Grundlagen der Immunologie

Transkript

1 Grundlagen der Immunologie 21. Vorlesung: Suppression der Immunantwort Zoltán Kellermayer

2 Wichtige Schritte der Immunantwort Erkennung Aktivierung Differenzierung Effektor Funktion Gedächtnis Suppression

3 1. Antigen als Hauptregulator Aktiviert T- und B-Zellen Antigen Art, Dosis und Lokalisierung beeinflussen die Immunantwort T H 1 vs T H 2 Elimination/Entfernung des Antigens stoppt weitere Aktivierung

4 1. Antigen als Hauptregulator

5 322Notwendigkeit Chapter 15 Immunologic Toleranceder and Autoimmunity 2. Co-Stimulation ago and was soon tions of populatio inhibitory signaling removing B7 on AC immune response T cell CTLA-4 B7 interest in the to of the dominant 1970s. However, t history, mainly be tions of suppresso AC were largely unsu idea had an impr CD28 T cell CD28 B7 better approaches tions of T lympho Signal block These cells are cal CTLA-4 inhibition of T cell erties and function activation Regulatory T ly whose function i maintain self-tole Regulatory T cell CD4+ regulatory T Reduced B7 interleukin-2 (IL-2 tion factor called costimulation ily of transcription inhibition of T cell and function of th activation with spontaneous Fig 15-6 in the foxp3 gene FIGURE 15-6 Mechanisms of action of CTLA-4. A, Engagement associated Abbas, Lichtmann and Cellular Molecular Immunology. 8th edition. Copyright 2015 byfurther Saunders, andisease imprint of Elsevier, Inc of illai. CTLA-4 on aand T cell may deliver inhibitory signals that terminate A Cell intrinsic B Blocking and

6 ailable to CD28 and blocking T cell activation. CTLA-4 mediated tion by regulatory T cells is a cell-extrinsic action of this inhibitory tor (since the responding T cells are suppressed by another cell). in the FOX3 gene and is associated with deficienc regulatory T cells. These observations have establis 3. Regulatorische T-Zellen Thymus Lymph node FOX3 FOX3 Recognition of self antigen in thymus Recognition of antigen in peripheral tissues Regulatory T cells Inhibition of T cell responses DC Naive T cell Effector T cells Inhibition of other cells NK cell B cell Fig 15-7 FIGURE 15-7 Regulatory T cells. Regulatory T cells are generated by self antigen recognition in the thymus (sometimes called natural regulatoryimmunology. cells) and (probably a lesser extent) bysaunders, antigen recognition Abbas, Lichtmann and illai. Cellular and Molecular 8th edition.tocopyright 2015 by an imprint of Elsevier, Inc

7 3. Regulatorische T-Zellen Abbas, Lichtmann and illai. Cellular and Molecular Immunology. 8 th edition. Copyright 2015 by Saunders, an imprint of Elsevier, Inc

8 3. Regulatorische T-Zellen hänotyp: CD3 + CD4 + CD25 + Fox3 + Fox3 Mutation: IEX Syndrom (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) Ursprung: Thymus (natürlich) oder eripherie (induziert) Suppressionsmechanismen: Zytokinsekretion: IL-10, TGFβ IL-10 -/- Mäuse: Colitis Block der Co-Stimulation durch CTLA-4 IL-2 Verbrauch durch IL-2Rα (CD25, hoch-affiner IL-2R) Abbas, Lichtmann and illai. Cellular and Molecular Immunology. 8 th edition. Copyright 2015 by Saunders, an imprint of Elsevier, Inc

9 4. Suppression durch Antikörperfeedback A BCR signaling leads to I 3 formation, which binds other signaling molecules, leading to activation olyvalent antigen B Fc receptor associated phosphatase, SHI, converts I 3 to I 2 in B cell receptor complex, blocking downstream signaling olyvalent antigen Antibody-antigen complex FcγRIIb Syk I 2 I 3 I3K BTK, LCγ, DK1 B cell activation I 2 I 3 Block in B cell receptor signaling, no activation Fig FIGURE Regulation of B cell activation by FcγRIIB. A, Antigen-antibody complexes can simultaneously bind to membrane Ig (through antigen) and the FcγRIIB receptor through the Fc portion of the antibody. B, As a consequence of this simultaneous ligation Abbas, Lichtmann and illai. Cellular and Molecular Immunology. 8 th of receptors, phosphatases associated with the edition. Copyright 2015 by Saunders, an imprint of Elsevier, Inc SHI

10 4. Suppression durch Antikörperfeedback Abbas, Lichtmann and illai. Cellular and Molecular Immunology. 8 th edition. Copyright 2015 by Saunders, an imprint of Elsevier, Inc Der hohe Antikörperspiegel blockt weiter B-Zell Aktivierung IgG + Antigen Immunkomplex inhibiert B-Zell function durch binding zu FcγRIIb (IgM + Antigen Immunkomplex fördert weitere B-Zell Aktivierung!)

11 5. Anti-idiotyp Antikörper Netzwerk Hypothese (Niels Jerne): Suppression durch Antikörper

12 5. Anti-idiotyp Antikörper Funktion: Suppression von B- und T-Zellen Bildung des funktionellen Gedächtnis Biologisches mimicry (insulin anti-insulin anti-anti-insulin)