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Ocular diseases:
immunological and molecular mechanisms
Jing Song1,
Yi-Fei Huang1,2, Wen-Jing
Zhang1 Xiao-Fei Chen2, Yu-Mian Guo1
1Department
of Ophthalmology, Affiliated Hospital of Logistics University of
People’s Armed Police Force, Tianjin 300161,
China
2Department
of Ophthalmology, General Hospital of PLA, Beijing 100853, China
Correspondence to: Yi-Fei
Huang. Department of Ophthalmology,
Clinical Division of Surgery, General Hospital of
PLA, Beijing 100853,
China. huangyf301yk@hotmail.com
Received: 2015-04-19
Accepted: 2015-09-07
Abstract
Many
factors, such as environmental, microbial and endogenous stress, antigen
localization, can trigger the immunological events that affect
the ending of the diverse spectrum of ocular disorders. Significant advances in
understanding of immunological and molecular mechanisms have been researched to
improve the diagnosis and therapy for patients with ocular inflammatory
diseases. Some kinds of ocular diseases are inadequately responsive to current
medications; therefore, immunotherapy may be a potential choice as an
alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the
immunological and molecular mechanisms concerning several typical and common ocular diseases;
second, the functions of
immunological roles in some of systemic autoimmunity will be discussed; third,
we will provide a summary of the mechanisms that dictate immune cell
trafficking to ocular local microenvironment in response to inflammation.
KEYWORDS: immunological
mechanism; ocular diseases;
systemic autoimmunity; immune response; chemokines
DOI:10.18240/ijo.2016.05.25
Citation: Song
J, Huang YF, Zhang WJ, Chen XF, Guo YM. Ocular diseases:
immunological and molecular mechanisms. Int J Ophthalmol 2016;9(5):780-788
INTRODUCTION
Immunological and molecular mechanisms of ocular
tissues prevent or resolve inflammation and maintain homeostasis. Indeed, the
immune system protect host by response efficiently to environmental and pathogenic
insults, maintaining tolerance to self-antigens and commensal microbial flora.
Activation is exactly regulated,
and immunological reaction requires the coordinated effort both the innate and
adaptive immune responses. The innate immune system is the first-line of
defense to control initial infection and coordinate the adaptive immune
response, which culminates in inducement of antigen-specific T and B cells,
decreases microbial destroy and generation of immunological molecular to
defense foreign invaders. Sometimes, aberrant activation of the immune system
could result in autoimmunity, which in turn destroy the ocular and associated
tissues. In fact, ocular diseases consist of a diverse stage of pathologies and
specific mechanisms. After ocular tissue destroyed by pathogenic factors, it
will incite and express
immunological response through its own anatomical and physiological features.
It has improved local or
systemic immunomodulation with anti-inflammatory agents have successfully
improved these conditions or bringing these conditions under control. Thus, it
is important for a more rational clinical approach to treat ocular diseases if
we can understand the immunological and molecular mechanisms by which the
ocular diseases participate in immune-inflammatory disorders.
The aim is to first
provide an overview of the immunological and molecular mechanisms of several
typical and common ocular diseases. Second, the functions of immunological
roles in some of systemic autoimmunity diseases will be discussed. Third, we
will provide a summary of the mechanisms that dictate immune cell trafficking
to ocular local microenvironment in response to inflammation.
CORNEA AND OCULAR SURFACE DISEASE
The cornea and ocular surface contacted with the
external world constantly and directly, are required a optimum and native immune protection system to defense damage in vivo or in vitro. The ocular surface consists of three distinct anatomical regions: the
cornea, limbus, and the conjunctiva, which function both in concert and
independently fight against microbial, immunogenic and traumatic attack.
For many years, the belief that essential absence of corneal antigen
presented cells (APCs) was assumed to be a critical role of corneal immune
privilege. However, this paradigm has now shifted with the demonstration of a
diverse population of resident APCs for recent research[1]. Dendritic cells (DCs) were recently found to
reside both in the peripheral cornea and in the central cornea[2]. While a large number of DCs are express major
histocompatibility complex (MHC) class II in the periphery, a large population
of MHC class II-negative immature/precursor
DCs are present both in the central epithelium and stroma. Immature DCs do
neither express MHC-II nor costimulatory molecules unless they are incited by
cytokines. It is improved that a large number of DCs in the cornea remain with
an undifferentiated state. That is to say, immune cells settled in the cornea
present constitutively as a participant in immune and inflammatory responses,
rather than a collagenous tissue that simply responds to the activity of
infiltrating cells.
Microbiotic Keratitis
Herpes simplex virus type-1 Ocular herpes simplex virus type-1 (HSV-1) infections, contributing to blindness in large measure secondary to
recurrent infection, include both epithelial keratitis and immune stromal
keratitis. Herpes stromal keratitis is a recurrent disease initiated after
mucosal infection with HSV-1 through attachment to cognate receptors of
epithelial cornea by its surface glycoproteins, in order to destroy the
integrity of the corneal epithelium[3-4]. The virion envelope, attach to and melt the host
cell plasma membrane. Upon HSV-1 infection and spread, apoptosis induction was
observed. HSV-1 can hide from host defenses and lead to recurrent infections and potentially
irreversible damage to the corneal tissue[5]. The
virion can be spread cell-to-cell by cell lysis and shed viral progeny. HSV
also can replicate in the corneal epithelial cells which layers are triggered.
After the host was infected, whether vial latency or resolution, it simply
depend on the initial viral quantity[6].
Data from researches show that the resulting
clinical disease is not associated with this viral replication in the cornea,
but rather is due to the host immune response to be restimulated by the latency
of the virus. Secreted factors from infected and uninfected epithelial cells
recruit a variety of leukocytes into the adjacent stromal tissue [e.g. neutrophils, polymorphonuclear
leukocytes (PMN), macrophages, NK cells, dendritic cells, and γδ T cells][7]. Cytokines IL-2 can be induced by various resident
corneal cells, and APCs can incur destructive effects by HSK on the stroma.
IL-2 knockout mice can be ameliorated by treat with recombinant IL-2. Facing a
conceivably blinding inflammatory attack, the cornea present many
immunosuppressive factors to reduce inflammation and neovascularization, such
as TGF-β, IL-1 receptor antagonists. However, the roles of Th1 T cell and IFN-γ
in the immunology response have two paradoxical sides[8-9]. It has been improved that IL-1 has an intimate relathionship with
corneal melting through induction of Langerhans cells (LCs) migration into the
cornea, which result the tissue into further destruction.
Corneal epithelium and stroma whichmaintain corneal
immune privilege through constitutively express IL-1 receptor antagonist (IL-1
RA) to neutralize IL-1[10]. Polymorphonuclear cells secrete Vascular
endothelial growth factor (VEGF) due to corneal neovascularization[11]. LCs, settling near the limbus, can be induced
into the site of inflammation quickely following HSV-1 infection [12]. The quantity of LCs in the cornea is pertinent with the extent of
stromal damage in HSK.
In the mouse models of HSK, CD4+ Th1
cells have been suggested to be key mediators in the immunopathogenesis of
HSV-1 infection[13]. As far as other local tissue factors are
concerned, a perfect balance between cytokines IL-12 and IFN-α, IL-4 and
IL-10, which mature Th0 cells into Th1 or Th2 respectively, orchestrates the
kind of T-helper response generated. An increasing expression of cytokines IL-2
and IFN-α in HSK further confirm the role of CD4+ Th1 immune
response in HSK pathogenesis[14].
Verjans et al[15] have a hypothesis that diverse clinical spectrum
of disease with recurrent HSK may either basis on a heterogeneous immune
response to the HSV epitopes, or, heterogeneity in the expression of corneal
autoantigens in the host[16].
Pseudomonas keratitis Pseudomonas keratitis is a painful and potentially blinding corneal
infection caused by the Gram-negative bacterium Pseudomonas aeruginosa (P.aeruginosa). Severe sight-threatening ulceration and necrosis destroy of the cornea
are predominant in Pseudomonal infections; which is a common contaminant of
contact lens wash solutions due to its innate and acquired resistance to
biocides. P.aeruginosa can adhere to the surface of the contact lens and
colonize; then adaptive and innate immune response are actively involved in
bacterial clearance of PA-induced keratitis. Pathological process of
Pseudomonal infections includes epithelial edema, mucopurulent exudate,
coagulative necrosis, suppurative stromal infiltrate, in addition to a hypopyon[17]. A Th1-dominant response is severe corneal disease
and perforation, whereas Th2-dominant response refers resistance to infection
and a milder process of disease without corneal perforation. Polymorphonuclear
neutrophils cells into the site of inflammation are the predominant
infiltrating cells through upregulating the expression intercellular adhesion
molecule-1 (ICAM-1). PMN and macrophages are recruited to engulf bacteria,
release lysosomal enzymes and oxidative compounds to kill P.aeruginosa.
Macrophage also produce
various pro-inflammatory cytokines enhanced the antibacterial immune response,
such as interleukin 6 (IL-6), IL-1β, tumor necrosis factor α (TNF-α) and
macrophage inflammatory protein 2 (MIP-2). IL-6 can express within 24h of P.aeruginosa invasion, and take part in
recruitment of PMN cells into the site of inflammation.
Sun et al[18] have reported that P.aeruginosa activates
expression of toll like receptors (TLR)-4/5 on resident corneal macrophages, inducing
transcription of chemokines and cytokines such as KC/CXCL1, as well as IL-1α
and IL-1β. In corneal ulcers, there is elevated expression of TLR2, TLR4, TLR5
and TLR9, the NLRP3 and NLRC4 inflammasomes[19]. These inflammatory mediators can promote bacterial clearance, however,
out of control, it may result in
excessively immunology response which can make a destroy. Therefore, a fast and
efficient role of immune response is critical in shortening the spread and
reducing severity of pseudomonas keratitis.
Fungal keratitis Fungal keratitis secondary to Aspergillus and
Candida species is an infection of the cornea by fungal pathogens. Since
its diagnosis is difficult, the availability of antifungal agents is limited
and its clinical outcome is poor, fungal keratitis is still a great challenge
in ophthalmologic clinic. Although received an accurate diagnosis and efficient
treatment, 20% of fungal keratitis patients may suffer from corneal perforation[20] , which may be attributed to secondary corneal
damage induced by excessive inflammatory responses. Fungal infection can be
induced by using two strains of fungi: aspergillus
fumigatus and candida albicans.
Once fungi attack the corneal stroma,
innate immune cells recognize pathogens with pattern-recognition
receptors (PRRs), especially C-type lectin receptors (CLRs). It is recently
reported that Dectin-1 is clearly expressed in the cornea and functions to
detect invading fungi. The clinical prognosis mainly depend on not only
pathogenic virulence but also host immune response. PRRs-mediated inflammatory
response enhances clearance of fungi and promote tissue repair. Aspergillus and
Candida are also be detected by
human corneal TLRs 2 and 4 for hosting an immune response. TLRs 2 and 4
recognize fungal zymosan and mannan, induce production of IL-6 and IL-1β when
fronted with Aspergillus, which is diminished by knocking down these
innate receptors [21]. In a recent study showed that suppressing TLR2
expression in the cornea results in a decrease in neutrophil infiltration,
allowing the cornea to preserve its morphological integrity. Suppressing TLR2
expression also caused a decrease in TNF-α, IL-1β, IL-6, IL-12, monocyte
chemoattractant protein (MCP-1)/CCL2 and MIP-2/CXCL2 expression[22]. It
seems if out of control, prolonged over-reactive host immune response may
amplify the inflammation, and lead to tissue injury, even corneal perforation.
Therefore, precise regulatory mechanisms are required to modulate the
inflammatory response in fungal keratitis.
Acanthamoeba keratitis
Amphizoic
amoebae became a threat due to their pathogenic potential as facultative
parasites, causative agents of vision-threatening Acanthamoeba keratitis (AK). Recently, AK incidences have been
reported worldwide, particularly in contact lens wearers with a predominance of
soft contact lens use[23]. Acanthamoeba
spp. is free-living organisms existing as vegetative mononuclear
trophozoites with characteristic acanthopodia and as double-walled dormant
cysts. They can intrude into human bodies from different
sources, colonize some organs, multiply, and exist as opportunistic parasites
causing pathogenic effects. The appropriate diagnosis needs laboratory identification of the specific
pathogen for confirmation. AK is a sight-threatening corneal disease that
manifests as severe eye pain, photophobia, blurred vision, and neuritis. Acanthamoeba genotypes related to
keratitis are mainly T3 and T4. In the research on the host immune mechanism of
AK, it is found that patients with severity of infection and incidence of
disease have lower tear levels of IgA compared with healthy controls, which
implicate the role of mucosa-mediated immunity in AK[24]. The innate immune response begins with migration of neutrophils and
macrophages, which are believed to play important role in resolution of AK.
Macrophages have a chemotactic ability to the pathogen, and an inherent
response to kill the trophozoites in vivo. Neutrophils, like
macrophages, also as the first-line defense against both Acanthamoeba cysts
and trophozoites. Meanwhile, secretion of IgA antibody has been improved as
adaptive immune system to defense AK through promoting neutrophil-mediated
killing of trophozoites and preventing adhesion of the trophozoites to the
corneal epithelium. Furthermore, it keeps from the corneal meltdown plant of
trophozoites by inhibiting mannose-induced cytopathic protein (MIP-133)-induced
digestion of the corneal epithelium and stroma. Most of the published
literature suggests that earlier detection of visualization of cysts in the
cornea based on in vivo confocal microscopy (IVCM) may be beneficial in
treatment of AK[25]. It is also suggested combination
anti-inflammatory therapy seems to be effective for treatment of AK.
Corneal
Transplantation serves as a simple
surgical disease to study mechanisms regulating immunity and angiogenesis.
Cornea is an avascular tissue and neovascularization of the corneal graft will
increase the chance of rejection. According to Collaborative Corneal
Transplantation Studies, the recipient cornea is considered “high-risk” once
neovascularization in stroma exists in two or more quadrants before operation.
Another factor, which leads to graft rejection, include growth of lymphatic
vessels into the cornea [26]. Aberrant growth of these vessels in the cornea
breaks its immune privilege. The relationship between angiogenesis and immune
system in the cornea is related because resident immune cells play a crucial
role in initiating and promoting angiogenesis. Inflamed and neovascularized
host beds carry a higher risk of graft rejection. Angiogenesis can induce
migration of LCs into the cornea; maturation of resident LCs and DCs of the
cornea, which can then serve as APCs[27]. Cytokines IL-1 and TNF- α have a high expression
by APCs, which lead to recruitment of neutrophils, suppression of anterior
chamber-associated immune deviation (ACAID), maturation of corneal APCs,
upregulation of vascular adhesion molecules, and recruitment of leukocytes[28]. An increasing expression of IL-6,
MCP-1 and IP-10 were found in aqueous humor during rejection of corneal
transplantation.
Many laboratories research has demonstrated the
presence of specific chemokines during the progression of allograft rejection.
In the cornea, there is a high expression of specific species, including
CCL2/MCP-1, CCL3/MIP-1α, CCL4/ MIP-1β, CXCL10/IP-10, and CCL5/RANTES after
corneal transplantation. These chemokines associate with particular receptors:
CCR1 with CCL3/MIP-1α and CCL5/RANTES; CCR5 with CCL3/MIP-1α, CCL4/MIP-1β, and
CCL5/RANTES; CCR2 with CCL2/MCP-1; and CXCR3 with CXCL10/IP-10[29]. However, there have been no studies to be showed
which the relationship between chemokine or chemokine receptor deficiency and
corneal transplant rejection has been examined. In addition, recipients of
high-risk transplants express very high levels of the IP-10/CXCL10 chemokine.
Chemokines function together with other molecular mediators including integrins
and adhesion molecules to direct the immune response toward the graft.
Dry Eye Disease Dry eye disease (DED) is a chronic condition that is characterized
by tear-film instability, tear
hyperosmolarity, ocular surface inflammation, and damage
resulting from reduced tear quality and/or quantity. It has a feature as increased
osmolarity of the tear film and inflammation of the ocular surface. The
composition of the tears can reflect the state of inflammation, and proteins
such as inflammatory mediators are thought to modulate DED and relate with
disease severity. ocular surface
inflammation was associated with excessive tear evaporation, which leads to
tear film instability. Recent report has shown an important role for chemokines in the
pathogenesis of dry eye syndromes (e.g.
IL-1, IL-6, IL-8, TNF-α). Corneal epithelial cells respond to stress signals by
producing cytokine mediators of inflammation such as TNF- α, IL-1β, IL- 8 and
MMPs[30-31]. The increase of these cytokines can lead to
proliferation of epithelial cell, keratinization, and angiogenesis, even more
could link ocular surface disease with a number of lid margin disorders, such
as rosacea. More recently, Th-17 associated cytokines and IL-17 have been found
in the ocular surface epithelium of DED. It has been hypothesized that
epithelial cells subjected to desiccation conditions promote DCs to secrete
IL-6, IL-23 and TGF-β, which in turn induce Th-17 cells[32]. The better understanding for the role of
chemokines and its receptors in DED could provide new methods for development
of molecular treatment for immune modulation in this ocular surface disorder.
Allergic Conjunctives Allergic
conjunctives (AC) are inflammation of the conjunctiva
secondary to an immune response to external antigens, usually called allergens.
Allergic disorders are primarily characterized as IgE- and/or T-lymphocyte-mediated
disorders that affect the cornea, conjunctiva, eyelids, and tear film.
Therefore, AC seems to be a syndrome affecting the entire ocular surface rather
than a single disease. It consists of diverse spectrum of ocular diseases, e.g. seasonal allergic conjunctives
(SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis
(VKC) and atopic keratoconjunctivitis (AKC) which are its chronic forms. In
recently research, giant papillary conjunctivitis (GPC), and contact or
drug-induced dermatoconjunctivitis (CDC) are seemed to be subtypes of AC,
because of their mechanism of allergy[33]. This pathological process of
allergic reaction consists of IgE-mediated and non-IgE mediated, atopy could
affect clinical evolution[34].
Many factors can affected signs and symptoms of AC, such as genetics, environment, and immune
regulation mechanisms, all of which work together in a complex immunological
response. This unbalance of immune homeostasis can result into a variety of
allergic ocular diseases (AOD).
The conjunctiva has an abundance of Langerhans’
cells that initiate allergen-induced immune response when these
antigen-presenting cells encounter an allergen on the conjunctiva[35]. The immune cells, such as lymphocytes, distributed
over the conjunctiva form a mucosal immune system known as the
conjunctiva-associated lymphoid tissue. IgE could be detected in
human tears of AC patients[36].
CD23+ CD21+ CD40+, subtype of B cells, located
in the conjunctival lymphoid, it infer that they might be precursors of
IgE-producing B cells and contribute to local IgE synthesis[37]. Activated mast cells can release several cytokines
(TNF-α, IL-4, IL-6, and IL-13) contributing to increase local inflammatory Th2
response[38-39], it also
can increase FcεRI density in chronic keratoconjunctivits[40-41].
Recent research
suggested that macrophages could be the aim for study in AC, since it seemed to
be act as APCs and affcet ocular
allergy[42-44];
nevertheless, further research will be paid more attention on the real role of
macrophages in AC.
Thymic stromal
lymphopoietin (TSLP), an epithelium-derived cytokine, is regarded as a novel
pro-allergic molecule and can strongly activate dendritic cells through
interaction with the TSLP receptor (TSLPR) to induce an inflammatory Th2-type
response that is essential for initiating allergic inflammation [45].
UVEITIS
Uveitis is defined as an
inflammation of the uveal tract or middle coat of the eye (iris, ciliary body,
and choroid). The
inflammatory pathways of autoimmune posterior uveitis are complex and have been
reviewed in detail in previous publications[46-48]. After immunization, Th1 and Th17 cells are activated by APCs in the
periphery, migrate to the ocular site, and overcome the local immune privilege.
The expression of pro-inflammatory cytokines and chemokines by immune cells and
resident cells attracts monocytes, macrophages, neutrophils, natural killer
(NK) cells, natural killer T cells, and γδ-T cells and supports the development
of a local nonspecific immune response, which results in tissue damage. The uveitogenic effector responses involve
different cytokine expression patterns (Th-1: IL-1, IL-15, IL-2, IL-6, IFN-γ,
TNF-α; Th-17: IL-17A, IL-17F, IL-21, IL-22, IL-6). Whereas IL-2 and IL-15 are
important factors for the activation and survival of T cells and NK cells,
IFN-γ and TNF-α represent important activators of cells in the innate immune system.
IL-1 and IL-6 are essential for the induction of Th-17 cells[49]. Sauer et al[50] presented an overview of the levels of the various
intraocular ILs that can be found in different forms of uveitis in humans,
revealing elevated levels of IL-1β, IL-2, IL-6, IFN-γ and TNF-α in most cases
of uveitis.
Although B cells and autoantibodies currently
appear to play only a minor role in autoimmune uveitis (EAU) inducement, levels
of Th2 cytokines (e.g. IL-4, IL-5,
and IL-10), which are necessary for the activation, proliferation, and
differentiation of B cells to antibody-producing plasma cells, are elevated[51-52]. In juvenile idiopathic arthritis (JIA), the
presence of anti-nuclear antibodies represents an important risk factor for the
development of uveitis. However, the role of B cells in the pathogenesis of
uveitis in humans is far not known.
In experimental animal models, increased levels of
IL-1β can break down the blood-retinal barrier and attract polymorphonuclear
cells and monocytes[53-56]. Furthermore, the importance of IL-1 has been
shown for the Th17 cell generation and for the development of autoimmune
responses[57]. IL-1R-deficient mice demonstrated less
inflammation in an immune complex-induced uveitis model than compare with the
control one[58]. In murine model, suppression of uveitis was achieved with IL-1R
antagonists[59-62]. Increased levels of IL-1β have also been found in
the serum or aqueous humor from patients with chronic uveitis[63-64]. IL-2, which is expressed by activated Th1
effector cells, is one of the cytokines predominantly secreted in uveitis[65-66]. Increased intraocular levels of IL-6 have been
observed in idiopathic uveitis and in uveitis associated with Behçet’s disease, sarcoidosis, Vogt-Koyanagi-Harada,
ankylosing spondylitis, and Fuchs cyclitis[67]. IL-6 is a key player in generating Th-17 cells, while it inhibits the
generation of regulatory T cells[68-69]. Thereby, IL-6 enhances acute inflammation and,
furthermore, triggers the progression to chronic inflammation. Th-17 cells,
which are specialized cells of the adaptive immune system in initiating an
inflammatory response, have also been found to be involved in the pathogenesis
of uveitis in humans[70] and in a mouse model of EAU[71]. The use of an anti-IL-17 antibody significantly reduced ocular
inflammation in the murine model of EAU[71].
UVEAL MELANOMA
Uveal melanoma is the most common cancer of the eye
and it metastasizes in up to 50% of patients with large tumors. Strategies have
been developed to control metastatic disease; however, success is limited and
metastatic uveal melanoma remains universally fatal. Immunotherapy is being
explored to be a potential option to prevent metastatic disease. Since uveal
melanomas develop in the immune-privileged environment of the eye, these tumors
may express novel and immunogenic tumor antigens to which the patient’s endogenous
T cells are not tolerated.
The immune system interacts with tumor cells via the innate and adaptive arms of the
immune response. Similar to cutaneous melanomas, tumor-infiltrating lymphocytes
(TIL) have been found in uveal melanomas[72-78]. CD8+ T cells from the peripheral blood of uveal melanoma
patients, or TIL isolated from primary uveal melanomas are capable of lysing
human uveal melanoma cells in vitro[79-80].
The loss or downregulation of HLA-I is an important
immune escape mechanism that is exploited by tumor cells to avoid T cell
recognition and promote tumor progression. In contrast to the majority of
tumors, in uveal melanoma HLA-I expression is upregulated during progression to
metastatic disease and correlates with a poor prognosis[81-82].
A number of directly immunosuppressive properties
of uveal melanomas have been identified and include local secretion of TGF-β[83], and IFN-γ-mediated induction of the enzyme
indoleamine 2, 3 dioxygenase
that depletes the local environment of tryptophan necessary for T cell clonal
expansion, proliferation and survival[84]. IFN-γ-induced expression of programmed death ligand-1 by primary uveal
melanomas and its metastases inhibits T cell activation via binding to program death-1 on the T cell[85]. Uveal melanoma cells are resistant to Fas
ligand-induced apoptosis by CTL, despite their expression of both Fas and Fas
ligand[86]. Furthermore, IFN-γ-stimulated uveal melanoma
cells become resistant to perforin-mediated cytolysis by
MHC-class-I-restricted, cytolytic CD8+ T cells[87]. Of note, although IFN-γ is an important cytokine
that supports T cell activation, it seems to have two faces in immunomodulation
of uveal melanoma.
Uveal melanoma cells can indirectly inhibit
antitumor immune responses via
induction of immunosuppressive lymphoid and myeloid cell populations in the
tumor microenvironment. Tumor-infiltrating T regulatory cells, which are
predominantly CD4+ FOXP3+ T lymphocytes that produce
TGF-β, have been observed in primary uveal melanoma tissue[88-89].
The clinical and genetic differences between
cutaneous and uveal melanomas can be found, therefore, somatic mutations in the
heterotrimeric G-protein α-subunit GNAQ, and its related gene GNA11, were
recently reported to be frequently found in uveal and absent in cutaneous
melanoma[90-91].
Zhou et al[92] reported that uveal melanoma cells as agents for
CD8+ T cells inhibited the activation of CD8+ T cells,
and attributed the inhibition to the lack of costimulation and HLA-II
expression. Two other studies reported the activation of CD8+ T
cells; however, most of these responses were not restricted to HLA-I, and it
was unclear if the activated CD8+ T cells were responding to uveal
melanoma tumor antigens or to alloantigens[93].
AGE-RELATED MACULAR DEGENERATION
Age-related macular
degeneration (AMD), a degenerative disease of the outer retina, take a
considerable challenge for doctors because its etiology has not yet been
clearly stated and treatment options are limited. Many scientific
literatures on AMD has pay more attention to markers of inflammatory cytokines
as well as the complement system, such as macrophages, inflammatory cytokins of
the innate immune system. The research of up-regulation, overexpression, and ectopic
expression of inflammatory cytokines, complement, macrophages and microglia that are closely
related to the innate immune system[94]. Increased levels of IL-17-both protein and mRNA-within AMD maculae and that the
ultrastructure of some IL-17 stimulated ARPE-19 cells clearly displays autophagy
and mitochondrial damage[95].
AMD represent an
age-related susceptibility to aberrant innate immune activation based on
acquisition of foreign-like structural motifs. In this way, AMD may be viewed
as a disease of the innate immune system[96]. Meanwhile, during the last few years, numerous trials have been started to verify the
therapeutic effects of various drugs aimed to directly downgrade the
retinochoroidal immune response in AMD patients[97]. In the next future, the outcomes of these clinical studies will be able
to provide a more exact explanation of the role of the agents directed against
the immune response in therapeutic recommendations for AMD patients.
IMMUNOLOGICAL MECHANISM
Inducement of immune response finely controls the
movement of distinct subsets of immune cells into and out of specific tissues.
Leukocyte, such as APCs and T cell, recruitment from blood to tissue, usually
exists in the multistep process. Because the accumulation of leukocytes in
tissues contributes to a wide variety of diseases, these “molecular codes” provide new targets for inhibiting tissue-specific
inflammation. However, immune cell migration is also a critical stage for
protective immune responses to tissues. Therefore, the reaction basis on
identifying trafficking molecules that will specifically inhibit key cell
subsets that drive disease processes without affecting the migration of
leukocytes required for protective immunity.
Chemokine receptors regulate leukocyte retention in
tissues. The migration of leukocytes to inflammatory sites depends on a cascade
of discrete events mediated by chemokines and their receptors. Evidence of
these immunological changes include altered levels of cytokines and chemokines,
changes in the numbers and activation states of various leukocyte populations.
Little is known about the constantly recruitment of DCs and macrophage
precursors into peripheral tissues in the absence of inflammation. The
behaviors of APCs are related to switching
in chemokine receptor expression by these cells. During
inflammation, CCL2, CCL5, and CXCL8 are produced to attract immature DCs that
express CXCR4 and CCR4 respectively. In addition, these DCs are suited for
migration into inflammatory sites by their expression of functional receptors.
Inflammatory signals induce resident DCs to undergo
maturation. Upon maturation, DCs downregulate pattern recognition receptors
necessary for surveillance of antigens and upregulate CCR7, a receptor
important in the homing of DCs to the lymph nodes. Maturing CCR7+
DCs then enter CCL21-expressing lymphatic vessels and travel to the draining
lymph nodes where CCR7 ligands are produced. DCs migration into and along
afferent lymphatics occurs including: 1) mobilization; 2) detachment; 3) interstitial migration; 4) entry into the afferent lymphatics; 5) transit via
lymph. Recent data have shown that lymphatic endothelial cells upregulate
E-selectin, chemokines (CCL5, CCL20, and CXCL5), and adhesion molecules (ICAM-1
and VCAM-1) after cytokine stimulation in vitro or in vivo. Once
in the draining lymph nodes, antigen-loaded mature DCs activate naive T cells,
which then proliferate and enter the blood and migrate back to the site of
inflammation.
The importance of this
observation relates to a general principle that sequences of peptides of some
ocular tissues may be important for the preservation of self-tolerance and
autoimmunity. Future studies should be focused on understanding the mechanism
of tolerance induction and how to use this information to create new
immunologically based pharmaceuticals to treat ocular injuries. Structural
analysis of receptors required for microbial pathogenesis, immunity, and
cell-cell contact are all likely to lead to new therapies.
CONCLUSION
The ocular tissues have developed many
immunological mechanisms to protect themselves against the potential harm from
these noxious agents (environmental pollutants and irritants, microbes, and
other potential agents), and regulate their response avoiding unwanted damage.
A clearer picture of immunological mechanism about ocular disease is being
painted from recent discoveries to explain the diverse features and severity of
clinical diseases. The role of immuno-inflammatory responses in ocular tissues
has continuously been and has been becoming the focus for therapeutic
approaches, therefore, identification of the critical pathways of immunological
will provide new molecular targets for pharmacological intervention in
inflammatory, infectious, alloimmune and autoimmune diseases and may lead to
novel highly specific strategies for immunotherapy.
Data from immunotherapy
of ocular diseases have shown some drugs to be beneficial and have a
satisfactory safety profile. However, a large number of problems should be considered in future and
urgent need to solve, as many ocular diseases are inadequately responsive to current
medications. For example, how the levels of immunological molecules are
regulated and whether they can be pharmacologically manipulated and offer novel
therapeutic approaches. Unique features of the accessible surfaces of the
ocular tissues offer opportunities for development of small molecules that
disrupt immunological or inflammatory processes. Therefore, it is crucial to
understand the immunological mechanism for handle with diverse ocular diseases.
ACKNOWLEDGEMENTS
Conflicts of Interest: Song J, None;
Huang YF, None;
Zhang WJ, None; Chen XF, None;
Guo YM, None
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