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Departments of
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Pathology and
Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In A/J mice, all corneas develop epithelial lesions 2 days after
infection with the RE strain of HSV-1. These lesions are caused by
virus replication in and destruction of epithelial cells, and are
associated with mild and transient inflammatory cell infiltration of
the cornea (1). Epithelial lesions heal by 4 days postinfection (p.i.)
in both normal and T cell-deficient mice. The corneas then appear
normal by both clinical and histopathologic criteria until around day
10 p.i. At that time, about 60% of infected corneas develop an
inflammation in the stromal layer that is referred to as herpes
stromal keratitis (HSK). It is now well established that HSK in this
model represents a CD4+ T cell-regulated inflammatory
response in which the Th1-type cytokines IL-2 and IFN-
play an
essential role in regulating neutrophil infiltration and destruction of
the cornea (2, 3, 4, 5, 6).
Because cytokine transcripts are labile in the absence of T cell stimulation (7), T cells that mediate inflammation require restimulation within the inflamed tissue. Unlike most tissues, the cornea lacks professional APC that are capable of presenting foreign Ags to CD4+ T lymphocytes (8). However, Langerhans cells (LC) are present in the contiguous conjunctival epithelium. Following HSV-1 corneal infection, LC migrate from the conjunctival epithelium into the central cornea (9, 10, 11), and corneal LC play an essential role in HSK (9, 12, 13). LC normally reside in tissue as immature cells with limited APC function, but cytokines that are produced by infected tissue, or the infectious agent itself, can stimulate LC migration and maturation (reviewed in 14 . There is evidence that some phenotypic maturation occurs as dermal LC migrate from the skin to the draining lymph nodes (LN) (15). However, such studies are hampered by the difficulty of observing the phenotype of LC within lymphatic vessels. The uniqueness of the cornea lies in the fact that large numbers of migrating LC can be observed, and maturational changes that occur in the LC as they migrate into the central cornea can be readily documented and associated with susceptibility to HSK.
Among the maturational events that enhance the capacity of LC to present Ags to CD4+ T cells is increased expression of the B7 family of costimulatory molecules (16, 17, 18). The capacity of B7-1 and B7-2 to deliver a costimulatory signal to T cells by binding to CD28 is well documented (reviewed in Refs. 19 and 20). Systemic treatment with mAb to B7 or with the ligand CTLA4-Ig can reduce the severity of T cell-mediated inflammatory processes, such as experimental autoimmune encephalomyelitis (21, 22, 23) and autoimmune diabetes (24, 25). However, the relative role of B7-1 and B7-2 costimulation appears to vary in these two disease models (21, 22, 23, 25, 26). Moreover, in these studies it was not clear whether B7 costimulation was required in the inductive phase of the T cell response in the lymphoid organs, in the effector phase of the T cell response in the inflamed tissue, or at both phases of the response. One study suggested that B7-2 costimulation was important in the inductive but not in the effector phase of a hapten-induced contact sensitivity response (27). This conclusion was based on the observation that the contact sensitivity response was reduced by systemic treatment with mAb to B7-2 1 h before sensitization, but was unaffected by similar treatment 1 h before skin challenge. Although the authors’ conclusion is reasonable, it is based on the assumption that systemic mAb treatment 1 h before sensitization affects only the inductive phase of the response, and that systemic mAb treatment 1 h before skin challenge is sufficient to block B7-2 costimulation within the challenge site.
There is evidence for B7 expression at sites of inflammation (28, 29, 30), but B7 expression on APCs was not demonstrated, and the requirement for B7 expression within the inflamed tissue was not established. Thus, while blocking B7/CD28 interaction might provide a new avenue of intervention in inflammatory diseases, developing such therapy will require an understanding of the relative role of B7-1 and B7-2 costimulation in a particular disease, and the anatomical site in which costimulation is required. The findings of this study address these important issues in a clinically relevant model of T cell-mediated inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female A/J mice (Frederick Cancer Research Center, Frederick, MD), 8 to 12 wk old, were anesthetized with 2 mg of ketamine hydrochloride (vetalar; Parke-Davis, Morris Plains, NJ) and 0.04 mg of acepromazine maleate (Aveco, Fort Dodge, IA) in 0.1 ml of HBSS. Topical corneal infection was then achieved by scarifying the central cornea 10 times with a 30-gauge needle in a crisscross pattern. A 3-µl HSV-1 RE stain virus suspension (5 x 104 plaque-forming U) was applied topically to the scarified cornea. The HSV-1 RE strain used was propagated on Vero cells and stored at -70°C as previously described (31). All experimental procedures conformed to the Association for Research in Vision and Ophthalmology resolution on the use of animals in research.
Clinical evaluation of HSV-1-infected mice
The severity of HSK was monitored by slit-lamp examination of mouse eyes by an observer who was unaware of the treatment group to which the animal belonged. The degree of stromal inflammation was scored on a scale of 0 to 4+, where 0 indicated no neovasculization and no opacity; 0.5+, slight neovasculization in the peripheral cornea, but no corneal opacity; 1+, neovasculization up to a quarter of the corneal radius, and mild corneal haze; 2+, neovasculization up to three quarters of the corneal radius, and moderate corneal opacity; 3+, neovasculization in the whole cornea with severe opacity, obliterating the view of the iris; and 4+, corneal perforation.
Preparation and staining of corneal epithelial sheets
Infected mouse eyes were enucleated, and epithelial sheets from the cornea and contiguous conjunctiva were separated from the underlying stroma after a 2-h incubation at 37°C in PBS containing 20 mM EDTA. Epithelial sheets were fixed in acetone for 30 min at 4°C and then washed extensively in PBS. For single color staining, the epithelial sheets were incubated overnight at 4°C with primary rat mAb to the DEC-205 Ag on LC (clone NLDC-145), or B7-2 (clone GL1), or with hamster mAb to B7-1 (clone 16-10A1). The sheets were washed and incubated for 40 min at 37°C with secondary Ab (FITC-conjugated AffiniPure goat anti-rat IgG; Jackson ImmunoResearch, West Grove, PA) for DEC-205 and B7-2 staining, and FITC-conjugated AffiniPure goat anti-hamster IgG (Jackson ImmunoResearch) for B7-1 staining. The epithelial sheets were then mounted flat on glass slides with PermaFluor (Lipshaw, Pittsburgh, PA) and examined by fluorescence microscopy using a 40x objective. The conjunctival epithelium is thinner and clearly distinguishable from the corneal epithelium under microscopic examination. For the two-color staining, the epithelial sheets were incubated with NLDC-145 overnight at 4°C, followed by a 40-min incubation at 37°C with rhodamine-conjugated AffiniPure goat anti-rat IgG (Jackson ImmunoResearch). The sheets were then blocked with rat IgG (Sigma, St. Louis, MO), then incubated with biotinylated anti-B7-1 mAb at 37°C for 1 h and with streptavidin-FITC (PharMingen, San Diego, CA) at 37°C for 40 min.
Cytokine assays
The draining (preauricular and submandibular) LN were excised on
the designated day after HSV-1 infection, and single cell suspensions
were prepared in assay medium (RPMI 1640 plus 5% FCS, 10 mM HEPES
buffer, and antibiotics). LN cells (4 x 106
cells in 2 ml) were stimulated with UV-inactivated HSV-1 in 24-well
plates at 37°C for 30 h (IL-2 and IL-4) or 60 h (IFN-),
and the cytokine content was measured in an ELISA.
ELISA
Ninety-six-well plates were coated overnight with primary
anti-cytokine capture Ab (4 µg/ml). The plates were washed twice
and blocked with 2% BSA in PBS. The supernatant from the LN cell
culture and standards were added. After overnight incubation at 4°C,
the plates were washed and developed by adding streptavidin-horseradish
peroxidase and its substrate. The reaction product was measured with an
enzyme immunoassay plate reader at 450 nm. The amount of cytokine in
each supernatant was extrapolated from the standard curve. The
capture/detection mAbs were as follows: IL-2, JES6-1A12/JES6-5H4; IL-4,
11B11/BVD6-24G2; IFN-, R4-6A2/XMG1.2 (all from PharMingen). The
sensitivity of detection is 31.3 pg/ml (IL-4) and 50 pg/ml (IL-2 and
IFN-).
Delayed-type hypersensitivity (DTH) assay
Fourteen days after HSV-1 corneal infection, DTH was elicited by injecting 2 x 105 plaque-forming U of UV-inactivated HSV-1 in a volume of 10 µl into the dorsal side of the mouse ear pinna. Ear swelling was measured 24 h later with a Mitutoyo engineers micrometer (Mitutoyo, Tokyo, Japan). The amount of ear swelling (i.e., postchallenge minus prechallenge ear thickness) in HSV-1-infected mice was compared with that of similarly challenged but nonimmunized mice.
In vivo blocking of B7
Beginning 4 days after HSV-1 corneal infection, groups of 12 mice received subconjunctival injections (50 µg in 14 µl) of hamster mAb to B7-1 (clone 16-10A1), rat mAb to B7-2 (clone GL1), or a combination of both mAbs. Mock-treated controls received similar injections of hamster mAb (anti-dinitrophenyl, clone UC8-1B9; American Type Culture Collection (ATCC), Rockville, MD) and rat mAb (anti-HLA-Bw6, clone SFR8-B6; ATCC). Injections were performed with a special apparatus from Hamilton (Reno, NV) that was previously described (32). The injections were given every other day until day 18 p.i. Preliminary experiments established that this treatment resulted in complete blocking of B7-1 or B7-2 expression in the cornea as assessed by immunofluorescent staining with the same mAb that was used to block.
In vivo T cell depletion
To determine whether LC migration and B7-1 expression required a function of T cells, mice were depleted of CD4+ and CD8+ T cells by i.p. injection of a mixture containing 250 µg each of mAb to CD4 (clone GK1.5) and CD8 (clone 2.43). Each mouse received four mAb injections. The first two injections were given at 3-day intervals, and the last two injections were given at 6-day intervals. One cornea of each mouse was infected with HSV-1, and B7-1+ LC were quantified in the corneas 5 days p.i. or 14 days p.i. The timing of the infection was such that both the 5-day p.i. and 14-day p.i. corneas were excised 1 day after the fourth mAb injection. The mAb treatment resulted in at least 98% depletion of CD4+ and CD8+ cells from the LN of randomly selected mice, as assessed by flow cytometric analysis 1 day after the last mAb treatment.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HSK develops in about 60% of A/J mice within 14 days after
corneal infection. Corneas that are free of inflammation 14 days p.i.
do not subsequently develop HSK. Although HSK is a Th1
cytokine-regulated inflammation in HSV-1-infected corneas,
susceptibility to HSK was not associated with differences in Th1
cytokine production by HSV Ag-stimulated LN cells, or with the capacity
to mount a DTH response to HSV Ags in the skin (Table I
). The DTH response to HSV Ags in this
model is mediated by CD4+ T cells, and in part by
IFN- (33). Thus, following HSV-1 corneal infection, Th1 effector
cells are generated in the LN, and can infiltrate and mediate
inflammation in infected tissue of mice that do not develop
HSK.
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Kinetics of LC migration into HSV-1-infected corneas
Groups of mice received corneal infections with HSV-1, and corneas
were excised at various days after infection. Flat mounts of epithelial
sheets from these corneas were stained with FITC-conjugated mAb to the
LC marker DEC-205, and migrating LC were counted by fluorescence
microscopy. LC began to migrate into the cornea 3 days after infection,
and continued to accumulate in the central cornea through day 21
p.i. (Fig. 1). The number of LC was
significantly (p < 0.0001) higher in corneas
that developed HSK than in those without HSK. However, there was little
variability in the number of migrating LC before disease onset. These
findings clearly establish a relationship between LC migration into
infected corneas and HSK, but do not establish the kinetics of LC
migration as a predisposing factor for HSK.
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The HSK model offered an opportunity to observe the relationship
between LC migration and regulation of B7 expression.
B7-1+ and B7-2+ LC were quantified in flat
mounts of corneal/conjunctival epithelium obtained at various times
after infection. Our analysis revealed that B7-2 was constitutively
expressed on LC within the conjunctival epithelium of normal eyes (Fig. 2A), and was uniformly
expressed on LC that migrated into the cornea after infection (Fig. 2B). Thus, there was no obvious relationship between
LC migration and B7-2 expression.
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, A and B).
However, B7-1 expression was up-regulated on migrating LC in the cornea
as early as 3 days after infection. It is noteworthy that not all of
the migrating LC expressed detectable B7-1 (Fig. 3, C and
D). Thus, LC migration and B7-1 expression can be
independently regulated. We also observed that through day 7 p.i.,
all B7-1+ cells in the cornea coexpressed the DEC-205 LC
marker. Between days 10 and 21 p.i., corneas with HSK contained
B7-1+ cells that exhibited a dendritic morphology and
coexpressed DEC-205, and small, round (lymphocyte-like) cells that were
negative for DEC-205 (not shown). Between days 14 and 21 p.i.,
corneas that failed to develop HSK had few, if any, B7-1+
cells. Those that were present exhibited dendritic morphology and
coexpressed DEC-205 (not shown).
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A shows a dichotomy in
the number of B7-1+ LC within individual corneas before
disease onset. About half of the corneas exhibited elevated numbers of
B7-1+ LC at 3 and 7 days p.i., before the onset of HSK.
This approximates the frequency of HSK in these mice. Thus, LC
expression of B7-1 could be a predisposing factor for HSK. The number
of B7-1+ LC in corneas increased dramatically after the
onset of HSK (Fig. 4B).
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The initial LC migration and B7-1 expression occurred at 3 days
p.i., coincident with active virus replication in the corneal
epithelium (days 2 to 5 p.i.). However, the massive accumulation
of B7-1+ LC in the infected cornea did not occur until
days 10 to 14 p.i., and coincided with the onset of inflammation.
We proposed that the early LC migration and B7-1 expression (on day
5 p.i.) was not controlled by T cells, whereas the latter
accumulation of B7-1+ LC in the cornea might be T cell
dependent. To test this possibility, mice were depleted of
CD4+ and CD8+ T cells by i.p. injection of
anti-CD4 and anti-CD8 mAb. Corneas of the T cell-depleted or
control mAb-treated mice were excised at 5 or 14 days p.i., and
B7-1+ LC were quantified within individual corneas. T cell
depletion did not influence the number of B7-1+ LC in
corneas obtained 5 days p.i., but did significantly reduce the number
of B7-1+ LC in corneas obtained 14 days p.i (Fig. 5). As expected, the corneas of T
cell-depleted mice failed to develop inflammation, and exhibited a
markedly reduced number of B7-1+ LC. Thus, LC migration and
B7-1 expression at 14 days p.i. are regulated directly or indirectly by
a T cell response in the cornea.
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A necessary role for B7 costimulation of CD4+ T
cells in the infected cornea was further established by in vivo
blocking experiments. Mice received corneal infection with HSV-1 and 4
days later were divided into four treatment groups. Groups of 12 mice
received subconjunctival injections of 50 µg of mAb to B7-1, B7-2,
B7-1, and B7-2, or control mAb of irrelevant specificity. Injections
were initiated on day 4 p.i., and repeated on alternate days
through day 18 p.i. Treatment with mAb to B7-1 alone, or a
combination treatment with mAb to B7-1 and B7-2 significantly reduced
the incidence of HSK in infected corneas (Fig. 6A). In contrast,
treatment with mAb to B7-2 did not significantly reduce HSK incidence.
However, treatment with mAb to B7-2 did significantly reduce the
severity of HSK (Fig. 6B). Thus, both B7-1 and B7-2
costimulation are required for normal progression of T cell-mediated
inflammation in HSV-1-infected mouse corneas.
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Following the observation period (on day 19 p.i.), LN-draining
eyes that received anti-B7 mAb or control mAb were excised; the LN
cells were stimulated with HSV Ags; and their production of IFN-,
IL-2, and IL-4 was compared. As shown in Table II, these response parameters did not
vary significantly when LN-draining anti-B7-treated eyes were
compared with those draining control mAb-treated eyes. The fact that
local anti-B7 mAb treatment did not influence T cell activation in
the LN can be explained in three ways: 1) sufficient numbers of
Ag-bearing LC migrated to the LN before mAb treatment to permit optimal
T cell activation; 2) LC that migrate from the eye to the LN after
anti-B7 treatment might shed or internalize the mAb and reexpress
B7 during migration; and 3) the locally administered mAb does not reach
the LN in sufficient quantity to alter T cell activation there.
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A) and severity (Fig. 7B) of HSK was significantly reduced in corneas that
received anti-B7 mAb when compared with the control mAb-treated
companion eyes. This experiment clearly established that local blocking
of B7 expression prevented the induction of T cell-mediated
inflammation in HSV-infected corneas.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Resident LC are in an immature state until they are activated by soluble factors that are released in tissues following infection or trauma (reviewed in 14 . In the resting state, LC display low motility and low or no expression of the costimulatory molecules that participate in T cell activation. When exposed to inflammatory cytokines, LC become motile (34, 35) and express phenotypic and functional changes that render them more effective APCs (36). These changes might begin as LC migrate through lymphatic channels en route to the draining LN. However, this interpretation is based on phenotypic changes observed after the LC entered the LN (15), or during migration in an organ culture model (37). In the former case, the phenotypic changes could have been influenced by the cytokine milieu within the LN, and in the latter case by ex vivo culture conditions. Our corneal infection model offers an opportunity to observe maturational events that occur during in vivo migration.
Following HSV-1 corneal infection, LC migrate in large numbers into the
central cornea, and their migration is readily detectable in epithelial
sheets. Our studies establish that the costimulatory molecule B7-2 is
constitutively expressed on LC in the conjunctival epithelium. In
contrast, B7-1 was not detectable until 3 days after infection, and
only on migrating LC. Not all migrating LC had detectable B7-1 on their
surface before HSK onset, suggesting that LC motility and B7-1
expression can be independently regulated. A variety of cytokines,
including granulocyte-macrophage-CSF, IL-1, and TNF-
, that are
produced in the cornea after HSV-1 infection (38) might differentially
regulate LC migration and maturation. TNF- is strongly implicated in
LC migration (35, 39), but its role in LC phenotypic maturation is
controversial (36, 40). IL-1 and granulocyte-macrophage-CSF up-regulate
expression of B7-1 and other costimulatory molecules on LC (16, 17, 36). We observed that depletion of T cells from mice did not affect the
number of B7-1+ cells in the cornea 5 days p.i. These
observations, coupled with the rapid kinetics of B7-1 up-regulation on
migrating LC (within 3 days after infection) are consistent with the
notion that LC migration and early up-regulation of B7-1 expression are
controlled by cytokines that are produced by corneal cells as a result
of HSV-1 infection.
Our studies did not reveal an obvious correlation between susceptibility to HSK and the generation of Th1 cytokine-producing T cells in the LN, or the DTH response to HSV Ags in the skin. It appeared, therefore, that resistance to HSK was probably not associated with 1) reduced generation of Th1 effector cells, 2) reduced capacity of the effector cells to infiltrate infected tissue, or 3) the rate of LC migration into the infected cornea. We did, however, note a correlation between the portion of infected corneas that exhibited elevated numbers of B7-1+ LC before disease onset, and the incidence of HSK. We hypothesize that the density of B7-1+ LC in the cornea at the time of CD4+ T cell infiltration might determine the likelihood that the CD4+ T cells will be stimulated to produce inflammatory cytokines. This possibility was supported by our observations that 1) LC were the only B7-1+ cells in the cornea at the time of HSK onset, and 2) blocking B7-1 prevented HSK.
During the period of 14 to 21 days p.i., corneas that developed HSK had a high density of LC, and most or all of the LC in these corneas were B7-1+. In contrast, corneas that did not develop HSK during this period showed a marked reduction of LC, and few if any of these LC were B7-1+. We propose that the massive accumulation of B7-1+ LC in corneas with HSK is due to the interaction between CD4+ T cells and the corneal LC. This proposal is supported by our observation that depletion of T cells from mice before HSV-1 corneal infection dramatically reduced the number of B7-1+ LC in the cornea 14 days p.i. It is well established that interactions between CD4+ T cells and LC can lead to activation of both the T cell and the LC (reviewed in 41 . For instance, the interaction of CD40 ligand on activated CD4+ T cells with CD40 on LC induces up-regulation of a variety of costimulatory molecules, including B7-1 by LC, and their production of factors that are chemotactic for LC (18). Such activation might also prevent LC from undergoing apoptotic cell death, which appears to be their ultimate fate (34).
A requisite role for B7 costimulation has been established in several models of inflammation. However, our studies are the first to establish that a T cell-mediated inflammatory response can be regulated by locally blocking B7 costimulation at the inflammatory site. The requirement for costimulation of T effector cells is controversial. It has been suggested that during acute infections, cytokines that are produced by parenchymal or inflammatory cells within the lesion may supplant the need for costimulation of effector T cells (reviewed in 42 . In our model, virus is no longer detectable in the cornea by 5 days p.i., whereas T cell-mediated inflammation is initiated around day 10 p.i. Thus, the initial activation of infiltrating effector T cells occurs in a noninflamed tissue that lacks replicating virus or immunohistochemically detectable viral Ags. The latter point has led to uncertainties about the Ags that activate the infiltrating CD4+ T cells. Two possibilities have been proposed. 1) Viral Ags that are processed and presented on conjunctival LC during the period of virus replication are carried by the LC to the central cornea, where they are presented to infiltrating HSV-reactive CD4 T cells. 2) Self-Ags that are released from the immune privileged cornea during virus replication are presented to autoreactive T cells that infiltrate the cornea. In either case, the requirement for costimulation of effector T cells may derive from a combination of weak TCR signaling and the absence of proinflammatory cytokines. Based on the strength of signal hypothesis (43), weak TCR signaling could also account for the preferential involvement of Th1 cytokines in the inflammatory process.
Our findings strongly suggest that susceptibility to HSK is determined by conditions within the microenvironment of the infected cornea. We also establish that B7 costimulation within the cornea is necessary for T cell activation and participation in HSK, suggesting that local manipulation of B7 costimulation might provide an effective means of intervention in this blinding disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert L. Hendricks, University of Illinois at Chicago, Department of Ophthalmology and Visual Sciences, 1855 West Taylor Street, Chicago, IL 60612.
3 Abbreviations used in this paper: HSV-1, herpes simplex virus type 1; HSK, herpes stromal keratitis; LN, lymph nodes; p.i., postinfection; DTH, delayed-type hypersensitivity; LC, Langerhans cells.
Received for publication October 22, 1997. Accepted for publication January 13, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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  S. J. Divito and R. L. Hendricks Activated Inflammatory Infiltrate in HSV-1-Infected Corneas without Herpes Stromal Keratitis Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1488 - 1495. [Abstract] [Full Text] [PDF]
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C. S. Brissette-Storkus, S. M. Reynolds, A. J. Lepisto, and R. L. Hendricks Identification of a Novel Macrophage Population in the Normal Mouse Corneal Stroma Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2264 - 2271. [Abstract] [Full Text] [PDF]
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J. T. Kaifi, E. Diaconu, and E. Pearlman Distinct Roles for PECAM-1, ICAM-1, and VCAM-1 in Recruitment of Neutrophils and Eosinophils to the Cornea in Ocular Onchocerciasis (River Blindness) J. Immunol., June 1, 2001; 166(11): 6795 - 6801. [Abstract] [Full Text] [PDF]
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L. D. Hazlett, S. McClellan, R. Barrett, and X. Rudner B7/CD28 Costimulation Is Critical in Susceptibility to Pseudomonas aeruginosa Corneal Infection: A Comparative Study Using Monoclonal Antibody Blockade and CD28-Deficient Mice J. Immunol., January 15, 2001; 166(2): 1292 - 1299. [Abstract] [Full Text] [PDF]
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H. Cheng, T. M. Tumpey, H. F. Staats, N. van Rooijen, J. E. Oakes, and R. N. Lausch Role of Macrophages in Restricting Herpes Simplex Virus Type 1 Growth after Ocular Infection Invest. Ophthalmol. Vis. Sci., May 1, 2000; 41(6): 1402 - 1409. [Abstract] [Full Text]
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). The corneas
were obtained before the time of HSK onset
(A), or after the time of disease onset
(B).
