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Birdshot chorioretinopathy is an inflammatory eye condition strongly associated with MHC-I allele HLA-A29. The striking association with MHC-I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16 positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express CD8A which is involved in MHC-I recognition on target cells, display gene signatures indicative of high cytotoxic activity (GZMB, PRF1 and ISG15), and signaling through NK cell receptor CD244 (SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identifies a population of CD8 bright CD244 bright NK cells, which rapidly declines to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8 bright CD244 bright NK cells in birdshot chorioretinopathy., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: To study the role of Toxoplasma IgG avidity in evaluating the stage of systemic infection during manifestation as toxoplasma retinochoroiditis and its clinical implications in eastern India., Methods: Retrospective chart review of Toxoplasma retinochoroiditis cases with Toxoplasma serology for IgG, IgM, and IgG avidity., Results: Included in this study were 17 eyes of 17 patients who had active retinitis located in the macula (14), mid-periphery (2), or periphery (1). They were either primary lesions (12) or reactivations (5). All the cases had Toxoplasma IgG positive; one case had IgM positivity, while all the cases had high IgG avidity values. IgG avidity had a positive correlation with the duration of symptoms., Conclusion: We observed high IgG avidity values in active retinochoroiditis in both primary ocular Toxoplasmosis and reactivation subgroups. These results indicate a late ocular manifestation after initial systemic infection with a possible incubation period ranging from 5 weeks to 5 months., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Toxoplasmic retinochoroiditis is a common, potentially blinding parasitic infection. We sought to define the spectrum and frequency of signs of active toxoplasmic retinochoroiditis by spectral domain optical coherence tomography (SD-OCT), and to identify clinical associations. Ninety eyes of 90 individuals presenting consecutively to a tertiary referral uveitis service with active toxoplasmic retinochoroiditis and gradable SD-OCT scans were evaluated prospectively. SD-OCT features were collated, and associations with lesion location, primary versus recurrent episode, serological status, human immunodeficiency virus infection and best-corrected Snellen visual acuity were explored. Active toxoplasmic retinochoroiditis presented with thickened (65%) and hyperreflective (61%) retina, choroidal thickening (55%) and hyporeflectivity (61%), hyperreflective vitreous dots (80%) and deposits (36%), and posterior hyaloid thickening (35%) on SD-OCT. Most signs occurred with similar frequency across clinical groups. Retinal hyporeflectivity (17%) was significantly associated with a visual acuity of 20/200 or worse at resolution. Our observations demonstrate that active toxoplasmic retinochoroiditis has diverse SD-OCT signs and that none are universally present. Retinal hyporeflectivity-suggesting liquefactive necrosis-predicts poor visual outcome., (© 2022. The Author(s).)

Purpose: We report a case of congenital toxoplasmosis associated with retinal detachment., Methods: A 9-month-old white boy presented a unilateral tractional retina detachment associated with congenital toxoplasmosis retinochoroiditis., Results: The diagnosis is supported by positive IgG (>400) for toxoplasmosis and intracranial calcification on magnetic resonance imaging, along with positive family history of Toxoplasma infection in the mother., Conclusion: Tractional retinal detachment is an infrequent and unconventional presentation of congenital Toxoplasma infection. Inflammatory interference with normal sequence of vitreous development may explain pathogenesis of tractional retinal detachments in the setting of congenital ocular toxoplasmosis.

Purpose: To investigate clinical and biological factors influencing recurrences of severe toxoplasmic retinochoroiditis (TRC) confirmed by aqueous humor analysis., Design: Retrospective case series., Methods: Retrospective analysis of 87 subjects with severe TRC, proven by positive Goldmann-Witmer coefficient (GWC), Toxoplasma gondii (T. gondii) immunoblot, or T. gondii-specific polymerase chain reaction (PCR) in aqueous humor. Cases with immunosuppression or retinal scars without previous recorded episode were excluded. Time-dependent, clinical, treatment-related, and biological factors were explored by univariate and multivariate shared frailty survival analyses., Results: Among 44 included subjects (age, 40.4 ± 17.6 years; follow-up, 8.3 ± 2.7 years), 22 presented recurrences. There was 0.11 recurrence/patient/year and mean disease-free interval was 5.0 ± 2.9 years. The risk of recurrence was higher immediately after an episode (P < .0001). Among recurrent cases, the risk of multiple recurrences was higher when the first recurrence occurred after longer disease-free intervals (P = .046). In univariate analysis, the recurrence risk declined with higher number of intense bands on aqueous T. gondii immunoblot (P = .006), and increased when venous vasculitis was present initially (P = .019). Multivariate analysis confirmed that eyes with more intense bands on immunoblot had fewer recurrences (P = .041). There was a near-significant risk elevation after pyrimethamine/azithromycin treatment (P = .078 and P = .054, univariate and multivariate). Intravenous corticosteroid administration, oral corticosteroid administration, aqueous GWC, and T. gondii PCR did not influence recurrences (P = .12, P = .10, P = .39, and P = .96, respectively)., Conclusions: Recurrences of severe TRC are not random and may be influenced by clinical and biological factors possibly related to blood-retinal barrier alterations. These results may contribute to identifying biomarkers for TRC reactivation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose : The purpose of this article is to analyze possible associations between systemic and ocular cytokine levels and specific clinical ophthalmologic signs from patients with a reactivation of toxoplasmic retinochoroiditis (RTR). Methods : A total of 18 patients with an active RTR episode, 8 patients with inactive scars, and 14 control patients were included in the study. Serum samples and aqueous humor (AH) samples were analyzed for IFN (interferon)-γ, interleukin (IL)-10, and IL-6 levels by ELISA. Inflammation grade, location, and size of the retinochoroidal active lesion, sampling time, and time to resolution were recorded. Results : A significantly negative correlation between AH and serum levels of IFN-γ was detected ( p  < 0.05). Patients with an AH IFN-γ/IL-10 ratio lower than 1 were associated with the longest time to resolution and/or severe complications. Conclusion : Serum IFN-γ levels may be used as a prognostic marker for both time to resolution and the development of possible severe complications during a given RTR episode.

Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A * 29:02), ankylosing spondylitis (HLA-B * 27), Behçet's disease (HLA-B * 51), and psoriasis (HLA-C * 06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

Purpose: Adaptive optics scanning laser ophthalmoscopy (AOSLO) allows en face visualization of specific layers of the retina. This pilot study evaluated the ability of AOSLO to visualize photoreceptor integrity in patients with birdshot chorioretinopathy (BCR)., Method: A total of 16 consecutive patients with HLA-A29+ BCR were imaged using the prototype Apaeros retinal imaging system. Images of high quality were aligned with infrared reflectance photos and correlated with spectral domain optical coherence tomography (SD-OCT)., Results: Images of four eyes of three patients were of sufficient quality to allow posterior pole montage and point-to-point correlation with SD-OCT. Areas of photoreceptor disruption on SD-OCT were seen as patchy areas of loss on AOSLO, whereas areas of intact interdigitation zone and inner segment/outer segment junction correlated with normal appearing photoreceptors on AOSLO., Conclusions: Using AOSLO, we found one instance of subclinical photoreceptor disruption not seen on SD-OCT. Ultimately, there are unique challenges associated with imaging BCR patients using AOSLO.

A 44-year-old male presented with a history of defective vision in the right eye for the past 5 months with the previous history of tubercular cervical lymphadenitis. On examination, right eye revealed panuveitis with dense vitritis and chorioretinitis in the superotemporal quadrant. His Mantoux test was positive (25 mm × 25 mm induration), QuantiFERON-TB Gold was test positive, aqueous aspirate was positive for Mycobacterium tuberculosis genome, negative for viruses and toxoplasma, and hence he was initiated on four-drug antitubercular therapy (ATT) with oral steroids. On follow-up, he had worsening of vitritis and intravenous methylprednisolone was given suspecting paradoxical reaction to ATT; however, a repeat AC tap was positive for toxoplasma B1 genome, IgG antitoxoplasma antibody was also positive in serum and aqueous; hence, we switched to systemic antitoxoplasma therapy. He underwent a therapeutic vitrectomy along with intravitreal clindamycin and dexamethasone for persistent vitreous membranes and vitritis. The patient responded well to the treatment with a reduction in vitritis and scarring of the lesion.

Purpose: To determine the prognostic factors of long-term visual outcome in birdshot retinochoroidopathy (BRC)., Methods: Design: Retrospective case series. Study Population: Successive HLA-A29+ BRC patients whose latest visit was between May and August 2013 at a single tertiary center (Pitié-Salpétrière Hospital, Paris)., Observation Procedure: Endpoint visual status (remission or deterioration) was determined for each patient based on clinical and ancillary data from the latest visit including optical coherence tomography (OCT), automated visual field (AVF), and angiograms. Main Outcome Measure: Epidemiologic, clinical, OCT, AVF, angiographic, and electrophysiological data at baseline were correlated to final visual status., Results: Fifty-five patients were included. Mean observation period was 8 years (range: 0.6-23 years). Mean disease duration was 9.8 years (range: 1.2-32.7 years). Female-to-male sex ratio was 1.6:1. Factors of good visual prognosis (remission vs deterioration) included at baseline: late age of disease onset (49.5 vs 45 years, P = .05), presence of vitreous inflammatory reactions >2+ (35.9% vs 6.2%, P = .04), vascular leakage on fluorescein angiograms (FA) (44.4% vs 12.5%, P = .03), absence of macular pigment epithelium atrophy on FA (88.9% vs 62.5%, P = .05), and presence of macular edema on OCT (33.3% vs 6.2%, P = .04). Preserved electrooculography light peak and Arden ratio (P = .06) and presence of choroidal spots on infracyanine green angiograms (80.0% vs 53.3%, P = .08) seemed associated with the best prognoses., Conclusion: This study suggests a series of prognostic factors of long-term visual outcome in BRC. Keeping in mind the insidious evolution of the disease, knowledge of such prognostic factors should help tailor the treatment and monitoring of birdshot patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The inflammatory diseases that are most strongly associated with major histocompatibility Complex class I (MHC-I) alleles are also influenced by endoplasmic reticulum aminopeptidase (ERAP) 1 and/or 2, often in epistasis with the susceptibility MHC-I allele. This review will focus on the four major MHC-I-associated inflammatory disorders: ankylosing spondylitis, birdshot chorioretinopathy, Behçet's disease and psoriasis. The genetics of ERAP1/ERAP2 association and the alterations induced by polymorphism of these enzymes on the risk MHC-I allotypes will be examined. A pattern emerges of analogous effects on peptide length, sequence and affinity of disparate peptidomes, suggesting that similar peptide-mediated mechanisms underlie the pathogenesis and the joint contribution of ERAP1/ERAP2 and MHC-I to distinct inflammatory diseases. Processing of specific antigens, peptide-dependent changes in global properties of the MHC-I molecules, such as folding and stability, or both may be pathogenic., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Ocular toxoplasmosis is a prominent and severe condition of high incidence in Brazil. The current study provides new insights into the immunological events that can be associated with retinochoroiditis in the setting of congenital toxoplasmosis in human infants., Methods: Flow cytometry of intracytoplasmic cytokines in leukocyte subsets following in vitro short-term antigenic recall in infants with congenital T. gondii infection., Results: Our data demonstrates that whereas neutrophils and monocytes from T. gondii-infected infants display a combination of proinflammatory and regulatory cytokine profiles, natural killer cells showed a predominantly proinflammatory profile upon in vitro T. gondii stimulation. The proinflammatory response of CD4(+) and CD8(+) T cells, characterized by the production of interferon γ (IFN-γ) and interleukin 17 in patients with an active retinochoroidal lesion, revealed the presence of IFN-γ and tumor necrosis factor α during early and late immunological events. This specific proinflammatory pattern is associated with early events and active retinochoroidal lesion, whereas a robust monocyte-derived interleukin 10-mediated profile is observed in children with cicatricial ocular lesions., Conclusions: These findings support the existence of a progressive immunological environment concomitant with the initial, apical, and cicatricial phases in the process of retinochoroidal lesion formation in infants with congenital toxoplasmosis that may be relevant in the establishment of stage-specific clinical management., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

In-vitro immunofluorescent assays/imaging are routinely used methods of detecting antigens. The ability to perform ocular angiography to study the choroidal and retinal vasculature in real time provides us with a unique opportunity to perform real time in-vivo immunofluorescent imaging. This unique combination of in-vivo immunofluorescent imaging and live imaging of choroidal and retinal circulation can help detect antigens of infective organisms in-vivo to diagnose causative infective aetiology in cases of choroiditis/retinitis. The following paper describes the basic designing of such an imaging platform., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Importance: To describe a cohort of patients with birdshot chorioretinopathy who did not manifest birdshot lesions on clinical examination but had retinal vasculitis, low-grade to moderate vitritis, and hypocyanescent lesions on indocyanine green angiography (ICGA)., Observations: Case series of 3 patients with mild to moderate vitritis and retinal vasculitis without definite birdshot lesions on clinical examination evaluated from January 2007 to December 2014 at 4 academic ophthalmology centers. All patients' results were positive for human leukocyte antigen-A29. All cases had hypocyanescent lesions visible on ICGA but not detectable on fluorescein angiography., Conclusions and Relevance: Patients with retinal vasculitis and low-grade vitritis with or without macular edema may have birdshot chorioretinopathy evident on ICGA before lesions are visible on clinical examination or fluorescein angiography. Expanding birdshot chorioretinopathy diagnostic criteria to include the presence of hypocyanescent lesions on ICGA could improve the sensitivity of diagnosis.

Birdshot chorioretinopathy (BSCR) is a bilateral chronic intraocular inflammation or posterior uveitis that preferentially affects middle-aged Caucasians. BSCR is characterized by distinctive multiple choroidal hypopigmented lesions in combination with retinal vasculitis and vitritis, and the extraordinary feature that virtually all patients are HLA-A29 positive. Its pathophysiology is still poorly understood. BSCR is the strongest documented association between HLA and disease in humans, which makes it an excellent model for studying the underlying immuno-genetic mechanisms of HLA class I-associated diseases. Although the association with HLA-A29 suggests that it is directly involved in the presentation of peptide antigens to T cells, the exact contribution of HLA-A29 to the pathophysiology of BSCR remains enigmatic. This article revisits the HLA-A29 peptidome using insights from recent studies and discusses why HLA-A29 can be considered a canonical antigen presenting molecule. The first genome-wide association study facilitated novel concepts into a disease mechanism beyond HLA-A29 that includes strong genetic predisposition for the ERAP2 gene that affects antigen processing for HLA class I. Furthermore, patients manifest with pro-inflammatory cytokine profiles and pathogenic T cell subsets that are associated with IL-17-linked inflammation. We are beginning to understand that the underlying biology of BSCR comprises various pathologic aspects branched into multiple molecular pathways. We propose to employ Systems Medicine to reveal their dynamic interplay for a holistic view of the immunopathology of this intriguing archetypal HLA class I-associated disease., (Copyright © 2014. Published by Elsevier Ltd.)

Birdshot retinochoroidopathy (BSRC) is a distinct type of posterior uveitis originally described in the 1940s. Its characteristics include minimal anterior segment inflammation and diffuse posterior choroidopathy with vitritis and retinal vasculitis. The precise etiology of this disease is yet to be elucidated. However, various treatment modalities have been employed with the ultimate goal of durable remission of this vision threatening intraocular disease. The purpose of this review is not only to emphasize the importance of recognizing BSRC, but also to discuss the new discoveries, immune mediators, current and new therapies, and techniques applied to monitor and accomplish disease remission.

Purpose of Review: Birdshot chorioretinopathy remains incompletely understood, but new insights into its pathogenesis have been reported recently, and treatment and monitoring options have also expanded. Central visual acuity may remain good until the late stages of the disease, but loss of visual field and peripheral retinal function is common., Recent Findings: The underlying pathogenesis of the disease has long been believed to be T-cell driven, but examination of the IL-17 pathway has now further refined the potential underlying mechanism. New imaging techniques, including extended depth imaging of the choroid with optical coherence tomography, have demonstrated promise in detecting disease activity earlier, enabling targeted treatment to be given. Treatment options have expanded with the advent of the biological agents, and these may yet improve outcomes, particularly in refractory patients., Summary: Laboratory research continues to investigate the underlying mechanisms of disease, but our understanding remains frustratingly incomplete for a disease with such a clear HLA association. Clinical research is increasingly being driven to improve the phenotyping of affected patients so that those at risk of visual loss can be identified early and treated more aggressively with individually targeted therapies such as the newer biological agents, but how successful this approach will ultimately prove to be remains to be seen.

Birdshot chorioretinopathy (BSCR), a progressive form of non-infectious uveitis, is the strongest HLA-associated disease described to date, with >95% of the patients displaying HLA-A29. Since indirect evidence indicates the involvement of T cells in the etiopathology of the disease, we now isolated, cultured and analyzed the vitreous fluid-infiltrating T cells from two BSCR patients with respect to their phenotype, cytokine profile, clonal distribution and antigen specificity. Phenotypic analyses revealed the predominant presence of both CD4(+) and CD8(+) T cells in vitreous fluid. Further analyses on short term expanded and cloned T cells suggested that eye-infiltrating T cells generally displayed a Th1 like cytokine profile with secretion of high levels of IFN-γ and TNF-α. In one patient an oligoclonal CD4(+) and CD8(+) T cell infiltration, with a moderate to strongly skewed TCR Vβ usage was suggestive for an antigen driven infiltration/expansion. Indeed, a number of intraocular CD4(+) and CD8(+) T cells responded to crude retinal and choroidal lysates. These results, which demonstrate for the first time the existence of eye-antigen-specific T cells in the vitreous fluid of BSCR patients, substantiate the current view on the role of eye-antigen specific T cells in the etiopathology of BSCR., (Copyright © 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Interleukin-17 (IL-17) has been associated with the pathogenesis of numerous autoimmune diseases. CD4+ T cells secreting IL-17 are termed Th17 cells. CD8+ T cells, designated Tc17 cells, are also capable of secreting IL-17. Here we describe a population of Tc17 cells characterized by the expression of surface CD146, an endothelial adhesion molecule. These cells display signatures of a human Tc17 genotype and phenotype. Circulating CD8+CD146+ T cells are present in low levels in healthy adults. Elevations in CD8+CD146+ T cells are found in Behcet's disease and birdshot retinochoroidopathy, which have been reported to have HLA class I associations. Sarcoidosis does not have a class I association and displays an increase in CD4+ CD146+ T cells but not in CD8+CD146+ T cells. CD146 on these cells may facilitate their ability to bind to, and migrate through, endothelium, as has been reported for CD4+CD146+ T cells., (Published by Elsevier Inc.)

Purpose: To report the clinical features of patients with focal chorioretinitis (FCR), as well as toxoplasma serology., Methods: We included 25 (4%) consecutive patients with FCR of 593 with uveitis. Controls consisted of 127 patients with posterior and panuveitis and clinical features other than FCR. Results of enzyme-linked immunosorbent assay for anti-Toxoplasma gondii immunoglobulin G (IgG) and IgM, demographic data, and clinical features of patients were registered., Results: Positive anti-T. gondii IgG levels were observed in 21 of 25 patients (84%) with FCR in contrast to 14 of 127 patients (11%) with non-FCR (P < 0.001, Fisher test). The IgG levels >600 IU were found in 19 of 25 patients (76%) with FCR and in none of the patients with non-FCR (P < 0.001). All cases had unilateral involvement. Ocular features consisting of FCR and vitritis were present in all patients, but associated chorioretinal atrophic scars were not commonly seen (7/25 eyes; 28%). Retinal vasculitis was found in 9 of 25 eyes (36%) and affected solely the arteries., Conclusion: The majority of patients with FCR in Thailand exhibit highly positive anti-T. gondii IgG levels suggesting the presence of active systemic infection, which is also consistent with the absence of old scars. The absence of old scars and retinal arteritis were the features distinct from typical ocular toxoplasmosis lesions reported in the European and the U.S. series.

Purpose: To determine the cytokine response to ocular lysates of peripheral blood mononuclear cells (PBMCs) from patients with birdshot chorioretinopathy (BSCR)., Methods: In the PBMCs of 19 patients with BSCR, T cell cytokine production in response to human retina and choroid lysates was analyzed with flow cytometry and compared to the responses against skin lysates. Five patients had active disease and had not yet been treated (naïve to systemic therapy); 14 patients had either immunomodulatory therapy (IMT) or inactive disease (referred as inactive/IMT). The PBMCs of 11 HLA-A29-positive healthy individuals were used as controls., Results: The levels of interleukin-17 (IL-17) in supernatant of cultures stimulated with retina lysate were higher in patients with active BSCR compared to the HLA-A29 positive controls. The levels of other T cell cytokines (IL-10 and interferon-γ [IFN-γ]) in PBMC cultures did not change significantly after stimulation with ocular lysate. The frequency of CD4(+) IL-17(+) (T helper 17 [Th17]) T cells but not of CD4(+) IFN-γ (Th1) T cells was elevated in the PBMCs of patients with active BSCR stimulated by retina lysates compared to skin lysates., Conclusions: Our data demonstrate that PBMCs exhibit an IL-17-mediated immune response to retina lysate in patients with active disease naïve to systemic therapy. This is accompanied by the enrichment of IL-17-producing CD4(+) T cells. These findings support the current concept of chronic Th17-cell mediated inflammation and provide evidence that links the Th17 signatures to ocular-specific immune responses in BSCR.

Purpose: To determine the peripheral levels of 20 immune mediators in serum samples from patients with birdshot retinochoroidopathy (BSRC)., Design: Single-center prospective case-control study., Methods: The serum of 17 BSRC patients during different phases of disease activity and therapy were analyzed with a quantitative multiplex sandwich enzyme-linked immunosorbent assay-based microarray to determine the levels of 20 immune mediators (T cell and proinflammatory). The serum of 12 healthy volunteers was used as controls., Results: Serum levels of interleukin (IL)-21 (P = .0005), IL-23 (P = .0005), and transforming growth factor (TGF)-β1 (P = .0011) were elevated in BSRC patients with active disease naïve to systemic therapy compared with that of controls. There was no significant difference in the serum levels of immune mediators between controls and BSRC patients who had a current or past history of IMT or who were in remission. The levels of IL-21, IL-23, and TGF-β1 were positively correlated (IL-23/IL-21, r = 0.91; TGF-β1/IL-21, r = 0.97; TGF-β1/IL-23, r = 0.87; for all, P < .0001)., Conclusions: BSRC patients with active disease naïve to systemic therapy have elevated serum levels of 3 key immune mediators known to promote T helper 17 (Th17) cells in autoimmune disease. Our results suggest that IL-21, IL-23, and TGF-β1 may play an important role in the development of site-specific Th17 cell-mediated inflammation in BSRC, which underscore the importance of systemic therapy and offer new insights into the potential of targeted treatments., (Copyright © 2013 Elsevier Inc. All rights reserved.)

TNF-α blockers are associated with reactivation of latent granulomatous infections and almost 6% of the world population has some chorioretinitis (CR) caused by Toxoplasma gondii. Thus, the blockade of TNF-α could reactivate a latent toxoplasmosis infection (LTxI). This study was conducted to evaluate the prevalence and incidence of chronic and active CR related to T. gondii in patients with ankylosing spondylitis (AS). A total of 74 eyes from 37 active AS outpatients starting TNFα blockers were compared with 35 AS patients, matched to age and sex, under conventional therapy in a prospective and controlled trial. All patients underwent serological tests for T. gondii, as well as periodic ophthalmologic examination during 12months. Active CR was defined if a white, focal retinochoroidal lesion with overlying vitreous inflammation had been found. Retinochoroidal lesions with sharp edges, hyperpigmented borders and atrophic center were defined as CR scars. At baseline, no patient had active CR. From the 144 eyes examined, almost 6% had CR scars and only 2.1% had a typical toxoplasmic CR scar and all of them were negative for HLA-B27. During 12months of follow-up, no recurrence or new CR were observed. AS patients using TNF-α blockers do not have a higher risk of acute or chronic CR caused by T. gondii., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To characterize the active retinochoroiditis lesion observed in patients with the classic clinical presentation of ocular toxoplasmosis (OT) utilizing spectral optical coherence tomography (SOCT)., Methods: Twenty-four patients with OT and satellite lesions underwent standardized ophthalmologic examination and multimodal fundus imaging. The SOCT findings observed at presentation were described., Results: The mean age of the fourteen (58.3%) women and ten (41.7%) men was 27.6 years. The mean LogMAR ETDRS best-corrected visual acuity was 0.58 (Snellen equivalent, 20/80(+1) ). On SOCT evaluation, the posterior hyaloid was diffusely thickened in 23 (95.8%) of 24 eyes, increased hyper-reflective signals in the vitreous were observed in 18 (75.0%), and vitreal spherical hyper-reflective depositions were observed in 12 (50.0%) eyes. In all patients, at the active OT lesion site, the inner retinal layers were abnormally hyper-reflective with full-thickness disorganization of the retinal reflective layers (smudge effect); associated choriocapillaris/choroidal optical shadowing was observed in 22 (91.7%) eyes. The retina was thickened in 22 (91.7%) eyes, the retinal pigment epithelium-Bruch membrane reflective complex was focally increased or contained focal splits in 16 (66.7%) eyes and the choroid appeared thickened in 17 (70.8%) eyes. Disorganization of the outer retinal highly reflective layers adjacent to the active OT lesion was observed in all eyes., Conclusion: Full-thickness disorganization of the retinal reflective layers, generally associated with some degree of posterior optical shadowing, was observed in the active OT lesion in all patients. The posterior hyaloid was often thickened and, adjacent to the OT lesion, the outer retina was consistently altered., (© 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To describe the histological findings of birdshot chorioretinopathy. DESIGN/PARTICIPANT: This is a case study of a single patient who has both birdshot chorioretinopathy and ciliochoroidal melanoma., Methods: A 55-year-old woman who was HLA-A29 positive and had birdshot chorioretinopathy had a large ciliochoroidal melanoma (T4b N0 M0) and underwent enucleation., Outcome Measures: Using histopathology, we hope to further define the pathological findings in an eye with both birdshot chorioretinopathy and coexistant ciliochoroidal melanomas., Results: The eye showed a ciliochoroidal melanoma. In addition, elsewhere, there were multiple choroidal nodules of lymphocytes that showed the presence of CD3-positive cells, which also stained for CD4 or CD8. There were only a few CD20-positive B cells and rare CD68-positive histiocytes. No granulomas were present., Discussion: To our knowledge, there are only two previous reports describing the histological findings in birdshot chorioretinopathy: one that was HLA-A29 negative showing choroidal granulomas and another that was HLA-A29 positive exhibiting histological findings similar to our case. Incidentally, the latter case had a history of cutaneous melanoma., Conclusion: Birdshot chorioretinopathy is a nongranulomatous nodular infiltration of the choroid.

Toxoplasma gondii is a protozoan of worldwide distribution. This unit describes murine models of acute T. gondii infection, toxoplasmic encephalitis, and Toxoplasma retinochoroiditis. T. gondii infection in SCID mice allows the study of T cell-independent mechanisms of defense. The uracil auxotroph strain cps1-1 and temperature-sensitive mutant strains of T. gondii allow studies of immunization and adoptive transfer. In vivo study of parasite host-interaction is possible with the use of parasites that express fluorescent proteins and model antigens, plus the use of transgenic mice that express the appropriate T cell receptor and fluorescently labeled leukocytes. Parasites that express bioluminescent markers make it possible to study the dynamics of infection in real time using bioluminescence imaging. Support protocols present methodology for evaluation of progression of infection and immune response to the parasite, the maintenance of T. gondii tissue cysts and tachyzoites, as well as preparation of T. gondii lysate antigens., (© 2012 by John Wiley & Sons, Inc.)

Our purpose was to examine toxoplasmic serology in relation to episodes of suspected acute toxoplasmic retinochoroiditis and evaluate its use in the appraisal of patients. The mean values of enzymatic immunoassay (EIA) titers for toxoplasmic antibodies were retrospectively compared in patients with active and inactive toxoplasmosis and in a third group of uveitis cases not caused by toxoplasmosis. The proportion of cases under and above a predefined serology value above cut-off was compared in all groups. Between 1995 and 2010, 97 out of 1,276 new uveitis cases seen at the Centre for Ophthalmic Specialized Care (COS), Lausanne, Switzerland were diagnosed as toxoplasmic retinochoroiditis, of which 51 had documented serology available. The mean EIA values for immunoglobulin (Ig) G were 147.75 ± 259.4 IU/ml for patients with active disease, 18.93 ± 23.09 (p < 0.05) for patients with inactive toxoplasmosis and 18.35 ± 20.82 for controls (p < 0.017). The proportion of cases under the designated limit value were 2/51 (4%) in the active retinitinochoroiditis group, 14/27 (52%) (p < 0.05) in the control group, and 7/7 (100%) in the inactive toxoplasmic group (p < 0.001). Three out of 51 cases showed high IgM values in addition to IgG elevation and were primary infections. Toxoplasmosis serology, contrary to popular belief, is useful to confirm active toxoplasmic retinochoroiditis; it is easy to perform, cheap and supports clinical diagnosis in up to 96% of cases, not only by showing positivity but by also showing a significant elevation of titers. In atypical cases serology is not only useful but essential.

Birdshot chorioretinopathy primarily affects patients of European descent. At least 96%, if not all patients, are HLA-A29 carriers. HLA-A*29:01 and HLA-A*29:02, the two main subtypes of HLA-A29, differ only by a single mutation. In the general population HLA-A*29:02 is most frequent in whites, while HLA-A*29:01 is more frequent in Asians. The differential distribution of HLA-A*29:01 and HLA-A*29:02 has been actively debated as an explanation for the selective development of the disease in patients of European descent, but is no longer a valid argument. Another factor, probably not HLA linked, is either protective in Asians and in Africans or, conversely, triggers an autoimmune reactivity that is possibly present in whites and absent in Asians and in Africans. HLA-A*29:02 transgenic mice in which a spontaneous posterior uveitis is observed after 6 months of age provide further evidence that the HLA-A29 molecule plays a role in the pathogenesis of the disease.

Purpose: To report a case of antiphospholipid syndrome (APS) following toxoplasma retinochoroiditis., Design: Interventional case report., Method: The patient was a 24-year-old female with an attack of visual loss due to toxoplasma retinochoroiditis concomitant with branch retinal vein occlusion. Retinitis resolved with anti-toxoplasma treatment. However, a recurrent episode of BRVO and vitreous hemorrhage occurred later., Result: In systemic evaluation, evidence of APS was detected, including high titers of anti-cardiolipin antibody, increased beta-2 microglobulin and anti-toxoplasma IgG antibody, and also low titers of C3, C4, and CH50., Conclusion: Ocular toxoplasmosis should be included in the list of etiologies of secondary APS. Systemic evaluation for detection of APS is a necessary approach to patients with toxoplasma retinochoroiditis and concomitant vascular accident.

Background and Aims: Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients., Methods: Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA., Results: The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis., Conclusions: The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.

Purpose: Toxoplasma gondii is a major cause of ocular disease, which can lead to permanent vision loss in humans. T cells are critically involved in parasite control, but little is known about the molecules that promote T-cell trafficking and migration in the retina. Thus, the aim of this study was to image and dissect the T-cell response during chronic toxoplasmic retinochoroiditis., Methods: C57BL/6 mice were infected with the Me49 strain of T. gondii, and T cells that infiltrated the eye were analyzed by flow cytometry and imaged using multiphoton microscopy. IFN-γ, CXCL9, CXCL10, and CXCR3 mRNA levels were measured by real-time PCR. To investigate the role of CXCL10, mice were treated with anti-CXCL10 antibodies, and histopathology and immunohistochemistry were performed to monitor changes in pathology, cellular infiltration, and parasite burden in the eye., Results: Infection with T. gondii leads to the infiltration of highly activated motile T cells into the eye. These cells express CXCR3 and are capable of producing IFN-γ and TNF-α, and CD8+ T cells express granzyme B. The expression of CXCL9 and CXCL10 in the retina was significantly upregulated during chronic infection. Treatment of chronically infected mice with anti-CXCL10 antibodies led to decreases in the numbers of CD3+, CD4+, and CD8+ T cells and the amount of IFN-γ mRNA expression in the retina and an increase in replicating parasites and ocular pathology., Conclusions: The maintenance of the T-cell response and the control of T. gondii in the eye during chronic infection is dependent on CXCL10.

Objective: To describe the clinical, molecular, and serologic findings of a case in which autoimmune retinopathy and early-onset heritable retinal degeneration were both considered in the differential diagnosis., Methods: A 3-year-old girl had clinical findings suggestive of a childhood-onset retinal degeneration. Samples of DNA and serum were collected. The coding regions of 11 genes associated with Leber congenital amaurosis were sequenced. The patient's serum reactivity to soluble and insoluble fractions of human retinal protein was compared with that of healthy control subjects (n = 32), patients with inflammatory eye disease (n = 80), and patients with molecularly confirmed retinal degenerations (n = 11). Two-dimensional gel electrophoresis and mass spectrometry were used to identify a protein that corresponded to a reactive band on Western blot., Results: No plausible disease-causing mutations were identified in any of the retinal disease genes tested. However, the patient's serum showed reactivity to a single retinal antigen of approximately 47 kDa. Two-dimensional gel electrophoresis and mass spectrometry revealed the major reactive species to be neuron-specific enolase (NSE). Autoantibodies targeting NSE were not observed in any healthy control subjects or patients with inflammatory eye disease. However, anti-NSE activity was found in 1 child with molecularly confirmed Leber congenital amaurosis., Conclusion: This patient's clinical and laboratory findings coupled with the recently discovered role of anti-NSE antibodies in canine autoimmune retinopathy suggest that autoantibodies targeting NSE are involved in the pathogenesis of her disease., Clinical Relevance: Infection or inflammation within the retina early in life may lead to an autoimmune phenocopy of early-onset inherited retinal degeneration.

Toxoplasma gondii infection is an important cause of ocular disease in both immunocompromised and immunocompetent subjects. The pathogenesis of retinochoroidal lesion associated with this infection is not fully understood. In this review, the role of the immune system in the control of Toxoplasma infection, especially in the eye, is discussed.

Background: Patients with ocular toxoplasmosis (OT) develop autoreactivity to several retinal antigens, including retinal S-antigen. By establishing an experimental rabbit model of systemic and of primary and secondary ocular toxoplasmosis, we wished to investigate the onset and development of humoral response to retinal S-antigen., Methods: Of twelve infection-naïve rabbits, six were left untreated, and the other six were infected subcutaneously with 5,000 tachyzoites of the highly virulent, non-cyst-forming BK-strain of Toxoplasma gondii. Three months later, the left eye of each animal was infected transvitreally with 5,000 tachyzoites of the same strain. The right eye of each rabbit served as an uninfected control. Blood and aqueous humor were collected prior to infection, and up to 90 days thereafter. Using the ELISA technique, all samples were analyzed in parallel for total IgG, and antibodies against toxoplasmic, bovine retinal S-antigen and peptide 35 from human S-antigen., Results: In infection-naïve rabbits Toxoplasma-specific antibodies were detected 10 to 15 days after systemic and ocular infection. Serum antibodies against retinal S-antigen and peptide 35 were not detected in response to systemic Toxoplasma infection. After ocular challenge, aqueous-humour levels of antibodies against retinal S-antigen and peptide 35 in the infected eye began to rise 10 to 15 days later in infection-naïve, but not in infection-immunized animals. During the early post-infection period, the concentrations of anti-retinal antibodies in the infected eye correlated with the severity of inflammatory tissue destruction, but returned to baseline later even though the inflammatory response persisted. In the uninfected partner eye, concentrations of anti-retinal and toxoplasmic antibodies did not correlate with each other., Conclusion: Our data afford no evidence of similarities between toxoplasmic and retinal antigens, nor of infection-induced humoral autoimmunity. They indicate rather that retinal autoantigens are liberated in the context of inflammatory tissue destruction due to ocular toxoplasmosis.

Objective: To report a rare case of congenital toxoplasmosis from an immunocompetent mother with chronic infection who had reactivation of ocular disease during pregnancy., Description: The newborn was asymptomatic at birth and identified by neonatal screening (IgM anti-Toxoplasma gondii in dried blood) among other 190 infants with congenital toxoplasmosis during a 7-month period. His mother had had a non-treated episode of reactivation of toxoplasmic retinochoroiditis during pregnancy, with stable IgG titers and negative IgM results. Results of IgM and IgG in the newborn's serum, as well as IgG immunoblotting were positive and active retinochoroidal lesions were detected in his peripheral retina. The neonate was treated with sulfadiazine, pyrimethamine and folinic acid. At 14 months of life, the child remained asymptomatic, with regression of retinochoroidal lesions and persistence of IgG., Comments: It is possible that systematic neonatal screening in areas with high prevalence of infection may identify these cases.

Toxoplasma gondii is the most frequent cause of chorioretinitis in immunocompetent patients. This paper highlights the case of a 15 years old girl, an immunocompetent patient, with an active chorioretinal focus in the LE and a chorioretinal scar in the RE. Serologically, the IgG antiToxoplasma titre is increased, but the IgM antibodies are negative. It is the bilateral character of the lesions and the serology found that make this case special.

Background/purpose: Toxoplasmosis is the most common cause of posterior uveitis in immunocompetent subjects. Taking into account the opposing needs of limiting parasite multiplication and minimizing tissue destruction, the infection imbalance most often involves CD4 and CD8 T lymphocytes that play the lead role in adaptive immunity to T. gondii. The aims of our study were to develop murine models of toxoplasmosis and to study the immune responses to the infection., Methods: Two murine models were studied: (i) intravitreal injection of T. gondii (primary infection) and (ii) intraperitoneal inoculation at birth and reinfection by intravitreal injection. Clinical and histological data were determined. mRNA-cytokine levels were measured in ocular samples obtained from mice with toxoplasma chorioretinitis using RT-PCR., Results: Intravitreal injection of T. gondii led to chorioretinitis. Primary infection was characterized by severe chorioretinitis when compared with reinfection. mRNA levels of IFN-gamma, TNF-alpha, and iNOS were increased in infected mice., Discussion: TH1 cells may mitigate chorioretinitis by limiting T. gondii proliferation. Further studies are needed to explore ocular immune regulation. These primary results may open new in vivo therapeutic approaches.

Toxoplasmosis is a worldwide zoonosis that generally produces an asymptomatic infection. In some cases, however, toxoplasmosis infection can lead to ocular damage. The immune system has a crucial role in both the course of the infection and in the evolution of toxoplasmosis disease. In particular, IFN-gamma plays an important role in resistance to toxoplasmosis. Polymorphisms in genes encoding cytokines have been shown to have an association with susceptibility to parasitic diseases. The aim of this work was to analyse the occurrence of polymorphisms in the gene encoding IFN-gamma (+874T/A) among Toxoplasma gondii seropositive individuals, including those with ocular lesions caused by the parasite, from a rural population of Santa Rita de Cássia, Barra Mansa, state of Rio de Janeiro, Brazil. Further, we verified which of these polymorphisms could be related to susceptibility to the development of ocular toxoplasmosis. This study included 34 individuals with ocular toxoplasmosis (ocular group) and 134 without ocular lesions (control group). The differences between A and T allele distributions were not statistically significant between the two groups. However, we observed that a higher frequency of individuals from the ocular group possessed the A/A genotype, when compared with the control group, suggesting that homozygocity for the A allele could enhance susceptibility to ocular toxoplasmosis in T. gondii infection.

The infection of humans with the rodent-borne lymphocytic choriomeningitis virus (LCMV) can lead to central nervous system disease in adults or severe neurological disease with hydrocephalus and chorioretinitis in children infected congenitally. Although LCMV-induced meningitis and encephalitis have been studied extensively, the immunopathological mechanisms underlying LCMV infection-associated ocular disease remain elusive. We report here that the intraocular administration of the neurotropic LCMV strain Armstrong (Arm) elicited pronounced chorioretinitis and keratitis and that infection with the more viscerotropic strains WE and Docile precipitated less severe immunopathological ocular disease. Time course analyses revealed that LCMV Arm infection of the uvea and neuroretina led to monophasic chorioretinitis which peaked between days 7 and 12 after infection. Analyses of T-cell-deficient mouse strains showed that LCMV-mediated ocular disease was strictly dependent on the presence of virus-specific CD8(+) T cells and that the contribution of CD4(+) T cells was negligible. Whereas the topical application of immunosuppressive agents did not prevent the development of chorioretinitis, passive immunization with hyperimmune sera partially prevented retinal and corneal damage. Likewise, mice displaying preexisting LCMV-specific T-cell responses were protected against LCMV-induced ocular disease. Thus, antibody- and/or T-cell-based vaccination protocols could be employed as preventive strategies against LCMV-mediated chorioretinitis.

Toxoplasma infection accounts for up to 50% of all cases of posterior uveitis worldwide. In this review the control of Toxoplasma infection generally, and specific in the eye, by the immune system is discussed.

Purpose: To determine the cause of retinochorioditis in a patient with a granulomatous retinal exudate and an exudative retinal detachment., Case: A 45-year-old man presented at another hospital with increased visual disturbances of the left eye. He was diagnosed with uveitis, and treated with topical steroids for 1 month. However, the uveitis worsened, and he was referred to our hospital. Ophthalmoscopy showed a yellowish-white granulomatous exudate, and an exudative retinal detachment in the lower peripheral retina. The retinal detachment worsened and affected the macula. Pars plana vitrectomy was performed, and the retina was reattached. During the surgery, ocular samples were collected for further examinations. The titers of antibodies against 12 kinds of ascaridis were examined, and elevated titers of specific antibodies against porcine ascarids were detected in the subretinal fluid, but not in the aqueous humor, vitreous, or serum., Conclusions: Vitrectomy with the collection of ocular samples, especially subretinal fluid, was a key procedure in the diagnosis and treatment of retinochoroiditis associated with the porcine ascarids.

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR-HLA gene combinations in disease. Here, we characterized KIR-HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR-HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4(T80)) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4(I80) and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4(I80) and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.