Azathioprine

Azathioprine is considered as a proven immuno-suppressive drug with considerably fewer side effects. Therefore it is acceptable as an alternative to cyclosporine A for the treatment of eye involvement in Beh et's disease. In a placebo controlled double-blind study, azathioprine (dosage of 2.5mg kg daily) was effective in controlling intraocular inflammation, maintaining visual acuity as well as preventing an onset or progression of eye disease 153 . Compared to those patients originally...

Epstein Barr Virus EBV Uveitis

Benign and transitory uveitis has been described during the course of EBV-associated infectious mononucleosis. Different forms of anterior uveitis, multifocal choroiditis and panuveitis have been attributed to EBV infection 58 . However, it is difficult to isolate a distinct entity to characterize EBV infections of the eye. This is probably due to the risk of blood contamination associated with the presence of EBV in mononuclear cells, which may be found after anterior chamber paracentesis....

HLApeptide B27PD as Oral Tolerogen

The 14-mer peptide B27PD (ALNEDLSS-WTAADT) has been shown to be highly effective for the treatment of experimental autoimmune uveitis in rats 80 . Therefore a prospective uncontrolled open trial for nine patients with chronic anterior, intermediate or posterior uveitis was initiated, using the encapsulated peptide for oral treatment 75 . All patients were on long-lasting conventional im-munosuppressive therapy and either suffered from severe side effects or were unresponsive to this treatment....

Systemic Corticosteroids

Corticosteroids are potent modulators of the immune system but have low specificity and serious side effects. Their well-known and serious side effects, including osteopaenia, weight gain, hyperglycaemia, hypercholesterolaemia, hypertension, and skin fragility, can occur with modest doses administered over relatively short periods. Despite this they are widely used in solid organ transplantation, where their combination with other immunosuppressive agents enables the use of lower doses of the...

Topical Steroid Treatment

Since JCA is not a distinct disease entity and the clinical manifestation of uveitis varies considerably, no standard treatment approach can be recommended. It cannot be overstressed that children with risk of ocular complications need to be identi fied as early as possible. In general, any first manifestation of anterior uveitis will initially undergo topical treatment with potent corticos-teroids such as prednisolone acetate, dexam-ethasone or betamethasone. No general advice on frequency and...

Gastrointestinal Manifestations

Gastrointestinal manifestations occur in 3-30 of patients. Differentiation from inflammatory bowel disease (IBD) is difficult. Main symptoms are abdominal pain (92 ), followed by diarrhoea (29 ) and gastrointestinal bleedings (5 ). Diffuse ulcerations (76 ) are more common than localized aphthous ulcers. The ulcerations are deep, and oesophagus and rectum may be affected. They are mainly localized in the ileocoecal region (96 ). Perforations are common (56 in a Japanese study). Histo-pathology...

Corticosteroids

Because of their high anti-inflammatory potential, corticosteroids are widely used in the management of ocular Behcet's disease. They are indicated to shorten the duration of an acute uveitis attack, but as a monotherapy they are not effective for long-term treatment, probably because the doses necessary for maintenance of remission would be too high, accompanied by unacceptable side effects 77 . Thus in most cases a steroid sparing immunosuppressive agent has to be added. An exception may...

Acute Retinal Necrosis

Antivirals represent the major tools in the treatment of viral retinopathies. Any delay in the initiation of antiviral therapy may be dangerous for the visual outcome of the patient. Despite a few reports on the efficacy of oral valacyclovir, intravenous administration of acyclovir remains the classical approach. It is effective against HSV and VZV. Close monitoring of the retina is necessary in order to confirm antiviral efficacy. Lesions must be stabilized after a mean period of 48 h. In...

Conclusion

At present very little can be done to modulate the immune response in patients having corneal transplants and at risk of rejection. Reducing inflammation by minimizing microsurgical trauma and generous use of topical corticos-teroids is all that is usually available. However, a strong case can be made for HLA-A, -B and -DR matching, but in many places this would demand a change in eye banking logistics. Conventional systemic immunosuppression, the mainstay of immunomodulation for solid organ...

Monoclonal Antibody Fragments

Antibody-based treatments have been used in transplantation for many years. Initially het-erologous antilymphocyte serum or globulin was used and more recently monoclonal antibodies have been employed. OKT3, an anti pan T-lymphocyte monoclonal antibody, has been used for the treatment of organ rejection. This systemic approach has not found a place in corneal transplantation. It can only be used once and the systemic administration can be hazardous. As with other approaches to systemic...

Glaucoma

Uveitic eyes with glaucoma should be evaluated for the feasibility of implantation of a glaucoma drainage device (GDD) at the time of PPV. Anterior segment inflammation can cause early failure of trabeculectomies and also severe complications of fibrosis surrounding anteriorly placed tubes of GDDs 3 . Placement of the GDD in the posterior segment through the pars plana can avoid these severe complications. Excellent cleanup of the peripheral vitreous and posterior cortical vitreous is necessary...

Lamellar Keratoplasty Penetrating Keratoplasty

The most common indications for penetrating keratoplasty (PK) and lamellar keratoplasty (LK) are corneal perforation and extensive corneal scarring 29 . However, the outcome of even successful PK is poor in eyes with endstage chronic cicatrizing conjunctival diseases such as OCP. This is primarily due to the im- munologically driven conjunctival inflammation, trichiasis distichiasis, severe dry eye and extensive corneal neovascularization. Graft failure occurs due to many factors either acting...

Clinical Features of Uveitis in JCA

The onset of uveitis in children with JCA is usually insidious, bilateral and anterior in type 8 . It is almost characteristic that even severe intraocular inflammation does not lead to ex-traocular signs and no alarming symptoms are recognized by the parents. Because of this asymptomatic onset there is often a significant delay of adequate diagnosis and treatment. It is not rare that children first seen by an ophthalmologist already present with secondary ocular 9.7 Complications of Uveitis in...

Inflammatory Cytokines Induce a Leukocyte Infiltrate

The leukocyte immigration is mediated by chemoattractants such as the leukotrienes released from mast cells but also by chemotactic cytokines (chemokines) produced in epithelial cells and stromal fibroblasts after stimulation by mast cell cytokines,namely by the inflamma tory cytokine TNF-a. TNF-a also initiates an upregulation of the cell adhesion molecule ICAM-1 on vascular endothelial cells and on epithelial cells. VCAM-i and E-selectin were also found to be inflammation dependent and...

Cyclosporine A CsA

Cyclosporine inhibits T cells by interfering with intracellular signalling pathways. After antigen recognition of the T cell, the T-cell receptor CD3 complex on the cell surface is activated and induces a cascade of intracellular signalling pathways, finally upregulating transcription of inflammatory cytokines like IL-2, -3, -4, IFN-g and expression of IL-2 receptor 43 . Cyclosporine as well as tacrolimus inhibit this signalling and therefore inhibit activation of T cells after antigen...

Steroidsparing agents have fewer preventable and reversible side effects in comparison to steroids for treatment of OCP

Ahmed AR, Foster S, Zaltas M, et al. (1991) Association of DQw7 (DQB1*0301) with ocular cicatricial pemphigoid. Proc Natl Acad Sci U S A 2. Ahmed AR, Konqui A, Park MS, Tiwari JL, Terasa-ki PI (1984) DR antigens in bullous pemphigoid. Arch Dermatol 120 795 3. Dantzig PI (1974) Immunosuppressive and cyto-toxic drugs in dermatology. Arch Dermatol 110 393-406 4. De Rotth A (1940) Plastic repair of conjunctival defects with fetal membranes. Arch Ophthalmol 5. Dohlman CH, Terada H (1998)...

Diagnosis

Diagnosis of LKC or dry eye disease is complicated by symptoms that are common to other ocular surface disorders as well. However, two sorts of complaints are suggestive of dry eye exacerbation of ocular irritation by environmental stress, such as the low humidity of airplanes, smoky environments, or drafts from air conditioners, and exacerbation by activities that require prolonged visual attention, such as reading or viewing a video display terminal. A history consistent with Sjogren's...

Mycophenolate Mofetil

Like methotrexate, mycophenolate mofetil (MMF) interferes with purine synthesis. Both drugs selectively and reversibly inhibit the enzyme inosine monophosphate dehydrogenase, which is important for guanosine and purine synthesis. With the exception of lymphocytes, most cells in the body can use salvage pathways to circumvent the inhibition of the de novo synthesis of purine. Since T and B cells depend exclusively on the de novo synthesis pathway, MTX and MMF impede cell growth and...

General consideration

Recent developments in molecular biology allow novel diagnostic approaches in intraocular 17.5 Postoperative Complications 279 inflammation. Genetic markers as well as species-specific sequences are used for the diagnosis of infection or masquerade syndromes. An established collaboration with a microbiology department to test for infectious agents in vitreous fluid as well as an immediate transfer of vitreous cells to a pathology department to prevent rapid autolysis of the cells are...

Clinical Symptoms and Findings

Patients usually consult because of loss of vision, metamorphopsias and scotomata. Photop-sias seem to be less in the foreground in serpiginous choroiditis than in other PICCPs. The anterior segment is usually uninflamed whereas minimal to mild vitreitis is usually associated with the choroiditis. The active lesions appear as grey-yellow-white deep lesions beginning in the peripapillary region and progressing in a centrifugal fashion. The type of progression of lesions and scar formation can...

Differential Diagnosis

In its classical presentation, CMV retinitis is easy to diagnose. However, it may simulate (or be masked by) a number of ocular conditions from which it can be distinguished by its presentation, time course, or response to treatment. When CMV retinitis starts adjacent to a blood vessel, it can either cause a vascular occlusion with the typical arcuate haemorrhages seen along the course of an occluded branch retinal vein (BRVO), or it may present as a frosted angiitis. In the latter case, the...

Basics

Dry eye disease has traditionally been defined as a tear deficiency. Research over the past decade, however, has led to an appreciation of the central role that ocular surface inflammation plays in dry eye disease. Dry eye may now be viewed as a syndrome in which an unstable tear film of altered composition fails to support ocular epithelial health and instead promotes ocular surface inflammation. Recent research has also led to recognition that the ocular surface and tear secreting glands act...

Fundamental Virology

Eight human herpesviruses have already been characterized. All of these viral agents can induce ocular inflammation. The family includes herpes simplex virus (HSV) type 1 and type 2, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes virus 6 (HHV-6), herpes virus 7 (HHV-7) and herpes virus 8 (HHV-8), also known as an agent of Kaposi's sarcoma, (KSHV). HSV and VZV are alpha herpesviruses that infect a wide variety of cell types, where they replicate rapidly...

Experimental Autoimmune Uveitis EAU

EAU is an animal model of posterior uveitis, which can be induced in genetically susceptible animal species by immunization with uveito-genic retinal antigens or by the adoptive transfer of antigen-specific T cells 6 . The EAU course is characterized by photoreceptor damage, vasculitis, choroiditis and vitritis, serous retinal detachment and retinal folding. EAU histopathology strikingly resembles lesions of ocular sarcoidosis,Vogt-Koyanagi-Harada (VKH) syndrome, sympathetic ophthalmia,...

Metabolism of Extracellular Matrix

The analysis of ECM in VKC demonstrated a reduction in proteoglycans and a substantial increase in total collagen with an altered ratio between collagen type I and III, due to a consistent increase in collagen type III 27 . Moreover, a high amount of procollagens type I and III in the tears during active tarsal VKC has also been reported. This increased deposition of collagen types I, III and IV in the giant papillae might be viewed as a result of increased expression of cytokines and growth...

Necrotizing Herpetic Retinopathies NHR

Acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN) and cytomegalovirus retinitis are well-defined entities. Diagnosis is quite unequivocal when the clinical presentation is typical, but fundus examination can be difficult in the presence of cloudy media. Cun- ningham et al. reported the first two cases of AIDS-associated herpetic retinitis, confirmed by PCR and restriction analysis of the vitreous biopsy 14 . The amount of herpes virus DNA, detectable by PCR techniques in...

Vascular Manifestations

Vascular manifestations occur in 28 and consist of thromboses and arterial aneurysms. Symptoms correlate with the localization and mostly occur 3-4 years after the first manifestation of BD.Venous thrombosis is more common than arterial complications. Most commonly occlusions of the superior or inferior vena cava, femoral veins, cerebral veins, veins of the upper extremities and liver veins (Budd-Chiari syndrome) occur. Rarely, also thrombosis of the renal veins, the portal vein with...

Anterior Chamber Paracentesis ACP

ACP seems to be safe, but it should be considered a surgical procedure and be performed by an experienced ophthalmologist. It can be performed at the slit lamp or under a microscope in the operating room after instillation of topical antibiotic and anaesthetic drops. Up to 0.2 ml can be obtained. In a retrospective study of 36i patients, Van der Lelij and Rothova reported no serious complications, such as cataract, keratitis or endophthalmitis after paracentesis 62 . Hy-phema was reported in...

Manifestation Prior to Initial Treatment

Often asymptomatic, CMV retinitis may be associated with a complaint of increasing floaters. If the disease is present centrally, it will lead to a permanent noticeable decrease in vision. Most CMV lesions do not start in the fovea, but are initially found somewhere in the peripheral retina, or along the arcades. In AIDS patiens not receiving HAART, untreated CMV retinitis will progress at 750 mm week 13 . In other immuno-suppressed patients, the progression rate is less, and is related to the...

Introduction

Keratoplasty, as an organ transplantation procedure, is enormously dependent on immunolog-ical mechanisms. The rejection rate in the otherwise normal and inflammation free ocular surface is relatively low because the normal cornea contains no blood vessels, no lymphocytes and only relatively few cells that express MHC class II. Furthermore, the anterior chamber appears to possess an immune privilege. This anterior chamber associated immune privilege (ACAID) induce stolerance against anti- Fig....

Neuropeptide and Growth Factor Involvement

Allergic inflammation might also follow the release of neuropeptides, mainly substance P, as observed in VKC 20 , which cause characteristic features of allergic inflammation, including vasodilatation, increased vascular permeability and a contribution to further release of hista-mine from MCs. Specifically, tryptase- and his-tamine-releasing factors might greatly contribute to SP release and to amplifying the chronic allergic reaction, triggering nerves to release neuropeptides by binding to...

Posner Schlossman Syndrome

Posner-Schlossman syndrome is strictly unilateral associating a granulomatous anterior uveitis with central KPs and secondary glaucoma. Posterior synechiae are absent. Intraocular synthesis of anti-CMV antibodies was previously reported by Bloch-Michel and associates 7 . The disease is probably multifactorial and different entities must be considered. Antiviral therapy based on acyclovir is not effective, but anti-CMV drugs may prevent recurrences and control ocular hypertension.

Visual Field Testing

Visual field testing objectively identifies the sco-tomata the patients report. They correspond to the areas of fundus discoloration that correspond also to the hypofluorescent zones on ICGA. If the size of the lesions is small, no scotomata and minimal fluorescein signs are present and the only way to make the diagnosis is by ICGA showing the typical dark dots up to the late phase of angiography without functional translation. Resolution of dark dots occurs in parallel with visual field...

Anatomy

The sclera is the durable, outer connective tissue layer of the eye that protects the intraocular contents and maintains the shape of the globe. The episclera is the most superficial layer, composed of an outer, parietal layer that merges with the overlying conjunctiva and a deeper, visceral layer that connects with the underlying sclera. The scleral stroma is formed of dense collagen bundles with an interlacing array of fibrils, responsible for the opaque appearance and rigidity of the sclera...

Dysfunction of the Afferent System

Decreased afferent sensory input from the ocular surface results in decreased lacrimal function and epithelial mucin production, which in turn can lead to LKC. For example, patients with familial dysautonomia (Riley-Day syndrome), a 2.2 Specific Pathologies of the Lacrimal Functional Unit hereditary sensory and autonomic neuropathy that causes corneal anaesthesia, produce a reduced amount of tears when crying and suffer from severe LKC. Their reflex lacrimation response to irritants such as...

Anterior Segment Changes

Anterior uveitis may be the only ocular manifestation in BD patients. Anterior uveitis is an inflammation, which is limited to the iris and the vitreous. The synonym of anterior uveitis is iridocyclitis. In the literature, the classic finding in BD patients is an anterior uveitis described as occurring together with hypopyon (Fig. i2.4) in 30 of cases ii, 2i, 96 . Nowadays, iridocyclitis occurs mostly in isolation, which is probably due to earlier and more aggressive treatment, resulting in...

Cytomegalovirus CMV Uveitis

CMV involvement of the anterior segment in immunocompetent patients was reported very recently 47 . This entity differs from HSV or VZV uveitis. Chronicity is a major characteris tic. Ocular inflammation lasts for a long time and seems to be mild to moderate. Small size KPs are brown and scattered in the lower part of the cornea. This disease occurs more frequently in elderly patients. Sectorial iris atrophy is not a common finding and posterior synechiae are rarely observed. Secondary glaucoma...

Herpes Simplex Virus HSV Infection

There is no direct correlation between herpetic keratitis and uveitis. Patients with stromal keratitis may present concurrent anterior uveitis. Fig. 10.3. Iris atrophy associated with HSV-1 infection Fig. 10.3. Iris atrophy associated with HSV-1 infection However, anterior uveitis may occur with no active corneal inflammation. Recurrent episodes can damage the eye and spread to the posterior segment, involving the vitreous and the retina. Despite virological confirmation, mostly by polymerase...

Lacrimal Keratoconjunctivitis Inflammation

Dysfunction of the lacrimal functional unit leads to ocular surface epithelial disease, which has been traditionally called keratoconjunctivitis sicca. We feel that the newly introduced term, lacrimal keratoconjunctivitis (LKC), more completely describes the array of pathological features associated with this syndrome (Table 2.3). Although our view of ocular surface pathology resulting from secretory dysfunction is incomplete, changes in tear fluid composition are clearly central in its...

Chronic Allergic Eye Diseases

Chronic allergic ocular disease encompasses several disorders, such as seasonal atopic conjunctivitis, perennial atopic conjunctivitis, atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) 7 . Seasonal atopic conjunctivitis (SAC) is a time-limited disease and in most cases conjunctivitis is only one manifestation of additional allergic reactions (rhinitis, hay fever or a hay fever like symptomatology, and in severe cases conjunctivitis is associated with different forms of...

Chlorambucil

Like cyclophosphamide, chlorambucil is an alkylating nitrogen mustard derivative. It interferes with DNA replication, transcription and RNA translation, resulting in cytotoxicity. Chlor-ambucil is readily resorbed after oral administration and metabolized in the liver to the active substance phenylacetic acid mustard. The major excretion route of this and other metabolites is through the kidney. Chlorambucil is used for the treatment of malignancies as well as autoimmune diseases with...

Neurological Manifestations

Neurological manifestations are present in 8-31 of all patients and mostly begin 4-6 years after the first manifestation of BD. In neuro-BD, parenchymal involvement is distinguished from non-parenchymal (vascular) involvement, where the parenchymal lesion, when it occurs, is secondary to another pathological process, such as large arterial or venous occlusion, haemorrhage, etc., and thus corresponds to a major vascular territory. Intracranial hypertension with or without dural sinus thrombosis...

Varicella Zoster Virus VZV

Uveitis is much more common after herpes zoster ophthalmicus. Nearly two-thirds of patients with herpes zoster involving the ophthalmic division of the trigeminal nerve may present ocular involvement, especially without acyclovir prophylaxis. Uveitis is less frequent after an episode of varicella. Ocular inflammation is often delayed relative to the onset of cutaneous lesions. An interval of 2-4 weeks may separate both diseases. Uveitis seems to be more severe when it is delayed and associated...

Daclizumab

T cells upregulate their receptor for IL-2 (IL-2R) upon activation. Targeting the a-chain of the high-affinity IL-2R will thus affect only activated T cells, the population that maintains the autoaggressive immune response, while leaving the pool of memory and nai've T cells untouched. In rodent experimental autoimmune uveitis the autoaggressive Th1 cells express large numbers of IL-2R 11 . In a non-human primate model, targeting IL-2 receptors could effectively downregulate experimentally...

Symptoms and Clinical Findings

A large proportion of patients are treated for a recurrent granulomatous uveitis that flares up with a still relatively high steroid treatment level. In 25 of cases there may be an isolated chorioretinitis and in 75 chorioretinitis is associated with an anterior granulomatous uveitis. On funduscopy, in long-lasting cases there are multiple bilateral chorioretinal scars sometimes strongly pigmented (Fig. 15.5 a) which may be associated with recent choroidal lesions presenting as yellow-grey deep...

Perioperative Immunosuppression

No valid data exist that demonstrate that perioperative control of inflammation reduces the risk of postoperative complications from PPV such as the development of hypotony or CME. Extrapolation from cataract surgery in uveitis patients suggests that surgical results in patients undergoing elective PPV may be better if the inflammation is well controlled. Immuno-suppressive treatment seemed to permit safe intraocular lens (IOL) implantation in selected JIA-uveitis children (five patients) 4 , a...

Fluorescein Angiography

Fluoresein angiography shows mainly signs of chorioretinal scarring, with window effects being associated with masking effects where there is pigment clumping. In the active phase FA may show faint late hyperfluorescence in areas corresponding to ICGA hypofluorescent dark dots, corresponding to new lesions (Fig. 14.5 c). The use of fluorescein angiography is, however, of little use for assessing and following active disease, as FA angiographic signs are often absent or faint in new areas of...

Complications of Uveitis in JCA

The overall prognosis and functional outcome in children with JCA may have improved nevertheless a number of ocular complications can lead to poor prognosis for vision. The most frequent complications include band keratopathy, secondary glaucoma, posterior synechiae, cataracta complicata, and cystoid macular edema (Table 9.3). Band keratopathy is not necessarily a visually disabling complication in JCA but can be frequently observed. The hydroxylapatite deposits at Bowman's layer are an...

Corneal Epithelial Disease

The decreased tear production and altered tear composition associated with dysfunction of the lacrimal functional unit contribute to poor lubrication of the ocular surface and a destabilized tear film. This is evident clinically as rapid tear break-up (see Sect. 1.4), with visible discontinuities in the tear film 24, 34 . The unstable tear film is associated with corneal epithelial surface irregularities that are detectable by computerized videokeratoscopy 4 .The blurred, fluctuating vision,...

Hlab51

Although the aetiology and pathogenesis of Be-hcet's disease remains unknown, HLA typing of affected individuals revealed a strong association with HLA-B*5i 44, 45 . HLA-B*5i was detected in 50-80 of patients with Behcet's disease in many ethnic populations from the Middle East to Japan, including Turkish, Greek, Italian, French, Tunisian, Saudi Arabian, Israeli, Chinese, Korean, and Japanese, as compared to its presence in only i0-20 of unaffected controls. Studies using HLA-B*5i transgenic...

Skin Lesions

Skin lesions occur in 41-94 of cases and are morphologically diverse. Papulopustules, ac-neiform pseudofolliculitis and erythema no-dosa are most common, but pyodermia, ulcerations, necrotizing lesions, Sweet syndrome and superficial thrombophlebitis may also occur. Polymorphic erythema or pyoderma gangreno-sum and pernio-like lesions are rare. Different skin lesions can occur in the same patient, either sequentially or at the same time. Histologi-cally, there is a leucocytic vasculitis with...

HLA Nomenclature

Historically, an individual's HLA type was determined serologically, and each new type described was given a number, for example HLA-B*27. A workshop number indicated by a w would be given when the HLA type was in the process of being established, for example HLA-DRw4. A subtype would be indicated by a decimal point, for example HLA-A29.1 and HLA-A29.2. Since the advent of polymerase chain reaction technology,DNA sequencing and other techniques to determine HLA genotypes, a different but...

Recirculation to EALT

In EALT, there is only sparse information so far about homing mechanisms and regulating factors. The presence of high endothelial venules in the normal human conjunctiva has been shown (for review see 26 ). The intestinal vascular ad-dressin MAdACAM-1 is not observed on high endothelial venules but other adhesion molecules like VAP-1, ICAM-1, VCAM-1 and E-se-lectin have been found and showed a weak or sporadic staining. These addressins are thought to be possibly involved in extraintestinal...

Core Messages

Immunogenetics is helpful to the clinician in evaluating patients with uveitis.The immunogenetics of disease also has implications for disease pathogenesis and nosology, which are important for designing both basic science and clinical research Human leukocyte antigen (HLA) associations are particularly strong in birdshot retinochoroidopathy,tubulointerstitial nephritis and uveitis syndrome,Vogt-Koyanagi-Harada disease in Asian populations, and acute anterior uveitis Additional, non-HLA...

Vogt KoyanagiHarada Disease

Vogt-Koyanagi-Harada (VKH) disease is a bilateral, granulomatous panuveitis with exudative retinal detachments associated with systemic manifestations such as meningeal signs and cutaneous signs (poliosis, alopecia, vitiligo) and dysacusis 6 . There is now enough evidence to indicate that the disease is caused by an autoimmune process against melanocytes or an antigen present in these cells, namely tyrosinase or tyrosinase related protein 7 . As for most of these autoimmune diseases an...

HLA Associations with Ocular Infections

While infections are clearly due to exogenous agents and therefore an environmental factor par excellence for ocular inflammatory disease, it is similarly clear that the host response is critical in determining disease outcome. An elegant animal model of herpes simplex virus (HSV) stromal keratitis that illustrates this, as well as the complexities of HLA in disease, has been reviewed elsewhere 16 . An HSV coat protein, UL-6, shares a seven amino acid sequence with IgG2a. Mice were protected...

Cytokines in EAU

Cells polarized towards a Th1 phenotype secrete interleukin-2 (IL-2) and interferon-g (IFNg), which are thought to be primarily responsible for cell-mediated inflammatory reactions, de-layed-type hypersensitivity (DTH), and tissue injury in autoimmune diseases (Fig. 8.2). In contrast, Th2 cells produce IL-4, IL-5, IL-6, IL-9 and IL-10 and are efficient promoters of antibody responses. The imbalance between these two types of response is considered to be involved in the pathogenesis of...

Immunosuppression in NonHIV Settings

Patients being immunosuppressed for organ transplantation are at a high risk of CMV infection. Initially, these patients are carefully followed for the development of systemic CMV antigenemia, and are given when needed prophylactic treatment with antivirals. In patients with increasing CMV titres, particularly those at high risk for CMV infection, retinitis may develop in spite of these measures. Usually symptomatic, they may require prolonged treatment 9 . CMV may manifest itself at a later...

Inflammation

Numerous studies, together with the therapeutic response of LKC to anti-inflammatory drugs, underscore the importance of inflammation in its pathogenesis. Cellular and soluble mediators act in a number of ways in a series of complex interactions to promote and modulate ocular surface inflammation. Some mediators act as chemokines, stimulating chemotaxis of migrating inflammatory cells to sites of inflammation on the ocular surface. Other mediators stimulate expression of adhesion molecules such...

Pathogenesis

An associated vasculitis or microangiopathy may play an important role in the pathogenesis of scleritis 11-13,29,41 . A proposed component underlying both necrotizing scleritis and systemic autoimmune conditions is an obliterative, immune complex mediated vasculitis. An immune complex mediated or type III reaction may be involved in the pathogenesis of scleritis 12 . Exogenous and endogenous or self antigens stimulate the immune system to produce antibodies, leading to immune complex deposition...

Interferona

Interferon-a and interferon-b (IFN-a, -b) are type 1 interferons, induced by viral infections and tumours or foreign cells. IFN- a subtypes are preferentially produced by monocytes macrophages, but mainly by plasmacytoid den dritic cells (PDC) during viral infections, triggered by DNA with viral or bacterial CpG-mo-tifs. IFN-a was thus primarily used for the treatment of chronic hepatitis B and C. The mechanism of action of recombinant IFN-a2a treatment is not yet fully understood. The effect...

Activation of TLymphocytes by Cytokines

TNF-a upregulates ICAM-1, which is known to be an important factor in lymphocyte adhesion and can provide co-stimulation during their activation, not only on endothelial and epithelial cells but also on eosinophils. The activated lymphocytes and other cell types in turn produce further cytokines. Thereby mast cell derived cytokines interrelate the innate immune response with a specific T-cell-mediated immune answer. Since it is shown that the conjunctiva contains a population of resident...

Actuarial Survival Data on Corneal Transplantation

Long-term data on corneal graft survival and the factors affecting survival are available from registries. Overall survival is around 50 at 10 years (Fig. 4.1) and the clinical indicators best predicting graft outcome are set out in Table 4.1 3 .With these data it is relatively easy to predict the probability of success or failure for a particular patient. What is more arbitrary is the definition of high-risk patients. There is no universal agreement about this in the literature, which makes...

And Immune Modulatory Therapy

The critical role of T cells in allograft rejection is well established. The prevailing view is that a specific T-cell response against HLA antigens is initiated through CD4+ cells. Further potentiation of the reaction then takes place via cyto- Fig.6.10. Antigen presentation and potential targets for immune modulation. Antigen presentation is performed by antigen presenting cells (APC) after intra-cellular antigen processing. Processed peptides are loaded on MHC-class-II molecules and...

And the Contribution of Fibroblasts

Tissue remodelling and formation of giant papillae are some of the consequences of chronic allergic disorders, including the eye 1,21 . Remodelling involves both production and deposition of extracellular matrix (ECM) components, as well as degradation and clearance of newly synthesized products 21 . Any inflammatory reaction can induce tissue damage and a resulting healing process, which is a very complex event involving interactions of both inflammatory and structural cells 1 . Three main...

Antiproliferative Agents

Azathioprine has been used for many years as an immunosuppressive agent it was the first immunosuppressive used after corticosteroids and continues to be widely used in the management of patients with organ transplants. Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). In vivo it is rapidly broken down into 6-MP, which readily crosses cell membranes and is converted into a number of purine analogues. These interfere with cell division and growth although the precise mechanisms...

Cellular Responses in EAU

Various lines of experimental evidence point to a central role for T lymphocytes in EAU. Uveito-genic antigens are classically presented by antigen presenting cells (APCs) to T lymphocytes. The presentation, in conjunction with MHC and costimulatory molecules, results in T-cell activation and, in susceptible animal strains, the T cells produce tissue-specific disease. Once stimulated, the activated T lymphocytes traffic to the target tissue, produce proinflammatory cytokines, and result in...

Diffuse Lymphoid Tissue in EALT

Similar relations of lymphoid cell types as in other diffuse MALT were found in immunohis-tological studies on biopsies of the human conjunctiva 6, 18, 53 including the regular presence of mucosa-specific lymphocytes 6, 18 . However, there were different, partly conflicting, reports concerning the amount and location of lymphoid cells. This is probably due to the topographical distribution of these cells as found in studies on normal human conjunctival whole-mount tissues. Lymphoid cells in the...

Effector Cells and Cytokine Release

Allergic conjunctivitis is due to direct exposure of the ocular mucosal surfaces to environmental allergens. The pathogenesis of allergic conjunc-tival disorders is multifactorial and not fully understood. Ragweed represents the primary responsible allergen (75 of cases of rhino-conjunctivitis). Conjunctival symptoms include itching, tearing, and perhaps burning. Clinical examination may reveal various forms of im- 1.4 Chemokines and Adhesion Molecules 3 munologic reaction, all of these...

Histology of the Mucosa

Mucosal tissues consist of two sheets (Fig. 6.1). The superficial sheet represents a unilayered or, at the ocular surface, a multilayered arrangement of epithelial cells. They usually have a strong mechanical connection by intercellular adherence junctions (e.g. desmosomes and zonulae adherentes) and are sealed by an apical tight junction complex that prevents entrance of foreign materials including potential antigens. Impairment of the epithelial integrity is a major reason for a deregulation...

HLA and Disease Pathogenesis

The HLA system has been associated with disease for over 30 years, but the precise role of HLA molecules in disease pathogenesis is not well established 16 . While microbial pathogens may play a more direct role than currently appreciated even in diseases we now consider due to autoimmunity, it is likely that in many cases HLA associated uveitis is at least in part an autoimmune process resulting from loss of tolerance to self antigens. While a discussion of the proposed mechanisms of loss of...

Human Leukocyte Antigens

The study of the genomic contribution to the immune system was initiated by the description of immune response genes. The genes involved in determining whether an animal was a high or low responder to specific antigens were mapped to a region that became known as the major his-tocompatibility complex (MHC) on chromosome 6 of the human. Although the MHC contains many genes involved in the immune system, the gene products primarily responsible for the immune response became known in the human as...

Immunological Characteristics of Keratoplasty

In order to undergo corneal graft rejection, three processes have been implicated 50 . The donor antigen has to be released, recognized and transported to lymphoid tissue that is present in the form of the organized follicular con-junctival CALT, on the ocular surface itself and in the draining lymph nodes (afferent arm). Al-loantigens have to be processed so that a specific cellular immune response might be generated (central stage). Finally in the efferent arm cellular and humoral effector...

Immunomodulation

When used correctly by properly trained doctors, this mode of therapy is not only effective, but also quite safe 9,12, 22, 25 . In fact, such medications can be safer to use than long-term systemic corticosteroids 12 . We recommend a stepwise approach to treating OCP. The first step involves assessment of a number of factors including patients' health and medical conditions, severity of disease, and the rate of progression of disease. Patients with end-stage disease often have irreversible...

Mast Cells

Mast cells are mesenchymal cells that occur in the connective tissue of most organs and serve as host defence 62 . They have a varying shape that is influenced by the tissue microenvironment but generally shows prominent granules inside the cytoplasm on histological and electron microscopic examination. The granules contain preformed bioactive agents, e. g. hista-mine and the enzymes tryptase and or chymase. According to the content of tryptase and or chy-mase, mast cells are divided into a...

Oral Tolerance Induction

The various treatment strategies discussed above have one major feature in common they generally suppress the immune system, but not only the autoaggressive immune response. Furthermore, the pharmaceutical and even some biological agents are burdened with severe side effects, which might even accumulate with duration of treatment. Although most of the side effects are dose dependent and can be reduced by combining different therapeutic agents, the side effects will limit efficiency of therapy...

Sensitization to Corneal Alloantigens

The foreign antigens introduced into the eye with the graft are on the cell membranes of the epithelial cells, stromal keratocytes and any other cells present in the stroma, and the corneal endothelium. Only the donor endothelial cells persist for the life of the graft. The epithelial cells are replaced within weeks or months by host epithelium. The stromal cells suffer a similar fate but the process may be somewhat slower. Early in the postoperative phase donor antigens could be shed from any...

Sulphasalazine

Sulphasalazine is a prodrug that is metabolized by commensal bacteria in the colon or in the liver into two products 5-aminosalicylic acid (5-ASA) and sulphapyridine. There is some controversy as to which of these two products is responsible for the activity of sulphasalazine. Whereas it is known that 5-ASA is therapeutical-ly effective, it is not clear whether sulphapyri-dine adds any further benefit. In the colon, the products created by the breakdown of sulpha-salazine work as...

Topical Corticosteroids

All patients receiving corneal transplants are given topical corticosteroids in the postoperative period. The topical administration of 11b-hydroxyl compounds such as prednisolone salts or dexamethasone is the mainstay of immuno-suppression for clinical corneal transplantation. There is argument about the appropriate dosage and the desirable period of administration. The unexpectedly good results in the Collaborative Corneal Transplantation Trial (CCTS) in both arms of the trial were attributed...

Vogt KoyanagiHarada Syndrome VKH

VKH is a multisystemic disorder involving eyes, ears, skin and meninges. It appears to be concentrated in certain racial and ethnic groups. The pathophysiology of VKH remains unclear. A specific antigen-driven immune response may occur in this disorder. However, the concept that VKH is a viral-induced disease has been attractive. EBV seems to be associated with VKH but molecular data are still needed before further conclusions are drawn 6 . Interestingly, atypical forms of VKH may occur in...

Vogt KoyanagiHarada Syndrome

VKH syndrome is a bilateral, granulomatous panuveitis associated with poliosis, vitiligo, and alopecia with both central nervous system and auditory manifestations 61 . This inflammatory syndrome is considered to be a T-cell-medi-ated autoimmune disorder against a melano-cytic antigen. Typical histopathological features, seen in the early phases of VKH, are a granulomatous T-cell inflammation that primarily involves the choroid, with similar milder inflammatory infiltration in the iris and...

Cyclophosphamide

Cyclophosphamide is a member of the nitrogen mustard agent family. Most of the orally ingested drug is resorbed (75 ) and readily distributed throughout the body. In the liver cyclo-phosphamide is metabolized into the cytotoxic agents phosphoramide mustard and hydroxy- cyclophosphamide 9 . These metabolites crosslink DNA, RNA and cellular proteins, thus ultimately leading to cytotoxicity. Although primarily secreted unaltered through the kidney, the metabolite acrolein is considered to be...

Intravitreal Corticosteroids

Intravitreal injection of dexamethasone is commonly performed in treatment of severe intraocular inflammation related to bacterial en-dophthalmitis, although its usefulness has been debated 13 . Use in PPV in uveitis has been limited. Expanding indications for intravitreal triamcinolone acetonide in the treatment of CME suggest that it may be useful both to reduce postoperative inflammation in uveitis and to treat residual CME after medical therapy. In-travitreal triamcinolone acetonide has...

Class II HLA

Class II HLA molecules were serologically defined as HLA-DP, HLA-DQ and HLA-DR. They are composed of alpha and beta chains, both coded for by genes in the MHC. The beta chains are generally more heterogeneic in fact, in some cases there is only one HLA alpha chain for a given Class II HLA type, in which case variations in the beta chain alone confer differences in subtypes and peptide binding repertoires. The class II HLA molecules are normally found primarily on antigen presenting cells such...

Summary for the Clinician

A basic function of MALT is the immune regulation at mucosal surfaces by balancing between an inflammatory immune defence of pathogens and a tolerance of the ubiquitous non-pathogenic antigens The preference is for a generation of tolerance mechanisms in order to avoid constant inflammatory destruction of the delicate mucosal surface Immune regulation is mainly performed by a special class of professional antigen presenting cells, dendritic cells (DC) Depending on external influences in the...

References

Ben Ezra D, Forrester JV (1995) Fundal white dots the spectrum of a similar pathological process. Br J Ophthalmol 856-860 2. Yannuzzi LA, Sorenson JA, Guyer DR, Slakter JS, Chang B, Orlock D (1994) Indocyanine green videoangiography current status. Eur J Ophthal-mol 4 69-81 3. Guyer DR, Yannuzzi LA, Slakter JS, Sorenson JA, Ho AC, Orlock D (1994) Digital indocyanine green videoangiography of central serous chori-oretinopathy. Arch Ophthalmol 112 1057-1062 4. Herbort CP, Borruat FX, de Courten...

Organized Lymphoid Tissue in EALT

Organized lymphoid follicles in the human conjunctiva have been reported in different numbers in individuals with a macroscopically normal conjunctiva (as reviewed in 28 ). Apart from the fact that most of these studies investigated only small tissue biopsies or selected con-junctival areas which do not represent the whole organ as found later, the amount of follicles also varies with age 44 . Recent results in normal whole-mount tissues of the human conjunctiva have shown that even in an old...

Langerhans Cells

With regard to the role of antigen presentation ocular DC, Langerhans cells (LHC), are considered as a keyelement of the afferentimmune process. These dendritic cells play a dominant role in processing and presentation of antigens and carry MHC-class-II antigens that are important stimulators of T and B cells. The distribution of LHC is compartmentally localized within specific regions of the ocular surface. The central cornea is normally devoid of LHC that are positive of MHC class II, but a...

Cyclosporine A

Cyclosporine A is the most widely used im-munosuppressive drug for ocular Beh et's disease. At dosages of 3-5 mg kg day or in combination with low dose corticosteroids it has proven to be a rapidly acting and effective medication not only to treat acute attacks but also to reduce recurrence rates of ocular inflammation 108,113,136 . However, nephrotoxicity, particularly at dosages higher than 5 mg kg per day, and relapses after discontinuation of therapy may limit the use of cyclosporine A 77 ....

Primary Inflammatory Choriocapillaropathy PICCP

This first group of diseases, formerly mostly included in the inadequate term of white dot syndromes, results from inflammation at the level of the choriocapillaris causing areas of chorio-capillaris non-perfusion and its ischaemic consequences both at the level of the choroid but also at the level of the outer retina that depends on the choriocapillaris for oxygen and nutrients. Acute posterior multifocal placoid pigmentary epitheliopathy (APMPPE) is a disease typically illustrating this type...

Epidemiology Definition and Characteristics of Dry

Dry eye disease is a widespread disruption of the normal homeostasis of the ocular surface that affects, depending on the tests applied for diagnosis in various studies, up to 10-30 of the population 56 . It is not homogeneously distributed in the population but more likely affects elderly people and preferentially women, which may point to certain risk factors such as age or hormonal status. It is caused, according to a definition of the American National Eye Institute (NEI) 30 , by an...

Unclassifiable Primary Inflammatory Choriocapillaropathies

It is important to realise that this is a spectrum of diseases involving the choriocapillaris in diverse fashions and diverse degrees of severity and that even when the entity seems to be defined it is important to perform a close follow-up. This situation is well illustrated by a case recently seen in our centre presenting with macular chorioretinal atrophy (Fig. 14.9 a). The 42-year-old male patient had presented an acute decrease of visual acuity and a central scotoma in his left eye 3 weeks...

Acute Zonal Occult Outer Retinopathy AZOOR

Rare disorder affecting mainly young myopic women. Shares clinical similarities with MEWDS, PIC, multifocal choroiditis and may be a variant in the spectrum of these entities Photopsia, scotoma, and visual loss are the main complaints Fundus findings acute stage minimal in contrast to electroretinogram alterations chronic stage retinal pigment epithelium hypopigmentation and mottling Electroretinography and visual field generally impaired before visible fundus modifications FA normal at the...

Punctate Inner Choroidopathy PIC

Punctate inner choroidopathy (PIC) is a subset of multifocal choroiditis characterized by a similar clinical picture as far as symptoms, fundus signs and neovascular complications are concerned except that the lesions are smaller. In the original description by Watzke and colleagues the disease is reported to be bilateral and predominant in myopic women 55 . In our experience the disease tended to be unilateral involving predominantly the more myopic of the two eyes. Like multifocal...

Presumed Ocular Histoplasmosis Syndrome POHS

Histoplasma capsulatum is a fungal organism endemic in the Mississippi and Ohio river valleys. Other known endemic regions are Italy, Central America, Turkey, Israel and Australia. In these geographic areas there is a type of multi-focal choroiditis that has distinctive features, called presumed ocular histoplasmosis syndrome (POHS) probably caused by the dissemination of the organism after pulmonary inhalation 57 . Diagnosis of exposure to histoplasma capsulatum is performed by performing...

NK Cells

Activity of NK cells is another controversial problem. While CD16+CD56+ NK cells and CD56+ T cells have been found in BD patients by some investigators 63, 138 , some have only shown increases of CD4+CD16+ and CD4+CD56+ T cells with a normal CD16+ CD56+ NK level 32 , or even a decrease of CD16+ cells 51 . There may also be NK-T cells involved which in a state of activation can express mRNA ofmacrophage migration inhibitory factor (MIF) 72 . In the serum of BD patients MIF levels are increased...

Conjunctival Epithelial Disease

Squamous metaplasia, a condition of hyperpro-liferation and abnormal differentiation of the conjunctival epithelium, occurs in a variety of ocular surface inflammatory diseases, including LKC 31 . An important feature of squamous metaplasia is significantly decreased numbers of mucin-producing goblet cells in both Sjogren's and non-Sjogren's LKC patients. Consistent with this, tear concentrations of the goblet cell-specific soluble mucin, MUC5A, were reduced in these patient populations 48 ....

Primary Stromal Choroiditis

Primary obligatory stromal choroiditis comprises several conditions where the inflammatory process is selectively targeting choroidal stromal structures. In Vogt-Koyanagi-Harada disease the target is probably a melanin-associated protein and a similar process is probably occurring in sympathetic ophthalmia. The regular pattern and the even distribution of choroidal lesions of birdshot chorioretinopathy shown in a recent histopathological report also strongly suggest targeted stromal...

Non Necrotizing Herpetic Retinopathies NNHR

This entity was reported recently 10 . Molecular analysis applied to ocular fluids confirmed the presence of herpes virus DNA in patients presenting with different forms of chronic and atypical posterior uveitis, such as Beh et's disease, retinal vasculitis and birdshot retino-choroidopathy. Non-necrotizing retinopathies associated with haemorrhages have been described (Fig. 10.7). The disease is usually bilateral. It is important to emphasize that all patients with NNHR are corticoresistant or...

Acute Macular Neuroretinopathy AMN

Acute macular neuroretinopathy (AMN) is a rare chorioretinopathy affecting young adults mono- or bilaterally, producing disturbing symptoms of photopsia and often occurring after a flu-like illness like many of the other PIC-CPs 72 . Visual loss is variable and fundus changes are characterized by large macular orange-brown plaques (Fig. 14.7). Fluorescein an-giography shows early choroidal hypofluores-cence or can be unremarkable. The visual field can show a central scotoma. The photopsias,...