Ocular Immunology & Inflammation, 17, 249–256, 2009

Copyright

C Informa Healthcare USA, Inc.
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.1080/09273940902999356

Immune Response Genes in Uveitis

Liping Du, MM
The First Affiliated Hospital, Chongqing
Medical University, Chongqing Key
Laboratory of Ophthalmology,
Chongqing, P. R. China
Aize Kijlstra, PhD
Eye Research Institute Maastricht,
Department of Ophthalmology,
University Hospital Maastricht,
Maastricht, The Netherlands
Peizeng Yang, PhD
The First Affiliated Hospital, Chongqing
Medical University, Chongqing Key
Laboratory of Ophthalmology,
Chongqing, P. R. China

ABSTRACT
Uveitis is defined as an intraocular inflammation induced by different etiologies. Though the pre-
cise pathogenesis is still unknown, accumulating evidence shows that both innate and adaptive
immune responses may be predominant mechanisms involved in the development of uveitis.
Toll-like receptors have been shown to be expressed in the human eye and play an important
role in infectious uveitis. The NOD proteins, expressed mainly in the cytosol by APCs, recog-
nize the products of bacteria and participate in the development of uveitis. HLA genes have been
associated with some uveitis entities, including acute anterior uveitis (HLA-B27), Behcet disease
(HLA-B51), birdshot retinochoroidopathy (HLA-A29), Vogt-Koyanagi-Harada syndrome (HLA-
DR4), sarcoidosis, sympathetic ophthalmia, juvenile idiopathic arthritis, tubulointerstitial nephritis
and uveitis (TINU) syndrome, and pars planitis (HLA-DR15). The exact mechanism whereby cer-
tain HLA genes predispose to a certain uveitis entity has not yet been elucidated. In addition,
several studies have demonstrate that polymorphisms in certain immune response genes, such as
tumor necrosis factor (TNF), MHC class I polypeptide-related sequence A (MICA), interleukin-1
(IL-1), and some chemokines, may contribute to the development of human uveitis. Polymorphisms
in the gene coding for the costimulatory molecule known as cytotoxic T-lymphocyte antigen 4
(CTLA-4) were recently found in Chinese patients with VKH syndrome but not in patients with
Behcet disease. Further developments in the unraveling of immune response genes may lead to a
better understanding of human uveitis and will hopefully allow the development of novel treatment
regimes.

Keywords: HLA; immune response; nucleotide-binding oligomerization domains; toll-like receptors; uveitis

Uveitis is defined as an inflammation involving the iris,
ciliary body, choroid, vitreous, retina, and its blood
vessels. It may be induced in genetically suscepti-
ble individuals by infection, autoimmune, traumatic,
or neoplastic events, though the precise etiology and
pathogenesis remain to be elucidated. Accumulating
evidence shows that the immune response may be a
Received 25 February 2009; Accepted 27 April 2009.
Address correspondence to Peizeng Yang, PhD, MD, The First Affil-
iated Hospital, Chongqing Medical University, Chongqing Key Lab-
oratory of Ophthalmology, Chongqing 400016, P. R. China. E-mail:
peizengycmu@126.com
predominant mechanism involved in the development
of various uveitis entities.
Immune responses have been classically divided into
innate and adaptive immune responses according to
the speed and specificity of the reaction. Innate im-
mune responses act as the first line of defense against
infection in every part of our body, including the uvea.
Antigen-presenting cells (APCs) are the critical com-
ponents of the innate immune response system. These
cells can bind to and take up microbial agents and their
products by a variety of receptors. APCs can subse-
quently degrade microbial products or autoantigens to
form small polypeptide fragments and present these

249
 L. Du et al.

Figure 1. Schematic diagram for the immune response in uveitis. APCs recognize microbial products by pattern recognition
receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domains (NOD), and present these
antigens with human leukocyte antigens (HLA) to their surfaces. CD4+ T cells activated by signals from both antigen-HLA-TCR
interaction and costimulatory molecule interaction initiate adaptive immune responses. When antigens are eliminated, immune
responses switch off. If the elaborate eye structure is destroyed by immune responses or antigens exist persistently, uveitis
arises or has recurrent attacks. Autoantigens lead to an autoimmune response.

polypeptides to the surface of APCs in association
with human leukocyte antigens (HLA). These antigenic
peptide–HLA complexes presented on the surface of
the APCs are the initiator and driving force for all
adaptive immune responses. Adaptive immune re-
sponses, especially those carried out by T cells and ini-
tiated by the antigenic peptide–HLA complex, specifi-
cally recognize individual antigens and can then start
with the process of eliminating the offending agent.
The degree of the inflammatory response associated
with the elimination of antigen will dictate whether
visual function is affected or not. In case of a severe
inflammatory response or an inadequate elimination of
250
antigen or when an autoimmune response is involved,
the response may lead to certain autoimmune diseases,
including severe relapsing uveitis episodes (Figure 1).
Innate immune responses play an important role in
uveitis entities induced by infection and adaptive im-
mune responses are considered to be responsible for
the uveitis entities induced by autoimmune responses.
Recent studies have shown that polymorphisms of a
number of immune response genes, including HLA
and non-HLA genes (such as TNF, MICA and some
chemokines), may contribute to the susceptibility to
some uveitis entities. The genetic polymorphisms may
contribute to the susceptibility to disease by influencing
the expression of genes or by influencing the function

of gene products. However, how gene polymorphisms
contribute to the susceptibility to uveitis is not clear
in most cases and studies on ocular microenvironment
changes associated with polymorphisms are scarce.
The following includes an overview on some immune
response genes that have been shown to be involved in
the development of uveitis.
GENES INVOLVED IN THE INNATE
IMMUNE RESPONSE
The principal function of innate immune responses,
including opsonization, phagocytosis, activation of
proinflammatory signaling pathways, and induction
of apoptosis, is mediated by a variety of pattern
recognition receptors (PRRs).1 Secreted PRR molecules,
such as C-creactive protein and serum amyloid pro-
tein, can function as opsonins by binding to bacte-
ria. PRRs expressed on the cell surface, such as the
C-type lectin family and the transmembrane Toll-like
receptors (TLRs), may function as phagocytic recep-
tors or lead to the activation of proinflammatory sig-
naling pathways. Several PRRs, such as protein kinase
PKR and nucleotide-binding oligomerization domains
(NOD), are expressed intracellularly where they detect
intracellular pathogens.
Another key component of innate immunity is the com-
plement system. Various proteins involved in the com-
plement system have been demonstrated to be present
in various ocular tissues, tears, aqueous and vitreous
humor. Sohn et al. demonstrated that the complement
system is continuously active at a low level in the nor-
mal rodent eye and further showed that control of com-
plement activation at the level of C3 convertase was
sufficient to prevent complement-mediated intraocu-
lar inflammation.2,3 The role of complement inhibitors
in ocular tissue protection has been recently reviewed.4
Apparently, innate immune responses play an impor-
tant role in uveitis induced by infection, such as uveitis
caused by toxoplasmosis, tuberculosis, syphilis, and
Lyme disease. Furthermore, evidence from a number
of clinical and experimental studies has also implicated
a potential role of innate immune responses to some
bacteria and its products in the pathogenesis of several
immune-mediated, noninfectious uveitis entities with
systemic involvement, including ankylosing spondyli-
tis, sarcoidosis, and Behcet disease.5−7
Toll-like Receptors
TLRs, a family of transmembrane receptors, are among
the most important genes involved in innate immu-
nity. Ten TLRs have been described to date in humans
Immune Response Genes in Uveitis
which recognize microbial components at the cell sur-
face or endosome.8 They are expressed in different cells
(mostly macrophages and dendritic cells) and each TLR
has a unique specificity for ligands. For instance, TLR2
recognizes peptidoglycans from gram-positive bacte-
ria; TLR4 recognizes lipopolysaccharide (LPS) of gram-
negative bacteria, and TLR9 recognizes CpG DNA of
bacteria.9 Recognition of pathogen-associated molecu-
lar patterns (PAMPs) by these receptors on APCs is able
to induce the expression of various pro-inflammatory
cytokines, chemokines, co-stimulatory molecules, and
MHC molecules. Therefore, these APCs can initiate
a rapid host defense against the invading pathogen.
Meanwhile, these APCs acquire the ability to activate
naı̈ve CD4+ T cells and induce their differentiation into
Th1, Th2, or Th17 cells. In this way, TLRs may also have
an effect on adaptive immune responses. When the ac-
tivated T cells are self-antigen specific, autoimmune
responses may ensue.10−12
TLRs are clearly expressed in the human eye. HLA-
DR+ resident APCs expressing both the LPS recep-
tor complex and TLR4 are strategically positioned in
a perivascular and subepithelial location within the
human uvea.13 In patients with acute anterior uveitis
(AAU), a significant reduction in the levels of TLR2
expression was observed on neutrophils and mono-
cytes when compared with that in healthy controls.14
A significant reduction in IL-6 and interferon-gamma
(IFN-γ ) production by whole-blood cells from patients
with active AAU was also observed when stimulated
by TLR4 activation.14 This reduction in production of
cytokines may be the result from a so called “endo-
toxin tolerance.” That is to say, preexposure to gram-
negative bacteria (LPS), a ligand for TLR4, may lead to
hyporesponsiveness to rechallenge of LPS.14 All these
results support a role of TLRs and microbial triggers
in the pathogenesis of human AAU.9,15 Recently, the
hypothesis that microbial products can trigger autoim-
mune ocular inflammation through TLRs was demon-
strated in an experimental system using mice, although
activities of the various TLRs may vary greatly.16 Fur-
ther studies will provide us a profound understanding
of the relationship among TLRs, microorganisms and
uveitis.
NOD1 and NOD2
The NOD proteins NOD1 and NOD2 are members of
the NACHT (domain present in NAIP, CIITA, HET-E,
and TP1)-LRR (leucine-rich repeat) family and they are
encoded by the caspase-recruitment domain (CARD)
4 gene and CARD 5 gene, respectively.17 Both NOD1
and NOD2 are composed of three domains: a C-
terminal LRR domain involved in ligand recognition, a
central NOD domain with ATPase-activity-mediated
251
 L. Du et al.
self-oligomerization, and an N-terminal CARD do-
main. The differences in structure of the two NOD pro-
teins are that protein NOD1 has one CARD domain
and protein NOD2 has two. They are expressed mainly
in the cytosol by APCs and epithelial cells.17 NOD1
senses peptidoglycan (PGN)-derived peptide γ -D-
glutamyl-meso-diaminopimelic acid (iE-DAP) mainly
from gram-negative bacteria. NOD2 ligands recognize
the PGN-derived peptide muramyl dipeptide (MDP)
from both gram-positive and gram-negative bacteria.
Most recently, the regulatory role of NOD on TLR sig-
naling pathways was reported. Watanabe et al.18 found
that NOD2 deficiency may lead to markedly higher
IL-12 production and enhanced Th1 responses. How-
ever, NOD2 was also found to upregulate production
of IL-8, TNF, IL-1β , and IL-10 from APCs mediated by
TLRs.19,20
The most striking finding of the involvement of NOD in
human uveitis is that certain mutations of NOD2 have
been identified as the cause of the autosomal domi-
nant disease Blau syndrome, which is characterized
by uveitis, early-onset granulomatous arthritis, and
skin rash with camptodactyly (a medical condition in-
volving fixed flexion deformity of the interphalangeal
joints of the little finger).21 These mutant proteins from
patients with Blau syndrome have been shown to
induce an increased basal NF-κ B activity, when com-
pared with wild-type NOD2. Davey et al.22 revealed
that NOD2 is expressed by endothelial cells in the hu-
man uveal tract and it could be detected in primary
ocular endothelial cell cultures. These endothelial cells
expressed an elevated NOD2 when stimulated with in-
flammatory cytokines such as TNF-α or IFN-γ . They
secreted large amounts of IL-6 when stimulated with
MDP. Rosenzweig et al.23 showed that MDP could in-
duce an acute uveitis in mice but not in NOD2 knockout
mice, suggesting that innate immune responses to bac-
terial products mediated by NOD2 may participate in
the development of uveitis. Most recently, these inves-
tigators demonstrated that NOD1, similar to NOD2, is
also expressed in the eye and promotes ocular inflam-
mation in a dose- and time-dependent fashion.24
GENES INVOLVED IN THE ADAPTIVE
IMMUNE RESPONSE
HLA Complex
Antigen recognition is the foundation of all adaptive
immune responses. In humans, the capacity of adap-
tive immune response to an antigen is genetically deter-
mined by products of the HLA system. HLA molecules,
which are located on chromosome 6 and divided into
three classes (class I, II, and III), are highly polymor-
phic and function as molecules that are capable of
252
presenting antigens. After APCs degrade antigens into
peptides, they present these peptides on their surface
via HLA molecules. CD4+ T cells recognize the peptide-
HLA complexes by their T-cell receptors (TCRs), which
lead to their activation. Thus, appropriate adaptive im-
mune responses are initiated by CD4+ T cells. Costim-
ulatory signals, such as CD28, are necessary for T cell
activation.
The association between the HLA-B27 serotype and
anterior uveitis was one of the first identified asso-
ciations between HLA genes and human disease.25
Some presumptions based on studies in the past sev-
eral decades, such as molecular mimicry, have been
proposed to explain the precise mechanism of the
association between HLA-B27 and anterior uveitis.26
However, the evidence for these theories is still unsat-
isfactory and HLA-B27 seems to be just one of mul-
tiple factors involved in HLA-B27-associated anterior
uveitis, since only about 1% of HLA-B27-positive in-
dividuals develop anterior uveitis in their lifetime.27
Specific HLA alleles do not directly cause uveitis and
the real causes for the association between HLA genes
and human diseases remains unknown. Up to now,
HLA genes have been shown to be associated with
a number of uveitis entities, including Behcet dis-
ease, birdshot retinochoroidopathy, Vogt-Koyanagi-
Harada (VKH) syndrome, sarcoidosis, sympathetic
ophthalmia, juvenile idiopathic arthritis, tubulointer-
stitial nephritis and uveitis (TINU) syndrome, and pars
planitis (Table 1). These associations have been re-
viewed recently.28−30
Costimulatory Molecules
The specific peptide–HLA-TCR interaction is not suffi-
cient to fully activate the T cell, and costimulatory sig-
nals must be present on the same cell. The most potent
costimulatory signals are mediated by a CD28–B7 in-
teraction (Figure 1). These two molecules are expressed
on T cells and dendritic cells respectively. The CD28–
B7 interaction has been shown to prolong and augment
the production of IL-2 and to prevent the induction of
tolerance. Cytotoxic T-lymphocyte antigen 4 (CTLA-4),
an alternative ligand for B7 (Figure 1), mediates an in-
hibitory signal to T cells and results in a decreased IL-2
production.
In a recent study, we investigated the association of
CTLA-4 gene polymorphisms (-1661A/G; -318C/T;
+49G/A, and CT60) with Behcet disease and VKH
syndrome in Chinese patients and normal controls.
The results showed that the frequency of the G al-
lele at the +49 site and the frequency of haplotype -
1661A:-318C:+49G:CT60G were significantly higher in
patients with VKH syndrome than that observed in

Table 1. Association of HLA and uveitis entities
Diseases HLA association
Birdshot retinochoroidopathy A29
AAU B27
Behcet disease B51
VKH syndrome DR1/DR4/DRw53
Pars planitis (multiple sclerosis) DR15
Sympathetic ophthalmia DRB1*04
TINU syndrome DRB1*0102
healthy controls.43 This association of these autoim-
mune diseases with the haplotype may result from
the deceased expression of sCTLA-4 in the suscepti-
ble haplotype +49G:CT60G.44 However, we failed to
find any association of CTLA-4 gene polymorphisms
with Behcet disease, which is in agreement with earlier
reports published on this subject.45 These discrepant
associations between CTLA-4 haplotypes with differ-
ent uveitis entities may partially be explained by the
different mechanisms involved in the pathogenesis of
these diseases.
SEVERAL IMMUNE RESPONSE GENES
CONTRIBUTING TO THE
SUSCEPTIBILITY TO UVEITIS
Tumor Necrosis Factor (TNF)
In addition to HLA genes, a variety of immune
response genes have been shown to be located in HLA
gene region. TNF is a multifunctional proinflamma-
tory cytokine located in the HLA gene region. TNF-α
is believed to play a pivotal role in Th1-mediated
diseases, such as Behcet disease. Polymorphisms in
the TNF gene have been studied extensively, though it
is difficult to determine whether the gene’s association
with uveitis is independent of a linkage disequilibrium
with certain HLA genes. Although earlier studies did
not support that some polymorphisms in the TNF
promoter region played a role in the susceptibility to
Behcet disease,46−48 Ahmad et al.49 reported that the
TNF-1031C allele is independently associated with
susceptibility to Behcet disease in Caucasian patients.
The association of the the TNF-1031C allele and Behcet
disease has now been confirmed by studies in patients
from Turkey, Tunisia, and Korea.50−53 Seki et al.54
showed that polymorphisms in the promoter region
of the TNF gene were associated with an increased
susceptibility to human T-cell lymphotropic virus type
I uveitis in the absence of HLA-B61 or DRB1*0901
Immune Response Genes in Uveitis
Relative risk References
50–220 31
26 32, 33
5–10 34–36
4.2–17.4 37, 38
2.86–7.20 39, 40
3.7 41
167 42
allele. A number of studies have also suggested that
promoter polymorphisms in the TNF gene contributed
to the susceptibility to ankylosing spondylitis and
idiopathic AAU.55−57 However, the pathogenesis of
TNF polymorphisms contributing to susceptibility to
these uveitis entities need further studies.
MHC Class I Polypeptide-related Sequence
A (MICA)
The expression of MICA is likely to be stress induced,
and it may provide an important role in the stimula-
tion of γ δ T cells through a stress-induced mechanism.
The association of MICA polymorphisms with uveitis,
especially with Behcet disease, has been studied ex-
tensively. The difficulty in evaluating this association
is due to the linkage disequilibrium with certain HLA
genes. Mizuki et al.58 reported that the (GCT/AGC)(6)
allele of a microsatellite polymorphism in the MICA
gene was presented in all HLA-B51-positive patients
and in an additional 13 HLA-B51-negative patients,
suggesting the possibility of a primary association of
Behcet disease with MICA rather than HLA-B. This
association of MICA polymorphisms with uveitis was
implied in subsequent studies.59,60 Wallace et al.61 in-
vestigated the association of the 16 described exter-
nal domain alleles and the triplet repeat microsatellite
polymorphism of MIC-A with BD in a Middle Eastern
population. They found that the MIC 009 allele was
more prevalent among patients compared with con-
trols. However, their data also indicated that both MIC-
A*009 and the triplet repeats polymorphism of MICA
were in strong linkage disequilibrium with HLA-B51;
they are unlikely to be the susceptibility gene for BD
but may be markers for additional risk factors. Subse-
quently, a study performed on three populations also
indicated that the pathogenic gene of BD is HLA-B51
itself and not other genes located in the vicinity of the
HLA-B region.36
253
 L. Du et al.
Interleukin (IL)-1
IL-1, a potent pro-inflammatory cytokine, has a criti-
cal role in autoimmune disease, such as Behcet disease.
The polymorphisms of the IL-1 gene cluster have also
been studied in certain uveitis entities. Karasneh et al.62
investigated the association of IL-1 gene cluster poly-
morphisms with Behcet disease and found that IL-1A
−889C and IL-1B +5887T haplotype contributed to the
susceptibility to Behcet disease. The association of IL-1
polymorphisms with Behcet disease has now been con-
firmed by another group.63 Studies have recently also
shown an association of an IL-1 polymorphism with the
chronicity and complications of anterior uveitis and the
recurrence of toxoplasmic retinochoroiditis.64,65
CHEMOKINES
Chemokines are chemotactic cytokines playing a criti-
cal role in cell migration during immune surveillance
and inflammation. More than 50 human chemokines
have been described and are now separated into
four families (CXCL, CCL, XCL, and CX3CL). Sev-
eral studies have demonstrated that neutrophils and
chemokines are involved in uveitis through directing
the migration and infiltration of leukocytes to the uveal
site. Studies on the polymorphisms of chemokine genes
may shed further light on susceptibility to uveitis.
Chen et al.66 reported a gender-specific association of
CCL2 and CCL5 polymorphisms with Behcet disease.
Wegscheider et al.67 demonstrated that the frequency
of CCL-2518G was significantly higher in patients with
HLA-B27 AAU than in HLA-B27 positive controls.
MCP-1 polymorphisms were also shown to be asso-
ciated with idiopathic anterior uveitis and posterior
uveitis.68,69 Lee et al.70 reported that genetic polymor-
phisms of IL-18 may contribute to the pathogenesis of
Behcet disease.
Others
Mannose-binding lectin (MBL), a member of the col-
lectin family, binds specifically to terminal mannose
residues, which are abundant on the surface of many
microorganisms. Inanc et al.71 found that patients with
Behcet disease showed lower MBL2 levels, suggesting
that MBL deficiency might contribute to the pathogene-
sis of Behcet disease. Studies also showed that possess-
ing the MBL2 haplotype HYPA increases the risk of Be-
hcet disease.72 We recently investigated the association
of small ubiquitin-like modifier 4 (SUMO4) polymor-
phisms with Behcet disease in a Chinese population
and showed a significantly increased frequency of the
+438 C allele and a significantly decreased frequency of
the AGAT haplotype in patients with Behcet disease.34
254
We also evaluated the association of Fc receptor-like
3(FCRL3) polymorphisms with Behcet disease. The re-
sults showed a significantly higher frequency of the G
allele at the -110 site in Behcet disease compared with
that observed in controls.73
CONCLUSION
Uveitis is not one condition, but a variety of types
and etiologies. It is a complicated pathologic process
in which various different cells are involved. The
development and prognosis of uveitis is regulated
by a series of genes of which only a few have now
been recognized. The significant variations in etiology,
pathogenesis, and clinical manifestations of uveitis
may result from the different genetic backgrounds,
or different immune responses involved in patients.
With the development of research techniques to study
the immune response and our increased knowledge
in immune response genes, we will be able to gain
a better understanding of human uveitis and will
hopefully develop novel treatment regimes.
ACKNOWLEDGMENTS
This study is supported by the Fund for Key Project of
Natural Science Foundation (30630064), National sup-
porting project of P. R. China (2007BAI18B10), Clini-
cal Key Project of Ministry of Health of P. R. China,
Chongqing Key Laboratory of Ophthalmology (CSTC,
2008CA5003), Key project of Health Bureau (2008-1-15)
and Key project of Science and Technology committee
of Chongqing (CSTC, 2009BA5037).
Declaration of interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of the paper.
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