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Purpose: To review the current and future approaches to investigating the intraocular immune response in human uveitis., Design: Perspective., Methods: Review of currently available methods for investigating the immune response in ocular tissues and fluids in patients with intraocular inflammation/ uveitis. The advantages and disadvantages of human studies have been compared to those of animal models of uveitis., Results: Animal models, while being excellent tools for mechanistic studies, do not replicate the clinical and immunologic heterogeneity of human uveitis. Opportunities for immunological studies in human uveitis are mostly limited to histological studies, or sampling of intraocular fluids and peripheral blood. Histopathological studies can be enhanced by revisiting published historical data, tissue repositories, or autopsy specimens. Intraocular fluids can be investigated by a variety of techniques. Among these, flow cytometry and single-cell RNA sequencing (scRNAseq) provide single-cell resolution. While the current technology is costly and labor-intensive, scRNAseq is less limited by the low cellular yield from intraocular fluids and allows unbiased immune profiling enabling discovery of new cellular subsets. Immunological phenotypes uncovered from human data can be further investigated in animal studies., Conclusion: The diversity of the intraocular immune response in uveitis patients remains challenging but can be studied by multiple techniques including histopathology, flow cytometry, and scRNAseq. Human data can be combined with animal studies for translating uveitis research into novel therapies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Idiopathic uveitis is frequently the most common diagnosis in series from uveitis clinics. This study sought to determine the percentage of patients initially diagnosed as idiopathic, noninfectious uveitis referred to a tertiary uveitis center who were subsequently found to have an identifiable cause of uveitis., Design: Retrospective case series., Methods: We performed a computerized database analysis of 179 consecutive patients who were referred to our practice with the diagnosis of idiopathic, noninfectious uveitis between 2008 and 2016. Patients were evaluated by a thorough history and ophthalmic examination with selected laboratory testing targeted by clues from the history and examination. Standardization of Uveitis Nomenclature (SUN) criteria were used to better assess different types of uveitis., Results: Fifty-two out of 179 (29.0%) patients initially diagnosed with idiopathic uveitis were subsequently diagnosed with an underlying condition. Among patients referred with a diagnosis of idiopathic disease, female patients were most commonly affected (121/179; 67.6%). Among subsequent diagnoses, sarcoidosis was the most common (19/52 or 36.5%), followed by HLA-B27-associated uveitis (11/52, 21.1%), infectious uveitis (6/52, 11.5%), tubulointerstitial nephritis with uveitis (6/52, 11.5%), and juvenile idiopathic uveitis (4/52, 7.7%). Other diagnosable conditions included Behçet disease, multifocal choroiditis, panuveitis, Crohn disease, multiple sclerosis, and relapsing polychondritis. An underlying condition was not found in 127 of 179 (70.9%) patients., Conclusions: We report that 29% of patients referred to our tertiary uveitis center diagnosed as "idiopathic" had an associated identifiable cause. Identifying an underlying condition associated with uveitis could be potentially lifesaving for some illnesses (eg, sarcoidosis with cardiac involvement) and is critical to management (eg, infection). Although we were able to use limited testing to classify many patients who had been previously incorrectly labeled with idiopathic uveitis, idiopathic uveitis remains the most common diagnosis in our uveitis clinic., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To assess the long-term efficacy of the most widely used anti-tumor necrosis factor alpha (TNFα) agents for treatment of HLA-B27-positive ankylosing spondylitis (AS)-related uveitis., Design: Retrospective cohort study., Methods: The medical records of 143 patients with HLA-B27-positive AS who visited Seoul St. Mary's Hospital and were taking an anti-TNFα agent for at least 1 year were studied. Subjects were divided into 3 groups according to anti-TNFα treatment: Group 1 (infliximab, 66), Group 2 (adalimumab, 45), and Group 3 (etanercept, 32)., Results: Mean age was 41.0 ± 13.0 years, and 97 patients (67.8%) were male. Mean follow-up period was 70.6 ± 37.9 months. In cases of active ocular inflammation at the onset of anti-TNFα treatment, patients showed improved activity of uveitis after 24.0 ± 15.0 days (Group 1), 17.9 ± 6.0 days (Group 2), and 25.9 ± 18.0 days (Group 3). After the anti-TNFα treatment, 71 of 94 patients (32 [76.2%] in Group 1, 26 [78.8%] in Group 2, and 13 [68.4%] in Group 3) remained without uveitis relapse. A reduction in the number of systemic medications was achieved in 129 patients (90.2%). Twenty-eight cases of minor side effects were observed, and 4 cases were tuberculosis leading to discontinuation of anti-TNFα treatment., Conclusions: Infliximab, adalimumab, and etanercept were effective for treating and reducing the number of uveitis relapses in HLA-B27-positive AS. However, the risk of serious infections was noted, so ophthalmologists should consider the possibility that prolonged use of biologic agents may result in systemic side effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To determine whether routine serologic screening for Borrelia burgdorferi and subsequent aqueous or vitreous humor analysis is useful in patients with uveitis., Design: Cross-sectional study., Methods: All patients referred to our tertiary uveitis referral clinic in the period of from January 1, 2004 to October 31, 2014, in whom routine serologic screening for Borrelia burgdorferi (IgG as determined by enzyme-linked immunosorbent assay and confirmed by immunoblot) was performed were retrospectively reviewed. In patients with an unclassified uveitis, aqueous and vitreous humor and cerebrospinal fluid were also analyzed. Local antibody production was determined by Goldmann-Witmer coefficient calculation or polymerase chain reaction for B burgdorferi. The seroprevalence of B burgdorferi among patients with uveitis was compared to the general population., Results: Borrelia burgdorferi screening was performed in 1126 uveitis patients (44.3% male, mean age 45.9 ± 19.6 years). The seroprevalence of B burgdorferi among uveitis patients was 3.7% (95% confidence interval 2.6%-4.8%) (n = 42) as compared to 5%-10% in the general Dutch population. Of these 42 patients, 14 (1.2% of all uveitis patients) had an unclassified uveitis, 7 of whom underwent aqueous humor (n = 5) or vitreous humor (n = 2) analysis and cerebrospinal fluid analysis (n = 2). None of the patients had local antibody production in either ocular or cerebrospinal fluid., Conclusion: The prevalence of immunoblot-confirmed B burgdorferi IgG seropositivity in our uveitis patients is only slightly lower as compared to the general Dutch population. Intraocular antibody production and DNA was absent in all tested patients. These findings do not support routine serologic examination for Borrelia in uveitis patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To identify potential predictors of permanent vision loss in patients with human leukocyte antigen (HLA)-B27-associated uveitis in a tertiary referral center., Design: Retrospective case-control study., Methods: The charts of 212 patients (338 eyes) with HLA-B27-associated uveitis that visited the University Medical Center Utrecht with a follow-up of at least 6 months were retrospectively studied. Clinical features at presentation and during follow-up were compared to final visual outcome in quiescent state. Eyes with (sub-) normal vision (>20/50) were compared with visually impaired (≤20/50) and blind (≤5/50, or a visual field of <10 degrees) eyes, using survival analysis. A multivariate Cox proportional hazards analysis was performed to analyze potential predictors for permanent vision loss., Results: Median follow-up was 10.4 years (range, 0.5-44.7 years). During follow-up 226 eyes (66%) experienced vision loss up to 20/50, but most recovered. Twenty patients (9%) became permanently visually impaired or blind in at least 1 eye because of uveitis, after a median of 9.7 years (range, 0-20.9 years). The main cause was secondary glaucoma or related to glaucoma surgery (12/22 eyes, 55%). Survival analysis showed, after adjustment for age and sex, an ocular pressure of >21 mm Hg, hypotony, and panuveitis to be potential predictors at presentation, and the development of secondary glaucoma or hypotony to be predictors of blindness or visual impairment during follow-up., Conclusions: The long-term visual prognosis of HLA-B27-associated uveitis is relatively good, but the true incidence of permanent vision loss is probably still underestimated. Our findings highlight the importance of proper control of intraocular pressure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the prevalence of immunologic and genetic markers in patients with idiopathic ocular inflammation and a family history of inflammatory bowel disease., Design: Matched case-control study., Methods: Patients with a diagnosis of idiopathic ocular inflammation and family history of inflammatory bowel disease who did not have inflammatory bowel disease themselves were identified and matched to control patients with idiopathic ocular inflammation. Serum was evaluated for immunologic markers using Prometheus IBD Serology 7. Genomic DNA was analyzed for single nucleotide polymorphisms (SNP) of the NOD2 gene associated with Crohn disease., Results: Fifteen patients with idiopathic ocular inflammation and family history of inflammatory bowel disease were matched to 15 control patients based on age, sex, and race. Eight of 15 patients (53%) with a family history of inflammatory bowel disease had elevated p-ANCA antibody levels compared to 3 of 15 controls (20%) (1-sided P = .04) with a matched analysis odds ratio of 6.0 (1-sided P = .06). Four of 15 patients (27%) with family history of inflammatory bowel disease tested positive for immunologic markers predicting ulcerative colitis, while no control patients tested positive (1-sided P = .06). Carrier rates of NOD2 SNPs did not differ significantly between the test and control groups., Conclusions: One-quarter of patients with idiopathic ocular inflammation and a family history of inflammatory bowel disease had immunologic markers predicting bowel disease, and one-half had elevated p-ANCA levels. Prometheus IBD Serology 7 may be useful in the evaluation of selected patients with unexplained uveitis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate United States Public Health Service (USPHS) guidelines for discontinuing anticytomegalovirus (CMV) therapy in patients with AIDS who have immune recovery and quiescent retinitis after initiating highly active antiretroviral therapy., Design: Cohort study of patients with CMV retinitis (Longitudinal Study of Ocular Complications of AIDS)., Methods: Participants had CMV retinitis and CD4+ T-cell counts of 50 cells/μL or fewer enrolled from 1998 through 2009 who demonstrated sustained immune recovery (2 consecutive CD4+ T-cell counts of 100 cells/μL or more at least 6 months apart) and inactive retinitis. Participants were classified into 2 groups according to anti-CMV treatment after immune recover: (1) continued anti-CMV therapy and (2) discontinued therapy. We evaluated survival, visual acuity, and CMV retinitis activity; we used propensity scores to adjust for confounding factors for these analyses., Results: Of 152 participants reviewed, 71 demonstrated immune recovery, 37 of whom discontinued therapy and 34 of whom continued therapy. At immune recovery, participants continuing therapy tended to be older (44 vs 40 years; P = .09), have bilateral retinitis (53% vs 32%; P = .10), and have lower CD4+ T-cell counts (148 vs 207 cells/μL; P < .001). There were no statistical differences in any of the clinical outcomes (death, retinitis progress, visual acuity, or incidence of bilateral retinitis). Both groups lost visual acuity during follow-up, on average 1.2 letters per year (P < .01)., Conclusions: Discontinuation of anti-CMV therapy after immune recovery did not increase the risk of poor outcomes. These results support the current guidelines for discontinuation of anti-CMV therapy after achievement of sustained immune recovery., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To verify the occurrence of keratoconjunctivitis sicca (KCS) and human T-cell lymphotropic virus type 1 (HTLV-1) associated uveitis (HAU) and to evaluate the immunologic status related to HTLV-1., Design: Cross-sectional study., Methods: Ophthalmic examination (both eyes) and immunophenotyping of peripheral blood lymphocytes were performed in 207 infected asymptomatic blood donors (AS), 55 controls (NI), and 55 patients with HTLV-1 associated myelopathy (HAM/TSP). Examiner was masked to patient's serologic status., Results: KCS was more frequent in HAM/TSP (30/55, 54.5%) than in NI and AS (07/55, 12.7% and 42/207, 20.3%, respectively). Presence of lacrimal hyposecretion in KCS individuals was higher in the HAM/TSP group (P < .001) as compared with NI and AS. HAU was found in 1/55 (1.82%) of HAM/TSP patients and 4/207 (1.93%) of HTLV-1 seropositive donors. Higher levels of activated CD4(+) and CD8(+) T cells were observed in HAM/TSP. Patients with HAU displayed higher percentage of both CD4(+) HLA-DR(+) and CD8(+)HLA-DR(+) when compared with NI and AS without HAU., Conclusions: Patients with HAM/TSP manifested more ophthalmologic symptoms than asymptomatic HTLV-1-infected individuals, with significantly higher KCS and immunologic alterations. Levels of activated CD8+ T cells could be used as a prognosis marker of inflammatory disease manifestation to follow-up AS individuals.

Purpose: To identify and describe long-term posterior and anterior segment complications of immune recovery uveitis in patients with inactive cytomegalovirus retinitis who are undergoing highly active antiretroviral therapy-mediated recovery of immune function., Methods: A prospective cohort study at a university medical center. Twenty-nine eyes of 21 patients with immune recovery uveitis and inactive cytomegalovirus retinitis were followed for 14.5 to 116 weeks (median, 43 weeks) after diagnosis of immune recovery uveitis., Results: Nine eyes of nine patients developed visually important complications involving the posterior segment, anterior segment, or a combination of both. Posterior segment complications included severe proliferative vitreoretinopathy in three eyes and spontaneous vitreous hemorrhage from avulsion of a blood vessel secondary to contraction of the inflamed vitreous in one eye. Proliferative vitreoretinopathy recurred in all cases after surgery, severely compromising the visual outcome. Anterior segment complications included posterior subcapsular cataracts with vision decrease in five eyes and persistent anterior chamber inflammation after cataract extraction, resulting in posterior synechiae and large visually important lens deposits in three eyes., Conclusion: Persistent inflammation in immune recovery uveitis may lead to vision-threatening complications, such as proliferative vitreoretinopathy, posterior subcapsular cataracts, and severe postoperative inflammation. Immune recovery uveitis is a chronic inflammatory syndrome that may result in complications months to years after the onset of inflammation.

Purpose: To investigate the clinical features associated with immune recovery in human immunodeficiency virus (HIV)-infected patients with cytomegalovirus retinitis who are taking highly active antiretroviral therapy., Methods: Sixteen patients were evaluated prospectively at the National Eye Institute, Bethesda, Maryland. Evaluation included a medical history and a complete ophthalmologic examination. The examination included best-corrected visual acuity score measured by means of logarithmic charts, slit-lamp biomicroscopy, dilated retinal examination, retinal photography, and fluorescein angiography. Immune-recovery uveitis was defined as the ocular inflammation associated with clinical immune recovery in patients taking potent antiretroviral regimens. The ophthalmic characteristics of immune-recovery uveitis were identified, and their effect on visual acuity was statistically analyzed., Results: The mean CD4+ T-lymphocyte count for the 16 patients taking highly active antiretroviral therapy at the time of evaluation was 393 cells/microl (range, 97-1,338 cells/microl). Immune-recovery uveitis was characterized by vitreitis and optic disk and macular edema. Clinically important complications of immune-recovery uveitis included cataract and epiretinal membrane formation. The visual acuity scores were significantly worse in the 23 eyes with cytomegalovirus retinitis (mean, 67.2 letters, 20/50) than in the nine eyes without cytomegalovirus retinitis (mean, 89.8 letters, 20/16) (P <.001). Regression analysis showed that a lower visual acuity score was associated with the presence of moderate to severe macular edema on fluorescein angiography and vitreous haze (P < or =. 001)., Conclusions: Immune-recovery uveitis is an important cause of visual morbidity in HIV-infected patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Although immune recovery associated with highly active antiretroviral therapy has allowed some patients to discontinue specific anticytomegalovirus therapy, the rejuvenated immune response can be associated with sight-threatening inflammation.

Purpose: To review the role of gene products from the human leukocyte antigen (HLA) complex in the normal functioning of the immune system, ocular inflammation, and models of autoimmunity., Method: A review of recently published reports., Results: Many chronic ocular inflammatory diseases are associated with specific alleles of the HLA complex. Understanding how HLA gene products function normally provides clues to the mechanism of disease associations. In the thymus, these molecules control the shape of the developing T-cell repertoire, leading to self-tolerance. In the periphery, HLA molecules bind and present peptide fragments to T cells, leading to a variety of effector functions. Although effector functions are for the most part beneficial, models are reviewed in which peptide-HLA interactions lead to T-cell responses with pathologic consequences. Herpes stromal keratitis is an informative animal model highlighting the role of self-tolerance, infection, and molecular mimicry in the development of autoimmunity., Conclusions: Human leukocyte antigen gene products may be associated with chronic inflammatory disorders through the unique presentation of "disease-inducing" peptides or the development of a T-cell repertoire prone to autoreactivity and molecular mimicry.

Purpose: To identify the frequency of recently acquired vs chronic systemic Toxoplasma gondii infections in patients with ocular toxoplasmosis., Methods: Serum samples from 22 patients with primary ocular toxoplasmosis (not from scars) and 42 patients with recurrent ocular toxoplasmosis were tested for the presence of anti-T. gondii IgM, IgG, and IgA antibodies and compared with samples from 24 patients with other causes of uveitis. Intraocular production of anti-T. gondii IgG and IgA, and the presence of T. gondii DNA was determined in patient s and control subjects from whom ocular fluid was available., Results: Serologic evidence of recently acquired infection was found for 11 (50%) of 22 patients with primary ocular toxoplasmosis and for one (2%) of 42 with recurrent ocular toxoplasmosis. In the uveitis control group, anti-T. gondii IgM antibodies could be detected in two (8%) of 24 patients, but anti-T. gondii IgA antibodies were not detectable. Patients with primary ocular toxoplasmosis and serologic markers of recently acquired systemic infection were significantly older than those with chronic infection (P = .008). Intraocular production of anti-T. gondii IgG was more frequently noted in patients with recurrent than primary ocular toxoplasmosis (81% vs 41%; P < .001), but intraocular T. gondii DNA was more frequently found in patients with primary ocular toxoplasmosis than in those with recurrent ocular toxoplasmosis (37% vs 4%; P < .01)., Conclusions: Primary ocular toxoplasmosis can be seen in either recently acquired or chronic T. gondii infection. Patients with ocular disease and recently acquired infection were older and more likely to have T. gondii DNA in intraocular fluids.

Purpose: To investigate the immunoglobulin classes associated with the intraocular anti-Toxoplasma gondii antibody response during clinical ocular toxoplasmosis and to determine which immunoglobulin class is most helpful in the diagnosis of this disease., Methods: Paired serum and intraocular fluid samples from 155 patients who had uveitis were tested for intraocular anti-T. gondii IgG, IgA, and IgM antibody production. The presence of T. gondii DNA was determined by polymerase chain reaction. Patients were divided into two groups, based on the initial clinical diagnosis; group 1 included 78 patients with presumed ocular toxoplasmosis, and group 2 included 77 patients with uveitis that was not clinically suspected to be ocular toxoplasmosis. Samples from 27 nonuveitis patients who underwent intraocular surgery were used as control subjects. The final diagnosis was based on the clinical course and interpretation of laboratory tests., Results: A final diagnosis of ocular toxoplasmosis was made in 88 of 155 patients (group 1, 68; group 2, 20). Among these patients, 65% had intraocular IgG production, 52% had intraocular IgA production, 37.5% had both IgG and IgA production, 27% had IgG production only, and 15% had IgA production only. Of the 13 patients tested, only one had intraocular IgM production. Intraocular IgA could not be detected in patients who had final diagnoses other than ocular toxoplasmosis or in control subjects. A positive polymerase chain reaction combined with a test that was positive for intraocular IgG production had a sensitivity of 77%, which increased to 91% after the detection of intraocular IgA production was added., Conclusions: Immunoglobulin G is the major class involved in the humoral immune response against the T. gondii parasite, followed by IgA. The determination of IgA production is useful as an additional test in the diagnosis of ocular toxoplasmosis.

Purpose: To compare the immune response to retinal antigens in a patient with a clinical condition resembling cancer-associated retinopathy with the immune responses of patients with other retinal degenerations or uveitis., Methods: Cellular and humoral immune responses to retinal S-antigen and recoverin were determined in one patient with disease resembling cancer-associated retinopathy, three patients with other retinal degenerations, and eight patients with uveitis., Results: A cellular immune response against recoverin was found only in the patient with the condition resembling cancer-associated retinopathy. Elevated levels of antibody against recoverin were found in this patient and in one of the three patients with a retinal degeneration, but in none of the eight patients with uveitis. In contrast, moderate lymphocyte responses to retinal S-antigen were found in most of the patients studied, and this response did not distinguish among the patient groups. Levels of serum antibodies against retinal S-antigen were also similar in all patients tested. Serum from the patient with disease resembling cancer-associated retinopathy produced strong immunostaining of the rods, cones, outer plexiform layer, and some cone bipolar cells, but serum from the patients with uveitis or other retinal degenerations did not show specific reactivity with the retina., Conclusions: We propose that this immunologically and clinically distinctive condition be termed recoverin-associated retinopathy, and we suggest that a cellular immune response against recoverin may be a distinguishing feature of the disorder.

The clinical features of idiopathic uveitis were compared by the seropositivity for human T-cell lymphotropic virus type I. The statistical analysis of various clinical variables disclosed that the uveitis seen in seropositive patients (93 patients) had a significantly higher incidence of floaters, vitreous opacities, retinal vasculitis, and intermediate uveitis than that in seronegative patients (222 patients) (P < .05). The odds ratios of the virus infection for these clinical manifestations were high and statistically significant, suggesting that the virus infection has a role as a risk factor for the development of these clinical manifestations. Although visual acuity at the initial examination was almost equal between the two groups, after the therapy with topical or systemic corticosteroids, or both, visual acuity in seropositive patients was much better than that in seronegative patients. The surface phenotype of peripheral lymphocytes in the two groups was compared as follows: CD4-positive T lymphocytes (P < .05), CD4/8 ratio (P < .01), and CD25-positive T lymphocytes (P < .05) were significantly higher in seropositive patients than in seronegative patients.

To investigate whether Fuchs' heterochromic iridocyclitis may be an immune complex vasculitis, we used an immunofluorescence technique to detect immunoglobulins and complement in iris biopsy specimens from nine patients with Fuchs' heterochromic iridocyclitis, 12 patients with other types of uveitis, and nine patients with glaucoma but without uveitis. No specific immune deposits were observed in the irises of the patients with Fuchs' heterochromic iridocyclitis. Immunoglobulin G, IgA, IgM, and complement were detected in patients with Fuchs' heterochromic iridocyclitis and patients with uveitis, and these results differed significantly (P less than .05) from the group without uveitis. The immune deposits were found only in the iris vessel walls. No light-microscopic evidence of an inflammatory vascular process could be detected. Further studies are necessary to investigate whether the immune reactants originate from the circulation or result from local formation.

We analyzed the local antibody production in vitreous humor samples collected during vitrectomy in patients with severe vision-threatening uveitis. In 24 patients, paired serum and undiluted vitreous humor samples were collected and tested for antibodies against Toxoplasma gondii, herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and Toxocara canis. Total IgG and the Goldmann-Witmer coefficient were determined. The initial diagnosis of ocular toxoplasmosis could be confirmed in six of the seven patients. The seventh patient showed a local antibody production against herpes simplex virus. One of the three patients with chronic panuveitis at initial diagnosis showed a local antibody production against T. gondii. These last two findings resulted in a change in medical treatment. Analysis of local antibody production in vitreous humor samples is a valuable diagnostic tool.

Using immunohistochemical techniques, we analyzed iris biopsy specimens from eight patients with Fuchs' heterochromic cyclitis, seven patients with various other types of uveitis, and eight glaucoma patients without uveitis. No specific abnormalities related to Fuchs' heterochromic cyclitis could be detected. Four of the patients with Fuchs' heterochromic cyclitis and four of the patients with uveitis showed evidence of an inflammatory cell infiltrate, which was a mixture of interleukin-2 receptor-negative T helper and suppressor cells, B lymphocytes, and plasma cells. Only an occasional T lymphocyte could be seen in two of the patients without uveitis. The class II antigen HLA-DR was expressed on iris stromal cells in every patient in the Fuchs' heterochromic cyclitis group and uveitis group and in six of the patients in the nonuveitis group. In six of the Fuchs' heterochromic cyclitis patients, including two without immunohistochemical evidence of inflammatory cell infiltrate, histologic abnormalities were present on hematoxylin and eosin sections.

Uveitis comprises a complex group of diseases in which morbidity may depend on the nature of the initial inflammation as well as on the genetic, hormonal, and emotional background of the patient. Uveitis is initiated in every instance by some form of tissue injury. This may occur as an attack on individual cells by organisms such as Toxoplasma gondii or Herpesvirus hominis. Autoimmune disease may be produced as a late result of microbe-induced injury. The development of specific forms of autoimmunity seems to be dependent upon genetic as well as hormonal factors, particularly estrogens. Tissue injury of immunologic origin takes several forms, such as cytotoxic damage from sensitized lymphocytes, immune complex-mediated injury, and injury from the oxidative products of inflammatory cells. In some cases, permanent alteration of uveal vascular permeability results. Recurrent uveitis may be attributed in some instances to the reappearance of infectious organisms in the target tissue. In other cases, recurrence of inflammation may be attributed to the localization of immune complexes in the uveal tract. Changes in immunoregulation can be attributed to pregnancy, aging, and emotional factors. Neurohumoral pathways related to stress-mediated changes in immunoregulation have recently been described in laboratory animals. These pathways may be linked with stress-related recurrences of uveitis in humans.

A syndrome of multifocal choroiditis, pigment epithelial disturbance, and inflammatory vitreous cells was found to be associated with Epstein-Barr virus specific antibodies. The ten patients in this series had positive viral capsid antigen IgM or Epstein-Barr early antigen antibody titers. Patients with this syndrome were generally healthy and had no history of a clinical episode of infectious mononucleosis. No patient from the control group with other ocular diseases had positive viral capsid antigen IgM or early antibody titers. All patients in the study group and most of the control patients had viral capsid antigen IgG and Epstein-Barr nuclear antigen antibodies, indicating a previous exposure to the virus as expected in an adult population.

We studied the serologic findings in serum and aqueous humor samples from 693 cases of uveitis. Specimens were tested for the presence of humoral antibodies against tuberculosis, toxoplasmosis, antistreptolysin-O, herpes simplex and herpes zoster viruses, mumps virus, and adenovirus. Serologic analyses rarely indicated tuberculous or streptococcal infections, but frequently showed toxoplasmosis and viral diseases.

Iridectomy specimens from 16 patients with clinically quiet chronic uveitis were analyzed by immunoperoxidase staining and compared to control iridectomy specimens from 11 non-uveitic patients. Nine of 16 uveitis specimens and none of the control specimens demonstrated a lymphocytic infiltrate consisting of interleukin-2 receptor-negative T helper and suppressor cells (P less than .003). Class II antigens were detected in the iris stroma in all uveitis specimens and six of the controls (P less than .006). Despite a quiescent clinical state, patients with chronic uveitis have increased expression of class II antigens in uveal tissue and have significant uveal infiltration of T helper and suppressor cells. These findings in a variety of types of uveitis give additional support for the importance of delayed type hypersensitivity mechanisms in human uveitic disease.

We determined the incidence of immune complex increases, the nature of immune complexes, and the correlation between the immune complex level and clinical uveitis status in patients with chronic iridocyclitis and chronic diffuse uveitis. Ten of 16 patients with chronic iridocyclitis had increased levels of immune complexes, and this correlated with disease activity. Immune complexes were detected in ten of 12 patients with chronic diffuse uveitis. These complexes have a molecular weight of approximately 2 X 10(6) daltons. The antibody component of immune complex is IgG; however; the antigenic component of the immune complexes is unclear.

We evaluated T-lymphocyte subsets in 18 patients with active untreated uveitis and in 20 controls by monoclonal OKT (Ortho-Kung-T cell) antibodies. Both OKT4- and OKT8-positive cells were detected in the aqueous humor of patients with uveitis. The percentage of OKT4-positive cells (21.1 +/- 7.4) was larger than that of OKT8-positive cells (15.2 +/- 5.3) and the OKT4-OKT8 ratio was 1.40 +/- 0.3. A comparison of aqueous humor and peripheral blood cells from patients with uveitis showed diminished frequencies of OKT4- and OKT8-positive cells. The OKT4-OKT8 ratios were not significantly different. A comparison of peripheral blood cells from patients with uveitis and from controls showed that patients with uveitis had lower OKT4-OKT8 ratios. Lower percentages of OKT4-positive cells were also observed in the peripheral blood cells of patients with uveitis.

Uveitis and ankylosing spondylitis coexisted in a family. Tissue typing of the family revealed the HL-A 27 antigen in five members: two had uveitis; two had ankylosing spondylitis; and one was asymptomatic. These diseases did not coexist in any one member of the family.

We studied characteristics of ocular inflammation associated with Yersinia infection in 23 patients. After an acute onset with fever, diarrhea, and abdominal pain, 22 patients developed arthritis, 11 patients developed myalgia, 11 patients developed Reiter's syndrome, 17 patients developed acute anterior uveitis, and nine patients developed conjunctivitis. Sacroiliitis was found in 12 patients. The patients had high erythrocyte sedimentation rates, leukocytosis, and lack of antinuclear antibodies and rheumatoid factor. All 17 patients tested had HLA-B27 antigen. The patients with acute anterior uveitis showed aqueous flare, cells, fine keratic precipitates, and often exudates, posterior synechiae, vitritis, and macular edema. Acute anterior uveitis was mostly unilateral and resolved during corticosteroids on the average during the first six weeks; recurrences were seen in about half of the cases. Conjunctivitis was generally mild with no chemosis, follicles, or keratitis; and it resolved in one week without treatment. Our results indicate that in HLA-B27 positive patients infective agents can trigger acute anterior uveitis or conjunctivitis, which often occur together with rheumatic diseases.

We evaluated the peripheral T-cell subsets in 32 adult patients with intraocular inflammatory disease and 12 age-matched normal controls by means of the OKT series of monoclonal antibodies in conjunction with the laser cytofluorograph, which quantitatively determines the fluorescence intensity of lymphocytes. We found no statistically significant difference in the ratio of OKT 4-positive (inducer) cells to OKT8-positive (suppressor) cells. However, this ratio was significantly decreased in patients with active posterior uveitis compared with controls (P less than .05). The number of OKT8-positive T lymphocytes in this group was significantly increased (P less than .01), causing a decrease in the OKT4-OKT8 ratio. In patients with positive in vitro cell-mediated responses to the retinal S-antigen, a statistically significant (P less than .05) decrease was found as well only in the patients with active disease.

We studied histopathologic and immunohistopathologic features of an eye from a patient who had hypopigmented choroidal lesions with subsequent development of progressive subretinal fibrotic tissue associated with minimal signs of vitreal inflammation. A 24-year-old woman had a rapid and severe onset of the disease, which led to blindness within a few months despite treatment with corticosteroids and cyclophosphamide. Histopathologic studies disclosed a marked gliotic retina and thick subretinal fibrotic tissue as well as a granulomatous lymphocytic infiltration in the choroid. Electron microscopy demonstrated that the subretinal tissue was derived from retinal pigment epithelial cells. The immunoperoxidase staining showed similar proportions of T and B lymphocytes, indicating a relative increase of B cells. There was a predominance of the helper/inducer T lymphocyte subset in the infiltrating area. The Müller cells in the retina expressed class II antigens of the major histocompatibility complex.

S-antigen, an organ-specific substance isolated from the retinal photoreceptor region, was shown to be a potent agent for the induction of experimental autoimmune uveitis. S-antigen and other ocular antigens were tested for their ability to induce blast transformation of lymphocytes from patients with a variety of ocular inflammatory diseases. Lymphocytes from 22% of patients tested manifested a positive memory response to the S-antigen prepared from bovine eyes. Responses to human S-antigen paralleled those found with the bovine. All of those with a positive response had active or inactive retinal lesions. Some posterior uveitis patients responded to crude retinal extracts but not to S-antigen, indicating the possible role of other retinal antigens still to be purified. Control subjects did not manifest a positive immune response to the S-antigen, nor did patients with anterior uveitis. Possibly, these responses play some role in the pathogenesis of the disease.

We studied an enucleated eye from a patient with a 30-year history of Vogt-Koyanagi-Harada syndrome using both conventional and immunohistochemical techniques. Clinically, the eye was in the end stage of Vogt-Koyanagi-Harada syndrome, and was characterized by the absence of inflammation, large areas of chorioretinal scarring, and pigmentary changes. Histopathologic examination showed marked retinal gliosis, extensive chorioretinal adhesion and scar formation, migration of pigment into the retina, and severe retinal pigment epithelial changes. However, foci of mild to moderate nongranulomatous inflammation of the uvea were observed. These foci contained infiltrating cells that were mainly T lymphocytes with B lymphocyte aggregates at the center. Scattered macrophages were also noted in the uvea and retina. These findings suggest that both the cell-mediated and humoral immune arms may play roles in the pathogenesis of Vogt-Koyanagi-Harada syndrome.

The aqueous humor and serum of patients with various ocular diseases were analyzed for the occurrence of rheumatoid factor or immune complexes. Rheumatoid factor was detected by its direct agglutinating activity on IgG-coated particles (latex) and immune complexes were detected by their ability to inhibit exogenous rheumatoid factor or the subunit q of the first component of complement (Clq). Rheumatoid factor or inhibitory activity were found in the aqueous humor of nine of 11 patients with Fuchs' syndrome. In some patients who were examined two or three times, agglutination alternated with inhibition. Among 13 patients with endogeous uveitis, five had either agglutinating or inhibitory activities in their aqueous humor. The tests were also positive in the aqueous humor of three of seven patients with choroidal melanoma. A high titer of rheumatoid factor was found in the aqueous humor in an accidentally perforated eye that resulted in sympathetic ophthalmitis. No inhibitory or agglutinating activity was detected in the aqueous humor of 20 patients with senile immature cataract.