Öz
Amaç:
Primer Sjögren sendromlu (PSS) hastaların üçte birinde anti-SSA veya -SSB antikorları negatiftir. PSS’de B-hücreli non-Hodgkin lenfoma (NHL) gelişme riski önemli ölçüde artar ve prevalansı yaklaşık %5’tir. PSS’de tanısal değere sahip olabilecek ve lenfoma gelişimini öngörebilecek yeni belirteçlere yönelik ihtiyaç devam etmektedir. Bu çalışmada, netrin-1’in PSS’de tanısal bir belirteç olarak kullanılabilirliğini ve onun hastalık aktivitesi ve lenfoma prediktörleri ile ilişkisini araştırmayı amaçladık.
Yöntem:
Çalışmaya 52 PSS hastası ve 62 sağlıklı gönüllü dahil edildi. PSS hastalarında sistemik hastalık aktivitesini değerlendirmek için Avrupa Romatoloji Dernekleri Birliği Sjögren sendromu hastalık aktivite indeksi (ESSDAI) kullanıldı. Netrin-1 değerleri ELISA kiti (Elabscience, Texas, ABD; katalog numarası: E-EL-H2328; lot numarası: GZWTKZ5SWK) kullanılarak kantitatif sandviç enzim immunoassay yöntemi ile hesaplandı.
Bulgular:
PSS [90,3 (43,87-166,41)] ve sağlıklı kontrollerde [111,6 (63,39-171,36)] serum netrin-1 düzeyleri benzerdi (p=0,190). Netrin-1 serum düzeyleri PSS’de lenfomanın prediktif belirteçlerinden sadece lenfopeni (p=0,014) ile ilişkili iken, diğer belirteçlerle (p>0,05) ve ESSDAI skoru (r=0,637, p=0,067) ile ilişkili değildi.
Sonuç:
Serum netrin-1 seviyeleri PSS’de yüksek değildir ve netrin-1 ile lenfoma prediktif değerlerden lenfopeni hariç diğerlerinin ve hastalık aktivite göstergelesi olan ESSDAI skorunun anlamlı korelasyon ilişkisi yoktur.
Anahtar Kelimeler: Primer Sjögren sendromu, netrin-1, lenfoma
Kaynakça
Du AX, Gniadecki R, Osman M. Biomarkers of B cell activation in autoimmune connective tissue diseases: More than markers of disease activity. Clin Biochem 2022;100:1-12.
Mielle J, Tison A, Cornec D, Le Pottier L, Daien C, Pers JO. B cells in Sjögren’s syndrome: from pathophysiology to therapeutic target. Rheumatology (Oxford) 2012;60:2545-60.
Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjögren’s syndrome. Clin Immunol 2012;145:251-5.
Chen Y, Zheng J, Huang Q, et al. Autoantibodies against the second extracellular loop of M3R Do neither induce nor indicate primary Sjogren’s syndrome. PLoS One 2016;11:e0149485.
Theander E, Jonsson R, Sjöström B, Brokstad K, Olsson P, Henriksson G. Prediction of Sjögren’s Syndrome Years Before Diagnosis and Identification of Patients With Early Onset and Severe Disease Course by Autoantibody Profiling. Arthritis Rheumatol 2015;67:2427-36.
Goules AV, Tzioufas AG. Lymphomagenesis in Sjögren’s syndrome: predictive biomarkers towards precision medicine. Autoimmun Rev 2019;18:137-43.
De Vita S, De Marchi G, Sacco S, Gremese E, Fabris M, Ferraccioli G. Preliminary classification of nonmalignant B cell proliferation in Sjögren’s syndrome: perspectives on pathobiology and treatment based on an integrated clinico-pathologic and molecular study approach. Blood Cells Mol Dis 2001;27:757-66.
De Vita S, Gandolfo S, Zandonella Callegher S, Zabotti A, Quartuccio L. The evaluation of disease activity in Sjögren’s syndrome based on the degree of MALT involvement: glandular swelling and cryoglobulinaemia compared to ESSDAI in a cohort study. Clin Exp Rheumatol 2018;36:150-6.
Baimpa E, Dahabreh IJ, Voulgarelis M, Moutsopoulos HM. Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine (Baltimore) 2009;88:284-93.
Quartuccio L, Isola M, Baldini C, et al. Biomarkers of lymphoma in Sjögren’s syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study. J Autoimmun 2014;51:75-80.
Brito-Zerón P, Kostov B, Fraile G, et al. Characterization and risk estimate of cancer in patients with primary Sjögren syndrome. J Hematol Oncol 2017;10:90.
Papageorgiou A, Ziogas DC, Mavragani CP, et al. Predicting the outcome of Sjogren’s syndrome-associated non-hodgkin’s lymphoma patients. PloS One 2015;10:e0116189.
Fragkioudaki S, Mavragani CP, Moutsopoulos HM. Predicting the risk for lymphoma development in Sjogren syndrome: an easy tool for clinical use. Medicine (Baltimore) 2016;95:e3766.
Tzioufas AG, Boumba DS, Skopouli FN, Moutsopoulos HM. Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren’s syndrome. Arthritis Rheum 1996;39:767-72.
Theander E, Vasaitis L, Baecklund E, et al. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren’s syndrome. Ann Rheum Dis 2011;70:1363-8.
Retamozo S, Gheitasi H, Quartuccio L, et al. Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients. Rheumatology (Oxford) 2016;55:1443-51.
De Vita S, Quartuccio L, Salvin S, Corazza L, Zabotti A, Fabris M. Cryoglobulinaemia related to Sjogren’s syndrome or HCV infection: differences based on the pattern of bone marrow involvement, lymphoma evolution and laboratory tests after parotidectomy. Rheumatology (Oxford) 2012;51:627-33.
Visser A, Doorenspleet ME, de Vries N, et al. Acquisition of N-glycosylation sites in immunoglobulin heavy chain genes during local expansion in parotid salivary glands of primary sjögren patients. Front Immunol 2018;9:491.
De Vita S, Gandolfo S. Predicting lymphoma development in patients with Sjögren’s syndrome. Expert Rev Clin Immunol 2019;15:929-38.
Tzioufas AG, Kapsogeorgou EK, Moutsopoulos HM. Pathogenesis of Sjögren’s syndrome: what we know and what we should learn. J Autoimmun 2012;39:4-8.
Moutsopoulos HM. Sjögren’s syndrome: autoimmune epithelitis. Clin Immunol Immunopathol 1994;72:162-5.
Teos LY, Alevizos I. Genetics of Sjögren’s syndrome. Clin Immunol 2017;182:41-7.
Retamozo S, Brito-Zerón P, Ramos-Casals M. Prognostic markers of lymphoma development in primary Sjögren syndrome. Lupus 2019;28:923-36.
Ly NP, Komatsuzaki K, Fraser IP, et al. Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci USA 2005;102:14729-34.
Mirakaj V, Thix CA, Laucher S, et al. Netrin-1 dampens pulmonary inflammation during acute lung injury. Am J Respir Crit Care Med 2010;181:815-24.
Rosenberger P, Schwab JM, Mirakaj V, et al. Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat. Immunol 2009;10:195-202.
VanGils JM, Derby MC, Fernandes LR, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol 2012;13:136-43.
Ramkhelawon B, Hennessy EJ, Ménager M, et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med 2014;20:377-84.
Mediero A, Ramkhelawon B, Perez-Aso M, Moore KJ, Cronstein BN. Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation. J Bone Miner Res 2014;30:837-54.
Mediero A, Wilder T, Ramkhelawon B, Moore KJ, Cronstein BN. Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB J 2016;30:3835-44.
Maraş Y, Kor A, Oğuz EF, Sarı A, Gök K, Akdoğan A. Serum netrin-1 levels in systemic sclerosis patients with capillary abnormalities. Egypt Rheumatol 2023;45:51-4.
Broutier L, Creveaux M, Vial J, et al. Targeting netrin-1/DCC interaction in diffuse large B-cell and mantle cell lymphomas. EMBO Mol Med 2016;8:96-104.
Nagoshi H, Taki T, Chinen Y, et al. Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance. Genes Chromosomes Cancer 2015;54:788-95.
Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 2017;69:35-45.
Seror R, Ravaud P, Bowman SJ, et al. EULAR Sjogren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis 2010;69:1103-9.
Kefeli U, Ucuncu Kefeli A, Cabuk D, et al. Netrin-1 in cancer: Potential biomarker and therapeutic target? Tumour Biol 2017;39:1010428317698388.
Schubert T, Denk A, Mägdefrau U, et al. Role of the netrin system of repellent factors on synovial fibroblasts in rheumatoid arthritis and osteoarthritis. Int J Immunopathol Pharmacol 2009;22:715-22.
Atalar E, Gök K, Oğuz EF, Kor A, Maraş Y. Plasma netrin-1 levels in Familial Mediterranean fever: a potential biomarker? J Exp Clin Med 2022;39:1202-6.
Bhattacharya S, Aggarwal A. M2 macrophages and their role in rheumatic diseases. Rheumatol Int 2019;39:769-80.
Funes SC, Rios M, Escobar-Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. Immunology 2018;154:186-95.
Ranganathan P, Mohamed R, Jayakumar C, Ramesh G. Guidance cue netrin-1 and the regulation of inflammation in acute and chronic kidney disease. Mediators Inflamm 2104;2014:525891.
Zhang Y, Chen P, Di G, Qi X, Zhou Q, Gao H. Netrin-1 promotes diabetic corneal wound healing through molecular mechanisms mediated via the adenosine 2B receptor. Sci Rep 2018;8:5994.
Ranganathan PV, Jayakumar C, Ramesh G. Netrin-1-treated macrophages protect the kidney against ischemia-reperfusion injury and suppress inflammation by inducing M2 polarization. Am J Physiol Renal Physiol 2013;304:948-57.
Gao R, Peng X, Perry C, et al. Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis. J Clin Invest 2021;131:e136542.
Sun H, Zhu Y, Pan H, et al. Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and bleomycin-Induced Pulmonary Fibrosis. Arthritis Rheumatol 2016;68:1251-61.
Mehlen P, Guenebeaud C. Netrin-1 and its dependence receptors as original targets for cancer therapy. Curr Opin Oncol 2010;22:46-54.
Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H. p53RDL1 regulates p53-dependent apoptosis. Nat Cell Biol 2003;5:216-23.
