Rallying call or death knell?
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Molecular Biology↗
Biomedical subjects
C S Foster
Publications and source records attributed to C S Foster.
Low-dose cyclosporine therapy in the treatment of birdshot retinochoroidopathy.
INTRODUCTION: Birdshot retinochoroidopathy is an uncommon uveitic syndrome of presumed autoimmune etiology. Therapy with systemic and periocular steroids is of inconsistent efficacy, attendant with numerous potential long-term side effects. Steroid-sparing strategies with more specific agents such as cyclosporine (Cyclosporin A, CSA) have been suggested as the first line treatment for this disease. PATIENTS AND METHODS: The records of 19 patients (35 eyes) with the clinical diagnosis of birdshot retinochoroidopathy were examined. Age at onset ranged from 33 to 69 years (mean, 46.1 years) in nine men and ten women. The median follow-up from disease onset was 36 months. Eight patients were treated with low-dose (2.5-5 mg/kg daily) CSA alone, six required the addition of azathioprine (1.5-2 mg/kg daily), and six received no systemic immunosuppressive therapy. RESULTS: HLA-A29 was positive in 94% (16 of 17) of patients tested. Vitreous inflammation was controlled in 23 (88.5%) treated eyes, with fewer bouts of recurrent inflammation, and a corresponding improvement or stabilization of visual acuity in 20 (83.3%) eyes. In contrast, intraocular inflammation never was controlled fully in untreated eyes, and visual acuity decreased in six (54.5%) eyes by an average of 2.5 Snellen lines. Nephrotoxic side effects of low-dose CSA therapy were not observed, but hypertension developed in two patients. CONCLUSION: Although the definitive strategy for the management of birdshot retinochoroidopathy is unknown, control of intraocular inflammation with a favorable visual outcome, together with a lack of demonstrable CSA-associated nephrotoxicity and secondary side effects in these patients with birdshot retinochoroidopathy indicate that vision preservation is possible with low-dose CSA alone or in combination with other steroid-sparing immunosuppressive agents as an alternative to the long-term use of corticosteroids.
Adult↗
Posterior segment ocular manifestations in patients with HLA-B27-associated uveitis.
PURPOSE: To describe a series of patients with seronegative arthritic syndromes and HLA-B27-associated uveitis with severe, sight-threatening, posterior segment ocular manifestations. METHODS: The authors reviewed the records of 29 patients (17.4%) with posterior segment involvement from a cohort of 166 patients with HLA-B27-associated uveitis. The inclusion criteria included individuals with a positive HLA-B27 who had at least one of the following findings: (1) severe vitreous inflammation; (2) papillitis; (3) retinal vasculopathy; or (4) pars plana exudates. The study population comprised 13 men and 16 women with a mean age at onset of uveitis of 35.2 years. The average duration of the uveitis was 5.3 years, and the median follow-up time was 26 months. FINDINGS: Posterior segment involvement occurred in 34 eyes of the 29 patients. The most common findings included severe and diffuse vitritis in 93.1% of the patients and papillitis in 24 patients (82.7%). Retinal vasculitis occurred in seven patients (24.1%), and pars plana exudates were present in two patients (6.8%). Cystoid macular edema (37.9%) and epiretinal membrane (17.2%) were common causes of visual impairment. Systemic immunosuppressive therapy was required for control of inflammation in 32% of the patients. CONCLUSION: HLA-B27-associated uveitis may be related to severe, sight-threatening posterior segment manifestations in some patients; this is an under-recognized phenomenon. These patients may require the use of aggressive systemic immunosuppressive therapy to control inflammation and preserve vision.
Adolescent↗
Cataract surgery in patients with sarcoidosis-associated uveitis.
PURPOSE: The authors analyzed the incidence of cataract development and the visual outcome of cataract surgery performed on patients with sarcoidosis-associated uveitis who were treated at the Immunology Service at the Massachusetts Eye and Ear Infirmary during a 17-year period. METHODS: The records of 102 patients with sarcoidosis-associated uveitis who were treated with topical and regional corticosteroids, systemic nonsteroidal anti-inflammatory drugs, systemic steroids, or with systemic immunosuppressive chemotherapy were reviewed. Cataract surgery was performed on those eyes in which cataract developed, resulting in decreased visual acuity of 20/100 or less. The incidence of cataract development and visual results of cataract extraction and intraocular lens implantation were analyzed. RESULTS: In this cohort of 102 patients, visually significant cataracts that warranted surgery developed in 10 (16 eyes). In addition, four patients (5 eyes) had a visually significant cataract at the time of first evaluation. A total of 14 patients (21 eyes) underwent cataract surgery. Posterior chamber lens implantation accompanied cataract surgery in 19 (90.5%) of 21 eyes. The average final visual acuity of the 21 eyes after cataract surgery was 20/51, and 61% of the eyes achieved a stable visual acuity of 20/40 or better. The major causes of the decreased visual acuity in patients who had less than 20/40 visual acuity were sequelae of chronic posterior uveitis, cystoid macular edema, epiretinal membrane, and glaucomatous optic nerve damage. CONCLUSION: Posterior chamber lens implantation and cataract surgery in patients with sarcoidosis-associated uveitis can be well tolerated when absolute control of the inflammation is achieved. Pre-existing retinal pathology and glaucoma as a result of uncontrolled inflammation resulting in permanent ocular structural damage were found to be the most important factors for determining the postoperative final visual acuity.
Adult↗
Severity of scleritis and episcleritis.
PURPOSE: Inflammation of the wall of the eyeball may extend to adjacent ocular tissues with blinding consequences and may be associated with potentially lethal systemic disorders. This study was undertaken to evaluate the ocular complications and systemic disease associations of the different types of scleritis and episcleritis. METHODS: Ocular complications and specific disease association were evaluated in 266 patients (358 eyes) with different types of scleritis (diffuse, nodular, necrotizing, scleromalacia perforans, and posterior) and episcleritis (simple and nodular). RESULTS: In patients with scleritis, decrease in vision occurred in 37%, anterior uveitis was present in 42%, peripheral ulcerative keratitis developed in 14%, glaucoma occurred in 13%, cataract formed in 17%, fundus abnormalities appeared in 6%, and specific disease association was uncovered in 57%. These findings were most commonly associated with necrotizing scleritis. In patients with episcleritis, decreased vision occurred in 2%, anterior uveitis was present in 11%, glaucoma developed in 4%, cataract formed in 2%, and specific disease association was uncovered in 32%. These findings were similar in simple and nodular episcleritis. CONCLUSIONS: In a patient with scleritis, examination of visual acuity, anterior uvea, cornea, lens, intraocular pressure, and fundus must be performed in every follow-up visit, and a meticulous approach for detection of a specific associated disease must be undertaken since the first visit. Scleritis is more severe than episcleritis, and necrotizing scleritis is the most severe type of scleritis. Classification of scleritis and episcleritis provides valuable prognostic information.
Adolescent↗
The role of natural killer cells in the development of herpes simplex virus type 1 induced stromal keratitis in mice.
Natural killer (NK) cells and acquired cell-mediated immunity effector cells (delayed type hypersensitivity (DTH) and cytotoxic T lymphocytes (CTL)) have been reported to play a vital role in the defence of the host against tumour and viral infections in locations other than the eye. A vigorous cellular inflammatory response to viral infections of the cornea, however, with the attendant damage to the corneal clarity, has obvious evolutionary disadvantages, and a substantial body of evidence indicates that in animals (e.g. mice) which are highly susceptible to inflammatory destruction of the cornea following corneal encounter with herpes simplex virus, it is the animal's immunological/inflammatory response which is responsible for the corneal damage. We examined the role of natural killer cells in the development of herpes stromal keratitis (HSK) in NK-deficient (C57BL/6J-bgj (beige)) mice and their NK-competent (C57BL/6J (black) relatives. The beige (NK-deficient) mice were just as resistant to HSK as were the black mice. We also studied the effects of NK cell depletion of BALB/c Igh-1 disparate congenic mice. C.AL-20 (Igh-1d) mice are ordinarily highly susceptible to necrotising HSK. In vivo NK-cell depletion in these mice significantly decreased the incidence and severity of HSK in these animals (p < 0.0005). Corneas from untreated C.AL-20 mice contained T cells, macrophages and NK cells. The corneal infiltrate from NK-depleted C.AL-20 mice consisted of T cells and macrophages but no NK cells. These data indicate that NK cells are participants in the development of HSK in the murine model of this disease.
3T3 Cells↗
A prospective randomized trial of oral acyclovir after penetrating keratoplasty for herpes simplex keratitis.
Corneal graft survival in 13 patients (14 eyes) receiving oral acyclovir after penetrating keratoplasty for herpes simplex keratitis was compared with that in nine patients (nine eyes) who underwent penetrating keratoplasty for herpes simplex keratitis without postoperative acyclovir. Mean age, duration of disease, and time of follow-up did not differ in the two groups. There were no recurrences of herpes simplex keratitis in any patient receiving acyclovir during a mean follow-up of 16.5 months compared with a 44% (four of nine) recurrence rate in patients without acyclovir during a mean follow-up of 20.6 months (p < 0.01). Graft failure occurred in 14% (2 of 14) of acyclovir treatment eyes compared with 56% (five of nine) without acyclovir. Long-term prophylactic oral acyclovir significantly decreased the recurrence of herpes simplex keratitis and reduced corneal graft failure in patients who had a history of recurrent herpes simplex keratitis and who had undergone penetrating keratoplasty.
Acyclovir↗
Peripheral ulcerative keratitis and malignancies.
Although systemic and local autoimmune diseases are the primary possibilities in the differential diagnosis of noninfectious peripheral ulcerative keratitis (PUK), other unusual etiologies such as systemic or local malignancies also must be considered. We report on two patients with PUK whose study led to the discovery and subsequent treatment of a chronic myelogenous leukemia and a sebaceous cell carcinoma of the eyelid, respectively. The results emphasize the need for meticulous diagnostic pursuit, including the possibility of malignancy in patients with peripheral ulcerative keratitis.
Adenocarcinoma, Sebaceous↗
Conjunctival epithelial basement membrane zone immunohistology: normal and inflamed conjunctiva.
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Basement Membrane↗
ANCA test in ophthalmic inflammatory disease.
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Antibodies, Antineutrophil Cytoplasmic↗
The role of invasive diagnostic testing in inflammatory eye diseases.
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Antibodies↗
The role of B lymphocytes in experimental herpes simplex viral retinitis.
The purpose of this study was to examine B cell participation in experimental herpes simplex virus (HSV) retinitis. Passive immunization with anti-herpes antibody protects BALB/c mice from herpes simplex retinitis (HSR). Using anti-Mu antibody treatment, we modified the B cell population of C.B-17 mice, normally resistant to HSR, in order to test the hypothesis that such treatment would render them susceptible to HSR by impairing their early antibody response to anterior chamber (AC) inoculation with HSV. We analysed the effect of anti-Mu treatment on their susceptibility to HSR and then employed Polymerase Chain Reaction (PCR) and ELISA techniques to study the patterns of immunoglobulin gene and protein expression, and the T-cell receptor alpha/beta (TCR alpha/beta) gene expression after AC inoculation of HSV. Immunohistopathologic analysis revealed that 100% of the B cell deficient mice (B-) developed contralateral retinitis following AC inoculation, confirming the hypothesis that anti-Mu antibody treatment would convert HSR-resistant mice into HSR-susceptible ones. Transfer of B cells from naive congenic donor mice resulted in 67% of recipient B- mice developing contralateral retinitis. Transfer of anti-HSV antibody conferred nearly complete protection, with only 11% of mice developing retinitis (P < 0.005). PCR and ELISA analysis showed that both untreated and B- C.B-17 mice showed similar dynamic patterns of mRNA IgG isotype expression and of anti-HSV IgG isotypic antibody response following AC inoculation. Thus, we were forced to reject the hypothesis that an impaired early antibody response is primarily responsible for the increased HSR susceptibility seen in B- mice. In contrast, PCR analysis of TCR alpha/beta mRNA expression revealed dramatic differences between susceptible and resistant mice, suggesting that TCR V beta selection and usage may be a critical factor influencing HSR-sensitivity in this murine model, and that B cells (and immunoglobulin isotype) may play a role in TCR V beta selection and usage after ocular encounter with HSV.
Animals↗
Modulated expression of human leucocyte antigen class I and class II determinants in hyperplastic and malignant human prostatic epithelium.
OBJECTIVES: To determine whether human prostatic carcinoma cells express Class I and/or Class II major histocompatibility complex (MHC) determinants and whether they might thus be immune-competent targets for cell-mediated cytotoxicity. MATERIALS AND METHODS: Immunohistochemistry, performed both before and after neuraminidase digestion, was employed to compare 13 benign prostatic hyperplasias with 42 primary and 44 metastatic prostatic carcinomas obtained from the United Kingdom and from the United States of America. Expression of beta 2-microglobulin was used as the marker of Class I and HLA-DR as the marker of Class II expression. RESULTS: Before desialylation, Class I MHC determinants were expressed in all of the benign hyperplasias, in 26% of primary carcinomas and in 14% of lymph node metastases. Cells expressing Class II determinants were identified in 69% of benign hyperplasias and in 2% of primary carcinomas, but in none of the lymph node metastases. After desialylation. Class I determinants were expressed in 100% of benign hyperplasias. 59% of primary carcinomas and 34% of the lymph node metastases. Class II determinants were expressed in 100% of benign hyperplasias, but only 19% of primary carcinomas and 5% of the lymph node metastases. While more than 50% of epithelial cells in each of the benign hyperplasias expressed MHCs, < 5% of the tumour cell populations in the positive malignant tissues (primary and metastatic) expressed MHCs, even after neuraminidase digestion. No correlation was found between expression of Class I or Class II MHC and Gleason morphological grade. CONCLUSIONS: Failure to express Class I and/or Class II MHC determinants is a common feature of the majority of human prostatic carcinoma cells. Absence of these recognition molecules may be associated with avoidance of immune-surveillance and contribute to the metastatic dissemination of this malignancy.
Epithelium↗
Herpes simplex virus type 2 induced retinal necrosis in BALB/c mice.
We injected herpes simplex virus type 2 of MS- or G-strain into the anterior chamber of BALB/c mice. In the contralateral eye inflammatory cell infiltration began in the ciliary body; focal retinitis, detected by day 8, led to total destruction of the retina by day 10. Contralateral disease was observed in 75% of mice inoculated with 8 x 10(3) pfu herpes simplex virus type 2, but in only 20% of mice receiving 80 pfu herpes simplex virus type 2. Still this low concentration, however, produced a suppressed delayed-type hypersensitivity response. Anti-herpes simplex virus type 2 antibody, first detected on day 8, reached high titers on day 10; by then, most of the mice had died of encephalitis. The G-strain of herpes simplex virus type 2 was more neurotoxic than the MS-strain, but produced the same incidence of contralateral retinitis. Herpes simplex virus type 2 products contralateral necrotizing retinitis comparable to that produced by herpes simplex virus type 1. These findings, like those of other authors, suggest a role for herpes simplex virus type 2 in some cases of acute retinal necrosis in humans.
Animals↗
CD4+V beta 8+ T cells mediate herpes stromal keratitis.
T lymphocytes are critical in mediating herpes simplex stromal keratitis (HSK). Using immunohistologic methods, we studied the T cell subsets and the T cell receptor variable region (TCR V beta) repertoire of T cells in the eye after corneal infection with HSV (KOS strain). We investigated the possibility that there might be differential V beta preferential usage in HSK resistant and susceptible BALB/c congenic mice that differ only in a small region associated with the Igh-1 gene locus. The inflamed corneas of HSK susceptible C.AL-20 mice were mainly infiltrated by CD4+ cells and by V beta 8 expressing cells. Such T cells were not seen in the corneas of resistant C.B-17 mice. Our results indicate that CD4+V beta 8+ cells are involved in mediating HSV-1 stromal keratitis.
Animals↗
Expression of fibronectin isoforms in rat cornea after an epithelial-scrape wound.
The polymerase chain reaction (PCR) technique was used to analyze the presence or absence of the EIIIB and V region fibronectin (FN) mRNA isoforms, generated by alternative splicing of the FN primary mRNA transcript during epithelial wound healing, in a rat cornea wound model. A central 4mm area of the cornea was denuded of epithelium. At 5, 15, 30, 45 minutes, 1, 2, 4, 8, 24, 48 hours, and 4 days post-wounding, the rats were euthanized and a 6mm diameter full thickness corneal biopsy was performed. cDNA was synthesized from extracted RNA, and specific FN sequences were amplified by PCR as directed by different sets of 5' and 3' primers specific for the alternatively spliced EIIIB and V region domains. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression was used to normalize the data. PCR products were analyzed by agarose gel electrophoresis and the identity of the bands were confirmed by direct nucleotide sequencing. The alternatively-spliced EIIIB and all three alternatively spliced isoforms of V domain FN mRNA were observed post-wounding. Similarly, in normal tissue, EIIIB and all three V region alternatively spliced FN isoforms were expressed. These findings suggest that in situ synthesis of cellular associated EIIIB FN and FN V domain may play a role in corneal wound healing.
Alternative Splicing↗
[T-cell-induced prevention of HSV-1 keratitis by immunization with the synthetic peptide of glycoprotein D].
C.AL-20 mice susceptible to herpes simplex virus (HSV) were protected against HSV keratitis (HSK) and encephalitis by subcutaneous immunization with synthetic peptide corresponding to the N-terminal amino acid residues 5-23 of HSV glycoprotein D, which is a dominant immunogen of HSV-1. Protection against HSV was related to a potent humoral anti-HSV response. FACScan analysis revealed that CD4+V beta 8(1.2)+ cells in the spleen were markedly decreased 2 days after HSV challenge, and CD8+ cells were increased. Numerous CD4+ and V beta 8(1.2)+ cells were found in the corneal tissue from HSV-infected sham-immunized mice; no such cells were seen in gD(5-23) immunized mice. No cytotoxic cells were detected in the corneas or spleens of gD(5-23) immunized mice, and these mice had decreased DTH responses. Protection against HSV through immunization with gD(5-23) involves humoral and cellular immune mechanisms. CD4+V beta 8(1.2)+ maybe critical in mediating the pathology of HSK. CD8+ cells may be protective by non-cytotoxic mechanisms. Our results suggest that gD peptides may be potent as vaccines against HSV.
Animals↗
The role of macrophages in the pathogenesis of HSV-1 induced chorioretinitis in BALB/c mice.
PURPOSE: To examine the effects of modification of immune effector cells, including macrophages, in the pathogenesis of herpes simplex virus retinitis in BALB/c mice. METHODS: Two intravitreal injections (2 microliters each) of anti-CD11b monoclonal antibody (mAb) [13 micrograms/microliters] were administered to the contralateral eyes of 10 BALB/c mice on days 6 and 8 after HSV inoculation into the right anterior chamber (AC) with HSV-1. A control group consisted of mice injected with anti-HLA-DR mAb in the same fashion. Specific macrophage depletion was performed in an additional group of 12 BALB/c mice by intravenous (i.v.) injection of dichloromethylene diphosphonate (Cl2MDP)-liposomes 7 days before AC HSV-1 inoculation into the eye. Control group consisted of mice receiving i.v. PBS-liposomes. Mice were clinically observed for 14 days postinfection, and the incidence of chorioretinal disease was confirmed by histopathologic studies. RESULTS: Intravitreal injections of anti-CD11b mAb produced a dramatic suppression of the contralateral retinal necrosis (2 of 10 mice) compared to 9 of 10 controls receiving an irrelevant antibody therapy (P < 0.05). Mice treated with i.v. Cl2MDP-liposomes also showed a significant inhibition of the development of contralateral chorioretinitis, with only 3 of 12 mice developing retinal disease compared to 9 of 12 mice from the control group (P < 0.05). FACS analysis performed on peripheral blood and spleen cells showed a significant depletion of Mac-1+ cells of Cl2MDP-liposome-treated but not of PBS-liposome-treated mice (controls). CONCLUSION: Intravitreal anti-CD11b mAb therapy, a broadly directed depletion strategy against many effector cells (macrophages, granulocytes, natural killer cells, and even cytotoxic T-cells) was most efficient in suppressing the HSV-1 induced contralateral disease. A more specific technique (i.v. Cl2MDP-liposome therapy) to deplete macrophages also produced a significant inhibition of HSV-1 induced contralateral chorioretinitis. These findings suggest that macrophages are important participants in the effector phase of the destructive inflammatory immune response induced by HSV-1 in the eye.
Animals↗