Immunologic Diseases of the Eye: Introduction

Ocular manifestations are a common feature of immunologic diseases even though,

paradoxically, the eye is also a site of immune privilege. The propensity for immunologic disease
to affect the eye derives from a number of factors, including the highly vascular nature of the
uvea, the tendency for immune complexes to be deposited in various ocular tissues, and the
exposure of the mucous membrane of the conjunctiva to environmental allergens. Inflammatory
eye disorders are more obvious (and often more painful) than those of other organs, such as the
thyroid or the kidney.
Immunologic diseases of the eye can be grossly divided into two major categories: antibodymediated and cell-mediated diseases. As is the case in other organs, there is ample opportunity
for the interaction of these two systems in the eye.
Antibody-Dependent & Antibody-Mediated Diseases
Before it can be concluded that a disease of the eye is antibody-dependent, the following criteria
must be satisfied:
1. There must be evidence of specific antibody in the patient's serum or plasma cells.
2. The antigen must be identified and, if feasible, characterized.
3. The same antigen must be shown to produce an immunologic response in the eye of an
experimental animal, and the pathologic changes produced in the experimental animal
must be similar to those observed in the human disease.
4. It must be possible to produce similar lesions in animals passively sensitized with
serum from an affected animal upon challenge with the specific antigen.
Unless all of the above criteria are satisfied, the disease may be thought of as possibly antibodydependent. In such circumstances, the disease can be regarded as antibody-mediated if only one
of the following criteria is met:
1. If antibody to an antigen is present in higher quantities in the ocular fluids than in the
serum (after adjustments have been made for the total amounts of immunoglobulins in
each fluid).
2. If abnormal accumulations of plasma cells are present in the ocular lesion.
3. If abnormal accumulations of immunoglobulins are present at the site of the disease.
4. If complement is fixed by immunoglobulins at the site of the disease.
5. If an accumulation of eosinophils is present at the site of the disease.
6. If the ocular disease is associated with an inflammatory disease elsewhere in the body
for which antibody dependency has been proved or strongly suggested.
Hay Fever Conjunctivitis (See Also Chapter 5)
This disease is characterized by edema and hyperemia of the conjunctiva and lids (Figure

161) and by itching, which is always present, and tearing. There is often an associated itching
sensation in the nose as well as rhinorrhea. The conjunctiva appears pale and boggy because of
the intense edema, which is often rapid in onset. There may be a distinct seasonal incidence,
patients being able to establish the onset of their symptoms at precisely the same time each year.
These times usually correspond to the release of pollens by specific grasses, trees, or weeds.

Figure 161.

Hay fever conjunctivitis. Note edema and hyperemia of the conjunctiva.

(Courtesy of M Allansmith and B McClellan.)

Immunologic Pathogenesis
Hay fever conjunctivitis is one of the few inflammatory eye disorders for which antibody
dependence has been definitely established. It is recognized as a form of atopic disease with an
implied hereditary susceptibility. IgE (reaginic antibody) is attached to mast cells lying beneath
the conjunctival epithelium. Contact of the offending antigen with IgE triggers the release of
vasoactive substances, principally leukotrienes and histamine, which results in vasodilation and
chemosis.
The role of circulating antibody to ragweed pollen in the pathogenesis of hay fever conjunctivitis
has been demonstrated by passively transferring serum from a hypersensitive person to a
nonsensitive one. When exposed to the offending pollen, the previously nonsensitive individual
reacted with the typical signs of hay fever conjunctivitis.
Immunologic Diagnosis
Victims of hay fever conjunctivitis show many eosinophils in Giemsa-stained scrapings of
conjunctival epithelium, and this is the test most commonly used to confirm the diagnosis. They
show the immediate type of response, with wheal and flare, when tested by scratch tests of the
skin with extracts of pollen or other offending antigens. Biopsies of the skin test sites have
occasionally shown the full-blown picture of an Arthus reaction, with deposition of immune
complexes in the walls of the dermal vessels. Passive cutaneous anaphylaxis can also be used to
demonstrate the presence of circulating antibody.
Immunologic Treatment
Immunotherapy with gradually increasing doses of sublingual or subcutaneously injected pollen

extracts or other suspected allergens appears to reduce the severity of allergic disease in some
individuals. The mechanism is presumed to be production of blocking antibodies in response to
the injection of small, graded doses of the antigen. Despite some benefit in the treatment of
respiratory allergies, immunotherapy does not seem to be effective in treating hay fever
conjunctivitis. As well, acute anaphylactoid reactions have occasionally resulted from
overzealous immunotherapy. Topical antihistamines and mast cell stabilizers are the mainstay of
treatment. Occasionally, mild nonpenetrating corticosteroids may be used in recalcitrant cases.
Other forms of treatment are discussed in Chapter 5.
Vernal Conjunctivitis & Atopic Keratoconjunctivitis (See Also Chapter 5)
These two diseases also belong to the group of atopic disorders. Both are characterized by
itching and lacrimation of the eyes but are more chronic than hay fever conjunctivitis.
Furthermore, both ultimately result in structural modifications of the lids and conjunctiva,
especially atopic keratoconjunctivitis.
Vernal conjunctivitis characteristically affects children and adolescents; the incidence decreases
sharply after the second decade of life. Like hay fever conjunctivitis, vernal conjunctivitis occurs
only in the warm months of the year. Most patients live in hot, dry climates. The disease
characteristically produces giant ("cobblestone") papillae of the tarsal conjunctiva (Figure
162). The keratinized epithelium from these papillae may abrade the underlying cornea,
giving rise to complaints of foreign body sensation or even producing frank epithelial loss
("shield ulcer"). Alternatively, in some individuals, this disease affects the limbal region,
producing a characteristic gelatinous thickening of the limbal conjunctiva, often associated with
white accumulations of eosinophils and desquamated epithelial cells ("Horner-Trantas dots").

Figure 162.

Giant papillae ("cobblestones") in the tarsal conjunctiva of a patient with vernal conjunctivitis.

Atopic keratoconjunctivitis affects individuals of all ages and has no specific seasonal
incidence. The skin of the lids has a characteristic dry, scaly appearance. The conjunctiva is pale
and boggy. Both the conjunctiva and the cornea may develop scarring in the later stages of the
disease. Staphylococcal blepharitis, manifested by scales and crusts on the lids, commonly
complicates this disease. These patients are also more prone to herpes simplex ocular infections,
cataract, and retinal detachment.
Although vernal and atopic disease may lie along a disease spectrum, often the two disorders can

be differentiated. Atopic disease tends to occur in older patients, and there is little or no seasonal
exacerbation. The papillae in atopic disease are smaller than in vernal disease and are as often
found on the lower palpebral conjunctiva as the upper. Furthermore, corneal vascularization and
conjunctival scarring are much more common in atopic disease. Finally, in atopic disease,
eosinophils on smears are less numerous and less often degranulated.
Immunologic Pathogenesis
Reaginic antibody (IgE) is fixed to subepithelial mast cells in both of these conditions. Contact
between the offending antigen and IgE is thought to trigger degranulation of the mast cell, which
in turn allows for the release of vasoactive amines in the tissues. It is unlikely, however, that
antibody action alone is responsible, sinceat least in the case of papillae of vernal
conjunctivitisthere is heavy papillary infiltration by mononuclear cells. Furthermore, hay
fever and asthma occur much more frequently in patients with vernal conjunctivitis and atopic
keratoconjunctivitis than in the general population. These and other findings suggest that T cell
dysregulation also plays a role in the pathogenesis of vernal and atopic conjunctivitis.
Immunologic Diagnosis
Patients with atopic keratoconjunctivitis and vernal conjunctivitis generally show large numbers
of eosinophils in conjunctival scrapings. Skin testing with food extracts, pollens, and various
other antigens reveals a wheal-and-flare type of reaction within 1 hour after testing, but the
significance of these reactions is not established. Furthermore, the exact identities of the inciting
antigens in these cases are usually unknown.
Immunologic Treatment
Avoidance of allergens (if known) is helpful; such objects as duck feathers, animal danders, and
certain food proteins (egg albumin and others) are possible offenders. Specific allergens have
been especially difficult to demonstrate in the case of vernal disease, although some workers feel
that such substances as rye grass pollens may play a causative role. Installation of air
conditioning in the home or relocation to a cool, moist climate is useful in vernal conjunctivitis.
Other treatments are discussed in Chapter 5.
Joint Diseases Affecting the Eye
The diseases in this category vary greatly in their clinical manifestations depending on the
specific disease entity and the age of the patient. Uveitis and scleritis (Chapter 7) are the
principal ocular manifestations associated with joint diseases. Juvenile idiopathic arthritis
affects females more frequently than males and is commonly accompanied by iridocyclitis of one
or both eyes (see Chapters 7, 15, and 17).
Ankylosing spondylitis affects males more frequently than females, and the onset is in the
second to sixth decades. It may be accompanied by iridocyclitis of acute onset, often with fibrin

in the anterior chamber (Figure 163).

Figure 163.

Acute iridocyclitis in a patient with ankylosing spondylitis. Note fibrin clot in anterior chamber.

Reiter's disease affects men more frequently than women. The first attack of ocular
inflammation usually consists of a self-limited papillary conjunctivitis. It follows, at a highly
variable interval, the onset of nonspecific urethritis and the appearance of inflammation in one or
more of the weight-bearing joints. Subsequent attacks of ocular inflammation may consist of
acute iridocyclitis of one or both eyes, occasionally with hypopyon (Figure 164).
Rheumatoid arthritis of adult onset may be accompanied by acute scleritis or episcleritis but
very rarely by uveitis (Figure 165) (see also Chapter 7).

Figure 164.

Acute iridocyclitis with hypopyon in a patient with Reiter's disease.

Figure 165.

Scleral nodules in a patient with rheumatoid arthritis.

(Courtesy of S Kimura.)

Immunologic Pathogenesis
Rheumatoid factor, an IgM autoantibody directed against the patient's own IgG, may play a
major role in the pathogenesis of rheumatoid arthritis. The union of IgM antibody with IgG is
followed by fixation of complement at the tissue site and the attraction of leukocytes and
platelets to this area. An occlusive vasculitis, resulting from this chain of events, is thought to be
the cause of rheumatoid nodule formation in the sclera as well as elsewhere in the body. The
occlusion of vessels supplying nutrients to the sclera is thought to be responsible for the "melting
away" of the scleral collagen that is so characteristic of rheumatoid arthritis (Figure 166).

Figure 166.

Scleral thinning in a patient with rheumatoid arthritis. Note dark color of the underlying uvea.

While this explanation may suffice for rheumatoid arthritis, patients with the ocular
complications of juvenile rheumatoid arthritis, ankylosing spondylitis, and Reiter's syndrome
usually have negative tests for rheumatoid factor, so other explanations must be sought.
Outside the eyeball itself, the lacrimal gland has been shown to be under attack by circulating
antibodies. Destruction of acinar cells within the gland and invasion of the lacrimal gland (as
well as the salivary glands) by mononuclear cells result in decreased tear secretion. The
combination of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) is known as
Sjgren's syndrome (see Chapter 15).
A growing body of evidence indicates that the immunogenetic background of certain patients
accounts for the expression of their ocular inflammatory disease in specific ways. Analysis of the
HLA antigen system shows that the incidence of HLA-B27 is significantly greater in patients
with ankylosing spondylitis and Reiter's syndrome than could be expected by chance alone. It is
not known how this antigen controls specific inflammatory responses. Other well-established
HLA disease associations include HLA-A11 in sympathetic ophthalmia, HLA-A29 in birdshot
choroidopathy, HLA-B51 in Behet's syndrome, and HLA-B7 in macular histoplasmosis.
However, it remains unclear whether these HLA associations are indicative of causation or
merely markers for other cosegregating genes that are responsible for disease.
Immunologic Diagnosis
Rheumatoid factor can be detected in the serum by several standard tests involving the
agglutination of IgG-coated erythrocytes or latex particles. Unfortunately, the test for rheumatoid
factor is not positive in the majority of isolated rheumatoid afflictions of the eye.

The HLA types of individuals suspected of having ankylosing spondylitis and related diseases
can be determined. HLA-B27 is associated with ankylosing spondylitis and Reiter's syndrome.
X-ray of the sacroiliac area is a valuable screening procedure that may show evidence of
spondylitis prior to the onset of low back pain in patients with the characteristic form of
iridocyclitis.
Other Antibody-Mediated Eye Diseases (See Also Chapter 15)
The following antibody-mediated diseases are infrequently encountered by the practicing
ophthalmologist.
Systemic lupus erythematosus, associated with the presence of circulating antibodies to DNA,
produces an occlusive vasculitis of the nerve fiber layer of the retina. Such infarcts result in
retinal cotton-wool spots (Figure 167).

Figure 167.

Cotton-wool spots in the retina of a patient with systemic lupus erythematosus.

Pemphigus vulgaris produces painful intraepithelial bullae of the conjunctiva. It is associated

with the presence of circulating antibodies to an intercellular antigen located between the deeper
cells of the conjunctival epithelium.
Cicatricial pemphigoid is characterized by subepithelial bullae of the conjunctiva. In the
chronic stages of this disease, cicatricial contraction of the conjunctiva may result in severe
dryness of the eyes, scarring of the cornea, and ultimately blindness. Pemphigoid is associated
with local deposits of tissue antibodies directed against one or more antigens located in the
basement membrane of the epithelium. Systemic immunosuppressive treatment is often needed
in the progressive stages of this disease.
Stevens-Johnson syndrome is believed to result from immune complex deposition in the dermis
and conjunctival stroma. This deposition may lead to a cicatrizing conjunctivitis, with the
potential for severe corneal dryness and scarring. The disease is most commonly incited by drugs
such as sulfonamides or disorders such as herpes simplex or mycoplasmal infection.
Lens-induced uveitis is a rare condition that may be associated with circulating antibodies to
lens proteins. It is seen in individuals whose lens capsules have become permeable to these
proteins as a result of trauma or other disease (see Chapter 7). It is believed that the anatomy of
the lens sequesters lens antigens during immune system maturation, thereby preventing the

development of tolerance.
Cell-Mediated Diseases
This group of diseases appears to be associated with cell-mediated immunity or delayed
hypersensitivity. Various structures of the eye are invaded by mononuclear cells, principally
lymphocytes and macrophages, in response to one or more chronic antigenic stimuli. In the case
of chronic infections such as tuberculosis, leprosy, toxoplasmosis, and herpes simplex, the
antigenic stimulus has clearly been identified as an infectious agent in the ocular tissue. Such
infections are often associated with delayed skin test reactivity following the intradermal
injection of an extract of the organism.
More intriguing but less well understood are the granulomatous diseases of the eye, for which no
infectious cause has been found. Such diseases are thought to represent cell-mediated, possibly
autoimmune processes, but their origin remains obscure.
Ocular Sarcoidosis
Ocular sarcoidosis is characterized by a panuveitis with occasional inflammatory involvement of
the optic nerve, conjunctiva, and retinal blood vessels (see Chapters 7 and 15).
Immunologic Pathogenesis
Although many infectious or allergic causes of sarcoidosis have been suggested, none has been
confirmed. Noncaseating granulomas are seen in the uvea, optic nerve, conjunctiva, and adnexal
structures of the eye as well as elsewhere in the body. The presence of macrophages and giant
cells suggests that particulate matter is being phagocytosed. Some studies have suggested that
mycobacterial infection is an etiological factor.
Patients with sarcoidosis are usually anergic to extracts of the common microbial antigens, such
as those of mumps, trichophyton, candida, and Mycobacterium tuberculosis. As in other
lymphoproliferative disorders, such as Hodgkin's disease and chronic lymphocytic leukemia, this
may represent suppression of T cell activity such that the normal delayed hypersensitivity
responses to common antigens cannot take place. Meanwhile, circulating immunoglobulins are
usually detectable in the serum at higher than normal levels.
Immunologic Diagnosis
The diagnosis is largely inferential. Negative skin tests to a battery of antigens to which the
patient is known to have been exposed are highly suggestive, and the same is true of the
elevation of serum immunoglobulins. Biopsy of a conjunctival nodule or enlarged lymph node
may provide positive histologic evidence of the disease. X-rays of the chest reveal hilar
adenopathy in many cases. Serum angiotensin-converting enzyme is often elevated.

Treatment
See Chapter 15.
Sympathetic Ophthalmia & Vogt-Koyanagi-Harada Syndrome
These two disorders are discussed together because they have certain common clinical features.
Both are thought to represent autoimmune phenomena affecting pigmented structures of the eye
and skin, and both may give rise to meningeal symptoms.
Clinical Features
Sympathetic ophthalmia is an inflammation in the second eye after the other has been damaged
by penetrating injury. In most cases, some portion of the uvea of the injured eye has been
exposed to the atmosphere for at least 1 hour. The uninjured or "sympathizing" eye develops
minor signs of anterior uveitis after a period ranging from 2 weeks to many years. However, the
vast majority of cases occur within 1 year. As a result of ciliary body inflammation, floating
spots and loss of the power of accommodation are among the earliest symptoms. The disease
may progress to severe iridocyclitis with pain and photophobia. Usually, however, the eye
remains relatively painless while the inflammatory disease spreads around the entire uvea. The
retina usually remains uninvolved except for perivascular cuffing of the retinal vessels with
inflammatory cells. There may be choroidal lesions, representing the macroscopic manifestation
of Dahlen-Fuchs nodules (see below). Optic nerve swelling and secondary glaucoma may occur.
The disease may be accompanied by vitiligo (patchy depigmentation of the skin) and poliosis
(whitening) of the eyelashes. For unknown reasons, the incidence of this disease has decreased
markedly over the last several decades.
Vogt-Koyanagi-Harada syndrome consists of inflammation of the uvea of one or both eyes
characterized by acute iridocyclitis, patchy choroiditis, and serous detachment of the retina (see
Chapter 15). It usually begins with an acute febrile episode with headache, dysacusis, and
occasionally vertigo. Patchy loss or whitening of scalp hair is described in the first few months
of the disease. Vitiligo and poliosis are commonly present but are not essential for the diagnosis.
Although the initial iridocyclitis may subside quickly, the course of the posterior disease is often
indolent, with long-standing serous detachment of the retina and significant visual impairment.
Immunologic Pathogenesis
In both sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome, a delayed
hypersensitivity to melanin-containing structures, in the eye, skin, and hair, is provoked. Soluble
materials from the outer segments of the photoreceptor layer of the retina (retinal S-antigens)
have been incriminated as possible autoantigens. Patients with Vogt-Koyanagi-Harada syndrome
are usually of Southeast Asian ancestry, which suggests an immunogenetic predisposition to the
disease.
Histologic sections of the traumatized eye from a patient with sympathetic ophthalmia may show

uniform infiltration of most of the uvea by lymphocytes, epithelioid cells, and giant cells. The
overlying retina is characteristically intact, but nests of epithelioid cells may protrude through the
pigment epithelium of the retina, giving rise to Dalen-Fuchs nodules. The inflammation may
destroy the architecture of the entire uvea, leaving an atrophic, shrunken globe.
Immunologic Diagnosis
Skin tests with soluble extracts of human or bovine uveal tissue are said to elicit delayed
hypersensitivity responses in these patients. Several investigators have shown that cultured
lymphocytes from patients with these two diseases undergo transformation to lymphoblasts in
vitro when extracts of uvea or rod outer segments are added to the culture medium. Circulating
antibodies to uveal antigens have been found in patients with these diseases, but such antibodies
are to be found in any patient with long-standing uveitis, including those suffering from several
infectious entities. The spinal fluid of patients with Vogt-Koyanagi-Harada syndrome may show
increased numbers of mononuclear cells and elevated protein in the early stages. Treatment of
both conditions requires at least systemic steroids and often oral immunosuppressive therapy.
Other Diseases of Cell-Mediated Immunity
Giant cell arteritis (temporal arteritis) (see Chapter 15) may have disastrous effects on the eye.
The condition presents in elderly individuals usually with headache and numerous systemic
complaints, including polymyalgia rheumatica. Ocular complications include anterior ischemic
optic neuropathy and central retinal artery occlusion. Such patients have an elevated
sedimentation rate. Biopsy of the temporal artery reveals extensive infiltration of the vessel wall
with giant cells and mononuclear cells.
Polyarteritis nodosa (see Chapter 15) is a vasculitis that predominantly affects small- to
medium-sized vessels. It can affect both the anterior and posterior segments of the eye. The
corneas of such patients may show peripheral thinning and cellular infiltration. The retinal and
ciliary vessels reveal extensive necrotizing inflammation characterized by eosinophil, plasma
cell, and lymphocyte infiltration.
Wegener's granulomatosis is another systemic vasculitis with potential ocular manifestations.
In this disorder, necrotizing granulomatous inflammation primarily involves the upper
respiratory tract and kidneys. Ophthalmic involvement usually consists of peripheral ulcerative
keratitis and scleritis, but retinal vasculitis can occur. The presence of cANCA is helpful in
making the diagnosis.
Behet's disease (see Chapter 15) has an uncertain place in the classification of immunologic
disorders. It is characterized by recurrent iridocyclitis with hypopyon and occlusive vasculitis of
the retinal vessels. Although it has many of the features of a delayed hypersensitivity disease,
dramatic alterations of serum complement levels at the very beginning of an attack suggest an
immune complex disorder. Furthermore, high levels of circulating immune complexes have
recently been detected in patients with this disease. Most patients with eye symptoms are
positive for HLA-B51, a subtype of HLA-B5, and are of eastern Mediterranean or Southeast

Asian ancestry.
Contact dermatitis of the eyelids represents a significant although minor disease caused by
delayed hypersensitivity. Topical medications such as brimonidine and atropine, eye drop
preservatives, perfumed cosmetics, materials contained in plastic spectacle frames, and other
locally applied agents may act as the sensitizing hapten. The lower lid is more extensively
involved than the upper lid when the sensitizing agent is applied in drop form. Periorbital
involvement with erythematous, vesicular, pruritic lesions of the skin is characteristic.
Phlyctenular keratoconjunctivitis (Figure 168) represents a delayed hypersensitivity
response to certain microbial antigens, principally those of M tuberculosis and Staphylococcus
aureus (see Chapters 5 and 6).

Figure 168.

Phlyctenule (arrow) at the margin of the cornea.

(Courtesy of P Thygeson.)

Corneal Graft Reactions

(See Figure 169) Blindness due to opacity or distortion of the central portion of the cornea is
a remediable disease. If all other structures of the eye are intact, a patient whose vision is
impaired solely by corneal opacity can expect great improvement from a graft of clear cornea
into the diseased area (see Chapter 6). Trauma, including chemical burns, is one of the most
common causes of central corneal opacity. Others include scars from herpetic keratitis,
endothelial cell dysfunction with chronic corneal edema (including pseudophakic bullous
keratopathy and Fuchs' dystrophy), keratoconus, and opacities from previous graft failures. All of
these conditions represent indications for corneal grafts, provided the patient's eye is no longer
inflamed and the opacity has been allowed maximal time to undergo spontaneous resolution
(usually 612 months). Over 40,000 corneal grafts are performed in the United States annually,
of which 90% can be expected to produce a beneficial result.

Figure 169.

A cornea severely scarred by chronic atopic keratoconjunctivitis, into which a central graft of
clear cornea has been placed. Note how distinctly the iris landmarks are seen through the
transparent graft.
(Reproduced, with permission, from Parslow TG et al [editors]: Medical Immunology, 10th ed.
McGraw-Hill, 2001.)

The cornea was one of the first human tissues to be successfully grafted. The fact that recipients
of corneal grafts generally tolerate them well can be attributed to (1) the absence of blood vessels
or lymphatics in the normal cornea; (2) the paucity of antigen-presenting cells; (3) expression of
Fas ligand by corneal endothelial and epithelial cells, which induces apoptosis of inflammatory
cells; and (4) anterior chamber acquired immune deviation (ACAID). The latter is a series of
unique immunologic properties of the anterior chamber, conferring on the graft area the status of
immune privilege. Local constitutive expression of transforming growth factor (TGF)-

plays a central role in ACAID by downregulating delayed type hypersensitivity reactions.

Reactions to corneal grafts do occur, however, particularly in individuals whose own corneas
have been damaged by previous inflammatory disease. Such corneas may have developed both
lymphatics and blood vessels and may possess greater numbers of antigen-presenting cells, thus
providing afferent and efferent channels for immunologic reactions in the engrafted cornea. Graft
rejection is a major cause of corneal graft failure.
Although attempts have been made to transplant corneas from other species into human eyes
(xenografts), particularly in countries where human material is not available for religious
reasons, most corneal grafts have been taken from human eyes (allografts). Except in the case of
identical twins, such grafts always represent the implantation of foreign tissue into a donor site;
thus, the chance for a graft rejection due to an immune response to foreign antigens is virtually
always present.
The cornea is a three-layered structure composed of a surface epithelium, an oligocellular
collagenous stroma, and a single-celllayered endothelium. Although the surface epithelium
may be sloughed and later replaced by the recipient's epithelium, certain elements of the stroma
and all of the donor's endothelium remain in place for the rest of the patient's life. This has been
firmly established by sex chromosome markers in corneal cells when donor and recipient were of
opposite sexes.
A number of foreign elements exist in corneal grafts that might stimulate the immune system of
the host to reject this tissue. In addition to the structural cells and proteins mentioned above, the
corneal stroma is regularly perfused with IgG and serum albumin from the donor, although none
of the other blood proteins are presentor only small amounts. While these serum proteins of

donor origin rapidly diffuse into the recipient stroma and are thus removed from the graft site,
they are theoretically immunogenic.
Overall, the endothelium is more important than the epithelium or stroma in stimulating corneal
graft rejection. Whenever possible, corneal graft surgery is limited to lamellar keratoplasty, in
which the epithelium and stroma but not the endothelium are transplanted, but this does not
totally prevent graft rejection.
HLA incompatibility between donor and recipient has been shown by several authors to be
significant in determining graft survival, particularly when the corneal bed is vascularized. It is
known that most cells of the body possess these HLA antigens, including the endothelial cells of
the corneal graft and certain stromal cells (keratocytes). The epithelium has been shown to
possess a non-HLA antigen that diffuses into the anterior third of the stroma. Thus, while much
foreign antigen may be eliminated by purposeful removal of the epithelium at the time of
grafting, that amount of antigen which has already diffused into the stroma is automatically
carried over into the recipient.
Despite numerous analytic studies supporting the role of HLA incompatibility in corneal graft
rejection, a multicenter clinical trial found no use in HLA typing high-risk grafts. In this study,
ABO blood typing did provide a slight protective effect in high-risk cases. More recent studies
have shown the potential benefit on corneal graft survival of HLA triplet string-matching
systems, originally developed for renal transplantation.
Both humoral and cellular mechanisms have been implicated in corneal graft reactions. It is
likely that early graft rejections (24 weeks from surgery) are cell-mediated reactions.
Cytotoxic lymphocytes have been found in the limbal area and stroma of affected individuals,
and phase microscopy in vivo has revealed an actual attack on the grafted endothelial cells by
these lymphocytes. However, CD8 T cell knockout mice have been shown to mount vigorous
rejection responses, with delayed type hypersensitivity inflammatory cells predominating, thus
indicating that cytolytic T cells may not be essential in graft rejection. Lymphocytes mediating
rejection generally move inward from the periphery of the cornea, making what is known as a
"rejection line" as they move centrally. The donor cornea becomes edematous as the endothelium
becomes compromised by an accumulation of lymphoid cells.
Late rejection of a corneal graft may occur several weeks to many months after implantation of
donor tissue into the recipient eye. Such reactions may be antibody-mediated, since cytotoxic
antibodies have been isolated from the serum of patients with a history of multiple graft reactions
in vascularized corneal beds. These antibody reactions are complement-dependent and attract
polymorphonuclear leukocytes, which may form dense rings in the cornea at the sites of
maximum deposition of immune complexes. In experimental animals, similar reactions have
been produced by corneal xenografts, but the intensity of the reaction can be markedly reduced
either by decomplementing the animal or by reducing its leukocyte population through
mechlorethamine therapy.

Treatment
The mainstay of the treatment of corneal graft reactions is corticosteroid therapy. This
medication is generally given in the form of frequently applied eye drops (eg, 1% prednisolone
acetate every hour) until the clinical signs abate. These clinical signs consist of conjunctival
hyperemia in the perilimbal region, a cloudy cornea, cells and protein in the anterior chamber,
and keratic precipitates on the corneal endothelium. The earlier treatment is applied, the more
effective it is likely to be. Some cases may require systemic or periocular corticosteroids in
addition to local eye drop therapy. High-dose intravenous steroids may also be efficacious if used
sooner than 8 days after onset of the rejection period. Occasionally, vascularization and
opacification of the cornea occur so rapidly as to make corticosteroid therapy useless, but even
the most hopeless-appearing graft reactions have occasionally been reversed by corticosteroid
therapy. Oral cyclosporine has been used successfully in the treatment of corneal graft rejection,
and some benefit may be derived from cyclosporine eye drops.
Patients known to have rejected many previous corneal grafts or at high risk of rejection for other
reasons are managed somewhat differently, particularly if disease affects their only remaining
eye. Some surgeons may choose to find a close HLA match between donor and recipient.
Pretreatment of the recipient with immunosuppressive agents such as azathioprine, cyclosporine,
or, most recently, mycophenolate mofetil has also been resorted to in some cases.
Recent Developments in Immunotherapy
While the initiators of ocular inflammatory diseases remain in many cases the subject of active
speculation, the complex immunomodulatory signals that mediate the inflammatory response are
rapidly being elucidated. Of paramount importance in many inflammatory diseases are T
cellmediated immune reactions. CD4 T-helper cells can be divided into two subsets known as
TH1 and TH2. TH1 cells direct the immune response down the cell-mediated immunity (CMI),
delayed type hypersensitivity route via the release of interleukin (IL)-2, tumor necrosis factor
(TNF
), and interferon
(IFN
). In contrast, activation of TH2

cells favors the development of humoral immune responses via the production of IL-4, IL-5, IL10, and IL-13. Individual genetic susceptibility (eg, HLA types), lymphatic system anatomy, and
cellular trafficking patterns as well as local tissue levels of still other regulatory cytokines, such
as TGF, appear important in modulating the relative responses of these TH1 and TH2

subsets.
While CMI plays a vital role in protecting against many infections through the activation of
macrophages and cytolytic T cells, the unregulated or inappropriate progression of CMI leads to
delayed type hypersensitivity with the potential for severe tissue damage. Indeed, TH1 profile

cytokines are now known to play a central role in numerous systemic inflammatory conditions,
such as rheumatoid arthritis, inflammatory bowel disease, and ankylosing spondylitis and even in
type 1 diabetes. Moreover, there is strong evidence that similar cytokines underpin numerous
forms of uveitis and scleritis. Therapies directed against these cytokines are now in clinical use.
Cyclosporine, which antagonizes the intracellular signaling initiated by IL-2, has been used
effectively in many inflammatory disorders, including Behet's disease. More recently, the
TNF
antagonists etanercept (a TNF
receptor fusion protein) and infliximab (a

chimeric monoclonal antibody directed against human TNF

) have been shown to have

positive effects in rheumatoid arthritis and other diseases such as ankylosing spondylitis and
scleroderma. It appears likely that these types of anticytokine medications will play an expanding
role in the therapy of inflammatory diseases in the near future.