{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T07:06:57Z","timestamp":1782025617044,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T00:00:00Z","timestamp":1659484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG)"},{"name":"University Hospital Essen"},{"name":"German Society for Strabism, Neuroophthalmology and Pediatric ophthalmology (Bielschowsky Foundation)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are often challenging to differentiate. Furthermore, it is still uncertain how chronic inflammation, such as IgG4-ROD, can lead to mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we aimed to evaluate the diagnostic value of gene expression analysis to differentiate orbital autoimmune diseases and elucidate genetic overlaps. First, we established a database of NSOI, relapsing NSOI, IgG4-ROD and MALT lymphoma patients of our orbital center (2000\u20132019). In a consensus process, three typical patients of the above mentioned three groups (mean age 56.4 \u00b1 17 years) at similar locations were selected. Afterwards, RNA was isolated using the RNeasy FFPE kit (Qiagen) from archived paraffin-embedded tissues. The RNA of these 12 patients were then subjected to gene expression analysis (NanoString nCounter\u00ae), including a total of 1364 target genes. The most significantly upregulated and downregulated genes were used for a machine learning algorithm to distinguish entities. This was possible with a high probability (p &lt; 0.0001). Interestingly, gene expression patterns showed a characteristic overlap of lymphoma with IgG4-ROD and NSOI. In contrast, IgG4-ROD shared only altered expression of one gene regarding NSOI. To validate our potential biomarker genes, we isolated the RNA of a further 48 patients (24 NSOI, 11 IgG4-ROD, 13 lymphoma patients). Then, gene expression pattern analysis of the 35 identified target genes was performed using a custom-designed CodeSet to assess the prediction accuracy of the multi-parameter scoring algorithms. They showed high accuracy and good performance (AUC ROC: IgG4-ROD 0.81, MALT 0.82, NSOI 0.67). To conclude, genetic expression analysis has the potential for faster and more secure differentiation between NSOI and IgG4-ROD. MALT-lymphoma and IgG4-ROD showed more genetic similarities, which points towards progression to lymphoma.<\/jats:p>","DOI":"10.3390\/ijms23158609","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T20:52:01Z","timestamp":1659559921000},"page":"8609","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Evaluation of Orbital Lymphoproliferative and Inflammatory Disorders by Gene Expression Analysis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5874-764X","authenticated-orcid":false,"given":"Karim","family":"Al-Ghazzawi","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0122-085X","authenticated-orcid":false,"given":"Sven Holger","family":"Baum","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, University of Duisburg-Essen, Kliniken-Essen-Mitte, 45136 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Pf\u00f6rtner","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, University of Duisburg-Essen, Kliniken-Essen-Mitte, 45136 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8077-3227","authenticated-orcid":false,"given":"Svenja","family":"Philipp","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Bechrakis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"G\u00f6rtz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian D.","family":"Mairinger","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-7689","authenticated-orcid":false,"given":"Michael","family":"Oeverhaus","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100885","DOI":"10.1016\/j.preteyeres.2020.100885","article-title":"Non-specific orbital inflammation: Current understanding and unmet needs","volume":"81","author":"Lee","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/IOP.0b013e3182a65109","article-title":"Orbital pseudotumor versus idiopathic nongranulomatous orbital inflammation","volume":"29","author":"Shields","year":"2013","journal-title":"Ophthalmic Plast. Reconstr. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1600-0420.1996.tb00069.x","article-title":"Idiopathic orbital inflammatory disease","volume":"74","author":"Gunalp","year":"1996","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1136\/bjo.2007.124156","article-title":"Idiopathic orbital inflammatory syndrome: Clinical features and treatment outcomes","volume":"91","author":"Swamy","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1097\/01.iop.0000203734.52333.93","article-title":"Idiopathic orbital inflammation: A pathogenetic construct and treatment strategy: The 2005 ASOPRS Foundation Lecture","volume":"22","author":"Harris","year":"2006","journal-title":"Ophthalmic Plast. Reconstr. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1001\/jamaophthalmol.2017.1581","article-title":"Consensus on Diagnostic Criteria of Idiopathic Orbital Inflammation Using a Modified Delphi Approach","volume":"135","author":"Mombaerts","year":"2017","journal-title":"JAMA Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.3174\/ajnr.A3986","article-title":"Orbital lymphoproliferative disorders (OLPDs): Value of MR imaging for differentiating orbital lymphoma from benign OPLDs","volume":"35","author":"Haradome","year":"2014","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1136\/bjophthalmol-2014-305545","article-title":"An analysis of IgG4-related disease (IgG4-RD) among idiopathic orbital inflammations and benign lymphoid hyperplasias using two consensus-based diagnostic criteria for IgG4-RD","volume":"99","author":"Andrew","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1080\/01676830490487980","article-title":"The differentiation of idiopathic inflammatory pseudotumor from lymphoid tumors of orbit: Analysis of 319 cases","volume":"23","author":"Yan","year":"2004","journal-title":"Orbit"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Reis, P.P., Waldron, L., Goswami, R.S., Xu, W., Xuan, Y., Perez-Ordonez, B., Gullane, P., Irish, J., Jurisica, I., and Kamel-Reid, S. (2011). mRNA transcript quantification in archival samples using multiplexed, color-coded probes. BMC Biotechnol., 11.","DOI":"10.1186\/1472-6750-11-46"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.prp.2013.09.007","article-title":"FFPE tissue as a feasible source for gene expression analysis\u2014A comparison of three reference genes and one tumor marker","volume":"209","author":"Walter","year":"2013","journal-title":"Pathol. Res. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s10384-021-00847-3","article-title":"Clinical features and symptoms of IgG4-related ophthalmic disease: A multicenter study","volume":"65","author":"Goto","year":"2021","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"622847","DOI":"10.3389\/fonc.2021.622847","article-title":"Clinical Features and Prognoses of IgG4-Positive and IgG4-Negative Lacrimal Lymphomas","volume":"11","author":"Liu","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1097\/IOP.0000000000001429","article-title":"Orbital Myositis: A Comprehensive Review and Reclassification","volume":"36","author":"McNab","year":"2020","journal-title":"Ophthalmic Plast. Reconstr. Surg."},{"key":"ref_15","first-page":"1539","article-title":"A clinicopathological study on IgG4-related ophthalmic disease","volume":"11","author":"Suimon","year":"2018","journal-title":"Int. J. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10384-014-0352-2","article-title":"Diagnostic criteria for IgG4-related ophthalmic disease","volume":"59","author":"Goto","year":"2015","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1007\/s10384-017-0513-1","article-title":"Immunophenotypic profiles for distinguishing orbital mucosa-associated lymphoid tissue lymphoma from benign lymphoproliferative tumors","volume":"61","author":"Ueda","year":"2017","journal-title":"Jpn. J. Ophthalmol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1097\/PAP.0b013e3181e4abdb","article-title":"Ocular adnexal lymphomas: A review","volume":"17","author":"McKelvie","year":"2010","journal-title":"Adv. Anat. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1053\/j.gastro.2013.08.046","article-title":"Molecular diagnosis of eosinophilic esophagitis by gene expression profiling","volume":"145","author":"Wen","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/art.37704","article-title":"Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis","volume":"65","author":"Yeremenko","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1093\/eurheartj\/ehu101","article-title":"Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling","volume":"35","author":"Lassner","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R168","DOI":"10.1186\/ar2855","article-title":"Insights in to the pathogenesis of axial spondyloarthropathy based on gene expression profiles","volume":"11","author":"Sharma","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17567","DOI":"10.1038\/s41598-017-17602-9","article-title":"High-throughput RNA sequencing reveals distinct gene signatures in active IgG4-related disease","volume":"7","author":"Higgs","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1097\/PAS.0000000000001167","article-title":"Morphologic Overlap Between Inflammatory Myofibroblastic Tumor and IgG4-related Disease: Lessons from Next-generation Sequencing","volume":"43","author":"Taylor","year":"2019","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Asakage, M., Usui, Y., Nezu, N., Shimizu, H., Tsubota, K., Umazume, K., Yamakawa, N., Umezu, T., Suwanai, H., and Kuroda, M. (2020). Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113458"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1001\/jamaophthalmol.2017.3458","article-title":"Gene Expression Profiling and Heterogeneity of Nonspecific Orbital Inflammation Affecting the Lacrimal Gland","volume":"135","author":"Rosenbaum","year":"2017","journal-title":"JAMA Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj2240001","article-title":"Control of gene expression by glucocorticoid hormones","volume":"224","author":"Rousseau","year":"1984","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/s41467-018-02892-y","article-title":"Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis","volume":"9","author":"Mizoguchi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/IOP.0000000000000690","article-title":"Clinical Features and Treatment Outcomes of Orbital Inflammatory Disease in Singapore: A 10-Year Clinicopathologic Review","volume":"33","author":"Young","year":"2017","journal-title":"Ophthalmic Plast. Reconstr. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1097\/PAS.0b013e31816148ad","article-title":"Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: A previously undescribed complication of IgG4-related sclerosing disease","volume":"32","author":"Cheuk","year":"2008","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1440-1827.2008.02257.x","article-title":"Ocular adnexal IgG4-related disease has uniform clinicopathology","volume":"58","author":"Sato","year":"2008","journal-title":"Pathol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/j.1365-2559.2011.04089.x","article-title":"Ocular adnexal IgG4-related disease: Comparative analysis with mucosa-associated lymphoid tissue lymphoma and other chronic inflammatory conditions","volume":"60","author":"Go","year":"2012","journal-title":"Histopathology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/modpathol.2012.72","article-title":"Consensus statement on the pathology of IgG4-related disease","volume":"25","author":"Deshpande","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3109\/s10165-011-0571-z","article-title":"Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011","volume":"22","author":"Umehara","year":"2012","journal-title":"Mod. Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1167\/iovs.62.1.15","article-title":"Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma","volume":"62","author":"Shimizu","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Walter, R.F.H., Werner, R., Vollbrecht, C., Hager, T., Flom, E., Christoph, D.C., Schmeller, J., Schmid, K.W., Wohlschlaeger, J., and Mairinger, F.D. (2016). ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP Were Identified as Reference Genes in Neuroendocrine Lung Cancer via the nCounter Technology. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165181"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9571","DOI":"10.2147\/CMAR.S219872","article-title":"Digital Immune-Related Gene Expression Signatures in High-Grade Serous Ovarian Carcinoma: Developing Prediction Models for Platinum Response","volume":"11","author":"Mairinger","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bates, D., and Watts, D.G. (1988). Nonlinear Regression Analysis and Its Applications, John Wiley & Sons, Inc.","DOI":"10.1002\/9780470316757"},{"key":"ref_39","unstructured":"Bonate, P.L. (2006). Nonlinear Models and Regression. Pharmacokinetic-Pharmacodynamic Modeling and Simulation, Springer."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1198\/106186006X133933","article-title":"Unbiased Recursive Partitioning: A Conditional Inference Framework","volume":"15","author":"Hothorn","year":"2006","journal-title":"J. Comput. Graph. Stat."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8609\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:01:41Z","timestamp":1760140901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,3]]},"references-count":40,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158609"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158609","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,3]]}}}