Cellular Immunology and Immune Regulation Department of Immunology and Transplantation Biomedical Research Foundation Academy of Athens pverginisbioacademygr Ανοσολογικη ανοχη και αυτοανοσια ID: 1047742
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1. Verginis PanosLaboratory of Cellular Immunology and Immune RegulationDepartment of Immunology and TransplantationBiomedical Research Foundation, Academy of Athenspverginis@bioacademy.gr Ανοσολογική ανοχή και αυτοανοσία
2. Autoimmunity is the failure of an organism in recognizing its own constituent parts as non self, which allows an immune response against its own cells and tissues. Any disease that results from such aberrant immune response is termed autoimmune disease. Horror autotoxicus: the horror of self-toxicityA term coined by the German immunologist Paul Ehrlich (1854-1915) to describe the body’s innate aversion to immunological self-destructionAutoimmunity is……
3. GenesEnvironmentImmune regulationAutoimmune diseasesAutoimmune diseases are multifactorial
4. Genetic basis of autoimmunity Multiple genes are associated with autoimmunityMost human autoimmune diseases are multigenicSingle gene defects reveal pathways of self-tolerance and why it fails (e.g. AIRE, Fas, Foxp3, many others) but are not involved in most, common autoimmune diseases Genes include HLA, many othersEach gene individually makes a small contribution Little predictive value4
5. 5Mapping Human Disease Variants with GWASAutoimmunePatientsNon-PatientsAutoimmuneDNANon-PatientDNA
6. 620052007200920142011GWAS Era
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8. 2 signals are required for the efficient activation of lymphocytes
9. Pathogenesis of autoimmunity9
10. Central tolerance is achieved by the deletion of autoreactive thymocytes through negative selection in thymusThe affinity of the T-cell receptor (TCR) for self-peptide–MHC ligands is the crucial parameter that drives developmental outcome in the thymus
11. Peripheral mechanisms of tolerance operate to maintain immune homeostasis
12. Immunologic ignorance (the sequestration of self-antigens by autoreactive clones)Immunologically Privileged sites: Brain, Anterior chamber of eye, Testis and UterusTissue grafts placed in these sites do not elicit an immune response – no rejectionMechanisms of immunologic ignorance: Lack of lymphatic drainage Presence of physical barriers between blood and tissue secretion of immunosuppressive factors
13. Blood brain barrier separates the circulating blood from brain
14. Fetal Tolerance
15. Clonal deletion (the physical loss of self-reactive clones)Apoptosis or antigen-induced cell death (AICD) is initiated upon by ligation of membrane-bound death receptors such as CD95/Fas, death receptors such as CD95L (FasL) or TNFR-related apoptosis-inducing ligand (TRAIL).T cell apoptosis ensures the proper removal of autoreactive T cells during thymic development as well as T cell homeostasis and the downregulation of immune responses against antigens in the periphery.
16. Fas-deficient mice spontaneously develop autoimmunityThe natural mutant lpr mouse (lymphoproliferative), which carries a mutation in the Fas gene and the FasL mutant gld mouse (generalized lymphoproliferative disorder), develop lymphadenopathy, splenomegaly and spontaneous autoimmunity lprB6autoimmune lymphoproliferative syndrome (ALPS) mutation in Fas gene
17. Full activation of T cells requires two signals
18. Immune regulation: the pivotal role of regulatory cell populationsVarious regulatory cell populations:Foxp3+ TregsIL-10-producing Tr1 cellsIL-10-producing Bregs
19. Scurfy Mouse (outside) X-linked recessive inheritance Lethality at 21-25 days Wasting syndrome Exfoliative dermatitisWild typeScurfy
20. Khattri et al. Nat Immunol. 2003 Apr;4(4):337-42 Spleen and lymph nodes at day 21 of age from littermate male Foxp3+ and Foxp3- miceFoxp3- mice succumb to an aggressive lymphoproliferative autoimmune syndrome
21. Adoptive transfer of CD4+CD25+ Tregs “rescue” scurfy mice from the autoimmune phenotype
22. Neonatal onset diabetes mellitus Hypothyroidism Enteritis (diarrhea/villous atrophy) Hemolytic anemia & thrombocytopenia. Dermatitis Dermatitis (eczema) Death by 1-2 years of ageImmunedysregulation Polyendocrinopathy Enteropathy X-linked syndrome (IPEX) Treg deficiency due to Foxp3 mutation
23. Treg cells are antigen specific♂ cell-immunizedPeptide-infused ♀♂ cell-immunized ♀CD4GITRFoxp3Gated on CD4+IAb-HY+ cells23.323.50.680.72Quantity of Foxp3 mRNArelative to -Actin mRNA02004006008001000120014001600180020005.154561845Immunized controlsImmunizedpeptide-infusedControl CD4+CD25+Verginis et al. PNAS 2008; 105 (9) 3479–3484
24. (CD25+CD4+) D TCRb+ cells + - - + from control B6 ♀(CD25+CD4+) D TCRb+ cells - + + - from HY-infused B6 ♀CD25+CD4+ cells from - - + + HY-infused B6 ♀
25. Regulatory T cells in Autoimmune Diseases
26. Essential role of Foxp3+ Treg cells in maintenance of self-toleranceFoxp3+CD25+CD4+ Treg cells play an indispensable role in the dominant mechanism of self-toleranceAn illustration of this is provided by the scurfy phenotype in miceHori S, et al., Science 2003Khattri R, et al., Nat. Immunol. 2003 Fontenot JD, et al., Nat. Immunol. 2003
27. Treg cell immunotherapy
28. Basic mechanisms of Treg cell function
29. The promise of low-dose IL-2 therapy in autoimmune and inflammatory diseasesKlatzmann and Abbas Nature reviews Immunology 2015
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32. But …..Tregs infiltrate tumors and assist in tumor immune evasion
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34. Other mechanisms that influence peripheral toleranceImmunoregulatory molecules: cytotoxic T-lymphocyte antigen 4 (CTLA-4) programmed death-1 (PD-1)
35. Therapy of immune disorders: rational approaches target lymphocyte activation and subsequent inflammation 35
36. Examples from the literature
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38. IFN-β treatment blocks Th1-induced EAE but exacerbates Th17-mediated EAE
39. Cytokine profile in RRMS patients
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42. Foxp3- T cellsFoxp3+ T regs LC3 Lamp-1p62merged*** p62 puncta/cell LC3 puncta/cell ***Foxp3- T cellsFoxp3+ TregsFoxp3+ Tregs inhibit the autophagolysosome formation in DCsFoxp3 T cellsDC isolationRag1-/-MOG35-55/CFA
43. Atg16l1fl/fl DCsAtg16l1ΔCd11c DCs2D2 T cellsEAE InductionRag1-/-MOG35-55/IFAautophagy KO DCs**********Mean Clinical scoredays post immunization***Max. severity of EAE(clinical score)Atg16l1flox/flox DCs Atg16l1ΔCd11c DCsDown-modulation of DC autophagy compromises auto-antigen presentation and EAE induction
44. LC3 puncta/cell p62 puncta/cell Foxp3+ Tregscontrolanti-CTLA4Foxp3+ Tregs/anti-CTLA4 LC3 Lamp-1p62mergedcontrolFoxp3+ Tregsanti-CTLA4Foxp3+ Tregs/anti-CTLA4Foxp3+ Tregs inhibit autophagy in DCs in a CTLA4-dependent manner
45. LC3 puncta/cellp62 puncta/cellLC3/Lamp-1/p62/dapiRosa26CreERTwt/wtCtla4fl/flwtiKO5uMRosa26Cre/ERT2+Ctla4fl/flCTLA4-deficient Foxp3+ Tregs did not inhibit autophagy on DCs
46. Abataceptanti-TNFαLc3b relative expression p62 puncta/cell ***IgG CTLA4-Ig LC3/p62 LC3 puncta/cell ***IgG CTLA4-Ig CTLA4-Ig IgG Relative intensity nuclear FoxO1p-mTORp-p85p-Akttotal mTORtotal p85total AktCTLA4-IgLy294002 - + CTLA4-Ig (Abatacept) diminishes autophagy in human DCs and promotes FoxO1 nuclear exclusion
47. Foxp3+ TregCTLA4Dendritic CellCD80/CD86TCRCD4+ T cellMHCIIPI3KPAKTPLC3BFoXO1PRegulatory T cells restrain autophagy in dendritic cells to ameliorate autoimmunity in a CTLA4-dependent fashion