DISCOVERY OF GLYCAN BIOMARKERS IN AUTOIMMUNE DISEASES: RECENT ADVANCES IN DIAGNOSIS AND TREATMENT

Öz

Glycans are complex sugar molecules that bind to numerous proteins secreted in the human body, significantly altering their structural and functional properties. Abnormalities in this process, known as glycosylation, are closely associated with various pathological conditions, including cancer, cardiovascular diseases, autoimmune disorders, and chronic inflammatory diseases. Particularly in autoimmune diseases, alterations in glycan structures play a crucial role in disease onset, progression, and treatment. Nowadays, advanced analytical techniques, such as mass spectrometry, are widely used to analyze glycan structure modifications, enabling the high-sensitivity profiling of glycans and the detection of disease-associated alterations. Early identification of these changes can significantly contribute to clinical decision-making, particularly in disease diagnosis, treatment strategy development, and therapeutic monitoring. This study explores the role of glycan modifications in various pathological conditions, with a particular focus on autoimmune diseases, and provides up-to-date insights into their potential as biomarkers. Furthermore, emerging technological approaches and future perspectives to enhance glycan biomarkers' clinical applicability are evaluated.

Anahtar Kelimeler

• Autoimmune Diseases
• Biomarker
• Glycan
• Mass Spectrometry

OTOİMMÜN HASTALIKLARDA GLİKAN BİYOBELİRTEÇLERİN KEŞFİ: TANI VE TEDAVİDE SON GELİŞMELER

Öz

Glikanlar, insan vücudunda salgılanan çok sayıda proteine bağlanarak bu proteinlerin yapısal ve işlevsel özelliklerinde önemli değişikliklere yol açan kompleks şeker molekülleridir. Glikozilasyon olarak bilinen bu süreçteki anormallikler, kanser, kardiyovasküler hastalıklar, otoimmün bozukluklar ve kronik inflamatuvar hastalıklar gibi birçok patolojik durumla yakından ilişkilidir. Özellikle otoimmün hastalıklarda, glikan yapılarındaki değişiklikler, hastalığın başlangıcı, ilerlemesi ve tedavi sürecinde kritik bir rol oynar. Günümüzde, glikan yapılarındaki değişikliklerin analizi için yaygın olarak kullanılan kütle spektrometresi gibi ileri analitik teknikler, glikan profillerinin yüksek hassasiyetle belirlenmesine ve hastalıkla ilişkili spesifik glikan modifikasyonlarının tespit edilmesine olanak tanır. Erken dönemde yapılan bu analizler, hastalığın tanısı, tedavi stratejilerinin belirlenmesi ve tedaviye yanıtın izlenmesi açısından klinik karar verme süreçlerine önemli katkılar sağlayabilir. Bu çalışmada, otoimmün hastalıklar başta olmak üzere çeşitli patolojik durumlarda glikan yapılarındaki değişikliklerin rolü ele alınmakta ve bu değişikliklerin potansiyel biyobelirteçler olarak kullanımına yönelik güncel bilgiler sunulmaktadır. Ayrıca, glikan biyobelirteçlerin klinik uygulamalarda kullanımını kolaylaştıracak yeni teknolojik yaklaşımlar ve gelecek perspektifleri de değerlendirilmektedir.

Anahtar Kelimeler

• Biyobelirteç
• Glikan
• Kütle Spektrometrisi
• Otoimmün Hastalıklar

Kaynakça

1. Ai, J., Leonhardt, J. M., & Heymann, W. R. (2003). Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations. Journal of the American Academy of Dermatology, 48(5), 641–662.
2. Alkuhlani, A., Gad, W., Roushdy, M., & Salem, A. B. M. (2021). Intelligent Techniques Analysis for Glycosylation Site Prediction. Current Bioinformatics, 16(6), 774–788.
3. Almaani, S., Meara, A., & Rovin, B. H. (2017). Update on lupus nephritis. Clinical Journal of the American Society of Nephrology, 12(5), 825–835.
4. Alvarez-Manilla, G., Atwood, J., Guo, Y., Warren, N. L., Orlando, R., & Pierce, M. (2006). Tools for glycoproteomic analysis: Size exclusion chromatography facilitates identification of tryptic glycopeptides with N-linked glycosylation sites. Journal of Proteome Research, 5(3), 701–708.
5. Alves, I., Santos-Pereira, B., Dalebout, H., Santos, S., Vicente, M. M., Campar, A., Thepaut, M., Fieschi, F., Strahl, S., Boyaval, F., Vizcaíno, R., Silva, R., Holst-Bernal, S., Vasconcelos, C., Santos, L., Wuhrer, M., Marinho, A., Heijs, B., & Pinho, S. S. (2021). Protein Mannosylation as a Diagnostic and Prognostic Biomarker of Lupus Nephritis: An Unusual Glycan Neoepitope in Systemic Lupus Erythematosus. Arthritis and Rheumatology, 73(11), 2069–2077.
6. Bermingham, M. L., Colombo, M., McGurnaghan, S. J., Blackbourn, L. A. K., Vučković, F., Pučić Baković, M., Trbojević-Akmačić, I., Lauc, G., Agakov, F., Agakova, A. S., Hayward, C., Klarić, L., Palmer, C. N. A., Petrie, J. R., Chalmers, J., Collier, A., Green, F., Lindsay, R. S., Macrury, S., … Colhoun, H. M. (2018). N-Glycan Profile and Kidney Disease in Type 1 Diabetes. Diabetes Care, 41(1), 79–87.
7. Bojar, D., & Lisacek, F. (2022). Glycoinformatics in the Artificial Intelligence Era. Chemical Reviews, 122(20), 15971–15988.
8. Bolon, B. (2012). Cellular and Molecular Mechanisms of Autoimmune Disease. Toxicologic Pathology, 40(2), 216–229.

9. Bondt, A., Selman, M. H. J., Deelder, A. M., Hazes, J. M. W., Willemsen, S. P., Wuhrer, M., & Dolhain, R. J. E. M. (2013). Association between galactosylation of immunoglobulin G and improvement of rheumatoid arthritis during pregnancy is independent of sialylation. Journal of Proteome Research, 12(10), 4522–4531.
10. Bournazos, S., Gupta, A., & Ravetch, J. V. (2020). The role of IgG Fc receptors in antibody-dependent enhancement. Nature Reviews Immunology, 20(10), 633–643.
11. Burska, A., Boissinot, M., & Ponchel, F. (2014). Cytokines as biomarkers in rheumatoid arthritis. Mediators of Inflammation, 2014(1), 545493.
12. Buszewski, B., & Noga, S. (2012). Hydrophilic interaction liquid chromatography (HILIC)-a powerful separation technique. Analytical and Bioanalytical Chemistry, 402(1), 231–247.
13. Castro, C., & Gourley, M. (2010). Diagnostic testing and interpretation of tests for autoimmunity. Journal of Allergy and Clinical Immunology, 125(2), S238–S247.
14. Chen, X. X., Chen, Y. Q., & Ye, S. (2015). Measuring decreased serum IgG sialylation: a novel clinical biomarker of lupus. Lupus, 24(9), 948–954.
15. Cindrić, A., Krištić, J., Martinić Kavur, M., & Pezer, M. (2021). Glycosylation and Aging. Advances in Experimental Medicine and Biology, 1325, 341–373.
16. Ciregia, F., Baiwir, D., Cobraiville, G., Dewael, T., Mazzucchelli, G., Badot, V., Di Romana, S., Sidiras, P., Sokolova, T., Durez, P., Malaise, M. G., & De Seny, D. (2020). Glycosylation deficiency of lipopolysaccharide-binding protein and corticosteroid-binding globulin associated with activity and response to treatment for rheumatoid arthritis. Journal of Translational Medicine, 18(1), 1–17.
17. Clerc, F., Novokmet, M., Dotz, V., Reiding, K. R., de Haan, N., Kammeijer, G. S. M., Dalebout, H., Bladergroen, M. R., Vukovic, F., Rapp, E., Satsangi, J., Nimmo, E. R., Ventham, N. T., Drummond, H., Kalla, R., Adams, A. T., O’Leary, K., Boyapati, R., Wilson, D. C., … Wuhrer, M. (2018). Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases. Gastroenterology, 155(3), 829–843.
18. Clerc, F., Reiding, K. R., de Haan, N., Koeleman, C. A. M., Hipgrave Ederveen, A. L., Manetti, N., Dotz, V., Annese, V., & Wuhrer, M. (2023). Immunoglobulin A Glycosylation Differs between Crohn’s Disease and Ulcerative Colitis. Journal of Proteome Research, 22(10), 3213–3224.
19. Clerc, F., Reiding, K. R., Jansen, B. C., Kammeijer, G. S. M., Bondt, A., & Wuhrer, M. (2015). Human plasma protein N-glycosylation. Glycoconjugate Journal, 33(3), 309–343.
20. Cobb, B. A. (2020). The history of IgG glycosylation and where we are now. Glycobiology, 30(4), 202-213.
21. Cojocaru, M., Cojocaru, I. M., Silosi, I., Vrabie, C. D., & Tanasescu, R. (2010). Extra-articular Manifestations in Rheumatoid Arthritis. Mædica, 5(4), 286.
22. Crimmins, E. M. (2015). Lifespan and Healthspan: Past, Present, and Promise. The Gerontologist, 55(6), 901–911.
23. Danchenko, N., Satia, J. A., & Anthony, M. S. (2006). Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus, 15(5), 308–318.
24. De Man, Y. A., Dolhain, R. J. E. M., Van De Geijn, F. E., Willemsen, S. P., & Hazes, J. M. W. (2008). Disease activity of rheumatoid arthritis during pregnancy: Results from a nationwide prospective study. Arthritis Care & Research, 59(9), 1241–1248.
25. Deng, G., Chen, X., Shao, L., Wu, Q., & Wang, S. (2024). Glycosylation in autoimmune diseases: A bibliometric and visualization study. Heliyon, 10(9), 30026.
26. Deng, X., Liu, X., Zhang, Y., Ke, D., Yan, R., Wang, Q., Tian, X., Li, M., Zeng, X., & Hu, C. (2023). Changes of serum IgG glycosylation patterns in rheumatoid arthritis. Clinical Proteomics, 20(1), 1–11.
27. Etxebarria, J., & Reichardt, N. C. (2016). Methods for the absolute quantification of N-glycan biomarkers. Biochimica et Biophysica Acta (BBA) - General Subjects, 1860(8), 1676–1687.
28. Flevaris, K., & Kontoravdi, C. (2022). Immunoglobulin G N-glycan Biomarkers for Autoimmune Diseases: Current State and a Glycoinformatics Perspective. International Journal of Molecular Sciences, 23(9), 5180.
29. Fröhlich, E., & Wahl, R. (2017). Thyroid autoimmunity: Role of anti-thyroid antibodies in thyroid and extra-thyroidal diseases. Frontiers in Immunology, 8(MAY), 265506.
30. Giacomelli, R., Afeltra, A., Alunno, A., Bartoloni-Bocci, E., Berardicurti, O., Bombardieri, M., Bortoluzzi, A., Caporali, R., Caso, F., Cervera, R., Chimenti, M. S., Cipriani, P., Coloma, E., Conti, F., D’Angelo, S., De Vita, S., Di Bartolomeo, S., Distler, O., Doria, A., … Tzioufas, A. G. (2019). Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis. Autoimmunity Reviews, 18(1), 93–106.
31. Gillespie, K. M. (2006). Type 1 diabetes: pathogenesis and prevention. CMAJ, 175(2), 165–170.
32. Gińdzieńska-Sieśkiewicz, E., Radziejewska, I., Domysławska, I., Klimiuk, P. A., Sulik, A., Rojewska, J., Gabryel-Porowska, H., & Sierakowski, S. (2016). Changes of glycosylation of IgG in rheumatoid arthritis patients treated with methotrexate. Advances in Medical Sciences, 61(2), 193–197.
33. Green, R. S., Stone, E. L., Tenno, M., Lehtonen, E., Farquhar, M. G., & Marth, J. D. D. (2007). Mammalian N-Glycan Branching Protects against Innate Immune Self-Recognition and Inflammation in Autoimmune Disease Pathogenesis. Immunity, 27(2), 308–320.
34. Gudelj, I., Salo, P. P., Trbojević-Akmačić, I., Albers, M., Primorac, D., Perola, M., & Lauc, G. (2018). Low galactosylation of IgG associates with higher risk for future diagnosis of rheumatoid arthritis during 10 years of follow-up. Biochimica et Biophysica Acta (BBA)- Molecular Basis of Disease, 1864(6), 2034–2039.
35. Gyebrovszki, B., Ács, A., Szabó, D., Auer, F., Novozánszki, S., Rojkovich, B., Magyar, A., Hudecz, F., Vékey, K., Drahos, L., & Sármay, G. (2022). The Role of IgG Fc Region N-Glycosylation in the Pathomechanism of Rheumatoid Arthritis. International Journal of Molecular Sciences, 23(10), 5828.
36. Hafkenscheid, L., Bondt, A., Scherer, H. U., Huizinga, T. W. J., Wuhrer, M., Toes, R. E. M., & Rombouts, Y. (2017). Structural analysis of variable domain glycosylation of anti-citrullinated protein antibodies in rheumatoid arthritis reveals the presence of highly sialylated glycans. Molecular and Cellular Proteomics, 16(2), 278–287.
37. Hafkenscheid, L., de Moel, E., Smolik, I., Tanner, S., Meng, X., Jansen, B. C., Bondt, A., Wuhrer, M., Huizinga, T. W. J., Toes, R. E. M., El-Gabalawy, H., & Scherer, H. U. (2019). N-Linked Glycans in the Variable Domain of IgG Anti–Citrullinated Protein Antibodies Predict the Development of Rheumatoid Arthritis. Arthritis & Rheumatology, 71(10), 1626–1633.
38. Hanić, M., Trbojević-Akmačić, I., & Lauc, G. (2019). Inflammatory bowel disease - glycomics perspective. Biochimica et Biophysica Acta. General Subjects, 1863(10), 1595–1601.
39. Haslund-Gourley, B. S., Wigdahl, B., & Comunale, M. A. (2023). IgG N-glycan Signatures as Potential Diagnostic and Prognostic Biomarkers. Diagnostics, 13(6), 1016.
40. Hu, Y., & Mechref, Y. (2012). Comparing MALDI-MS, RP-LC-MALDI-MS and RP-LC-ESI-MS glycomic profiles of permethylated N-glycans derived from model glycoproteins and human blood serum. Electrophoresis, 33(12), 1768–1777.
41. Huang, C., Liu, Y., Wu, H., Sun, D., & Li, Y. (2017). Characterization of IgG glycosylation in rheumatoid arthritis patients by MALDI-TOF-MSn and capillary electrophoresis. Analytical and Bioanalytical Chemistry, 409(15), 3731–3739.
42. Ippolito, A., Wallace, D. J., Gladman, D., Fortin, P. R., Urowitz, M., Werth, V., Costner, M., Gordon, C., Alarcón, G. S., Ramsey-Goldman, R., Maddison, P., Clarke, A., Bernatsky, S., Manzi, S., Bae, S. C., Merrill, J. T., Ginzler, E., Hanly, J. G., Nived, O., … Petri, M. (2011). Autoantibodies in systemic lupus erythematosus: comparison of historical and current assessment of seropositivity. Lupus, 20(3), 250–255.
43. Iskandar, H. N., & Ciorba, M. A. (2012). Biomarkers in inflammatory bowel disease: current practices and recent advances. Translational Research : The Journal of Laboratory and Clinical Medicine, 159(4), 313–325.
44. Iwaki, J., & Hirabayashi, J. (2018). Carbohydrate-Binding Specificity of Human Galectins: An Overview by Frontal Affinity Chromatography. Trends in Glycoscience and Glycotechnology, 30(172), S137–S153.
45. Kam, R. K. T., & Poon, T. C. W. (2008). The potentials of glycomics in biomarker discovery. Clinical Proteomics, 4(3–4), 67–79.
46. Katsarou, A., Gudbjörnsdottir, S., Rawshani, A., Dabelea, D., Bonifacio, E., Anderson, B. J., Jacobsen, L. M., Schatz, D. A., & Lernmark, A. (2017). Type 1 diabetes mellitus. Nature Reviews Disease Primers, 3(1), 1–17.
47. Kaul, A., Gordon, C., Crow, M. K., Touma, Z., Urowitz, M. B., Van Vollenhoven, R., Ruiz-Irastorza, G., & Hughes, G. (2016). Systemic lupus erythematosus. Nature Reviews. Disease Primers, 2.
48. Kerr, M. A. (1990). The structure and function of human IgA. Biochemical Journal, 271(2), 285.
49. Kissel, T., Hafkenscheid, L., Wesemael, T. J., Tamai, M., Kawashiri, S. ya, Kawakami, A., El-Gabalawy, H. S., van Schaardenburg, D., Rantapää-Dahlqvist, S., Wuhrer, M., van der Helm-van Mil, A. H. M., Allaart, C. F., van der Woude, D., Scherer, H. U., Toes, R. E. M., & Huizinga, T. W. J. (2022). IgG Anti-Citrullinated Protein Antibody Variable Domain Glycosylation Increases Before the Onset of Rheumatoid Arthritis and Stabilizes Thereafter: A Cross-Sectional Study Encompassing ~1,500 Samples. Arthritis & Rheumatology (Hoboken, N.J.), 74(7), 1147–1158.
50. Kolarz, B., Podgorska, D., & Podgorski, R. (2021). Insights of rheumatoid arthritis biomarkers. Biomarkers, 26(3), 185–195.
51. Kosanović, M., Milutinović, B., Goč, S., Mitić, N., & Janković, M. (2017). Ion-Exchange Chromatography Purification of Extracellular Vesicles. BioTechniques, 63(2), 65–71.
52. Lee, H. J., Li, C. W., Hammerstad, S. S., Stefan, M., & Tomer, Y. (2015). Immunogenetics of autoimmune thyroid diseases: A comprehensive review. Journal of Autoimmunity, 64, 82–90.
53. Li, D. P., Han, Y. X., He, Y. S., Wen, Y., Liu, Y. C., Fu, Z. Y., Pan, H. F., & Cao, F. (2023). A global assessment of incidence trends of autoimmune diseases from 1990 to 2019 and predicted changes to 2040. Autoimmunity Reviews, 22(10), 103407.
54. Li, H., Chiang, A. W. T., & Lewis, N. E. (2022). Artificial intelligence in the analysis of glycosylation data. Biotechnology Advances, 60, 108008.
55. Li, W., Liu, Y., Zheng, X., Gao, J., Wang, L., & Li, Y. (2019). Investigation of the Potential Use of Sialic Acid as a Biomarker for Rheumatoid Arthritis, Annals of Clinical & Laboratory Science, 49(2), 224- 231.
56. Liang, P. H., Wu, C. Y., Greenberg, W. A., & Wong, C. H. (2008). Glycan arrays: biological and medical applications. Current Opinion in Chemical Biology, 12(1), 86–92.
57. Lu, G., Crihfield, C. L., Gattu, S., Veltri, L. M., & Holland, L. A. (2018). Capillary Electrophoresis Separations of Glycans. Chemical Reviews, 118(17), 7867–7885.
58. Lu, X., Wang, L., Wang, M., Li, Y., Zhao, Q., Shi, Y., Zhang, Y., Wang, Y., Wang, W., Ji, L., Hou, H., & Li, D. (2023). Association between immunoglobulin G N-glycosylation and lupus nephritis in female patients with systemic lupus erythematosus: a case-control study. Frontiers in Immunology, 14, 1257906.
59. Lundborg, M., & Widmalm, G. (2011). Structural analysis of glycans by NMR chemical shift prediction. Analytical Chemistry, 83(5), 1514–1517.
60. Lyman, D. F., Bell, A., Black, A., Dingerdissen, H., Cauley, E., Gogate, N., Liu, D., Joseph, A., Kahsay, R., Crichton, D. J., Mehta, A., & Mazumder, R. (2022). Modeling and integration of N-glycan biomarkers in a comprehensive biomarker data model. Glycobiology, 32(10), 855–870.
61. Maahs, D. M., West, N. A., Lawrence, J. M., & Mayer-Davis, E. J. (2010). Epidemiology of Type 1 Diabetes. Endocrinology and Metabolism Clinics, 39(3), 481–497.
62. Mahajan, A., Amelio, J., Gairy, K., Kaur, G., Levy, R. A., Roth, D., & Bass, D. (2020). Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression. Lupus, 29(9), 1011–1020.
63. Mahan, A. E., Tedesco, J., Dionne, K., Baruah, K., Cheng, H. D., De Jager, P. L., Barouch, D. H., Suscovich, T., Ackerman, M., Crispin, M., & Alter, G. (2015). A method for high-throughput, sensitive analysis of IgG Fc and Fab glycosylation by capillary electrophoresis. Journal of Immunological Methods, 417, 34–44.
64. Marrack, P., Kappler, J., & Kotzin, B. L. (2001). Autoimmune disease: why and where it occurs. Nature Medicine, 7(8), 899–905.
65. Martin, K., Talukder, R., Hay, F. C., & Axford, J. S. (2001). Characterization of changes in IgG associated oligosaccharide profiles in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis using fluorophore linked carbohydrate electrophoresis. The Journal of Rheumatology, 28(7), 1531–1536.
66. Martin, T. C., Šimurina, M., Ząbczyńska, M., Kavur, M., Rydlewska, M., Pezer, M., Kozłowska, K., Burri, A., Vilaj, M., Turek-Jabrocka, R., Krnjajić-Tadijanović, M., Trofimiuk-Müldner, M., Ugrina, I., Lityn, A., Hubalewska-Dydejczyk, A., Trbojevic-Akmacic, I., Lim, E. M., Walsh, J. P., Pocheć, E., … Lauc, G. (2020). Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases. Molecular & Cellular Proteomics : MCP, 19(5), 774–792.
67. Maverakis, E., Kim, K., Shimoda, M., Gershwin, M. E., Patel, F., Wilken, R., Raychaudhuri, S., Ruhaak, L. R., & Lebrilla, C. B. (2015). Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: A critical review. Journal of Autoimmunity, 57, 1–13.
68. Nakajima, S., Iijima, H., Shinzaki, S., Egawa, S., Inoue, T., Mukai, A., Hayashi, Y., Kondo, J., Akasaka, T., Nishida, T., Kanto, T., Morii, E., Mizushima, T., Miyoshi, E., Tsujii, M., & Hayashi, N. (2011). Functional analysis of agalactosyl IgG in inflammatory bowel disease patients. Inflammatory Bowel Diseases, 17(4), 927–936.
69. Nemčić, M., Shkunnikova, S., Kifer, D., Plavša, B., Vučić Lovrenčić, M., Morahan, G., Duvnjak, L., Pociot, F., & Gornik, O. (2024). N-glycosylation of immunoglobulin A in children and adults with type 1 diabetes mellitus. Heliyon, 10(9).
70. Nemčić, M., Tijardović, M., Rudman, N., Bulum, T., Tomić, M., Plavša, B., Vučković Rebrina, S., Vučić Lovrenčić, M., Duvnjak, L., Morahan, G., & Gornik, O. (2023). N-glycosylation of serum proteins in adult type 1 diabetes mellitus exposes further changes compared to children at the disease onset. Clinica Chimica Acta, 543, 117298.
71. Nimmerjahn, F., & Ravetch, J. V. (2006). Fcγ receptors: Old friends and new family members. Immunity, 24(1), 19–28.
72. Ohtsubo, K., & Marth, J. D. (2006). Glycosylation in cellular mechanisms of health and disease. Cell, 126(5), 855–867.
73. Pan, H., Wang, J., Liang, Y., Wang, C., Tian, R., Ye, H., Zhang, X., Wu, Y., Shao, M., Zhang, R., Xiao, Y., Li, Z., Zhang, G., Zhou, H., Wang, Y., Wang, X., Li, Z., Liu, W., & Liu, L. (2023). Serum IgG Glycan Hallmarks of Systemic Lupus Erythematosus. Engineering, 26, 89–98.
74. Parekh, R. B., Dwek, R. A., Sutton, B. J., Fernandes, D. L., Leung, A., Stanworth, D., Rademacher, T. W., Mizuochi, T., Taniguchi, T., Matsuta, K., Takeuchi, F., Nagano, Y., Miyamoto, T., & Kobata, A. (1985). Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature, 316(6027), 452–457.
75. Parekh, R. B., Isenberg, D. A., Ansell, B. M., Roitt, I. M., Dwek, R. A., & Rademacher, T. W. (1988). Galactosylation Of Igg Associated Oligosaccharides: Reduction In Patients With Adult And Juvenile Onset Rheumatoid Arthritis And Relation To Disease Activity. The Lancet, 331(8592), 966–969.
76. Pasala, C., Sharma, S., Roychowdhury, T., Moroni, E., Colombo, G., & Chiosis, G. (2024). N-glycosylation as a Modulator of Protein Conformation and Assembly in Disease. Biomolecules, 14(3), 282.
77. Paton, B., Suarez, M., Herrero, P., Canela, N., Cairo, W., Garozzo, D., & Pshezhetsky, A. V. (2021). Glycosylation Biomarkers Associated with Age-Related Diseases and Current Methods for Glycan Analysis. International Journal of Molecular Sciences, 22(11), 5788.
78. Pilkington, C., Yeung, E., Isenberg, D., Lefvert, A. K., & Rook, G. A. W. (1995). Agalactosyl IgG and Antibody Specificity in Rheumatoid Arthritis, Tuberculosis, Systemic Lupus Erythematosus and Myasthenia Gravis. Autoimmunity, 22(2), 107–111.
79. Pisetsky, D. S. (2023). Pathogenesis of autoimmune disease. Nature Reviews Nephrology 19(8), 509–524.
80. Poland, D. C. W., Schalkwijk, C. G., Stehouwer, C. D. A., Koeleman, C. A. M., Van Het Hof, B., & Van Dijk, W. (2001). Increased α3-fucosylation of α1-acid glycoprotein in Type I diabetic patients is related to vascular function. Glycoconjugate Journal, 18(3), 261–268.
81. Pons-Estel, G. J., Ugarte-Gil, M. F., & Alarcón, G. S. (2017). Epidemiology of systemic lupus erythematosus. Expert Review of Clinical Immunology, 13(8), 799–814.
82. Pučić, M., Knežević, A., Vidič, J., Adamczyk, B., Novokmet, M., Polašek, O., Gornik, O., Šupraha-Goreta, S., Wormald, M. R., Redžic, I., Campbell, H., Wright, A., Hastie, N. D., Wilson, J. F., Rudan, I., Wuhrer, M., Rudd, P. M., Josić, D., & Lauc, G. (2011). High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Molecular and Cellular Proteomics, 10(10), M111.010090.
83. Radu, A. F., & Bungau, S. G. (2021). Management of Rheumatoid Arthritis: An Overview. Cells, 10(11), 2857.
84. Reily, C., Stewart, T. J., Renfrow, M. B., & Novak, J. (2019). Glycosylation in health and disease. Nature Reviews Nephrology, 15(6), 346–366.
85. Renaudineau, Y., Brooks, W., & Belliere, J. (2023). Lupus Nephritis Risk Factors and Biomarkers: An Update. International Journal of Molecular Sciences, 24(19).
86. Robbe Masselot, C., Cordier, C., Marsac, B., Nachury, M., Leonard, R., & Sendid, B. (2023). Human Fecal Mucin Glycosylation as a New Biomarker in Inflammatory Bowel Diseases. Inflammatory Bowel Diseases, 29(1), 167–171.
87. Rombouts, Y., Willemze, A., Van Beers, J. J. B. C., Shi, J., Kerkman, P. F., Van Toorn, L., Janssen, G. M. C., Zaldumbide, A., Hoeben, R. C., Pruijn, G. J. M., Deelder, A. M., Wolbink, G., Rispens, T., Van Veelen, P. A., Huizinga, T. W. J., Wuhrer, M., Trouw, L. A., Scherer, H. U., & Toes, R. E. M. (2016). Extensive glycosylation of ACPA-IgG variable domains modulates binding to citrullinated antigens in rheumatoid arthritis. Annals of the Rheumatic Diseases, 75(3), 578–585.
88. Rook, G. A. W., Steele, J., Brealey, R., Whyte, A., Isenberg, D., Sumar, N., Nelson, J. L., Bodman, K. B., Young, A., Roitt, I. M., Williams, P., Scragg, I., Edge, C. J., Arkwright, P. D., Ashford, D., Wormald, M., Rudd, P., Redman, C. W. G., Dwek, R. A., & Rademacher, T. W. (1991). Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. Journal of Autoimmunity, 4(5), 779–794.
89. Rudman, N., Kifer, D., Kaur, S., Simunović, V., Cvetko, A., Pociot, F., Morahan, G., & Gornik, O. (2022). Children at onset of type 1 diabetes show altered N-glycosylation of plasma proteins and IgG. Diabetologia, 65(8), 1315–1327.
90. Scherer, H. U., Häupl, T., & Burmester, G. R. (2020). The etiology of rheumatoid arthritis. Journal of Autoimmunity, 110, 102400.
91. Seeling, M., Brückner, C., & Nimmerjahn, F. (2017). Differential antibody glycosylation in autoimmunity: sweet biomarker or modulator of disease activity? Nature Reviews Rheumatology, 13(10), 621–630.
92. Sharma, C., Hamza, A., Boyle, E., Donu, D., & Cen, Y. (2024). Post-Translational Modifications and Diabetes. Biomolecules, 14(3), 310.
93. Shipman, J. T., Nguyen, H. T., & Desaire, H. (2020). So You Discovered a Potential Glycan-Based Biomarker; Now What? We Developed a High-Throughput Method for Quantitative Clinical Glycan Biomarker Validation. ACS Omega, 5(12), 6270–6276.
94. Šimurina, M., de Haan, N., Vučković, F., Kennedy, N. A., Štambuk, J., Falck, D., Trbojević-Akmačić, I., Clerc, F., Razdorov, G., Khon, A., Latiano, A., D’Incà, R., Danese, S., Targan, S., Landers, C., Dubinsky, M., Campbell, H., Zoldoš, V., Permberton, I. K., … Lauc, G. (2018). Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. Gastroenterology, 154(5), 1320-1333.
95. Sjöwall, C., Zapf, J., Von Löhneysen, S., Magorivska, I., Biermann, M., Janko, C., Winkler, S., Bilyy, R., Schett, G., Herrmann, M., & Muñoz, L. E. (2015). Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus. Lupus, 24(6), 569–581.
96. Smith, J., Mittermayr, S., Váradi, C., & Bones, J. (2017). Quantitative glycomics using liquid phase separations coupled to mass spectrometry. Analyst, 142(5), 700–720.
97. Stadlmann, J., Pabst, M., Kolarich, D., Kunert, R., & Altmann, F. (2008). Analysis of immunoglobulin glycosylation by LC-ESI-MS of glycopeptides and oligosaccharides. Proteomics, 8(14), 2858–2871.
98. Stafford, I. S., Kellermann, M., Mossotto, E., Beattie, R. M., MacArthur, B. D., & Ennis, S. (2020). A systematic review of the applications of artificial intelligence and machine learning in autoimmune diseases. Npj Digital Medicine, 3(1), 1–11.
99. Su, Z., Xie, Q., Wang, Y., & Li, Y. (2020). Abberant Immunoglobulin G Glycosylation in Rheumatoid Arthritis by LTQ-ESI-MS. International Journal of Molecular Sciences, 21(6), 2045.
100. Sun, D., Hu, F., Gao, H., Song, Z., Xie, W., Wang, P., Shi, L., Wang, K., Li, Y., Huang, C., & Li, Z. (2019). Distribution of abnormal IgG glycosylation patterns from rheumatoid arthritis and osteoarthritis patients by MALDI-TOF-MSn. Analyst, 144(6), 2042–2051.
101. Tekin, B., & Gurbanov, R. (2024). Kütle Spektrometresinden Glikan Mikrodizilerine: Glikomikte Analitik Tekniklere Genel Bir Bakış. Bilecik Şeyh Edebali Üniversitesi Fen Bilimleri Dergisi, 11(1), 218–235.
102. Tektonidou, M. G., & Ward, M. M. (2011). Validation of new biomarkers in systemic autoimmune diseases. Nature Reviews Rheumatology, 7(12), 708.
103. Theodoratou, E., Campbell, H., Ventham, N. T., Kolarich, D., Pučić-Baković, M., Zoldoš, V., Fernandes, D., Pemberton, I. K., Rudan, I., Kennedy, N. A., Wuhrer, M., Nimmo, E., Annese, V., McGovern, D. P. B., Satsangi, J., & Lauc, G. (2014). The role of glycosylation in IBD. Nature Reviews Gastroenterology & Hepatology , 11(10), 588–600.
104. Tomana, M., Schrohenloher, R. E., Koopman, W. J., Alarcän, G. S., & Paul, W. A. (1988). Abnormal glycosylation of serum igg from patients with chronic inflammatory diseases. Arthritis & Rheumatism, 31(3), 333–338.
105. Tomana, M., Schrohenloher, R. E., Reveille, J. D., Arnett, F. C., & Koopman, W. J. (1992). Abnormal galactosylation of serum IgG in patients with systemic lupus erythematosus and members of families with high frequency of autoimmune diseases. Rheumatology International, 12(5), 191–194.
106. Trbojevic Akmacic, I., Ventham, N. T., Theodoratou, E., Vučković, F., Kennedy, N. A., Krištić, J., Nimmo, E. R., Kalla, R., Drummond, H., Štambuk, J., Dunlop, M. G., Novokmet, M., Aulchenko, Y., Gornik, O., Campbell, H., Pučić Baković, M., Satsangi, J., & Lauc, G. (2015). Inflammatory bowel disease associates with proinflammatory potential of the immunoglobulin G glycome. Inflammatory Bowel Diseases, 21(6), 1237–1247.
107. Van de Geijn, F. E., Wuhrer, M., Selman, M. H. J., Willemsen, S. P., de Man, Y. A., Deelder, A. M., Hazes, J. M. W., & Dolhain, R. J. E. M. (2009). Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: Results from a large prospective cohort study. Arthritis Research and Therapy, 11(6), 1–10.
108. Vučkovïc, F., Krištïc, J., Gudelj, I., Teruel, M., Keser, T., Pezer, M., Pučïc-Bakovïc, M., Štambuk, J., Trbojevïc-Akmačïc, I., Barrios, C., Pavïc, T., Menni, C., Wang, Y., Zhou, Y., Cui, L., Song, H., Zeng, Q., Guo, X., Pons-Estel, B. A., … Lauc, G. (2015). Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis and Rheumatology, 67(11), 2978–2989.
109. Wen, W., Li, Y., Cheng, Y., He, J., Jia, R., Li, C., Guo, J., Sun, X., & Li, Z. (2018). Lipopolysaccharide-binding protein is a sensitive disease activity biomarker for rheumatoid arthritis. Clin Exp Rheumatol, 36(2), 233–240.
110. Wuhrer, M., De Boer, A. R., & Deelder, A. M. (2009). Structural glycomics using hydrophilic interaction chromatography (HILIC) with mass spectrometry. Mass Spectrometry Reviews, 28(2), 192–206.
111. Wuhrer, M., Koeleman, C. A. M., Hokke, C. H., & Deelder, A. M. (2004). Nano-scale liquid chromatography-mass spectrometry of 2-aminobenzamide-labeled oligosaccharides at low femtomole sensitivity. International Journal of Mass Spectrometry, 232(1), 51–57.
112. Xu, Z., Liu, Y., He, S., Sun, R., Zhu, C., Li, S., Hai, S., Luo, Y., Zhao, Y., & Dai, L. (2023). Integrative Proteomics and N-Glycoproteomics Analyses of Rheumatoid Arthritis Synovium Reveal Immune-Associated Glycopeptides. Molecular & Cellular Proteomics : MCP, 22(5).
113. Yang, H., Ye, J., You, Y., Zhou, Z., & Wu, J. (2024). AB1112 The Correlation Between Glycosylation Of Anti-Dsdna Antibody And Lupus Nephritis. Annals of the Rheumatic Diseases, 83(Suppl 1), 1886–1887.
114. Yao, M., Gao, C., Zhang, C., Di, X., Liang, W., Sun, W., Wang, Q., & Zheng, Z. (2020). Identification of Molecular Markers Associated With the Pathophysiology and Treatment of Lupus Nephritis Based on Integrated Transcriptome Analysis. Frontiers in Genetics, 11.
115. Yuan, S., Li, Q., Zhang, Y., Huang, C., Wu, H., Li, Y., Liu, Y., Yu, N., Zhang, H., Lu, G., Gao, Y., Gao, Y., & Guo, X. (2015). Changes in anti-thyroglobulin IgG glycosylation patterns in Hashimoto’s thyroiditis patients. The Journal of Clinical Endocrinology and Metabolism, 100(2), 717–724.
116. Ząbczyńska, M., Link-Lenczowski, P., Novokmet, M., Martin, T., Turek-Jabrocka, R., Trofimiuk-Müldner, M., & Pocheć, E. (2020). Altered N-glycan profile of IgG-depleted serum proteins in Hashimoto’s thyroiditis. Biochimica et Biophysica Acta. General Subjects, 1864(3).
117. Ząbczyńska, M., Link-Lenczowski, P., & Pocheć, E. (2021). Glycosylation in Autoimmune Diseases. Advances in Experimental Medicine and Biology, 1325, 205–218.
118. Zhang, Y. Z., & Li, Y. Y. (2014). Inflammatory bowel disease: Pathogenesis. World Journal of Gastroenterology : WJG, 20(1), 91.
119. Zhao, L., Liu, M., Gao, Y., Huang, Y., Lu, G., Gao, Y., Guo, X., & She, B. (2013). Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases. European Journal of Endocrinology, 168(4), 585–592.
120. Zhou, X., Motta, F., Selmi, C., Ridgway, W. M., Gershwin, M. E., & Zhang, W. (2021). Antibody glycosylation in autoimmune diseases. Autoimmunity Reviews, 20(5), 102804.
121. Ziegler, A. G., Rewers, M., Simell, O., Simell, T., Lempainen, J., Steck, A., Winkler, C., Ilonen, J., Veijola, R., Knip, M., Bonifacio, E., & Eisenbarth, G. S. (2013). Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children. JAMA, 309(23), 2473–2479.
122. Zou, X., Yoshida, M., Nagai-Okatani, C., Iwaki, J., Matsuda, A., Tan, B., Hagiwara, K., Sato, T., Itakura, Y., Noro, E., Kaji, H., Toyoda, M., Zhang, Y., Narimatsu, H., & Kuno, A. (2017). A standardized method for lectin microarray-based tissue glycome mapping. Scientific Reports 2017 7:1, 7(1), 1–12.