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Host immune cellular
reactions in corneal neovascularization
Nizar S. Abdelfattah1,
2, Mohamed Amgad3, Amira A Zayed4
1Doheny Eye Institute, University of
California, Los Angeles, CA 90033, USA
2Ophthalmology Department, David Geffen School of Medicine,
University of California, Los Angeles, CA 90033, USA
3Faculty of Medicine, Cairo
University, Cairo 11956, Egypt
4Department of Surgery, Mayo Clinic,
Rochester, Minnesota 55904, USA
Correspondence
to: Nizar
S.
Abdelfattah. 1355 San Pablo Street, Suite 100, Los Angeles, CA 90033,
USA. nizar@ucla.edu
Received:
2015-05-16
Accepted: 2015-06-29
Abstract
Corneal neovascularization (CNV) is a
global important cause of visual impairment. The immune mechanisms leading to
corneal heme- and lymphangiogenesis have been extensively studied over the past
years as more attempts were made to develop better prophylactic and therapeutic
measures. This article aims to discuss immune cells of particular relevance to
CNV, with a focus on macrophages, Th17 cells, dendritic cells and the
underlying immunology of common pathologies involving neovascularization of the
cornea. Hopefully, a thorough understanding of these topics would propel the
efforts to halt the detrimental effects of CNV.
KEYWORDS: corneal neovascularization;
macrophage; Th17 cells;
dendritic cells; herpes simplex keratitis; keratoplasty; angiogenesis;
lymphangiogenesis; contact lenses.
Citation: Abdelfattah NS, Amgad M, Zayed AA.
Host immune cellular reactions in corneal neovascularization. Int J Ophthalmol 2016;9(4):625-633
Introduction
Aberrant neovascularization (NV) of the cornea is a prevalent
cause of visual impairment in all age groups representing a major public health
concern worldwide. Angiogenesis is defined as the process of developing new
blood vessels from pre-existing ones, up till now, remaining as an incompletely
understood process that involves multiple interactions between different immune
cell types[1-2].
Optical quality of vascularized corneas is reduced by five
mechanisms: 1) opacity caused by the circulating blood cells in the vascular
channels, 2) irregular architecture of the vascular walls inducing high-order
aberrations, 3) alterations in the spacing of stromal collagen between blood vessels,
4) fluid leakage, edema, and lipid deposition in the tissue surrounding
permeable blood vessels, and 5) in the case of superficial pannus, corneal
surface irregularity[3-4].
Understanding how different diseases can react on the
cellular and molecular level to develop corneal angiogenesis requires reviewing
normal immune structure inside the cornea and strategies incorporated in
different disease processes.
Normal Immune Cells of the Cornea
Innate defense immunity When an infection reaches the cornea,
it is first confronted by innate immunity[5]. Components of innate immunity are nonspecific first line
systems that are present since birth. Physical barriers, such as the bony orbit
and the eyelids, guard against traumatic events, while infections are guarded
against by more physiologically adjusted corneal elements, including tears,
corneal nerves, epithelium, keratocytes, polymorphonuclear cells, and some
cytokines.
Tears Tears are the
physical barrier that flushes foreign bodies out of the corneal surface and
mediates transfer of plasma anti-infective proteins (lactoferrin, lysozyme,
lipocalin, and beta-lysin) and immunoglobulins to the cornea, thereby locally
fighting infection. One of the major highly concentrated immunoglobulins in
tears is immunoglobulin (Ig) A. Secretory IgA binds to bacteria and prevents
their adherence to epithelium. Tear IgG as well as IgA can neutralize some
viruses and bind bacteria and hence sharing in corneal defense[6-7].
Epithelial cells Corneal epithelial cells are capable
of secreting cytokines to activate immune responses; thus protecting against
microbial invasion. When epithelial cells are lysed by infection or trauma,
they release the cytokine interleukin (IL)-α[7–9]. This capacity to secrete IL-1α is also shared by stromal
keratocytes. When cell lysis occurs on a chronic basis, IL-1α secretion would
lead to enhanced immune invasion, inflammation, neovascularization and hence
destruction of cornea. Interestingly, in physiological conditions, the corneal
epithelium can secrete the soluble and membrane-bound forms of the IL-1α
receptor (IL-1RII)[10] which is a natural IL-1α antagonist.
Keratocytes Keratocytes have the capacity to
secrete IL-6 and defensins after activation by IL-1α and tumor necrosis factor
(TNF)-α[11–13]. IL-6 synergizes with these factors
as immune modulators. Defensins hold therapeutic potential in ocular infections
as they have a broad spectrum of antimicrobial activity (against bacteria,
fungi, and viruses) and accelerate epithelial healing[14-15].
Corneal nerves Corneal nerves have a physical
indirect barrier mechanism of the cornea by receiving sensory information
leading to reflex lid closure to protect the eye[16]. Sensations of discomfort
and pain may also secrete neuropeptides inducing cytokine action. Moreover,
terminal ends of corneal sensory neurons have a chemical barrier mechanism of
defense by secreting calcitonin gene-related peptide and substance P in response
to pain[17-18]. Both chemicals can bind
to epithelial cells and induce IL-8 synthesis leading to neutrophilic influx.
Complement The complement system is a strictly
organized pathway of proteins that activate each other to generate biologically
active enzymes, opsonins, anaphylotoxins, and chemotaxins. Peripheral cornea
has more concentrations of all seven complement components as compared to the
central cornea due to diffusion of complement components from limbal vessels
into the cornea[19].
Interferons Interferons (IFN) are a group of
cytoprotective proteins made by virally-infected cells, inducing a generalized
viro-immune state in the surrounding normal cells[20]. IFN-α is secreted by
leucocytes, whereas IFN-β is secreted by fibroblasts, and IFN-ɣ by T-cells and natural killer (NK) cells. Furthermore,
IFNs enhance major histocompatibility complex (MHC) class I molecules
production; thereby enhancing capacity of cells infected by viruses to present
viral antigens to T-cells[20].
Cells of innate immunity
Neutrophils Neutrophils are one of the normally
encountered cells in the cornea, they move through endothelial cells of the
limbal vasculature by diapedesis to act as a critical factor in innate immunity
through phagocytosis and microbial killing[21].
Eosinophils On the cell membrane of every
eosinophil lie surface receptors for IgE and complement components. Activation
of these eosinophils can be achieved through IL-3, IL-5, and granulocyte
colony-stimulating factor. Moreover, in parasitic infestations, eosinophils
release several pertinent granule proteins, such as major basic protein and
cationic protein[22].
Macrophages Macrophages possess phagocytic and
antigen presenting properties as well as the ability to secrete inflammatory
cytokines. Having been thought to be residing only in the conjunctiva,
macrophages have been recently found in the stroma of mice corneas,
contributing to host immune responses[23].
Natural killer cells Apart from other T and B-lymphocytes,
NK cells lack membrane bound antigen recognition molecules[24]. However, MHC class I
molecules are bound to NK cells through surface receptors delivering inhibitory
signals to NK cells. Thereby, target cells that lack MHC class I molecules are
destroyed immediately by NK cells, as frequently occurs in virally-infected
cells, antibody-coated cells, undifferentiated cells, and tumor cells[24-25]. In addition, NK cells
can secrete TNF-α and IFN-α.
Acquired
Defenses Immunity If a microorganism was
able to bypass and challenge innate immunity with persistence of infective
antigens, cell mediated immunity would take over and bring microbial replication
under control. This can be achieved via
Langerhans cells action and the release of cytokines.
Langerhans Cells Langerhans cells are antigen
presenting cells of the cornea that are responsible for recognition,
processing, and presentation of antigens[26]. They were previously
thought to be residing only in the periphery of the cornea and characterized by
carrying MHC class II antigens. However, Langerhans cells have been isolated in
the central cornea of human infants[27] and, recently, MHC class
II-negative Langerhans cells have been demonstrated in the central cornea of
BALB/c mice[28] and at the basal epithelium of donor human corneal
tissue[26]. Generally speaking, when
Langerhans cells are urgently required, recognition and identification of
non-self antigen is carried out. Consequently, antigen is processed and is
transported to the surface by MHC molecules, either class I or II[29]. T-cell receptor binding
to antigen on MHC molecule leads to activation of T-cells. This way maturating
T-cells into effector cell, which is CD4 positive if the MHC
molecules were class II, or CD8 positive if the MHC were class I. And thereby
the T-cells either directly kill foreign microorganisms (CD8 positive
T-cytotoxic cells) or secrete cytokines (CD4 positive T-helper cells) calling
for chemotaxis of other effector cells, mainly macrophages, leading to lysis of
pathogens and activating other inflammatory cascades.
Cytokines Cytokines release varies according to
the secreting T-cell. Two major subsets of T helper cells, Th1 and Th2, have been described with differential
cytokine production profiles[30-31]. A third subset, Th17 has
only been recently discovered[32]. Table 1 summarizes the known types and functions of Th cells. The
rate limiting factor controlling type of immune response produced is cytokine
expression controlled by specific cellular chemotaxis at sites of cellular
immune response.
|
T-helper 1 |
T-helper 2 |
T-helper 17 |
|
|
Secretion |
IL-2 and IFN-α |
IL-4 and IL-5 |
IL-17, IL-17F, IL-21,
IL-22 |
|
Cytolysis |
Cytolytic |
Non-cytolytic |
N/A |
|
Antibody production |
IgA, IgM, IgG, but not
IgE |
IgA, IgM, IgG, and IgE |
N/A |
|
Immune selectivity |
Cases of delayed type
hypersensitivity and low antibody production |
Cases of allergy and
persistent antibody production. |
Have a role in
transplant rejection and autoimmune diseases |
Immune Privilege and Angiogenic Versus Antiangiogenic
Proteins Cornea has been designated
as an “angiogenesis privileged site”, that requires low levels of angiogenic
factors and high levels of anti-angiogenic factors to maintain its avascularity
and hence transparency. Rupture of this homeostasis in a wide variety of
diseases leads significantly to the occurrence of corneal neovascularization[3].
Angiogenesis occurs in
tissues when the balance between angiogenic and anti-angiogenic factors is
disturbed in favor of angiogenic molecules. It has to be clear that
neovascularization requires not only up-regulation of angiogenic factors, but
also the down-regulation of anti-angiogenic factors[33].
Steps of Corneal New Blood and Lymph
Vessel Formation Corneal NV consists of the
formation of new vascular structures in previously avascular areas. In an in-vivo experimental corneal model, the
growth of a capillary involves an ordered sequence of events: the release of angiogenic factors, vascular endothelial cell activation,
lysis of the basement membrane of a
parent venule, vascular
endothelial cell proliferation, migration
of capillary endothelial cells towards the angiogenic stimulus, lumen formation, development of branches, and anastomosis of the tip of one tube with
another to form a loop[34].
Lymphatic capillaries are blind-ended
vessels that are made of a single layer of lymphatic endothelial cells (LEC's),
have no basement membrane, are not surrounded by smooth muscles or pericytes
and have inter-junctional gaps to allow for entry of immune cells[35-36]. Collecting lymph vessels, on the
other hand, are surrounded by smooth muscles, have continuous inter-endothelial
junctions, and contain valves to prevent backflow of lymph[35-37].
Whereas blood vessels are responsible
for delivering oxygen and nutrients to tissues and disposing of the products of
cellular respiration and metabolism, lymphatic vessels return excess fluid,
colloid and extravasated leukocytes back into circulation. The presence of
lymph nodes along the lymphatic circuit allows for immune clearance of
pathogens and provides a niche where antigen-presenting cells interact with
vast numbers of lymphocytes, allowing for sensitization against foreign
antigens.
Corneal NV can be derived from stroma, which is mainly
associated with stromal keratitis. It can also develop from the superficial
corneal periphery, which is mainly associated with ocular surface disorders,
such as Stevens-Johnson syndrome, ocular pemphigoid, and thermal or chemical
burns[38-39]. Although NV may involve
several corneal layers, a study has demonstrated that the main locations of
vascularized corneal buttons are in the upper and middle third areas of the
anterior stroma[40]. Similarly, induced
lymphatic vessels are localized to the corneal sub-epithelium and stromal
layers in the wounded cornea.
Selected Immunologic Topics of Particular Relevance to
Corneal Neovascularization
Role of macrophages in hemangiogenesis Macrophages are derived from
monocytes that exit the bloodstream and niche into peripheral tissues[41]. They are either
classically-activated by the Th1 cytokines (M1) or alternatively-activated by
Th2 pathway (M2)[42]. M1 macrophages are
mostly involved in eliciting the inflammatory response through secretion of
matrix metalloproteinases, NO and TNF-α, while M2 are involved in the removal
of cell debris, resolving inflammation and wound healing. Thus, it is M2
macrophages which are most relevant to angiogenesis[43-44].
There are three primary mechanisms by which macrophages
promote hemangiogenesis: 1) macrophages drill tunnels to
facilitate subsequent growth of new capillaries by removing debris (phagocytic
function) and degrading connective tissue, thus providing a temporary scaffold
for the new vessels[45];
2) macrophages
provide paracrine support for vascular networks that is VEGF-independent
("non-canonical") and physically-interact with blood vessels during
vascular remodeling[46];
3) macrophages
act as a major source of epithelial growth factors and angiogenic factors[47].
Macrophages were shown to have a role in angiogenesis in the
granulation tissue during the early phases
of the repair process. Furthermore, they participate in vascular maturation and
stabilization during the latter stages[48]. In fact, M2 macrophages participate in both vascular network formation and neural development[49]. However, macrophages are
heterogenic in nature and can express pro as well as anti-angiogenic factors.
In a study by Chen et al[50],
depletion of macrophages as a whole was found not to have apparent effects on
alkali-induced CNV; because CCR2- and CX3CR1-expressing macrophages exhibited
opposite effects on angiogenesis[51]. Also, accumulation of
CX3CR1-positive macrophages intraocularly was found to dampen alkali-induced
CNV by producing antiangiogenic factors such as TSP-1 and ADAMTS-1[52].
Role of macrophages in lymphangiogenesis Macrophages are known to express a
number of markers used for their characterization and localization during
experimental assays. These include F4/80, CD 11b and CD 68[53–55]. LEC's also are
characterized by a number of markers, including Lymphatic Vascular Endothelial
Hyaluran Receptor (LYVE-1), a transmembrane receptor first described by
Kaipainen et al[56]. Other specific LEC
markers include Prox-1[57], which is a transcription
factor and Podoplanin, a membrane glycoprotein[58-59]. Having said that, there
are three main mechanisms by which macrophages promote lymphangiogenesis:
1) macrophages
transdifferentiate into endothelial cells, thus participate-structurally-in lymphatic vessels. This
is evidenced by the fact that some F4/80 positive, CD11b positive murine
macrophages have been shown to express LYVE-1 in vitro and in tumor granulation tissue [60-61]. Moreover, mesenchymal
cells co-expressing CD45 (a leukocyte marker) and LYVE and Prox-1 (LEC markers)
have been detected at areas of lymphangiogenesis[62-63]. In fact, macrophages
alone can form LYVE positive/Podoplanin positive tube-like structures. Nonetheless, some
experimental accounts negate this structural role. For example, Runx1-targeted
mice (which have defective hematopoeisis) display normal development of
lymphatic sacs[63-64];
2) macrophages
secrete paracrine factors, most importantly VEGF-C and VEGF-D which bind to
VEGF receptor 3 (VEGFR-3) and activate nuclear factor kappa-B signaling (NFκ-B) in sprouting
lymphatics[65]. They also secrete
VEGF-A, which acts to promote lymphangiogenesis, both directly (by acting on
VEGFR-2) or indirectly by recruiting more macrophages into the site[66-67];
3) macrophages
are found at the tips of sprouting lymphatics and act as "bridge
cells" that guide tip cells into finding and anastomosing with tip cells
from other sprouting lymphatics. This process is VEGF-independent [68-69].
Role of Th17 in corneal neovascularization Th17 is a distinct set of T-helper cells
that has been recently discovered and found to have a role in a variety of
immune events, including transplant rejection [70]. Th17 cells secrete IL-21,
IL-22, IL-17F and, most relevant to
our discussion here, IL-17[71-72]. CD4+CD25+Foxp3+
Tregs (T-regulatory cells) have a role in "tuning down" the immune
response and are thus one of the factors opposing rejection of transplanted
organs. Indeed, a higher level of Foxp3 expression in Tregs is correlated with
longer graft survival[73].
One mechanism by which Th17 cells participate in transplant
rejection is through shifting of the Th1: Treg axis towards the Th1
side[74]. Indeed, IL-17 promotes
the recruitment of Th1 cells by inducing the expression of chemokines[75]. Moreover, dual
regulation between Th17 cells and Treg cells has been reported in the
literature [76-77]. IL-17 has a similar
regulatory effect on Th1 cells, by influencing the secretion of IL-12 by
antigen-presenting cells [74]. Overall, Th17 cells were
found to be more important during the early stages of corneal allograft
rejection while Th1 cells were responsible for the late stages[74].
IL-17 stimulates both hemangiogenesis and lymphangiogenesis.
It causes macrophages to secrete IL-1b, TNF-a and stromelysin[78]. IL-1b, thereafter, causes migration of
vascular endothelial cells and the development of microvessel-like structures[79]. Furthermore, IL-17 has
been shown to increase the expression of IL-8, IL-6 and PGE2 and intracellular
adhesion molecule-1 (ICAM-1) by fibroblasts and keratinocytes. IL-17 also
upregulates the expression of VEGF, KC, MIP-2, PG's and NO by fibroblasts,
further supporting the development of new blood vessels[79–83].
More importantly, IL-17 increases VEGF-D secretion and
VEGFR-3 expression. Although VEGF-D expression is inhibited by IL-1B (whose
secretion is also stimulated by IL-17), the net result of VEGF-D, A and C
stimulation of VEGFR-3 is pro-lymphangiogenic. VEGFR-3 stimulation induces LEC
proliferation and tube formation[84].
A Closer Look at Herpes Stromal Keratitis With most
strains of HSV-1, live virus is cleared from the corneal surface within 1wk of
infection. During this period, the innate immune system, including neutrophils,
NK cells, and γδ T-cells, are activated and recruited to the site of infection
within the cornea. Upon entry into the cornea, these cells release cytokines
that can inhibit viral replication, but can also cause tissue damage and
attract further immune cells to the site[85].
Corneal stromal disease begins after
most viral antigens are cleared from the epithelium. Herpes simplex keratitis
(HSK) begins to develop 7-10d after murine corneal infection, as indicated by
corneal opacity, blood vessel growth into the avascular cornea, and substantial
infiltration of leukocytes[86].
Early studies demonstrated that T-cell-deficient mice do not develop HSK, and
T-cell adoptive transfer could reconstitute the disease[87-88]. Subsequent studies demonstrated a
major role for CD4 T-cells and their Th1 cytokines in mediating HSK[89-90]. Costimulatory interactions,
including B7.1/B7.2 on antigen-presenting cells with CD28 on T-cells, in the
cornea are required for efficient HSK immunopathology, while OX40-OX40 ligand
and CD40-CD40 ligand interactions appear to be dispensable for disease
development[91–93].
In addition, CD8 T-cells were shown
to mediate a transient form of HSK in the absence of CD4 T-cells, or when mice
are infected with certain strains of HSV-1[94-95]. Progression of herpes simplex-1
stromal keratitis immune response following infection runs through the
following stages[86]: 1) stage 1: right after infection,
innate immune cells are recruited and secrete cytokines and chemokines;
infected epithelial cells secrete VEGF; and antigen-presenting cells capture
viral antigens before trafficking to draining lymph nodes; 2) stage 2:
in response to chemokines, CD4 T-cells infiltrate the cornea and orchestrate a
more chronic inflammation dominated by neutrophils and facilitated by ingrowth
of blood and lymphatic vessels; 3) stage 3:
recurrent bouts of corneal inflammation result in stromal scarring and
subsequent visual loss; 4) stage 4:
corneal transplantation may be attempted once scarring occurs, but
immunomediated graft rejection is common in hosts with previous HSK. Ideally,
future treatments will block HSK pathogenesis before scarring occurs.
A Closer Look at Corneal Graft Versus Host Disease Boisgérault et al[96]
based their work on the fact that corneal allografts are naturally devoid of
MHC class II+APCs and minor Ag-mismatched corneal grafts are more readily
rejected than their MHC-mismatched counterparts. Accordingly, it has been
hypothesized that these transplants do not trigger direct T-cell alloresponse,
but that donor Ags are presented by host APCs, i.e. in an indirect fashion. So in their study, they determined the
Ag specificity, frequency, and phenotype of T-cells activated. They found that
in rejecting mice the T-cell response was mediated by two T-cell subsets: 1)
CD4 positive T-cells that recognize alloantigens exclusively through indirect
pathway and secrete IL-2, and 2) IFN-ɣ producing CD8 T-cells recognizing donor
MHC in a direct fashion. Surprisingly, CD8 positive T-cells activated directly
were not required for graft rejection. They concluded that only CD4 positive
cells via indirect allorecognition
have the ability to reject allogeneic corneal grafts. Although alloreactive CD8
positive T-cells activated T-cells via the direct pathway, they are not fully
competent and cannot contribute to the rejection unless they receive an
additional signal provided by professional APCs in the periphery.
Chen et al[50] investigated the role of very late
antigen 1 (VLA-1) (also known as integrin receptor α1β1) in CNV, and found that
corneal angiogenesis and lymphangiogenesis were both significantly suppressed
in VLA-1 knockout mice. After transplantation, both blood [CD31 positive vessels (CD31 positive
LYVE-1 negative LYVE-1 positive)]
and lymph were significantly decreased in the VLA-1 knockout recipients;
improving corneal graft survival. The surprisingly high survival rate in
VLA-1-blockade or VLA-1-deficient conditions may be explained by the fact that
this molecular pathway is involved in both innate and adaptive aspects of
corneal transplantation immunity, since both innate (neutrophil and macrophage)
and T-cell infiltrations are suppressed.
Barcia et al[97]
studies suggest that endothelial destruction during graft rejection may be due
to apoptotic cell death. Furthermore, increased expression of anti-apoptotic
genes in the corneal endothelium is a potential approach for improving
allograft survival. They found that Bcl-xL protected cultured corneal
endothelial cells from apoptosis and that lentiviral delivery of Bcl-xL to the
corneal endothelium of donor corneas significantly improved the survival of
allografts. They observed a significant increase in the survival rate despite a
relatively modest (15%) transduction efficiency. Given that stress induces
corneal endothelial cells to secrete pro-apoptotic cytokines such as TNF-α, INF-c and
IL-1, it is possible that Bcl-xL overexpressing cells do not generate these
cytokines and thereby reduce the overall intensity of the apoptotic insult.
Hanson et al[98]
showed that when human embryonic stem cells were transplanted onto a human
corneal button (without limbus) with the epithelial layer partially removed for
up to 9d; the transplanted cells established and expanded on Bowman’s membrane,
forming a 1-4 cell layer surrounded by host corneal epithelial cells.
Expression of the corneal marker PAX6 appeared 3d after transplantation, and
after 6d, the cells were expressing both PAX6 and CK3, showing that it is
possible to transplant cells originating from hESCs onto Bowman’s membrane with
the epithelial layer partially removed and to get these cells to establish,
grow and differentiate into corneal epithelial-like cells in vitro.
Shen et al[99] showed that PD-L1, but not PD-L2, is
constitutively expressed at high levels by the corneal epithelial cells, and at
low levels by corneal CD45 positive cells in the stroma, whereas it is
undetectable on stromal fibroblasts and corneal endothelial cells. Inflammation
induces PD-L1 up-regulation by corneal epithelial cells, and infiltration of
significant numbers of PD-L1 positive CD45 positive CD11b positive cells.
Blockade with anti-PD-L1 mAb dramatically enhances rejection of C57BL/6 corneal
allografts by BALB/c recipients. BALB/c grafts placed in PD-L1-/- C57BL/6 hosts
resulted in pronounced T cell priming in the draining lymph nodes, and
universally underwent rapid rejection.
Role of Draining Lymphatics in Corneal Graft Versus
Host Disease Yamagami
et al[100]
transplanted corneas in mice that had their cervical lymph nodes (CLN) excised
before transplantation, and compared their IFN-ɣ and IL-2 expressing cells with
mice that retained their CLN. Additionally, they evaluated splenectomized mice
(Sp-), and hosts without either CLN or
spleen. As a result; 100% of high-risk grafts among CLN positive hosts were
rejected, while 92% of CLN negative hosts accepted their high-risk allografts,
and demonstrated suppressed allospecific delayed type hypersensitivity
response. Moreover, significantly lower numbers of IFN-ɣ and IL-2 expressing
cells were infiltrating corneal grafts in CLN negative group. All Sp- hosts
rejected corneal allografts, whereas 86% of CLN-Sp- hosts accepted their
allografts. This suggests the idea that draining CLN plays a critical role in
alloimmunity and rejection of high-risk corneal grafts.
Afterwards, Jin et al[101]
proved that passage of corneal APCs through draining LNs is a significant
inducer of immune responses. The investigation involved expression and function
of chemokine receptor CCR-7 in controlling corneal APC migration during
inflammatory responses. Results have shown that CCR-7 and its ligand CCL-21
expressed significant upregulation in corneal inflammation. According to Geissmann et al[102], immature CCR-7 positive dendritic
cells (DC) mostly will be poor in stimulating T-cells and thereby can induce a
state of immune tolerance. This area of association between CCR-7-mediated
corneal DC trafficking and immune stimulation versus tolerance needs supplementary
studying. Although normal cornea lacks lymphatic vessels in all its layers, it
can easily allow lymphatic growth once exposed to inflammatory stimulation[103]. This neolymphangiogenesis
accompanied by normally present conjunctival lymphatics facilitates admission
of APCs to corresponding submandibular lymph node[104]. Their finding of CCR7 positive DC
close to CCL21 positive and LYVE-1 positive lymphatics suggests that CCL21-CCR7
interactions promote DC access to the lymphoid compartments.
Role of Dendritic Cells in Keratoplasty and Herpes Simplex
Keratitis Antigen-presenting
cells, such as DCs and macrophages, which were previously thought to be
absent in the cornea, are now known to be located in the basal layer of the
corneal epithelium and throughout the corneal stroma, respectively[105].
When inflammation takes place,
maturation of dendritic cells to express MHC class II and B7 (CD80/CD86)
co-stimulatory molecules occurs. In keratoplasty, dendritic cells of donor
cornea migrate to host cervical lymph nodes through inflamed bed lymphatics,
thereby activating host T-cells. This shows clearly the corneal diverse
capabilities of antigen presentation methods[106].
During HSV-1 infection of the
epithelium, these DCs may play a role in priming the immune response by
acquiring viral antigens from infected epithelial cells in the cornea, and
directly presenting them to naive T-cells in the lymph nodes, or by becoming
infected and migrating to the lymph nodes, where resident lymph node DCs could
cross-present viral antigens to T-cells, as seen in the cutaneous HSV-1
infection model[107].
An initial DC infiltration from the limbus at approximately 5d postinfection is
followed by a second massive DC infiltration into the cornea at 10d
postinfection, coincident with HSK onset[91].
Studies that involved depletion of DCs suggest a role for these cells in the
presentation of HSV-1 antigens to CD4 T-cells, which also infiltrate the cornea
during HSK. An HSK reactivation model showed a direct correlation between the
quantity of DCs in the cornea and corneal opacification[108].
Furthermore, bilateral HSV-1
infection of mice following monocular DC depletion showed HSK development in
the non-depleted eye only, indicating that DCs may be involved in the effector
phase of the inflammatory response[109].
However, one caveat to these early depletion experiments is uncertainty about
the specificity of depletion for DCs and the efficacy in depleting all DC
subpopulations. Therefore, further studies employing more specific methods of
DC depletion are needed to clarify the role of DCs in HSK. Despite extensive
investigations into the mechanisms of CD4 T-cell mediated HSK, the nature of
the stimulus/stimuli that activate CD4 T-cells within the corneal stroma
remains controversial[86].
Recent discoveries about the roles of immune cells such as
macrophages, dendritic cells and Th17 cells in CNV, as well as the underlying
immune mechanisms of common CNV-related pathologies uncover exciting and
promising new potentials. A thorough understanding of the immunological cells
and interactions involved in neovascularization of the cornea is needed to
develop better targeted and more potent treatments against CNV.
ACKNOWLEDGEMENTS
Conflicts of interest: Abdelfattah
NS, None; Amgad M, None; Zayed AA, None.
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