Keine Immunantwort, Tolerant oder Gendefekt?

Präsentation zum Thema: "Keine Immunantwort, Tolerant oder Gendefekt?"—  Präsentation transkript:

1 Keine Immunantwort, Tolerant oder Gendefekt?
Einführungsvorlesung 1 Themenblock 8 Beda M. Stadler Diese Folien stehen auch als PPT Files zum download bereit unter: Einige der Folien werden als Illustration verwendet und sind nicht Lernstoff. Sie sind so wie hier entweder orange unterlegt oder umrandet EV1

2 KV1 im Überblick Wiederholung einiger Grundlagen Keine Immunantwort
Umgehung der Immunantwort Toleranz Immunopathologie Immunmangel Erkrankungen EV1

3 Aktivierung durch fremd
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4 Der immunologische Reissverschluss
Kofaktoren Adhäsionsmoleküle Integrine / Selektine Zytokine Zytokinrezeptoren EV1

5 Immunantwort und Zytokine
IL-1, IL-2, IL-4, IL-5, IL-6, IL-8 Familie, IL-10, IL-12, IFN-g, TNF, TGF b, GM-CSF, EPO EV1

6 Klonale Selektion die Grundlage für Spezifität und Gedächnis
Lokale Antwort Proliferation EV1

7 und falls das ausbleibt?
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8 2. Keine Immunantwort Resistenz
“Loch” im Immunrepertoire (Hepatitis B?) Antigen Shift/Drift (Influenza Antigene (HA,NA)…) Antigen Variation (Trypanosomen, Salmonellen…) Latenz (Herpes simplex, EBV (Burkitt’s Lymphom)…) Versteckt in Immunzellen (M. tuberculosis, L. monocytogenes, C. burnetti…) Alter (Säugling / Senioren) EV1

9 Resistenz gegen HIV

10 Antigen Variation: HIV-1 env
Pat.4 Pat.2 HIV1U35926 Pat.7 Pat.5 HIVU95460 HIV1U36148 Pat.6 HIV1U36073 HIV1U36015 HIV1U35980 Pat.8 Pat.3 Pat.1 10% EV1

11 3. Umgehung der Immunantwort: Virale Strategien
Hemmung der humoralen Immunantwort viral codierte Fc, oder C Rezeptoren (H. simplex) C Kontrollproteine (Vaccinia) Hemmung der Entzündungsreaktion viral codierte Zytokine oder -Rezeptoren (Cytomeg.) Adäsionsmoleküle (EBV) Hemmung der Antigen Prozessierung und Präsentation MHC Klasse I Expression, TAP Transport (H. simplex) Immunsuppression viral codiertes IL-10 Homolog (EBV) EV1

12 4. Toleranz Toleranz = keine Immunantwort eines Individuums auf ein bestimmtes Antigen mögliche Mechanismen Klonale Deletion Blockierung der Ag Rezeptoren Suppressor Zell Aktivität EV1

13 4. Arten der Toleranz Zentrale Toleranz Periphere Toleranz
B Zell Toleranz T Zell Toleranz Periphere Toleranz Ignoranz Immun-privilegierte Orte Immun-Suppression Erworbene Toleranz EV1

14 Klonale Deletion positiv/negativ Selektion Eigentoleranz Zelltod
eigen Proteine unreife T Zellen im Thymus positiv/negativ Selektion erkennen / binden = Apopthose Eigentoleranz Zelltod EV1

15 5. Immunopathologie Überschiessende Immunantwort
Überempfindlichkeit (Typ I-IV) Fälschliche Erkennung von Eigenantigen Autoimmunität Normale aber medizinisch unwillkommene Immunantwort erworbene Immunmangel Syndrome Ineffiziente Immunantwort wegen Gendefekten angeborene Immunmangel Syndrome EV1

16 5.1 Überschiessende Immunantwort
Überempfindlichkeit (Typ I-IV) Type I: Immediate hypersensitivity Type II: Cytotoxic hypersensitivity Type III: Immune complex hypersensitivity Type IV: Cell-mediated Hypersensitivity (Delayed Hypersensitivity) Siehe kurze Zusammenfassung in “Notizen” des ppt Files Hypersensitivity (a)                    Hypersensitivities are inappropriate immune responses to foreign material that is either within or in contact with the body (b)                    Essentially, the body mounts a sometimes dramatic immune response against an otherwise harmless, or at least less-harmful substance, thereby doing more harm to the body in the course of the immune response than might have the original allergen (c)                    Hypersensitivities may be divided into four types: (i)                      Type I: Immediate hypersensitivity (ii)                    Type II: Cytotoxic hypersensitivity (iii)                   Type III: Immune complex hypersensitivity (iv)                  Type IV: Cell-mediated Hypersensitivity (Delayed Hypersensitivity) (d)                    [hypersensitivity reactions (3) Anaphylaxis (anaphylactic shock) (a)                    Anaphylaxis is a general term used to describe the detrimental effect(s) associated with hypersensitivities (b)                    Anaphylaxis may be localized (annoying but not life threatening) or generalized (systemic and life threatening) (c)                    Anaphylactic shock is a generalized anaphylaxis characterized by a significant, life-threatening drop in blood pressure (d)                    [hypersensitivity reactions ] (4) Prophylaxis (a)                    Prophylaxis refers to the protective effects associated with an immune response (b)                    [prophylaxis ] (5) Immediate hypersensitivity (type I hypersensitivity; allergy) (a)                    Immediate hypersensitivity occurs following the production of IgE antibodies against typically otherwise-harmless foreign antigens (which are known as allergens) (b)                    Type I sensitivities are allergies (c)                    [immediate hypersensitivity, allergy, reagin and (anaphylaxis OR hypersensitivity) ] (6) Allergen (a)                    An allergen is an antigen, the exposure to which results in a hypersensitivity reaction (b)                    Note that allergens are non-self (i.e., foreign) antigens (c)                    Since hypersensitivity (e.g., immediate hypersensitivity) is the result of a kind of specific immunity, an individual must be exposed to the allergen at least once (to sensitize the individual by inducing B cells that produce specific IgE antibodies) before exposures (subsequently) result in an allergic response (d)                    [allergen ] (7) Histamine (degranulation) (a)                    The signs and symptoms of immediate hypersensitivity are a consequence of the release of histamine and other chemical mediators from body cells (b)                    In the case of histamine, release occurs when IgE antibodies bound to basophils or mast cells bind to allergens (c)                    Histamine is found intracellularly within vesicles (the granules within these cells) and degranulation is the term used to describe the release of histamine via the fusion of these vesicles with the basophil or mast-cell plasma membranes (d)                    (in addition to histamine, prostoglandins and leukotrienes are reaction mediators that play important roles in mediating airway constriction) (e)                    See Figure 18.1, The mechanism of immediate (Type I) hypersensitivity, or anaphylactic hypersensitivity (f)                      [histamine, degranulation, degranulation and histamine ] (8) Cytotoxic hypersensitivity (type II hypersensitivity) (a)                    The term cytotoxic in cytotoxic hypersensitivity refers to host-cell damage caused by an over-zealous immune response (b)                    Recall that a normal aspect of both specific and non-specific immune responses is extracellular killing, particularly the killing of host cells that are thought to be pathogen-infected (c)                    Cytotoxic hypersensitivities are mediated by the binding of antibody's to body tissues which leads to the lysis of cells (either via ADCC or via the activation of complement) (d)                    The negative consequences of not correctly matching blood types for transfusions are examples of the damaging effects of cytotoxic hypersensitivities (erythroblastosis fetalis is a related, additional example of a cytotoxic hypersensitivity) (e)                    [cytotoxic hypersensitivity, type II hypersensitivity ] (9) Immune complex hypersensitivity (type III hypersensitivity) (a)                    One role of phagocytic cells (macrophages) is the removal of debris from body tissues (e.g., blood) and one kind of debris that results from specific immune reactions (specifically humoral immunity) are large complexes of antibody and antigen (b)                    These complexes form as a consequence of the multivalent nature of both antibodies and antigens (i.e., an individual antibody molecule can bind to more than one epitope and thus, potentially, more than one antigen, while a large antigen or organism can display large numbers of individual epitopes) (c)                    The phrase immune complex as in immune complex hypersensitivity refers to these antigen-antibody complexes, and type III hypersensitivity refers to an immune response that produces an excess of these immune complexes, particularly faster than macrophages (and the liver) can remove them (d)                    The accumulation of these immune complexes can result in their depositing in otherwise healthy tissues followed by a damaging hypersensitivity immune response in those tissues to the not-engulfed immune complexes (e)                    Certain autoimmune diseases (rheumatoid arthritis and lupus) are consequences of type III hypersensitivities as well as the serum sickness that results from a second exposure to an antitoxin (f)                      [immune complex hypersensitivity ] (10) Cell-mediated hypersensitivity (type IV hypersensitivity, delayed hypersensitivity) (a)                    Cell-mediated hypersensitivity is mediated by T lymphocytes (rather than by antibodies) (b)                    Cell-mediated hypersensitivity is also known as delayed hypersensitivity because the time between exposure to the eliciting antigen and the occurrence of symptoms can take many hours (c)                    A common example of type IV hypersensitivity is poison ivy sensitivity (where, of course, the rash appears only after many hours—e.g., next day—following exposure to the poison ivy urushiol, the triggering oil) (d)                    [cell-mediated hypersensitivity, delayed hypersensitivity ] EV1

17 5.2 Fälschliche Erkennung von Eigenantigen Ursachen für Autoimmunität I
Toleranzverlust gegen ein Antigen Erkennen von verstecktem (hidden) Autoantigen “Priviledged Immunity” Entstehen von neuen antigenen Determinanten Neoantigene Molekulares Mimikry Virus Infektion: Veränderung der Zelloberfläche Kreuzreaktion mit Xenoantigenen (Mikroorganismen) Hapten Bindung an Zellantigene Versagen der Ts Zell Funktion EV1

18 Ursachen für Autoimmunität II
Hormonelle Faktoren EV1

19 Ursachen für Autoimmunität III
Genetische Faktoren SNP’s (Alloreaktion?) Mikrochimärismus und Sclerodermie 1500 1000 Resampled frequency 500 3.564 (p < ) -1 1 2 3 4 D mean coding SNPs EV1

20 ... und weitere Modelle Zytokin Defekte B Zell Defekte EV1

21 Ursachen für Autoimmunität (Zusammenfassung)
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22 6. Immunmangel Erkrankungen
6.1 Normale aber medizinisch unwillkommene Immunantwort erworbene Immunmangel Syndrome 6.2 Ineffiziente Immunantwort angeborene Immunmangel Syndrome EV1

23 Der Immunstatus I (zellulär)
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24 Der Immunstatus II (humoral)
Normal Serumwerte 1 IU IgE = 2.4 ng/ml EV1

25 6.1 Erwobener Immunmangel sekundäre Immundefizienz
gewöhnlich nach Immunsuppression Chemotherapie (Zytotoxität für T Zellen) Strahlentherapie viralem Infekt (AIDS) Tumor Erkrankung T Zell Defizienz durch Protein Unterenährung Verbrennungen – Immunoglobulin Verlust EV1

26 HIV (siehe Basislehrbuch/Fall)
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27 Transiente Immundefizienz des Neugeborenen
IgM 100 mütterliches IgG IgG % des Erwachsenen Ig Spiegel IgA -6 -3 Geburt 3 9 1 3 5 Monate Jahre EV1

28 Alter und Immunsystem anfälliger für Infektionen, Krebs und Autoimmunerkrankungen Abnahme der B Zell Aktivität geringere Impfantwort aber mehr Autoantikörper Abfall der T Zell Funktionalität (Atrophie des Thymus, maximal während Pubertät ~70 g Abnahme bis zu 3 g im Alter) EV1

29 Überblick 6.2 angeborene Immunmangel Syndrome
B-Zell Mangel T- & B-Zell Mangel Thymus Aplasie Phagozytose Mangel Komplement Mangel EV1

30 Überblick Lymphozytendefekte
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31 X-linked Immunmangel EV1

32 Molekulare Grundlage für XLA
EV1 btk=Bruton's tyrosine kinase

33 Selektiver IgA Mangel EV1

34 Hyper IgM Syndrom EV1

35 DiGeorge Syndrom Congenitale Thymus Aplasie
(22q11.2 Deletion mit vielen Symptomen) characteristische Gesichtzüge Athymic (nude) mouse. EV1

36 Severe Combined Immunodeficiency Diseases (SCID)
Weitere Gendefekte (die nächsten drei Folien als Illustration) Purin Stoffwechsel (ADA) Rekombination (RAG1/RAG2) Interleukin-2 Rezeptor EV1

37 Purin Katabolismus Pathway
ADA Mangel ADENOSINE INOSINE HYPOXANTHINE XANTHINE URIC ACID GUANOSINE GUANINE Purin Katabolismus Pathway Adenosine Deaminase Purine Nucleoside Phosphorylase Xanthine Oxidase Guanase EV1

38 Severe Combined Immunodeficiency Diseases (SCID)
RAG-1 and RAG-2 (Recombinations Aktivierungs Gene) Critical for development of both T and B cells Need to be expressed together in the precursor cell EV1

39 IL-2 R: gemeinsame gc-Kette
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40 Phagozytose Dysfunktion
EV1

41 Chronische Granulomatose
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42 Komplement Mangel EV1

43 EV1 im Überblick Keine Immunantwort, Tolerant oder Gendefekt?
Strategien von Mikroorganismen Toleranz Hypothesen Immunopathologie überschiessende Immunantwort Überempfindlichkeit (Typ I-IV) fälschliche Erkennung von Eigenantigen Autoimmunität Normale aber medizinisch unwillkommene Immunantwort erworbene Immunmangel Syndrome Ineffiziente Immunantwort wegen Gendefekten angeborene Immunmangel Syndrome EV1