Immunology and Uveitis

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Levin MH, Pistilli M, Daniel E, Gangaputra SS, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster SC, Jabs DA, Levy-Clarke GA, Kempen JH. Incidence of visual improvement in uveitis cases with visual impairment caused by macular edema. Ophthalmology 2014;121(2):588-95.e1.Abstract
PURPOSE: Among cases of visually significant uveitic macular edema (ME), to estimate the incidence of visual improvement and identify predictive factors. DESIGN: Retrospective cohort study. PARTICIPANTS: Eyes with uveitis, seen at 5 academic ocular inflammation centers in the United States, for which ME was documented to be currently present and the principal cause of reduced visual acuity (<20/40). METHODS: Data were obtained by standardized chart review. MAIN OUTCOME MEASURES: Decrease of ≥ 0.2 base 10 logarithm of visual acuity decimal fraction-equivalent; risk factors for such visual improvement. RESULTS: We identified 1510 eyes (of 1077 patients) with visual impairment to a level <20/40 attributed to ME. Most patients were female (67%) and white (76%), and had bilateral uveitis (82%). The estimated 6-month incidence of ≥ 2 lines of visual acuity improvement in affected eyes was 52% (95% confidence interval [CI], 49%-55%). Vision reduced by ME was more likely to improve by 2 lines in eyes initially with poor visual acuity (≤ 20/200; adjusted hazard ratio [HR] 1.5; 95% CI, 1.3-1.7), active uveitis (HR, 1.3; 95% CI, 1.1-1.5), and anterior uveitis as opposed to intermediate (HR, 1.2), posterior (HR, 1.3), or panuveitis (HR, 1.4; overall P = 0.02). During follow-up, reductions in anterior chamber or vitreous cellular activity or in vitreous haze each led to significant improvements in visual outcome (P <0.001 for each). Conversely, snowbanking (HR, 0.7; 95% CI, 0.4-0.99), posterior synechiae (HR, 0.8; 95% CI, 0.6-0.9), and hypotony (HR, 0.2; 95% CI, 0.06-0.5) each were associated with lower incidence of visual improvement with respect to eyes lacking each of these attributes at a given visit. CONCLUSIONS: These results suggest that many, but not all, patients with ME causing low vision in a tertiary care setting will enjoy meaningful visual recovery in response to treatment. Evidence of significant ocular damage from inflammation (posterior synechiae and hypotony) portends a lower incidence of visual recovery. Better control of anterior chamber or vitreous activity is associated with a greater incidence of visual improvement, supporting an aggressive anti-inflammatory treatment approach for ME cases with active inflammation.
Llop SM, Davoudi S, Stanwyck LK, Sathe S, Tom L, Ahmadi T, Grotting L, Papaliodis GN, Sobrin L. Association of Low Vitamin D Levels with Noninfectious Uveitis and Scleritis. Ocul Immunol Inflamm 2018;:1-8.Abstract
PURPOSE: To determine whether an association between Vitamin D and noninfectious ocular inflammation exists. METHODS: Retrospective case-control study with 765 patients (333 uveitis cases, 103 scleritis cases, 329 controls). Logistic regression models examined the relationship between hypovitaminosis D and ocular inflammation. RESULTS: The odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels in the multivariate analysis [odds ratio (OR) = 1.92, 95% Confidence Interval (CI) = 1.36-2.72, p = 2.32 × 10]. A secondary analysis demonstrated that the odds of developing uveitis or scleritis were 5% lower and 4% lower, respectively, for every unit increase in Vitamin D level (uveitis: OR = 0.95, 95% CI = 0.94-0.97, p = 9.87 × 10; scleritis: OR = 0.96, 95% CI = 0.93-0.99, p = 0.009). CONCLUSION: Hypovitaminosis D was associated with increased risk of ocular inflammation in this retrospective study.
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Ma L, You C, Hernandez M, Maleki A, Lasave A, Schmidt A, Stephenson A, Zhao T, Anesi S, Foster SC. Management of Ocular Cicatricial Pemphigoid with Intravenous Immunoglobulin Monotherapy. Ocul Immunol Inflamm 2018;:1-7.Abstract
PURPOSE: To assess the long-term efficacy and safety of IVIg monotherapy in patients with recalcitrant ocular cicatricial pemphigoid (OCP). METHODS: A chart review of all OCP patients seen at the Massachusetts Eye Research and Surgery Institution (MERSI) between 2005 and 2015 was completed. Stage was graded by using the Foster grading system. IVIg infusion was 2g/kg/cycle administered in 3 consecutive days monthly. RESULTS: Of 512 OCP patients, 17 patients (34 eyes) treated with IVIg monotherapy were identified. Seven were female and ten were male. The average age at diagnosis was 60.7-year-old. The follow up time ranged from 12 to 140 months. Twenty-six eyes (76.5%) achieved remission. Nine remission eyes received cataract surgeries, and 2 of them had relapse (22.2%). The other 17 eyes did not undergo ocular surgery and remained in remission. IVIg monotherapy showed high efficacy in stage 1 OCP (7/7, 100%). Ocular surgery can be associated with OCP relapse (Table 2). CONCLUSIONS: IVIg monotherapy is an effective and safe therapy in patients with recalcitrant OCP. Ocular surgery can be associated with OCP relapse.
Maleki A, Meese H, Sahawneh H, Foster SC. Progress in the understanding and utilization of biologic response modifiers in the treatment of uveitis. Expert Rev Clin Immunol 2016;12(7):775-86.Abstract

Uveitis is the third most common cause of blindness in developed countries. Considering the systemic and local complications of long-term corticosteroid therapy and the intolerance due to side effects and ineffectiveness of conventional chemotherapy, use of biologic response modifiers is a reasonable alternative in the treatment of non-infectious uveitis and persistent uveitic macular edema. The majority of the evidence presented here comes from open uncontrolled analyses. Based on these studies, tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, have been shown to be effective in the treatment of non-infectious uveitis in numerous studies. More research is necessary, particularly multi-center randomized clinical trials, to address the choice of biologic response modifier agent and the length of treatment as we employ biologic response modifiers in different types of uveitis and persistent uveitic macular edema.

Maleki A, Look-Why S, Asgari S, Manhapra A, Gomez S, Foster SC. Acquired Vitelliform-Like Lesion in Uveitis: A case-series. Ocul Immunol Inflamm 2021;:1-10.Abstract
PURPOSE: To study acquired vitelliform-like lesions (AVLL) and their diagnostic and prognostic values in uveitis. PATIENTS AND METHODS: This was a retrospective case series. The clinical course, diagnostic value, and prognostic significance of AVLL were compared between uveitic patients with AVLL and uveitic patients without AVLL. RESULTS: Twelve patients (21 eyes) with both uveitis and AVLL (study group) and thirteen patients (24 eyes) without AVLL (control group) were included in the study. Macular leakage (p = .005), the presence of vasculitis (p = .01), the presence of active choroiditis (p = .01), and the presence of CME on OCT (p = .008) were significantly higher in the AVLL group compared to the control group. Best-corrected visual acuity was significantly lower at presentation (p < .001) and the last follow-up visit (p = .014) in the AVLL group. CONCLUSION: The presence of acquired vitelliform-like lesion can have both a diagnostic (uveitis as a differential diagnosis) and prognostic value in patients with different types of uveitis.
Maleki A, Swan RT, Silpa-Archa S, Preble JM, He Y, Foster SC. Short-Wavelength Automated Perimetry Parameters at Baseline and Following Remission in Patients With Birdshot Retinochoroidopathy. Am J Ophthalmol 2016;163:83-92.e6.Abstract

PURPOSE: To identify changes in short-wavelength automated perimetry patterns and parameters between the active and inactive states. DESIGN: Retrospective cohort study with age-matched, normal controls. METHODS: setting: Private tertiary referral center. STUDY POPULATION: Seventy-five eyes of 38 patients with active birdshot retinochoroidopathy and 37 eyes of 37 historical normal controls. INTERVENTION: Thirty-seven patients received immunomodulatory therapy. A fluocinolone acetonide intravitreal implant (Retisert) was implanted in both eyes of 1 patient as an initial treatment. MAIN OUTCOME MEASURES: Changes in short-wavelength automated perimetry total deviation scores, pattern deviation scores, mean deviation, and pattern standard deviation in the active phase and the remission state. RESULTS: Mean deviation (P = .006), pattern standard deviation (P = .001), total deviation score (P = .002), and pattern deviation score (P = .007) were significantly different from the active phase to the remission state. The length of time required to achieve remission did not significantly affect the changes in mean deviation (regression coefficient = 0.01; P = .92), pattern standard deviation (regression coefficient = 0.01; P = .87), total deviation score (regression coefficient = -0.1; P = .32), or pattern deviation score (regression coefficient = 0.1; P = .36) from the active phase to the remission state. CONCLUSION: There was significant improvement in total deviation score, pattern deviation score, mean deviation, and pattern standard deviation on short-wavelength automated perimetry as patients achieved remission. Short-wavelength automated perimetry appears to be a useful and complementary modality in monitoring disease activity in birdshot retinochoroidopathy.

Maleki A, Gomez S, Asgari S, Bosenberg Z, Manhapra A, Walsh M, Weng A, Tseng C, He C, Anesi SD, Foster SC. Diagnostic and Prognostic Roles of Serum Interleukin-6 Levels in Patients with Uveitis. Ocul Immunol Inflamm 2020;:1-6.Abstract
PURPOSE: To examine the diagnostic and prognostic roles of serum interleukin-6 levels in patients with uveitis. METHODS: This was a retrospective observational case series. Demographic and clinical characteristics were compared between Group One (sixty patients) with normal serum IL-6 levels and Group Two (twenty patients) with high serum interleukin-6 levels. RESULTS: Mean IL-6 level was 1.77 ± 0.97 pg/ml and 10.2 ± 9.7 pg/ml in Group One and Group Two respectively. Age, presence of systemic disease, and mean number of flare-ups were statistically significant ( = .015, = .000, = .03, respectively). Multivariate analysis was performed on variables that were statistically significant in univariate analysis and showed that three variables had significant correlation with IL-6 levels in both groups: systemic disease (OR = 10.83, < .001), Age (OR = 0.95, = .03) and number of flare-ups (OR = 2.9, = .02). CONCLUSION: Serum IL-6 levels can provide diagnostic and prognostic information in regard to the course of disease and its treatment.
Maleki A, Garcia CM, Asgari S, Manhapra A, Foster CS. Response to the Second TNF-α Inhibitor (Adalimumab or Infliximab) after Failing the First One in Refractory Idiopathic Inflammatory Retinal Vascular Leakage. Ocul Immunol Inflamm 2021;:1-10.Abstract
: To determine the response to the second TNF-α inhibitor (adalimumab and infliximab) after failing the first agent in idiopathic inflammatory retinal vascular leakage.: This was a retrospective observational case series. Patients with the diagnosis of idiopathic inflammatory retinal vascular leakage who had received both infliximab and adalimumab were included in the study.: Twelve and 15 patients received adalimumab (Group one) and infliximab (Group two) as the first treatment, respectively. The remission rates between Group one (58.3%) and Group two (66.7%) were not statistically significant. ( = .4) As the second agent, adalimumab was more effective in younger patients (27.5 ± 20.6) compared to older patients (48.75 ± 10.2). ( = .03). Moreover, patients with lower vision responded marginally better to infliximab as the second treatment ( = .06).: Either TNF-α inhibitor, adalimumab and infliximab, can be employed in the treatment of the patients with idiopathic inflammatory retinal vascular leakage who fail one of these agents.
Maleki A, Cao JH, Silpa-Archa S, Foster SC. VISUAL OUTCOME AND POOR PROGNOSTIC FACTORS IN ISOLATED IDIOPATHIC RETINAL VASCULITIS. Retina 2016;36(10):1979-85.Abstract

PURPOSE: To describe the clinical course, visual outcome, and prognosis of isolated, idiopathic retinal vasculitis. METHODS: Eighty patients (150 eyes) with isolated, idiopathic retinal vasculitis were included. Demographic data, clinical data, complications at the initial visit and during follow-up, fluorescein angiography, and optical coherence tomography findings were collected from the Massachusetts Eye Research and Surgery Institution (MERSI) database from September 2005 to February 2015. RESULTS: Seventy-five (93.7%) patients required treatment with immunomodulatory therapy. Of those 75 patients, 60 (75%) patients were able to achieve durable remission. Factors which were independently significant predictive of poor visual outcome were lower initial visual acuity (OR: 3.78; 95% CI: 1.75-8.16; P = 0.001), cystoid macular edema (OR: 5.54; 95% CI: 1.81-16.99; P = 0.003), and macular ischemia (OR: 5.12; 95% CI: 1.12-23.04; P = 0.036). CONCLUSION: The majority (67.25%) of our patients enjoyed a good visual outcome (most recent visit best-corrected visual acuity equal to or better than 20/40 and within one line or better from the baseline) with immunomodulatory therapy. We found that cystoid macular edema, macular ischemia, and lower best-corrected visual acuity during the first consultation visit were significant independent risk factors for poor visual outcome.

Maleki A, Swan RT, Lasave AF, Ma L, Foster SC. Reply. Ophthalmology 2017;124(8):e64-e65.
Maleki A, Anesi SD, Look-Why S, Manhapra A, Foster SC. Pediatric uveitis: A comprehensive review. Surv Ophthalmol 2021;Abstract
Pediatric uveitis accounts for 5-10% of all uveitis. Uveitis in children differs from adult uveitis in that it is commonly asymptomatic and can become chronic and cause chronic damage to ocular structures. The diagnosis might be delayed for multiple reasons, including the preverbal age and difficulties in examining young children. Pediatric uveitis may be infectious or non-infectious in etiology. The etiology of non-infectious uveitis is presumed to be autoimmune or autoinflammatory. The most common causes of uveitis in this age group are idiopathic and juvenile idiopathic arthritis-associated uveitis. The stepladder approach for the treatment of pediatric uveitis is based on expert opinion and algorithms proposed by multidisciplinary panels. Uveitis morbidities in pediatric patients include cataract, glaucoma, and amblyopia. Pediatric patients with uveitis should be frequently examined until remission is achieved. Once in remission, the interval between follow-up visits can be extended; however, it is recommended that even after remission the child should be seen every 8-12 weeks depending on the history of uveitis and the medications used. Close follow up is also necessary as uveitis can flare up during immunomodulatory therapy. It is crucial to measure the impact of uveitis, it's treatment, and it's complications on the child and the child's family. Visual acuity can be considered as an acceptable criterion for assessing visual function. Additionally, the number of cells in the anterior chamber can be a measure of disease activity. We review different aspects of pediatric uveitis. We discuss the mechanisms of noninfectious uveitis, including autoimmune and autoinflammatory etiologies, and the risks of developing uveitis in children with systemic rheumatologic diseases. We address the risk factors for developing morbidities, the Standardization of Uveitis Nomenclature (SUN) criteria for timing and anatomical classifications and describe a stepladder approach in the treatment of pediatric uveitis based on expert opinion and algorithms proposed by multi-disciplinary panels. We describe the most common entities for each type of anatomical classification and complications of uveitis for the pediatric population. Additionally, we address monitoring of children with uveitis and evaluation of Quality of Life.
Maleki A, Ueberroth JA, Walsh M, Foster F, Chang PY, Anesi SD, Foster CS. Combination of Intravenous Methotrexate and Methylprednisolone Therapy in the Treatment of Severe Ocular Inflammatory Diseases. Ocul Immunol Inflamm 2020;:1-5.Abstract
: To evaluate the efficacy of intravenous methotrexate and methylprednisolone in severe, sight-threatening ocular inflammatory conditions.: This was a retrospective observational case series. Patients who had received intravenous methotrexate for ocular inflammation with at least 24 months of follow-up were included in the study.: Ten patients (20 eyes) were included in this study. Mean age of the patients was 47.2 ± 17.7 (range:19-74). At 1-month follow-up visit, nine patients showed improvement and one patient failed treatment. At 12-month follow-up visit, all patients were in remission. Two patients were only on intravenous methotrexate infusions. At twenty-four-month follow-up visit, only one patient, in remission, was on intravenous methotrexate therapy. Leukopenia was the only adverse effect observed.: Intravenous methotrexate and methylprednisolone infusions can be an effective method of treatment in patients with severe, sight-threatening ocular inflammatory conditions.
Maleki A, Swan RT, Lasave AF, Ma L, Foster SC. Selective Laser Trabeculoplasty in Controlled Uveitis with Steroid-Induced Glaucoma. Ophthalmology 2016;123(12):2630-2632.
Maleki A, Sahawneh HF, Ma L, Meese H, He Y, Foster SC. INFLIXIMAB THERAPY IN PATIENTS WITH NONINFECTIOUS INTERMEDIATE UVEITIS RESISTANT TO CONVENTIONAL IMMUNOMODULATORY THERAPY. Retina 2017;37(5):836-843.Abstract

PURPOSE: To examine the efficacy and safety of infliximab therapy in the treatment for noninfectious intermediate uveitis resistant to conventional immunomodulatory therapy. METHODS: Forty-four eyes of 23 patients with resistant noninfectious intermediate uveitis who were treated with infliximab infusions for a minimum period of 3 months were included. Demographic data, clinical data, and fluorescein angiography and optical coherence tomography findings were collected from the Massachusetts Eye Research and Surgery Institution database between August 2005 and February 2014. Clinical response, improvement in ancillary test findings, and major side effects were evaluated. RESULTS: Nineteen patients (82.6%) achieved remission. The mean duration of treatment to induce remission was 3.99 ± 3.06 months (range, 2-14.7). Cystoid macular edema was the only complication observed during the course of the treatment in 1 eye (2.27%). One patient (4.3%) developed major side effects. None of the patients developed central or peripheral demyelinating neuropathies or multiple sclerosis. At 6 months after remission, logarithm of the minimum angle of resolution visual acuity (P = 0.006) and central macular thickness (P = 0.03) showed significant improvement in patients who achieved remission. CONCLUSION: A significant number of patients achieved remission on infliximab therapy. The incidence of major side effects in our cohort was low.

Maleki A, Anesi SD, Look-Why S, Asgari S, Manhapra A, Foster SC. Clinical course and poor prognostic factors of Vogt-Koyanagi-Harada disease in a tertiary uveitis clinic. Can J Ophthalmol 2021;
Mazzarino RC. Targeting Future Pandemics, a Case for De Novo Purine Synthesis and Basic Research. Front Immunol 2021;12:694300.Abstract
We are currently experiencing a deadly novel viral pandemic with no efficacious, readily available anti-viral therapies to SARS-CoV-2. Viruses will hijack host cellular machinery, including metabolic processes. Here, I provide theory and evidence for targeting the host de novo purine synthetic pathway for broad spectrum anti-viral drug development as well as the pursuit of basic science to mitigate the risks of future novel viral outbreaks.
McKay MK, Borkar DS, Sevgi DD, Susarla G, Papaliodis GN, Sobrin L. Comparison of Modified Posterior Sub-Tenon's vs. Trans-Septal Triamcinolone Injection for Non-infectious Uveitis. Ocul Immunol Inflamm 2020;:1-8.Abstract
: To compare the safety and efficacy of trans-septal vs. modified posterior sub-Tenon's (PST) corticosteroid injections for noninfectious uveitis.: Retrospective comparison of periocular triamcinolone injection by modified PST (n = 36) vs. traditional trans-septal (n = 79) techniques. Safety and efficacy outcomes were analyzed with regression models.: There was no significant difference in visual acuity improvement between the groups at 6 months. There were higher rates of vitritis resolution in the modified PST group but this was not statistically significant (85.7% vs 62.9%, = .07). Intraocular pressure (IOP) elevation rate trended higher with the modified PST injection (21.9% vs 9.0%, = .06), with no instances of glaucoma surgery in either group. Two modified PST injection patients with refractory IOP rises had IOP normalization after corticosteroid depot removal. One year cataract surgery rates were similar.: Modified PST injection offers clinical efficacy but with possibly higher IOP response rate which could be managed with corticosteroid removal.
McKay MK, Apostolopoulos N, Dahrouj M, Nguyen HV, Reddy A, Blazes M, Lacy M, Pepple KL, Lee AY, Lee CS. Assessing the Uniformity of Uveitis Clinical Concepts and Associated ICD-10 Codes Across Health Care Systems Sharing the Same Electronic Health Records System. JAMA Ophthalmol 2021;Abstract
Importance: Big data studies may allow for the aggregation of patients with rare diseases such as uveitis to answer important clinical questions. Standardization of uveitis-related variables will be necessary, including the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes used to identify patients of interest. There are currently limited data on the uniformity of diagnosis mapping to ICD-10 codes for uveitis diagnoses among different health systems. Objective: To assess the degree of uniformity in mapping of uveitis clinical concepts to ICD-10 codes across health care systems using the same electronic health record (EHR) system. Design, Setting, and Participants: This multicenter survey study was conducted between September 14 and October 9, 2020, at 5 academic health care systems that use the Epic EHR. Researchers from the University of Washington, Harvard University, Stanford University, Yale University, and the University of California, San Francisco queried 54 uveitis-related diagnostic terms and recorded the associated ICD-10 codes. Main Outcomes and Measures: The degree of uniformity for uveitis clinical concepts and associated ICD-10 codes. Results: Fifty-four uveitis-related diagnostic terms were queried within the Epic EHR at 5 different health care systems. There was perfect agreement among all 5 centers for 52 of the 54 diagnostic terms. Two diagnostic terms had differences in ICD-10 coding: juvenile idiopathic arthritis associated chronic uveitis and intermediate uveitis. Intermediate uveitis was associated with codes H20.1x (ICD-10 description: chronic iridocyclitis) or H20.9 (ICD-10 description: unspecified iridocyclitis) in 3 centers while being associated with code H30.2x (ICD-10 description: posterior cyclitis) at the 2 remaining centers. The discrepancies appear to be related to a recent update in diagnostic mapping in the Epic EHR. Conclusions and Relevance: This study suggests that ICD-10 code mapping to uveitis diagnostic terminology appears to be highly uniform at different centers with the Epic EHR. However, temporal changes in diagnosis mapping to ICD-10 codes and a lack of 1-to-1 mapping of diagnosis to ICD-10 code add additional sources of complexity to the interpretation of big data studies in uveitis.
Minkus CL, Pistilli M, Dreger KA, Fitzgerald TD, Payal AR, Begum H, Kaçmaz OR, Jabs DA, Nussenblatt RB, Rosenbaum JT, Levy-Clarke GA, Sen NH, Suhler EB, Thorne JE, Bhatt NP, Foster SC, Buchanich JM, Kempen JH, for Group SITED (SITE) CSR. Risk of Cataract in Intermediate Uveitis. Am J Ophthalmol 2021;Abstract
PURPOSE: To determine the incidence of and predictive factors for cataract in intermediate uveitis. DESIGN: Retrospective cohort study METHODS: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study, in which medical records were reviewed to determine demographic and clinical data of every eye/patient at every visit at five participating United States tertiary care uveitis centers. The primary outcome was development of vision-compromising cataract as defined by a decrease in visual acuity to 20/40 or less, or requiring cataract surgery. Survival analysis assessed visually defined cataract to avoid bias due to timing of surgery vis-à-vis inflammatory status. RESULTS: Among 2,190 eyes of 1,302 patients with intermediate uveitis the cumulative incidence of cataract formation was 7.6% by one year (95% CI=6.2-9.1%), increasing to 36.6% by ten years (95% CI=31.2-41.6%). Increased cataract risk was observed in eyes with concurrent anterior uveitis causing posterior synechiae (HR=2.68, 95% CI=2.00-3.59, p<0.001), and in eyes with epiretinal membrane formation (HR=1.54, 95% CI=1.15-2.07, p=0.004). Higher dose corticosteroid therapy was associated with significantly higher incidence of cataract, especially time-updated use of topical corticosteroids ≥2 times/day or ≥4 periocular corticosteroid injections. Low dose corticosteroid medications (oral prednisone 7.5mg daily or less, or topical corticosteroid drops <2 times/day) were not associated with increased cataract risk. CONCLUSIONS: Our study found that the incidence of clinically important cataract in intermediate uveitis is moderate. The risk is higher with markers of severity, and with higher doses of corticosteroid medications, the latter being potentially modifiable.
Muhammad F, Wang D, Montieth A, Lee S, Preble J, Foster SC, Larson TA, Ding K, Dvorak JD, Lee DJ. PD-1 melanocortin receptor dependent-Treg cells prevent autoimmune disease. Sci Rep 2019;9(1):16941.Abstract
Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1FoxP3 Tregs in uveitis patients was similar compared to healthy controls, but was significantly reduced with melanocortin stimulation. Further, lower body mass index correlated with responsiveness to stimulation of this pathway. These observations indicate an importance of the PD-1/PD-L1 pathway to provide resistance to relapsing uveitis and shows a reduced capacity of uveitis patients to induce Tregs when stimulated through melanocortin receptors, but that it is possible to bypass this part of the pathway through direct stimulation of A2Ar.

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