f ac ute in traocular
inflammation a nd t he indi vidual ef fects o f mo dulating
these pathways, there is still much to be learned. For exam-
ple, the critical initial processes involved in the breakdown
of o cular immune privilege, the restriction of inf lamma-
tion to one eye, the triggering of recurrent attacks of AAU,
or t he processes responsible f or t he progression o f AAU
Summary for the Clinician
■ Environmental fac tors, in pa rticular micr obial
triggers, are c learly im portant in t he pathogen-
esis of AAU.
■ Chlamydia trachomatis and Gram-negative bac-
teria ha ve b een im plicated in t he pa thogenesis
of HLA-B27+ AAU, including certain species of
Salmonella, S higella, C ampylobacter, K lebsiella
and Yersinia.
■ Microbial products, such as LPS of Gram- negative
bacteria, have been used to induce various animal
models of AAU. The most widely adopted model
of AAU is endotoxin-induced uveitis (EIU).
■ Patients with HLA-B27 AAU are at increased risk
of developing an associated systemic inflamma-
tory disease, and vice versa.

14 2 Acute Anterior Uveitis and HLA-B27: What’s New?
2
to chronic inflammation are unknown. The elucidation of
these immune mechanisms may lead to the development
of truly revolutionary therapies for halting AAU early and
preventing t he de velopment o f sig ht-threatening, r ecur-
rent or chronic anterior uveitis.
2.5.1 Cytokines
Cytokines are soluble mediators produced by various cells
of the innate and adaptive immune system that orchestrate,
coordinate a nd in tegrate t hese tw o a rms of t he immune
response. C ytokines typ ically ha ve p leiotropic ef fects,
including pro-inflammatory, anti-inflammatory and che-
moattractant functions. Leukocyte extravasation from the
blood into the tissue is a regulated multistep process involv-
ing a series of coordinated interactions between leukocytes
and endo thelial cells in volving s electin-mediated rolling,
integrin-mediated firm adhesion, and chemokine-mediated
migration. Chemo kines are o f pathogenic importance in
the selective intraocular recruitment of neutrophils, mono-
cytes and CD4+ T lymphocytes in uveitis.
Each step of the cell recruitment process is important
in t he pa thogenesis o f exp erimental AAU, a nd s elec-
tively inhib iting a ny st ep will pa rtially a brogate u veal
inflammation. Ther e is signif icant r edundancy in t he
process, with another pro-inflammatory pathway being
able to la rgely t ake over t he role o f one that has b een
selectively inhibited.
High aqueous humor levels of various pro-inflamma-
tory c ytokines, suc h as TNF -γ, IFN- γ, IL -2 a nd IL -12,
and low intraocular expression of the anti-inflammatory
cytokine IL -10 ha ve b een sho wn in h uman AA U [8].
Elevated aqueous humor expression of chemokines that
selectively recruit t he ac ute inf lammatory cells in AA U
have b een demo nstrated in pa tients wi th ac tive AA U.
IL-8/CXCL8 (r ecruits neu trophils), in terferon-gamma-
inducible p rotein (IP)-10/CX CL10, M CP-1/CCL2,
RANTES (r egulated u pon ac tivation, no rmal T cell
expressed and secreted)/CCL5 and macrophage inflam-
matory p rotein (MIP)-1 β/CCL4 (r ecruits mo nocytes
and activated T cells) w ere significantly elevated during
the active stages of AAU and correlated with the clinical
severity of the disease [34].
2.5.2 Toll-Like Receptors (TLR)
Recent p rogress in o ur knowledge o f a fa mily o f innate
immune r eceptors called T oll-like r eceptors (TLRs) has
shed new light on our understanding of the normal host
immune defense against microbes and the pathogenesis of
a wide range of infectious and noninfectious autoimmune
diseases. TLRs a re a fa mily of so-called pattern recogni-
tion receptors (PRR) t hat recognize “signature patterns”
of micr obes called “ pathogen-associated mo lecular pa t-
terns” (PAMPs). Ten h uman TLRs ha ve b een iden tified
to date, each of w hich recognize PAMPs f rom a uniq ue
class of microbes; for example, TLR4 r esponds to LPS o f
Gram-negative bacterial cell wall whilst TLR2 recognizes
Gram-positive bacterial cell wall co mponents [9, 23, 30].
Thus, t he dis covery o f TLRs has co nferred a degr ee o f
specificity to innate immunity that had not been previ-
ously recognized [23]. Activation of TLRs by their ligands
results in the initiation of a pro-inflammatory cascade, the
activation of the transcription factor NFκB, leading to the
production o f p ro-inflammatory c ytokines, c hemokines
and activation of immune cells. Thus, t hese PRRs allo w
the innate immune system to respond rapidly to microbes
at host/environment interfaces that express high levels of
TLRs [9, 30]. Ther e has b een immense research on this
family of receptors in the past decade, and they have since
been implicated in the pathogenesis of a variety of inflam-
matory diseases, including IBD, AS a nd ps oriasis [5, 30,
36]. Notably, all o f t hese diseases can b e complicated by
AAU and are recognized systemic associations with HLA-
B27+ AAU. In IBD, it is t hought that inappropriate a nd
hyper-responsive inflammation triggered by various TLRs
to commensal gut bacteria may play a cr itical role in t he
observed chronic intestinal inflammation.
Functional TLR4 expression by uveal antigen-presenting
cells (APC) in t he no rmal h uman ir is a nd cilia ry b ody
has been recently demonstrated [4, 7, 9]. This p rovides a
novel mechanism by which the various implicated micro-
bial triggers could initiate t he de velopment of AAU, and
explains t he apparent hig h sensitivity of t he u vea to LPS
(now recognized as being the ligand for TLR4). LPS activa-
tion of perivascular TLR4-expressing uveal dendritic cells
(DCs) could lead to the production of pro-inflammatory
cytokines a nd t he ac tivation o f vas cular adhesio n mo l-
ecules, a b reakdown in t he blood–ocular barrier, and the
recruitment of inflammatory cells t o the AC [7, 9]. TLR4
is absolutely essential for inflammatory responses to LPS.
In the animal model for AAU, the C3H/HeN strain of mice
(which are highly sensitive to developing EIU) has normal
functional TLR4, whilst the congenic C3H/HeJ strain with
nonfunctional TLR4 does not develop EIU [9, 30].
Perturbations in the expression and function of TLR4
and TLR2 ha ve b een obs erved in pa tients wi th ac tive
AAU, further supporting the potential pathogenic role of
these PRRs in the development of AAU [10]. These TLRs
could p rovide t he missin g mo lecular link b etween th e

2.6 Clinical Features of Acute Anterior Uveitis 15
observations o f micr obial tr iggers a nd t he de velopment
of AAU and other immune-mediated inflammatory
disorders, but further studies are still required.
■ Increased le vels o f p ro-inflammatory c ytokines
and chemokines are found in the aqueous humor
of patients with active AAU
■ Toll-like receptors (TLR) a re a fa mily of pattern
recognition receptors that recognize a variety of
microbial products and lead to inflammation
■ TLRs have b een implicated in t he pathogenesis
of n umerous inf lammatory dis eases, inc luding
HLA-B27-associated AS, IBD and AAU
■ EIU, t he a nimal mo del f or AA U, is cr itically
dependent on functional TLR4, t he receptor for
LPS of Gram-negative bacteria
■ Uveal APCs in the human eye express TLR4, and
perturbations in the TLRs have been observed in
patients with AAU
Summary for the Clinician
2.6 Clinical Features of Acute Anterior Uveitis
2.6.1 HLA-B27 and Clinical Phenotype
AAU presents with the clinical features of acute inflam-
mation in the anterior segment of the eye (primarily the
iris, ciliary body and AC). The typical phenotype of HLA-
B27-positive AAU is t hat o f a brupt o nset o f unila teral,
often alternating, nongranulomatous AAU, characterized
by the acute onset of a red, photophobic, painful eye and
significant cell ular a nd p rotein extra vasation in to t he
aqueous humor, clinically detectable as AC cells and flare
on slit lamp examination. There is a st andardized inter-
national gradin g syst em f or gradin g AC cells a nd f lare
activity (Table 2.3, Standardization of Uveitis Nomencla-
ture) [16]. HL A-B27-positive AAU has a hig h tendency
to recur, and shows a signif icant ass ociation with other
HLA-B27-related systemic diseases [8]. An ep isode lasts
6–8 weeks on average, and in cases of recurrent AAU, the
intervals b etween t he recurrent attacks are hig hly va ri-
able (from months to years).
In contrast, HL A-B27-negative anterior uveitis tends
to be a mo re heterogeneous entity that is mo re likely to
become bilateral or chronic uveitis, and which is inf re-
quently ass ociated wi th syst emic dis eases. Rec urrent
inflammation is no t unco mmon in HL A-B27-negative
AAU [8]. Ther e is a subs et o f idio pathic HL A-B27-
negative AA U t hat is c linically dif ficult t o distin guish
from HLA-B27-positive AAU.
2.6.2 Ocular Complications
Although AAU is generally associated with a good visual
prognosis, i t is no t wi thout i ts co mplications o r visual
morbidity, esp ecially wi th r ecurrent a ttacks o f o cular
inflammation. In a study on the causes of visual impair-
ment a nd b lindness in in traocular inf lammatory dis-
eases, 10% of patients with HLA-B27-associated anterior
uveitis suf fered legal b lindness o r s evere visual im pair-
ment [28]. Another case series found that 7% of their 175
patients with HL A-B27-associated uveitis demonstrated
significantly decr eased f inal visual ac uity (>2 S nellen
lines) [24]. The most im portant cause of reduced vision
in patients with AAU is c ystoid macular edema (CME),
which has been reported to be as high as 17–25% [8, 24,
25], al though t hese f igures a re almost cer tainly hig her
than those seen in the community, due to the influence of
referral bias in these studies.
Posterior synec hiae is b y fa r t he co mmonest co mplica-
tion o f AAU. W ith t he de velopment o f r ecurrent AAU o r
chronic inflammation, cataract and secondary glaucoma (as
complications of the inflammation itself or induced by corti-
costeroid therapy) frequently cause visual impairment. Com-
plications in patients with HLA-B27 related AAU are related
to the number of recurrent attacks [27, 33].
Table 2.3. Standardized (SUN
a
) grading system for AC cell and
flare severity [30]
Grade AC cells AC flare
0 None None
0.5+ 1–5 cells in the field
b
-
1+ 6–15 cells
b
Faint
2+ 16–25 cells
b
Moderate (iris and lens
details are clear)
3+ 26–50 cells
b
Marked (iris and lens
details are hazy)
4+ >50 cells
b
Intense (fibrin or
plasmoid aqueous)
a
Standardization of Uveitis Nomenclature (SUN)
b
Field size used is a 1 mm by 1 mm slit beam. The presence or
absence of a hypopyon should be noted separately in addition
to the AC cellular activity grade

16 2 Acute Anterior Uveitis and HLA-B27: What’s New?
2
■ HLA-B27-positive AA U exhib its a distinc t
clinical p henotype co mpared t o i ts HL A-B27
negative counterpart. This inc ludes a t endency
for recurrent attacks of inflammation, increased
tendency f or mo re s evere A C inf lammation
including f ibrinous r eaction a nd h ypopyon
formation, a nd signif icant ass ociations wi th
extraocular inflammatory disease.
■ There is a ne w international grading system for
AC inf lammatory ac tivity (t he S tandardized
Uveitis Nomenclature).
■ About 10% of patients with HLA-B27-associated
anterior u veitis suf fer signif icant visual im pair-
ment due to sight-threatening complications such
as CME, cataracts and secondary glaucoma.
Summary for the Clinician
2.7 Clinical Management of AAU
The in vestigation o f AA U sho uld b e g overned b y t he
clinical history, t he review of systems, and examination
findings. In pa rticular, ca reful attention should b e paid
to sym ptoms o f p ossible ass ociated syst emic dis eases,
such as inflammatory back pain of AS, skin c hanges
of psoriasis, or gastrointestinal symptoms of IBD. Dilated
fundus exa mination is ma ndatory in t he ass essment o f
any patient with “anterior uveitis,” in order to ensure that
the disease is co nfined to the anterior segment and that
the symptomatic anterior uveitis is no t part of an inter-
mediate or panuveitis.
There is no co nsensus on the extent of investigations
indicated f or t he f irst episode of AAU. We r ecommend
HLA-B27 typing, a c hest X ra y and syphilis serology as
the minimum investigations for patients with their first
attack of AAU. The HLA-B27 status has significant impli-
cations regarding the p otential risk of further recurrent
episode(s) o f AA U (o ften a p rimary co ncern f or t he
patient suffering their first attack) and the risk of develop-
ing HLA-B27 associated SpA. Syphilis serology remains a
cost-effective in vestigation f or syp hilis, a n incr easingly
common, treatable infectious cause of all forms of uveitis,
including AAU [13]. A chest X-ray is recognized as being
a useful screening investigation for asymptomatic pulmo-
nary sarcoidosis, which may present as acute uveitis.
The ma instay o f AA U tr eatment co nsists o f t opical
corticosteroids, t he in tensity o f administra tion o f w hich
is tailored to the severity of the AC inflammation. The g en-
eral principle is to hit the inflammation hard early on in its
course with intensive topical steroids, such as wi th pred-
nisolone acet ate 1% dr ops ho urly ini tially. M ore s evere
inflammation associated with fibrin formation, hypopyon
or severe pain may require subconjunctival steroid therapy
or o ral co rticosteroids. T opical c ycloplegic ag ents, suc h
as atropine or homatropine, are ess ential f or minimizing
posterior synec hiae f ormation a nd p roviding sym pto-
matic relief f rom pain and photophobia. Topical steroids
are slowly tapered over 6–8 weeks once the inflammatory
activity is co ntrolled. The t otal tr eatment co urse sho uld
cover a t le ast 6–8 w eeks t o minimize p remature cess a-
tion of topical steroids, which would be associated with a
relapse in t he partially treated inflammation (rather than
a true recurrence) and would ultimately prolong the over-
all tr eatment co urse a nd incr ease t he r isk o f de veloping
chronic uveitis.
Systemic treatment with corticosteroids may be required
to tr eat v ery s evere u veitis t hat is r esistant t o maximum
topical a nd lo cal co rticosteroid t herapy. Ot her imm uno-
suppressive ag ents a re ra rely needed t o ma nage pa tients
with r ecurrent AA U. Dr ugs suc h as s alazopyrine a nd
methotrexate are commonly us ed t o tr eat IBD a nd S pA,
and anecdotally there is evidence that this may decrease the
frequency and severity of attacks of AAU. Chronic anterior
uveitis ass ociated with CME a nd r educed vision may, in
selected patients, benefit from systemic immunosuppres-
sive therapy. Exciting new biologic treatment modalities are
being evaluated, including anti-TNFα therapy, anti-VEGF
(vascular endo thelial gr owth fac tor) t herapy, a nd HL A-
B27 peptide o ral t olerance [8]. H owever, t here is in suf-
ficient evidence to support the use of these newer agents
at present, and more studies are required to establish their
clinical indications, efficacy and safety.
2.8 Conclusions
AAU is a co mmon co ndition t hat a ffects r elatively
young patients and can cause signif icant distress to the
patient, wi th r ecurrent, un predictable a ttacks o f ac ute
inflammation. Furthermore, AAU can be associated with
sight-threatening complications such as CMO, and there-
fore it represents an important cause of visual impairment.
The unique association between HLA-B27 AAU and its
related systemic inflammatory diseases demands a com-
prehensive a nd ho listic a pproach t o ma naging pa tients
with AAU, often requiring careful follow-up and liaison
between multiple specialists. The great majority of uveitis
cases seen by the general ophthalmologist will b e AAU,
and a bout half o f t hese will b e HL A-B27+ AA U, t hus
highlighting t heir clinical importance. Recent ad vances
in our understanding of t he genetics, immunology and
pathogenesis o f t his co ndition will ho pefully le ad t o
improved care of our patients suffering from AAU.

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