Cytokines in Immune-mediated “Non-infectious” Uveitis

Abstract

Uveitis is a significant cause of ocular morbidity and accounts for approximately 5 – 10% of visual impairments worldwide, particularly among the working-age population. Infections are the cause of ~ 50% cases of uveitis, but it has been suggested that infection might also be implicated in the pathogenesis of immune-mediated “non-infectious” uveitis. There is growing evidence that cytokines (i.e., interleukins, interferons, etc.) are key mediators of immune-mediated “non-infectious” uveitis. For example, activation of the interleukin-23/interleukin-17 signalling pathway is involved in immune-mediated “non-infectious” uveitis. Studies in animal models have been important in investigating the role of cytokines in uveitis. Recent studies of clinical samples from patients with uveitis have allowed the measurement of a considerable array of cytokines even from very small sample volumes (e.g., aqueous and vitreous humour). The identification of complex patterns of cytokines may contribute to a better understanding of their potential pathogenetic role in uveitis as well as to an improved diagnostic and therapeutic approach to treat these potentially blinding pathologies. This review provides further insights into the putative pathobiological role of cytokines in immune-mediated “non-infectious” uveitis.

Zusammenfassung

Uveitis stellt weltweit eine bedeutende Ursache für Augenerkrankungen dar und trägt insbesondere bei der erwerbsfähigen Bevölkerung zu etwa 5 – 10% der Sehbehinderungen bei. Etwa 50% der Uveitisfälle werden durch Infektionen verursacht, jedoch wird vermutet, dass Infektionen auch an der Entstehung einer immunvermittelten „nicht infektiösen“ Uveitis beteiligt sein könnten. Es gibt zunehmend Hinweise darauf, dass Zytokine (wie Interleukine, Interferone usw.) wichtige Mediatoren der immunvermittelten „nicht infektiösen“ Uveitis sind. Beispielsweise ist die Aktivierung des Interleukin-23-/Interleukin-17-Signalwegs an dieser Form der Uveitis beteiligt. Studien an Tiermodellen haben eine wichtige Rolle bei der Erforschung der Rolle von Zytokinen bei Uveitis gespielt. Kürzlich ermöglichten Studien an klinischen Proben von Patienten mit Uveitis die Messung einer beträchtlichen Anzahl von Zytokinen, selbst aus sehr kleinen Probenvolumina (wie Kammerwasser und Glaskörper). Die Identifizierung komplexer Zytokinmuster kann zu einem besseren Verständnis ihrer potenziellen pathogenetischen Rolle bei Uveitis beitragen und zu verbesserten diagnostischen und therapeutischen Ansätzen für diese potenziell zur Erblindung führenden Krankheitsbilder führen. Diese Übersicht liefert weitere Einblicke in die mutmaßliche pathobiologische Rolle von Zytokinen bei der immunvermittelten „nicht infektiösen“ Uveitis.

Key words

uveitis - cytokines - autoimmune - non-infectious - diagnosis - treatment

Schlüsselwörter

Uveitis - Zytokine - autoimmun - nicht infektiös - Diagnose - Behandlung

Publication History

Received: 24 May 2023

Accepted: 30 October 2023

Article published online:
22 December 2023

• References

• 1 Nicholson LB. The immune system. Essays Biochem 2016; 60: 275-301
• 2 Chaplin DD. Overview of the immune response. J Allergy Clin Immunol 2010; 125 (2 Suppl. 2): S3-S23 DOI: 10.1016/j.jaci.2009.12.980.
• 3 Netea MG, Domínguez-Andrés J, Barreiro LB. et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol 2020; 20: 375-388
• 4 Cohen IR, Efroni S. The Immune System Computes the State of the Body: Crowd Wisdom, Machine Learning, and Immune Cell Reference Repertoires Help Manage Inflammation. Front Immunol 2019; 10: 10 DOI: 10.3389/fimmu.2019.00010.
• 5 Theofilopoulos A, Kono D, Baccala R. The multiple pathways to autoimmunity. Nat Immunol 2017; 18: 716-724 DOI: 10.1038/ni.3731.
• 6 Liu C. et al. Cytokines: From Clinical Significance to Quantification. Adv Sci (Weinh) 2021; 8: e2004433 DOI: 10.1002/advs.202004433.
• 7 Miserocchi E, Fogliato G, Modorati G. et al. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol 2013; 23: 705-717 DOI: 10.5301/ejo.5000278.
• 8 Tsirouki T, Dastiridou A, Symeonidis C. et al. A Focus on the Epidemiology of Uveitis. Ocul Immunol Inflamm 2018; 26: 2-16 DOI: 10.1080/09273948.2016.1196713.
• 9 Krishna U, Ajanaku D, Denniston AK. et al. Uveitis: a sight-threatening disease which can impact all systems. Postgrad Med J 2017; 93: 766-773 DOI: 10.1136/postgradmedj-2017-134891.
• 10 Hou S, Kijlstra A, Yang P. Molecular Genetic Advances in Uveitis. Prog Mol Biol Transl Sci 2015; 134: 283-298 DOI: 10.1016/bs.pmbts.2015.04.009.
• 11 Egwuagu CE, Alhakeem SA, Mbanefo EC. Uveitis: Molecular Pathogenesis and Emerging Therapies. Front Immunol 2021; 12: 623725 DOI: 10.3389/fimmu.2021.623725.
• 12 Mölzer C, Heissigerova J, Wilson HM. et al. Immune Privilege: The Microbiome and Uveitis. Front Immunol 2021; 11: 608377 DOI: 10.3389/fimmu.2020.608377.
• 13 Forrester JV, Kuffova L, Dick AD. Autoimmunity, Autoinflammation, and Infection in Uveitis. Am J Ophthalmol 2018; 189: 77-85 DOI: 10.1016/j.ajo.2018.02.019.
• 14 Pan J, Kapur M, McCallum R. Noninfectious immune-mediated uveitis and ocular inflammation. Curr Allergy Asthma Rep 2014; 14: 409
• 15 Zhong Z, Su G, Kijlstra A. et al. Activation of the interleukin-23/interleukin-17 signalling pathway in autoinflammatory and autoimmune uveitis. Prog Retin Eye Res 2021; 80: 100866 DOI: 10.1016/j.preteyeres.2020.100866.
• 16 Takeuchi M, Mizuki N, Ohno S. Pathogenesis of Non-Infectious Uveitis Elucidated by Recent Genetic Findings. Front Immunol 2021; 12: 640473 DOI: 10.3389/fimmu.2021.640473.
• 17 Chi W, Yang P, Li B. et al. IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol 2007; 119: 1218-1224 DOI: 10.1016/j.jaci.2007.01.010.
• 18 Chi W, Zhu X, Yang P. et al. Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci 2008; 49: 3058-3064 DOI: 10.1167/iovs.07-1390.
• 19 Guo K, Zhang X. Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis. J Immunol Res 2021; 2021: 6693542 DOI: 10.1155/2021/6693542.
• 20 Powell MD, Read KA, Sreekumar BK. et al. Ikaros Zinc Finger Transcription Factors: Regulators of Cytokine Signaling Pathways and CD4⁺ T Helper Cell Differentiation. Front Immunol 2019; 10: 1299 DOI: 10.3389/fimmu.2019.01299.
• 21 Lee Y, Awasthi A, Yosef N. et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 2012; 13: 991-999
• 22 Wu Tian X J, Wang S. Insight into non-pathogenic Th17 cells in autoimmune diseases. Front Immunol 2018; 9: 1112
• 23 Weinstein JE, Pepple KL. Cytokines in uveitis. Curr Opin Ophthalmol 2018; 29: 267-274 DOI: 10.1097/ICU.0000000000000466.
• 24 Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 1948; 29: 58-69
• 25 Keino H, Horie S, Sugita S. Immune Privilege and Eye-Derived T-Regulatory Cells. Immunol Res 2018; 2018: 1679197 DOI: 10.1155/2018/1679197.
• 26 Wakefield D, Clarke D, McCluskey P. Recent Developments in HLA B27 Anterior Uveitis. Front Immunol 2021; 11: 608134 DOI: 10.3389/fimmu.2020.608134.
• 27 Kalogeropoulos D, Barry R, Kalogeropoulos C. The association between intestinal microbiome and autoimmune uveitis. Arch Soc Esp Oftalmol (Engl Ed) 2022; 97: 264-275 DOI: 10.1016/j.oftale.2021.01.012.
• 28 Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J 2018; 285: 2944-2971 DOI: 10.1111/febs.14466.
• 29 Kany S, Vollrath JT, Relja B. Cytokines in Inflammatory Disease. Int J Mol Sci 2019; 20: 6008
• 30 Agrawal R, Iyer J, Connolly J. et al. Cytokines and biologics in non-infectious autoimmune uveitis: bench to bedside. Indian J Ophthalmol 2014; 62: 74-81 DOI: 10.4103/0301-4738.126187.
• 31 Balamurugan S, Das D, Hasanreisoglu M. et al. Interleukins and cytokine biomarkers in uveitis. Indian J Ophthalmol 2020; 68: 1750-1763 DOI: 10.4103/ijo.IJO_564_20.
• 32 Casaletto KB, Elahi FM, Fitch R. et al. A comparison of biofluid cytokine markers across platform technologies: Correspondence or divergence?. Cytokine 2018; 111: 481-489 DOI: 10.1016/j.cyto.2018.05.032.
• 33 Curnow SJ, Falciani F, Durrani OM. et al. Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis. Invest Ophthalmol Vis Sci 2005; 46: 4251-4259 DOI: 10.1167/iovs.05-0444.
• 34 Lacomba MS, Martin CM, Chamond RR. et al. Aqueous and serum interferon gamma, interleukin (IL) 2, IL-4, and IL-10 in patients with uveitis. Arch Ophthalmol 2000; 118: 768-772 DOI: 10.1001/archopht.118.6.768.
• 35 Ang M, Cheung G, Vania M. et al. Aqueous cytokine and chemokine analysis in uveitis associated with tuberculosis. Mol Vis 2012; 18: 565-573
• 36 Takase H, Futagami Y, Yoshida T. et al. Cytokine profile in aqueous humor and sera of patients with infectious or noninfectious uveitis. Invest Ophthalmol Vis Sci 2006; 47: 1557-1561 DOI: 10.1167/iovs.05-0836.
• 37 Atan D, Fraser-Bell S, Plskova J. et al. Cytokine polymorphism in noninfectious uveitis. Invest Ophthalmol Vis Sci 2010; 51: 4133-4142 DOI: 10.1167/iovs.09-4583.
• 38 El-Asrar AM, Struyf S, Kangave D. et al. Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis. Clin Immunol 2011; 139: 177-184 DOI: 10.1016/j.clim.2011.01.014.
• 39 El-Asrar AMA, Berghmans N, Al-Obeidan SA. et al. Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities. Invest Ophthalmol Vis Sci 2018; 59: 2222-2228 DOI: 10.1167/iovs.17-23225.
• 40 El-Asrar AM, Berghmans N, Al-Obeidan SA. et al. The CC chemokines CCL8, CCL13 and CCL20 are local inflammatory biomarkers of HLA-B27-associated uveitis. Acta Ophthalmol 2019; 97: e122-e128 DOI: 10.1111/aos.13835.
• 41 El-Asrar AM, Berghmans N, Al-Obeidan SA. et al. Expression of interleukin (IL)-10 family cytokines in aqueous humour of patients with specific endogenous uveitic entities: elevated levels of IL-19 in human leucocyte antigen-B27-associated uveitis. Acta Ophthalmol 2019; 97: e780-e784 DOI: 10.1111/aos.14039.
• 42 El-Asrar AM, Berghmans N, Al-Obeidan SA. et al. The Cytokine Interleukin-6 and the Chemokines CCL20 and CXCL13 Are Novel Biomarkers of Specific Endogenous Uveitic Entities. Invest Ophthalmol Vis Sci 2016; 57: 4606-4613 DOI: 10.1167/iovs.16-19758.
• 43 Bonacini M, Soriano A, Cimino L. et al. Cytokine Profiling in Aqueous Humor Samples From Patients With Non-Infectious Uveitis Associated With Systemic Inflammatory Diseases. Front Immunol 2020; 11: 358 DOI: 10.3389/fimmu.2020.00358.
• 44 Ohira S, Inoue T, Iwao K. et al. Factors Influencing Aqueous Proinflammatory Cytokines and Growth Factors in Uveitic Glaucoma. PLoS One 2016; 11: e0147080 DOI: 10.1371/journal.pone.0147080.
• 45 Matas J, Llorenç V, Fonollosa A. et al. Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema. Front Immunol 2020; 11: 579005 DOI: 10.3389/fimmu.2020.579005.
• 46 Takeda A, Hasegawa E, Yawata N. et al. Increased vitreous levels of B cell activation factor (BAFF) and soluble interleukin-6 receptor in patients with macular edema due to uveitis related to Behçetʼs disease and sarcoidosis. Graefes Arch Clin Exp Ophthalmol 2022; 260: 2675-2686 DOI: 10.1007/s00417-022-05600-1.
• 47 Errera MH, Pratas A, Fisson S. et al. Cytokines, chemokines and growth factors profile in human aqueous humor in idiopathic uveitis. PLoS One 2022; 17: e0254972 DOI: 10.1371/journal.pone.0254972.
• 48 Muhaya M, Calder V, Towler HM. et al. Characterization of T cells and cytokines in the aqueous humour (AH) in patients with Fuchsʼ heterochromic cyclitis (FHC) and idiopathic anterior uveitis (IAU). Clin Exp Immunol 1998; 111: 123-128 DOI: 10.1046/j.1365-2249.1998.00428.x.
• 49 Pohlmann D, Schlickeiser S, Metzner S. et al. Different composition of intraocular immune mediators in Posner-Schlossman-Syndrome and Fuchsʼ Uveitis. PLoS One 2018; 13: e0199301 DOI: 10.1371/journal.pone.0199301.
• 50 Simsek M, Cakar Ozdal P, Akbiyik F. et al. Aqueous humor IL-8, IL-10, and VEGF levels in Fuchsʼ uveitis syndrome and Behçetʼs uveitis. Int Ophthalmol 2019; 39: 2629-2636 DOI: 10.1007/s10792-019-01112-w.
• 51 Xu J, Qin Y, Chang R. et al. Aqueous cytokine levels in four common uveitis entities. Int Immunopharmacol 2020; 78: 106021 DOI: 10.1016/j.intimp.2019.106021.
• 52 Wakefield D, Yates W, Amjadi S. et al. HLA-B27 Anterior Uveitis: Immunology and Immunopathology. Ocul Immunol Inflamm 2016; 24: 450-459 DOI: 10.3109/09273948.2016.1158283.
• 53 Jawad S, Liu B, Agron E. et al. Elevated serum levels of interleukin-17A in uveitis patients. Ocul Immunol Inflamm 2013; 21: 434-439 DOI: 10.3109/09273948.2013.815786.
• 54 Ooi KG, Galatowicz G, Towler HM. et al. Multiplex cytokine detection versus ELISA for aqueous humor: IL-5, IL-10, and IFNgamma profiles in uveitis. Invest Ophthalmol Vis Sci 2006; 47: 272-277 DOI: 10.1167/iovs.05-0790.
• 55 Kumar A, Sharma SP, Agarwal A. et al. Tear IL-6 and IL-10 levels in HLA-B27-Associated Uveitis and Its clinical Implications. Ocul Immunol Inflamm 2021; 29: 237-243 DOI: 10.1080/09273948.2019.1704022.
• 56 Carreño E, Portero A, Herreras JM. et al. Cytokine and chemokine tear levels in patients with uveitis. Acta Ophthalmol 2017; 95: e405-e414 DOI: 10.1111/aos.13292.
• 57 Matsou A, Tsaousis KT. Management of chronic ocular sarcoidosis: challenges and solutions. Clin Ophthalmol 2018; 12: 519-532 DOI: 10.2147/OPTH.S128949.
• 58 Takeuchi M, Taguchi M, Sato T. et al. Association of High-Mobility Group Box-1 With Th Cell-Related Cytokines in the Vitreous of Ocular Sarcoidosis Patients. Invest Ophthalmol Vis Sci 2017; 58: 528-537 DOI: 10.1167/iovs.16-20324.
• 59 Kojima K, Maruyama K, Inaba T. et al. The CD4/CD8 ratio in vitreous fluid is of high diagnostic value in sarcoidosis. Ophthalmology 2012; 119: 2386-2392 DOI: 10.1016/j.ophtha.2012.05.033.
• 60 Davatchi F. Behçetʼs disease. Int J Rheum Dis 2018; 21: 2057-2058 DOI: 10.1111/1756-185X.13465.
• 61 Mizuki N, Meguro A, Ota M. et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçetʼs disease susceptibility loci. Nat Genet 2010; 42: 703-706 DOI: 10.1038/ng.624.
• 62 Cunningham jr. ET, Tugal-Tutkun I, Khairallah M. et al. Behçet Uveitis. Ocul Immunol Inflamm 2017; 25: 2-6 DOI: 10.1080/09273948.2017.1279840.
• 63 Tugal-Tutkun I, Onal S, Altan-Yaycioglu R. et al. Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol 2004; 138: 373-380 DOI: 10.1016/j.ajo.2004.03.022.
• 64 Mesquida M, Molins B, Llorenç V. et al. Proinflammatory cytokines and C-reactive protein in uveitis associated with Behçetʼs disease. Mediators Inflamm 2014; 2014: 396204 DOI: 10.1155/2014/396204.
• 65 Zheng W, Wang X, Liu J. et al. Single-cell analyses highlight the proinflammatory contribution of C1q-high monocytes to Behçetʼs disease. Proc Natl Acad Sci U S A 2022; 119: e2204289119 DOI: 10.1073/pnas.2204289119.
• 66 Takeda A, Hasegawa E, Yawata N. et al. Increased vitreous levels of B cell activation factor (BAFF) and soluble interleukin-6 receptor in patients with macular edema due to uveitis related to Behçetʼs disease and sarcoidosis. Graefes Arch Clin Exp Ophthalmol 2022; 260: 2675-2686 DOI: 10.1007/s00417-022-05600-1.
• 67 Tan S, Feng X, Liu Z. et al. The pro-inflammatory effect of triglyceride on human CD4⁺ T cells and experimental autoimmune uveitis. Clin Immunol 2022; 240: 109056 DOI: 10.1016/j.clim.2022.109056.
• 68 Du L, Kijlstra A, Yang P. Vogt-Koyanagi-Harada disease: Novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res 2016; 52: 84-111 DOI: 10.1016/j.preteyeres.2016.02.002.
• 69 Joye A, Suhler E. Vogt-Koyanagi-Harada disease. Curr Opin Ophthalmol 2021; 32: 574-582 DOI: 10.1097/ICU.0000000000000809.
• 70 Urzua CA, Herbort jr. CP, Takeuchi M. et al. Vogt-Koyanagi-Harada disease: the step-by-step approach to a better understanding of clinicopathology, immunopathology, diagnosis, and management: a brief review. J Ophthalmic Inflamm Infect 2022; 12: 17 DOI: 10.1186/s12348-022-00293-3.
• 71 Vitale AT. Birdshot retinochoroidopathy. J Ophthalmic Vis Res 2014; 9: 350-361 DOI: 10.4103/2008-322X.143376.
• 72 Kuiper JJ, Mutis T, de Jager W. et al. Intraocular interleukin-17 and proinflammatory cytokines in HLA-A29-associated birdshot chorioretinopathy. Am J Ophthalmol 2011; 152: 177-182.e1 DOI: 10.1016/j.ajo.2011.01.031.
• 73 Yang P, Foster CS. Interleukin 21, interleukin 23, and transforming growth factor β1 in HLA-A29-associated birdshot retinochoroidopathy. Am J Ophthalmol 2013; 156: 400-406.e2 DOI: 10.1016/j.ajo.2013.03.004.
• 74 Trombke J, Loyal L, Braun J. et al. Analysis of peripheral inflammatory T cell subsets and their effector function in patients with Birdshot Retinochoroiditis. Sci Rep 2021; 11: 8604 DOI: 10.1038/s41598-021-88013-0.
• 75 Kalogeropoulos D, Asproudis I, Stefaniotou M. et al. Diagnostic and therapeutic considerations in pediatric uveitis. Spektrum Augenheilkd 2021; DOI: 10.1007/s00717-021-00503-8.
• 76 Asproudis I, Katsanos A, Kozeis N. et al. Update on the Treatment of Uveitis in Patients with Juvenile Idiopathic Arthritis: A Review. Adv Ther 2017; 34: 2558-2565 DOI: 10.1007/s12325-017-0635-3.
• 77 Sijssens KM, Rijkers GT, Rothova A. et al. Cytokines, chemokines and soluble adhesion molecules in aqueous humor of children with uveitis. Exp Eye Res 2007; 85: 443-449 DOI: 10.1016/j.exer.2007.06.011.
• 78 Haasnoot AM, Kuiper JJ, Hiddingh S. et al. Ocular Fluid Analysis in Children Reveals Interleukin-29/Interferon-λ1 as a Biomarker for Juvenile Idiopathic Arthritis-Associated Uveitis. Arthritis Rheumatol 2016; 68: 1769-1779 DOI: 10.1002/art.39621.
• 79 Mandeville JT, Levinson RD, Holland GN. The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol 2001; 46: 195-208 DOI: 10.1016/s0039-6257(01)00261-2.
• 80 Rytkönen SH, Kulmala P, Autio-Harmainen H. et al. FOXP3⁺ T cells are present in kidney biopsy samples in children with tubulointerstitial nephritis and uveitis syndrome. Pediatr Nephrol 2018; 33: 287-293 DOI: 10.1007/s00467-017-3796-z.
• 81 Tan Y, Yu F, Qu Z. et al. Modified C-reactive protein might be a target autoantigen of TINU syndrome. Clin J Am Soc Nephrol 2011; 6: 93-100 DOI: 10.2215/CJN.09051209.
• 82 Vitale AT. Birdshot retinochoroidopathy. J Ophthalmic Vis Res 2014; 9: 350-361 DOI: 10.4103/2008-322X.143376.
• 83 Hettinga YM, Scheerlinck LM, Lilien MR. et al. The value of measuring urinary β2-microglobulin and serum creatinine for detecting tubulointerstitial nephritis and uveitis syndrome in young patients with uveitis. JAMA Ophthalmol 2015; 133: 140-145 DOI: 10.1001/jamaophthalmol.2014.430.
• 84 Lee RW, Nicholson LB, Sen HN. et al. Autoimmune and autoinflammatory mechanisms in uveitis. Semin Immunopathol 2014; 36: 581-594 DOI: 10.1007/s00281-014-0433-9.
• 85 Li H, Zhu L, Wang R. et al. Aging weakens Th17 cell pathogenicity and ameliorates experimental autoimmune uveitis in mice. Protein Cell 2022; 13: 422-445 DOI: 10.1007/s13238-021-00882-3.
• 86 Yu CR, Yadav MK, Kang M. et al. Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege. Int J Mol Sci 2022; 23: 8156 DOI: 10.3390/ijms23158156.
• 87 Soriano-Romaní L, Mir FA, Singh N. et al. CD47 Binding on Vascular Endothelial Cells Inhibits IL-17-Mediated Leukocyte Adhesion. Int J Mol Sci 2022; 23: 5705 DOI: 10.3390/ijms23105705.
• 88 Huang J, Li Z, Hu Y. et al. Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis. J Neuroinflammation 2022; 19: 124 DOI: 10.1186/s12974-022-02477-z.
• 89 Silver PB, Horai R, Chen J. et al. Correction: Retina-Specific T Regulatory Cells Bring About Resolution and Maintain Remission of Autoimmune Uveitis. J Immunol 2015; 195: 393 DOI: 10.4049/jimmunol.1501038.
• 90 Lee EJ, Napier RJ, Vance EE. et al. The innate immune receptor Nlrp12 suppresses autoimmunity to the retina. J Neuroinflammation 2022; 19: 69 DOI: 10.1186/s12974-022-02425-x.
• 91 Okunuki Y, Mukai R, Nakao T. et al. Retinal microglia initiate neuroinflammation in ocular autoimmunity. Proc Natl Acad Sci U S A 2019; 116: 9989-9998 DOI: 10.1073/pnas.1820387116.
• 92 Li B, Yang L, Bai F. et al. Indications and effects of biological agents in the treatment of noninfectious uveitis. Immunotherapy 2022; 14: 985-994 DOI: 10.2217/imt-2021-0303.
• 93 Dingerkus VLS, Becker MD, Doycheva D. Biologics in the Treatment of Uveitis. Klin Monbl Augenheilkd 2022; 239: 686-694 DOI: 10.1055/a-1737-4425.
• 94 Thomas AS. Biologics for the treatment of noninfectious uveitis: current concepts and emerging therapeutics. Curr Opin Ophthalmol 2019; 30: 138-150 DOI: 10.1097/ICU.0000000000000562.
• 95 Gupta S, Shyamsundar K, Agrawal M. et al. Current Knowledge of Biologics in Treatment of Noninfectious Uveitis. J Ocul Pharmacol Ther 2022; 38: 203-222 DOI: 10.1089/jop.2021.0098.
• 96 Valade S, Darmon M, Zafrani L. et al. The use of ICU resources in CAR-T cell recipients: a hospital-wide study. Ann Intensive Care 2022; 12: 75 DOI: 10.1186/s13613-022-01036-2.
• 97 Shimabukuro-Vornhagen A, Gödel P, Subklewe M. et al. Cytokine release syndrome. J Immunother Cancer 2018; 6: 56 DOI: 10.1186/s40425-018-0343-9.
• 98 Kalinina Ayuso V, de Boer JH, Byers HL. et al. Intraocular biomarker identification in uveitis associated with juvenile idiopathic arthritis. Invest Ophthalmol Vis Sci 2013; 54: 3709-3720 DOI: 10.1167/iovs.12-10865.
• 99 Aqrawi LA, Galtung HK, Vestad B. et al. Identification of potential saliva and tear biomarkers in primary Sjögrenʼs syndrome, utilising the extraction of extracellular vesicles and proteomics analysis. Arthritis Res Ther 2017; 19: 14 DOI: 10.1186/s13075-017-1228-x.
• 100 Aluru SV, Shweta A, Bhaskar S. et al. Tear Fluid Protein Changes in Dry Eye Syndrome Associated with Rheumatoid Arthritis: A Proteomic Approach. Ocul Surf 2017; 15: 112-129 DOI: 10.1016/j.jtos.2016.09.005.
• 101 Angeles-Han ST, Yeh S, Patel P. et al. Discovery of tear biomarkers in children with chronic non-infectious anterior uveitis: a pilot study. J Ophthalmic Inflamm Infect 2018; 8-17 DOI: 10.1186/s12348-018-0156-5.
• 102 Velez G, Tang PH, Cabral T. et al. Personalized Proteomics for Precision Health: Identifying Biomarkers of Vitreoretinal Disease. Transl Vis Sci Technol 2018; 7: 12 DOI: 10.1167/tvst.7.5.12.
• 103 Velez G, Roybal CN, Colgan D. et al. Precision Medicine: Personalized Proteomics for the Diagnosis and Treatment of Idiopathic Inflammatory Disease. JAMA Ophthalmol 2016; 134: 444-448 DOI: 10.1001/jamaophthalmol.2015.5934.
• 104 Sharma SM, Fu DJ, Xue K. A Review of the Landscape of Targeted Immunomodulatory Therapies for Non-Infectious Uveitis. Ophthalmol Ther 2018; 7: 1-17 DOI: 10.1007/s40123-017-0115-5.