Chapter 16:
Immunologic Diseases of the Eye
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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: antibody-mediated 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:
There must be evidence of specific antibody in the patient's serum or plasma cells.
The antigen must be identified and, if feasible, characterized.
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.
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 antibody-dependent. In such circumstances, the disease can be regarded as antibody-mediated if only one of the following criteria is met:
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).
If abnormal accumulations of plasma cells are present in the ocular lesion.
If abnormal accumulations of immunoglobulins are present at the site of the disease.
If complement is fixed by immunoglobulins at the site of the disease.
If an accumulation of eosinophils is present at the site of the disease.
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 16-1) and by itching, which is always present, and watering of the eyes. 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 is a distinct seasonal incidence, some 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.
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 leuko-trienes and histamine, in this area, and this in turn 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 subcutaneously injected pollen extracts or other suspected allergens appears to reduce the severity of the disease in some individuals if started well in advance of the season. The mechanism is presumed to be production of blocking antibodies in response to the injection of small, graded doses of the antigen. This procedure cannot be recommended routinely, however, in view of the generally good results and relatively few complications of antihistamine therapy. Acute anaphylactoid reactions have occasionally resulted from overzealous immunotherapy. Topical antihistamines are the mainstay of treatment, and occasionally mast cell stabilizers and mild nonpenetrating corticosteroids.
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 of its victims live in hot, dry climates. The disease characteristically produces giant ("cobblestone") papillae of the tarsal conjunctiva (Figure 16-2). 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").
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. Atopic cataract has also been described. 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.
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, since-at least in the case of papillae of vernal conjunctivitis-there is heavy papillary infiltration by mononuclear cells. Hay fever and asthma occur much more frequently in patients with vernal conjunctivitis and atopic keratoconjunctivitis than in the general population. Of the criteria outlined above for demonstration of possibly antibody-dependent diseases, (2), (5), and (6) have been met by atopic keratoconjunctivitis.
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 identification of the inciting antigens in these cases is 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, though 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 upon 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 rheumatoid arthritis affects females more frequently than males and is commonly accompanied by iridocyclitis of one or both eyes (see Chapter 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 16-3).
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 16-4). Rheumatoid arthritis of adult onset may be accompanied by acute scleritis or episcleritis but very rarely by uveitis (Figure 16-5). (See also Chapter 7.)
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 16-6).
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), dry mouth (xerostomia), and rheumatoid arthritis is known as Sjögren'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 histocompatibility leukocyte antigen (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 Behçet's syndrome, and HLA-B7 in macular histoplasmosis.
Immunologic Diagnosis
Rheumatoid factor can be detected in the serum by a number of 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 16-7).
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 scarring of the cornea, dryness of the eyes, and ultimate blindness. Pemphigoid is associated with local deposits of tissue antibodies directed against one or more antigens located in the basement membrane of the epithelium. Immunosuppressive treatment is often needed in the progressive stages of this disease.
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). Interest in this field dates back to Uhlenhuth (1903), who first demonstrated the organ-specific nature of antibodies to the lens. Witmer showed in 1962 that antibody to lens tissue may be produced by lymphoid cells of the ciliary body.
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10.1036/1535-8860.ch16