zurück zur Startseite
Zentrale Tel.: 06221-560

 

 

The role of extracellular vesicles in the pathogenesis of autoimmune diseases

The investigation of extracellular vesicle (EV) biology is an innovative and rapidly growing research field. EVs are released from cells after activation or apoptosis induction. To date, two main forms of EVs can be discriminated:

Microvesicles represent large EVs (200-1000nm) released from the outer cellular membrane. As we have shown previously, these vesicles are mostly released after apoptosis induction.

Exosomes are released from an intracellular compartment, the multivesicular body. These vesicles are smaller in size (50-100nm) and are mainly released after cellular activation.

During the last years, we intensively studied EV biology. We and others demonstrated that EVs are important players in the regulation of immune responses. Further, a cell-to-cell transfer of genetic information by EVs has been demonstrated.

In systemic lupus erythemtosus (SLE) a dysregulated accumulation of apoptotic cells and EVs seems to be a central pathogenic feature. We have systematically characterized the release mechanisms, the morphology and molecular composition (e.g. proteins, DNA, RNA, glycokalyx) of EVs. Importantly, we demonstrated an accumulation of SLE-specific autoantigens within EVs.

The cargo of distinct EVs (exosomes/microvesicles) is tightly regulated and we have observed a directed transport of proteins and nuclear autoantigens into EVs. EVs have also been shown to influence the immunological function of a variety of responder cells: we have shown that EVs can initiate a type-1 interferon response (the marker cytokine of SLE) and an alternative maturation of dendritic cells. Upon stimulation with EVs dendritic cells from SLE patients showed a rather inflammatory phenotype when compared to normal healthy donor cells. This phenotype strictly correlated to the disease activity of the respective patient.

 

Publications:

1.     Classen L, Tykocinski LO, Wiedmann F, Birr C, Schiller P, Tucher C, Krienke S, Raab MS, Blank N, Lorenz HM and Schiller M. Extracellular vesicles mediate intercellular communication: Transfer of functionally active microRNAs by microvesicles into phagocytes. Eur J Immunol. 2017 Sep;47(9):1535-1549.

2.     Shen G, Krienke S, Schiller P, Nießen A, Neu S, Eckstein V, Schiller M, Lorenz HM, Tykocinski LO. Microvesicles released by apoptotic human neutrophils suppress proliferation and IL-2/IL-2 receptor expression of resting T helper cells. Eur J Immunol. 2017 May;47(5):900-910.

3.     Niessen A, Heyder P, Krienke S, Blank N, Tykocinski LO, Lorenz HM and Schiller M. Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response. J Cell Sci. 2015 Jul 15;128(14):2443-53.

4.      Franz S, Munoz LE, Heyder P, Herrmann M, Schiller M. Unconventional apoptosis of polymorphonuclear neutrophils (PMN): Staurosporine delays exposure of phosphatidylserine and prevents phagocytosis by MΦ-2 macrophages of PMN. Clin Exp Immunol. 2015 Jan;179(1):75-84.

5.     Schiller M, Heyder P, Ziegler S, Niessen A, Claßen L, Lauffer A and Lorenz HM. During apoptosis HMGB1 is translocated into apoptotic cell-derived membraneous vesicles. Autoimmunity. 2013 Aug;46(5):342-6.

6.      Parcina M, Miranda-Garcia MA, Durlanik S, Ziegler S, Over B, Georg P, Foermer S, Ammann S, Hilmi D, Weber KJ, Schiller M, Heeg K, Schneider-Brachert W, Götz F and Bekeredjian-Ding I. Aberrant activation of plasmacytoid dendritic cells de-regulates the B cell response in Staphylococcus aureus infection. J Immunol. 2013 Feb 15;190(4):1591-602.

7.      Fehr EM, Spoerl S, Heyder P, Herrmann M, Bekeredjian-Ding I, Blank N, Lorenz HM and Schiller M. Apoptotic-cell-derived membrane vesicles induce an alternative maturation of human dendritic cells which is disturbed in SLE. J Autoimmun. 2013 Feb;40:86-95.

8.      Sarter K, Janko C, Andre S, Munoz LE, Schorn C, Winkler S, Rech J, Kaltner H, Lorenz HM, Schiller M, Andreoli L, Manfredi AA, Isenberg DA, Schett G, Herrmann M, and Gabius HJ. Autoantibodies against galectins are associated with antiphospholipid syndrome in patients with systemic lupus erythematosus. Glycobiology, 2013 Jan;23(1):12-22.

9.      Schiller M, Parcina M, Heyder P, Foerme S, Ostrop J, Leo A, Heeg K, Herrmann M, Lorenz HM, Bekeredjian-Ding I. Induction of type I interferon is a physiological immune reaction to apoptotic cell-derived membrane microparticles. J Immunol. 2012 Aug 15;189(4):1747-56. Epub 2012 Jul 11.

10.    Janko C, André S, Munoz LE, Briand JP, Schorn C, Winkler S, Schiller M, Andreoli L, Manfredi AA, Isenberg DA, Schett G, Gabius HJ, Muller S and Herrmann M. Autoantibodies against galectin-2 peptides as biomarkers for the antiphospholipid syndrome. Lupus. 2012;21(7):781-783.

11.    Bilyy RO, Shkandina T, Tomin A, Muñoz LE, Franz S, Antonyuk V, Kit YY, Zirngibl M, Fürnrohr BG, Janko C, Lauber K, Schiller M, Schett G, Stoika RS, Herrmann M. Macrophages discriminate glycosylation patterns of apoptotic cell-derived microparticles. J Biol Chem. 2012 Jan 2;287(1):496-503. Epub 2011 Nov 10.

12.    Feldmeyer N, Wabnitz G, Leicht S, Luckner-Minden C, Schiller M, Franz T, Conradi R, Kropf P, Müller I, Ho AD, Samstag Y, Munder M. Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes. Int Immunol. 2012 May;24(5):303-13. Epub 2012 Feb 16.

13.    Rau M, Schiller M, Krienke S, Heyder P, Lorenz H, Blank N. Clinical manifestations but not cytokine profiles differentiate adult-onset Still's disease and sepsis. J Rheumatol. 2010 Nov;37(11):2369-76. Epub 2010 Sep 1.

14.    Meesmann HM, Fehr EM, Kierschke S, Herrmann M, Bilyy R, Heyder P, Blank N, Krienke S, Lorenz HM, Schiller M. Decrease of sialic acid residues as an eat-me signal on the surface of apoptotic lymphocytes. J Cell Sci. 2010 Oct 1;123(Pt 19):3347-56. Epub 2010 Sep 7

15.    Luckner-Minden C, Fischer I, Langhans CD, Schiller M, Kropf P, Müller I, Hohlfeld JM, Ho AD, Munder M. Human eosinophil granulocytes do not express the enzyme arginase. J Leukoc Biol. 2010 Jun;87(6):1125-32. Epub 2010 Mar 3.

16.    Seehaus S, Shahzad K, Kashif M, Vinnikov IA, Schiller M, Wang H, Madhusudhan T, Eckstein V, Bierhaus A, Bea F, Blessing E, Weiler H, Frommhold D, Nawroth PP, Isermann B. Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholipase-Cbeta-, phosphoinositide 3-kinase-, and nitric oxide-dependent signaling in monocytes and promotes plaque stability. Circulation. 2009 Sep 1;120(9):774-84. Epub 2009 Aug 17.

17.    Parcina M, Schiller M, Gierschke A, Heeg K, Bekeredjian-Ding I. PDC expressing CD36, CD61 and IL-10 may contribute to propagation of immune tolerance. Autoimmunity. 2009 May;42(4):353-5.

18.    Heyder P, Bekeredjian-Ding I, Krienke S, Lorenz HM, Schiller M. Cells induced to undergo apo in the presence of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone stimulate Mo derived phagocytes to secrete proinflammatory cytokines. Autoimmunity. 2009 May;42(4):328-30.

19.    Fehr EM, Kierschke S, Max R, Gerber A, Lorenz HM, Schiller M. Apoptotic cell-derived membrane vesicles induce CD83 expression on human mdDC. Autoimmunity. 2009 May;42(4):322-4.

20.    Blank N, Max R, Schiller M, Briem S, Lorenz HM. Safety of combination therapy with rituximab and etanercept for patients with rheumatoid arthritis. Rheumatology (Oxford). 2009 Apr;48(4):440-1. Epub 2009 Jan 19.

21.    Bekeredjian-Ding I, Doster A, Schiller M, Heyder P, Lorenz HM, Schraven B, Bommhardt U, Heeg K. TLR9-activating DNA up-regulates ZAP70 via sustained PKB induction in IgM+ B cells. J Immunol. 2008 Dec 15;181(12):8267-77.

22.    Kriegel MA, Adam-Klages S, Gabler C, Blank N, Schiller M, Scheidig C, Kalden JR, Lorenz HM. Anti-HLA-DR-triggered monocytes mediate in vitro T cell anergy. Int Immunol. 2008 Apr;20(4):601-13. Epub 2008 Feb 28.

23.    Schiller M, Franz S, Heyder P, Voll RE, Gaipl US, Lorenz HM, Kalden JR, Herrmann M. Hypothesis: human serum-borne albumin bound lipids promote cellular survival after apoptosis induction by a variety of stimuli. Apoptosis. 2008 Feb;13(2):319-28.

24.    Schiller M, Bekeredjian-Ding I, Heyder P, Blank N, Ho AD, Lorenz HM. Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis. Cell Death Differ. 2008 Jan;15(1):183-91. Epub 2007 Oct 12.

25.    Blank N, Schiller M, Krienke S, Busse F, Schätz B, Ho AD, Kalden JR, Lorenz HM. Atorvastatin inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme A reductase without decreasing cholesterol synthesis. J Immunol. 2007 Sep 15;179(6):3613-21.

26.    Schiller M, Blank N, Franz S, Gaipl US, Ho AD, Lorenz HM. Apoptotic bodies derived from apoptotic lymphoblasts contain a distinct pattern of antigens. Autoimmunity. 2007 Jun;40(4):340-1.

27.    Heyder P, Bekeredjian-Ding I, Parcina M, Blank N, Ho AD, Herrmann M, Lorenz HM, Heeg K, Schiller M. Purified apoptotic bodies stimulate plasmacytoid dendritic cells to produce IFN-alpha. Autoimmunity. 2007 Jun;40(4):331-2.

28.    Blank N, Schiller M, Krienke S, Wabnitz G, Ho AD, Lorenz HM. Cholera toxin binds to lipid rafts but has a limited specificity for ganglioside GM1. Immunol Cell Biol. 2007 Jul;85(5):378-82. Epub 2007 Feb 27.

29.    Kriegel MA, Tretter T, Blank N, Schiller M, Gabler C, Winkler S, Kalden JR, Lorenz HM. Interleukin-4 supports interleukin-12-induced proliferation and interferon-gamma secretion in human activated lymphoblasts and T helper type 1 cells. Immunology. 2006 Sep;119(1):43-53. Epub 2006 Jun 6.

30.    Schiller M, Blank N, Heyder P, Herrmann M, Gaipl US, Kalden JR, Lorenz HM. Induction of apoptosis by spermine-metabolites in primary human blood cells and various tumor cell lines. Apoptosis. 2005 Oct;10(5):1151-62.

31.    Blank N, Schiller M, Gabler C, Kalden JR, Lorenz HM. Inhibition of sphingolipid synthesis impairs cellular activation, cytokine production and proliferation in human lymphocytes. Biochem Pharmacol. 2005 Dec 19;71(1-2):126-35. Epub 2005 Nov 2.

32.    Gabler C, Blank N, Hieronymus T, Schiller M, Berden JH, Kalden JR, Lorenz HM. Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis. Ann Rheum Dis. 2004 Sep;63(9):1135-44.

33.    Blank N, Gabler C, Schiller M, Kriegel M, Kalden JR, Lorenz HM. A fast, simple and sensitive method for the detection and quantification of detergent-resistant membranes. J Immunol Methods. 2002 Dec 20;271(1-2):25-35.

34.    Stockmeyer B, Schiller M, Repp R, Lorenz HM, Kalden JR, Gramatzki M, Valerius T. Enhanced killing of B lymphoma cells by granulocyte colony-stimulating factor-primed effector cells and Hu1D10--a humanized human leucocyte antigen DR antibody. Br J Haematol. 2002 Sep;118(4):959-67.

Print Diese Seite per E-Mail weiterempfehlen