Top

Published in:

Open Access 01-12-2015 | Review

The clinical relevance of animal models in Sjögren’s syndrome: the interferon signature from mouse to man

Authors: Naomi I Maria, Petra Vogelsang, Marjan A Versnel

Published in: Arthritis Research & Therapy | Issue 1/2015

Abstract

Mouse models have been widely used to elucidate the pathogenic mechanisms of human diseases. The advantages of using these models include the ability to study different stages of the disease with particular respect to specific target organs, to focus on the role of specific pathogenic factors and to investigate the effect of possible therapeutic interventions. Sjögren’s syndrome (SS) is a systemic autoimmune disease, characterised by lymphocytic infiltrates in the salivary and lacrimal glands. To date, effective therapy is not available and treatment has been mainly symptomatic. Ongoing studies in murine models are aimed at developing more effective and targeted therapies in SS. The heterogeneity of SS will most probably benefit from optimising therapies, tailored to specific subgroups of the disease. In this review, we provide our perspective on the importance of subdividing SS patients according to their interferon signature, and recommend choosing appropriate mouse models for interferon-positive and interferon-negative SS subtypes. Murine models better resembling human-disease phenotypes will be essential in this endeavour.

Fox RI, Howell FV, Bone RC, Michelson P. Primary Sjogren syndrome: clinical and immunopathologic features. Semin Arthritis Rheum. 1984;14:77–105.PubMedCrossRef

Fox RI, Kang HI. Pathogenesis of Sjogren’s syndrome. Rheum Dis Clin North Am. 1992;18:517–38.PubMed

Nguyen CQ, Peck AB. Unraveling the pathophysiology of Sjogren syndrome-associated dry eye disease. Ocul Surf. 2009;7:11–27.PubMedCentralPubMedCrossRef

Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8.PubMedCrossRef

Delaleu N, Nguyen CQ, Peck AB, Jonsson R. Sjogren’s syndrome: studying the disease in mice. Arthritis Res Ther. 2011;13:217.PubMedCentralPubMedCrossRef

Bave U, Nordmark G, Lovgren T, Ronnelid J, Cajander S, Eloranta ML, et al. Activation of the type I interferon system in primary Sjogren’s syndrome: a possible etiopathogenic mechanism. Arthritis Rheum. 2005;52:1185–95.PubMedCrossRef

Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren’s syndrome. Proc Natl Acad Sci U S A. 2006;103:2770–5.PubMedCentralPubMedCrossRef

Wildenberg ME, van Helden-Meeuwsen CG, van de Merwe JP, Drexhage HA, Versnel MA. Systemic increase in type I interferon activity in Sjogren’s syndrome: a putative role for plasmacytoid dendritic cells. Eur J Immunol. 2008;38:2024–33.PubMedCrossRef

Emamian ES, Leon JM, Lessard CJ, Grandits M, Baechler EC, Gaffney PM, et al. Peripheral blood gene expression profiling in Sjogren’s syndrome. Genes Immun. 2009;10:285–96.PubMedCentralPubMedCrossRef

10.

Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren’s syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis. 2013;72:728–35.PubMedCentralPubMedCrossRef

11.

Maria NI, Brkic Z, Waris M, van Helden-Meeuwsen CG, Heezen K, van de Merwe JP, et al. MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjogren’s syndrome. Ann Rheum Dis. 2014;73:1052–9.PubMedCentralPubMedCrossRef

12.

Hjelmervik TO, Petersen K, Jonassen I, Jonsson R, Bolstad AI. Gene expression profiling of minor salivary glands clearly distinguishes primary Sjogren’s syndrome patients from healthy control subjects. Arthritis Rheum. 2005;52:1534–44.PubMedCrossRef

13.

Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6:823–35.PubMedCrossRef

14.

Hall JC, Casciola-Rosen L, Berger AE, Kapsogeorgou EK, Cheadle C, Tzioufas AG, et al. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A. 2012;109:17609–14.PubMedCentralPubMedCrossRef

15.

Chiche L, Jourde-Chiche N, Whalen E, Presnell S, Gersuk V, Dang K, et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol. 2014;66:1583–95.PubMedCentralPubMedCrossRef

16.

Deane JA, Pisitkun P, Barrett RS, Feigenbaum L, Town T, Ward JM, et al. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity. 2007;27:801–10.PubMedCentralPubMedCrossRef

17.

Desnues B, Macedo AB, Roussel-Queval A, Bonnardel J, Henri S, Demaria O, et al. TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice. Proc Natl Acad Sci U S A. 2014;111:1497–502.PubMedCentralPubMedCrossRef

18.

Jackson SW, Scharping NE, Kolhatkar NS, Khim S, Schwartz MA, Li QZ, et al. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J Immunol. 2014;192:4525–32.PubMedCentralPubMedCrossRef

19.

Nandula SR, Scindia YM, Dey P, Bagavant H, Deshmukh US. Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjogren’s syndrome-like disease. Oral Dis. 2011;17:801–7.PubMedCentralPubMedCrossRef

20.

Szabo A, Rajnavolgyi E. Collaboration of Toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses. Am J Clin Exp Immunol. 2013;2:195–207.PubMedCentralPubMed

21.

Szabo A, Magyarics Z, Pazmandi K, Gopcsa L, Rajnavolgyi E, Bacsi A. TLR ligands upregulate RIG-I expression in human plasmacytoid dendritic cells in a type I IFN-independent manner. Immunol Cell Biol. 2014;92:671–8.PubMedCrossRef

22.

Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637–50.PubMedCrossRef

23.

Szczerba BM, Kaplonek P, Wolska N, Podsiadlowska A, Rybakowska PD, Dey P et al. Interaction between innate immunity and Ro52-induced antibody causes Sjögren’s syndrome-like disorder in mice. Ann Rheum Dis. 2015. doi:2010.1136/annrheumdis-2014-206297.

24.

Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol. 2012;8:522–33.PubMedCrossRef

25.

Kosenda K, Ichii O, Otsuka S, Hashimoto Y, Kon Y. BXSB/MpJ-Yaa mice develop autoimmune dacryoadenitis with the appearance of inflammatory cell marker messenger RNAs in the lacrimal fluid. Clin Exp Ophthalmol. 2013;41:788–97.CrossRef

26.

Gottenberg JE, Ravaud P, Puechal X, Le Guern V, Sibilia J, Goeb V, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial. JAMA. 2014;312:249–58.PubMedCrossRef

27.

Zhu FG, Jiang W, Bhagat L, Wang D, Yu D, Tang JX, et al. A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice. Autoimmunity. 2013;46:419–28.PubMedCrossRef

28.

Stohl W. Future prospects in biologic therapy for systemic lupus erythematosus. Nat Rev Rheumatol. 2013;9:705–20.PubMedCrossRef

29.

Goldberg A, Geppert T, Schiopu E, Frech T, Hsu V, Simms RW, et al. Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014;16:R57.PubMedCentralPubMedCrossRef

30.

Nandula SR, Dey P, Corbin KL, Nunemaker CS, Bagavant H, Deshmukh US. Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling. J Oral Pathol Med. 2013;42:66–72.PubMedCentralPubMedCrossRef

31.

Yin H, Vosters JL, Roescher N, D’Souza A, Kurien BT, Tak PP, et al. Location of immunization and interferon-gamma are central to induction of salivary gland dysfunction in Ro60 peptide immunized model of Sjogren’s syndrome. PLoS One. 2011;6, e18003.PubMedCentralPubMedCrossRef

32.

Vincent FB, Morand EF, Schneider P, Mackay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. 2014;10:365–73.PubMedCrossRef

33.

Jacob CO, Yu N, Guo S, Jacob N, Quinn 3rd WJ, Sindhava V, et al. Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor. Arthritis Rheum. 2013;65:1043–54.PubMedCentralPubMedCrossRef

34.

Jacob CO, Pricop L, Putterman C, Koss MN, Liu Y, Kollaros M, et al. Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF. J Immunol. 2006;177:2671–80.PubMedCentralPubMedCrossRef

35.

Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, Schneider P, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109:59–68.PubMedCentralPubMedCrossRef

36.

Espinosa A, Dardalhon V, Brauner S, Ambrosi A, Higgs R, Quintana FJ, et al. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med. 2009;206:1661–71.PubMedCentralPubMedCrossRef

37.

Boneparth A, Davidson A. B-cell activating factor targeted therapy and lupus. Arthritis Res Ther. 2012;14:S2.PubMedCentralPubMedCrossRef

38.

Ramanujam M, Bethunaickan R, Huang W, Tao H, Madaio MP, Davidson A. Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 mice. Arthritis Rheum. 2010;62:1457–68.PubMedCentralPubMedCrossRef

39.

Pontarini E, Fabris M, Quartuccio L, Cappeletti M, Calcaterra F, Roberto A, et al. Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjogren’s syndrome. Rheumatology (Oxford). 2015. doi: 10.1093.

40.

Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, et al. Efficacy and safety of belimumab in primary Sjogren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74:526–31.PubMedCrossRef

41.

Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;4551109–13.

42.

Lodde BM, Mineshiba F, Kok MR, Wang J, Zheng C, Schmidt M, et al. NOD mouse model for Sjogren’s syndrome: lack of longitudinal stability. Oral Dis. 2006;12:566–72.PubMedCrossRef

43.

Cha S, van Blockland SC, Versnel MA, Homo-Delarche F, Nagashima H, Brayer J, et al. Abnormal organogenesis in salivary gland development may initiate adult onset of autoimmune exocrinopathy. Exp Clin Immunogenet. 2001;18:143–60.PubMedCrossRef

44.

Roescher N, Lodde BM, Vosters JL, Tak PP, Catalan MA, Illei GG, et al. Temporal changes in salivary glands of non-obese diabetic mice as a model for Sjogren’s syndrome. Oral Dis. 2012;18:96–106.PubMedCentralPubMedCrossRef

45.

Cha S, Peck AB, Humphreys-Beher MG. Progress in understanding autoimmune exocrinopathy using the non-obese diabetic mouse: an update. Crit Rev Oral Biol Med. 2002;13:5–16.PubMedCrossRef

46.

Li X, Wu K, Edman M, Schenke-Layland K, MacVeigh-Aloni M, Janga SR, et al. Increased expression of cathepsins and obesity-induced proinflammatory cytokines in lacrimal glands of male NOD mouse. Invest Ophthalmol Vis Sci. 2010;51:5019–29.PubMedCentralPubMedCrossRef

47.

Hamm-Alvarez SF, Janga SR, Edman MC, Madrigal S, Shah M, Frousiakis SE, et al. Tear cathepsin S as a candidate biomarker for Sjogren’s syndrome. Arthritis Rheumatol. 2014;66:1872–81.PubMedCentralPubMedCrossRef

48.

Schenke-Layland K, Xie J, Magnusson M, Angelis E, Li X, Wu K, et al. Lymphocytic infiltration leads to degradation of lacrimal gland extracellular matrix structures in NOD mice exhibiting a Sjogren’s syndrome-like exocrinopathy. Exp Eye Res. 2010;90:223–37.PubMedCentralPubMedCrossRef

49.

Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol. 2005;23:447–85.PubMedCrossRef

50.

Robinson CP, Yamachika S, Bounous DI, Brayer J, Jonsson R, Holmdahl R, et al. A novel NOD-derived murine model of primary Sjogren’s syndrome. Arthritis Rheum. 1998;41:150–6.PubMedCrossRef

51.

Lindqvist AK, Nakken B, Sundler M, Kjellen P, Jonsson R, Holmdahl R, et al. Influence on spontaneous tissue inflammation by the major histocompatibility complex region in the nonobese diabetic mouse. Scand J Immunol. 2005;61:119–27.PubMedCrossRef

52.

Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome. Nat Genet. 2013;45:1284–92.PubMedCrossRef

53.

Robinson CP, Brayer J, Yamachika S, Esch TR, Peck AB, Stewart CA, et al. Transfer of human serum IgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjogren’s syndrome. Proc Natl Acad Sci U S A. 1998;95:7538–43.PubMedCentralPubMedCrossRef

54.

Nakahara M, Nagayama Y, Ichikawa T, Yu L, Eisenbarth GS, Abiru N. The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages. Autoimmunity. 2011;44:504–10.PubMedCrossRef

55.

Ellis JS, Wan X, Braley-Mullen H. Transient depletion of CD4+ CD25+ regulatory T cells results in multiple autoimmune diseases in wild-type and B-cell-deficient NOD mice. Immunology. 2013;139:179–86.PubMedCentralPubMedCrossRef

56.

Cha S, Nagashima H, Brown VB, Peck AB, Humphreys-Beher MG. Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjogren’s syndrome) on a healthy murine background. Arthritis Rheum. 2002;46:1390–8.PubMedCrossRef

57.

Delaleu N, Nguyen CQ, Tekle KM, Jonsson R, Peck AB. Transcriptional landscapes of emerging autoimmunity: transient aberrations in the targeted tissue’s extracellular milieu precede immune responses in Sjögren’s syndrome. Arthritis Res Ther. 2013;15:R174.PubMedCentralPubMedCrossRef

58.

Jonsson R, Theander E, Sjostrom B, Brokstad K, Henriksson G. Autoantibodies present before symptom onset in primary Sjogren syndrome. JAMA. 2013;310:1854–5.PubMedCrossRef

59.

Horvath S, Nazmul-Hossain AN, Pollard RP, Kroese FG, Vissink A, Kallenberg CG, et al. Systems analysis of primary Sjogren’s syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model. Arthritis Res Ther. 2012;14:R238.PubMedCentralPubMedCrossRef

60.

Ronnblom L, Eloranta ML. The interferon signature in autoimmune diseases. Curr Opin Rheumatol. 2013;25:248–53.PubMedCrossRef

61.

Peck AB, Nguyen CQ. Transcriptome analysis of the interferon-signature defining the autoimmune process of Sjogren’s syndrome. Scand J Immunol. 2012;76:237–45.PubMedCentralPubMedCrossRef

62.

Nguyen CQ, Peck AB. The interferon-signature of Sjogren’s syndrome: how unique biomarkers can identify underlying inflammatory and immunopathological mechanisms of specific diseases. Front Immunol. 2013;4:142.PubMedCentralPubMedCrossRef

63.

Szczerba BM, Rybakowska PD, Dey P, Payerhin KM, Peck AB, Bagavant H, et al. Type I interferon receptor deficiency prevents murine Sjogren’s syndrome. J Dent Res. 2013;92:444–9.PubMedCentralPubMedCrossRef

64.

Cha S, Brayer J, Gao J, Brown V, Killedar S, Yasunari U, et al. A dual role for interferon-gamma in the pathogenesis of Sjogren’s syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse. Scand J Immunol. 2004;60:552–65.PubMedCrossRef

65.

Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R, et al. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren’s syndrome. Ann Rheum Dis. 2011;70:1363–8.PubMedCentralPubMedCrossRef

66.

Gatumu MK, Skarstein K, Papandile A, Browning JL, Fava RA, Bolstad AI. Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjogren’s syndrome in salivary glands of non-obese diabetic mice. Arthritis Res Ther. 2009;11:R24.PubMedCentralPubMedCrossRef

67.

Fava RA, Kennedy SM, Wood SG, Bolstad AI, Bienkowska J, Papandile A, et al. Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjogren’s syndrome. Arthritis Res Ther. 2011;13:R182.PubMedCentralPubMedCrossRef

68.

Roescher N, Vosters JL, Lai Z, Uede T, Tak PP, Chiorini JA. Local administration of soluble CD40:Fc to the salivary glands of non-obese diabetic mice does not ameliorate autoimmune inflammation. PLoS One. 2012;7, e51375.PubMedCentralPubMedCrossRef

69.

Yin H, Nguyen CQ, Samuni Y, Uede T, Peck AB, Chiorini JA. Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL/6.NOD-Aec1Aec2 mouse model of Sjogren’s syndrome. Arthritis Res Ther. 2012;14:R40.PubMedCentralPubMedCrossRef

70.

Nguyen CQ, Yin H, Lee BH, Chiorini JA, Peck AB. IL17: potential therapeutic target in Sjogren’s syndrome using adenovirus-mediated gene transfer. Lab Invest. 2011;91:54–62.PubMedCentralPubMedCrossRef

71.

Lee BH, Carcamo WC, Chiorini JA, Peck AB, Nguyen CQ. Gene therapy using IL-27 ameliorates Sjogren’s syndrome-like autoimmune exocrinopathy. Arthritis Res Ther. 2012;14:R172.PubMedCentralPubMedCrossRef

72.

Jin JO, Kawai T, Cha S, Yu Q. Interleukin-7 enhances the Th1 response to promote the development of Sjögren’s syndrome-like autoimmune exocrinopathy in mice. Arthritis Rheum. 2013;65:2132–42.PubMedCrossRef

73.

Bikker A, Kruize AA, van der Wurff-Jacobs KM, Peters RP, Kleinjan M, Redegeld F, et al. Interleukin-7 and Toll-like receptor 7 induce synergistic B cell and T cell activation. PLoS One. 2014;9, e94756.PubMedCentralPubMedCrossRef

74.

Shi H, Yu CQ, Xie LS, Wang ZJ, Zhang P, Zheng LY. Activation of TLR9-dependent p38MAPK pathway in the pathogenesis of primary Sjogren’s syndrome in NOD/Ltj mouse. J Oral Pathol Med. 2014. doi:10.1111/jop.12209.

75.

Gilboa-Geffen A, Wolf Y, Hanin G, Melamed-Book N, Pick M, Bennett ER, et al. Activation of the alternative NFkappaB pathway improves disease symptoms in a model of Sjogren’s syndrome. PLoS One. 2011;6, e28727.PubMedCentralPubMedCrossRef

76.

Wu Q, Yang Q, Lourenco E, Sun H, Zhang Y. Interferon-lambda1 induces peripheral blood mononuclear cell-derived chemokines secretion in patients with systemic lupus erythematosus: its correlation with disease activity. Arthritis Res Ther. 2011;13:R88.PubMedCentralPubMedCrossRef

77.

Puig M, Tosh KW, Schramm LM, Grajkowska LT, Kirschman KD, Tami C, et al. TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo. J Leukoc Biol. 2012;91:147–58.PubMedCrossRef

Title: The clinical relevance of animal models in Sjögren’s syndrome: the interferon signature from mouse to man
Authors: Naomi I Maria
Petra Vogelsang
Marjan A Versnel
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2015
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-015-0678-2

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2015

IL-17 sequestration via salivary gland gene therapy in a mouse model of Sjogren’s syndrome suppresses disease-associated expression of the putative autoantigen Klk1b22

IL2RA is associated with persistence of rheumatoid arthritis

Mitochondrial respiration and redox coupling in articular chondrocytes

Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy

p21 deficiency is susceptible to osteoarthritis through STAT3 phosphorylation

Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials