Autoimmune diseases, their pathogenic mechanisms and treatment of unwanted immune responses (Janeway s Immunobiology) Picture source: https://www.klini kum.uniheidelberg.de/fil eadmin/pressest elle/pm_neu/20 13/05_2013/PM _MS_EPO_Dieh m_060513.jpg (26.06.2016) Ann-Britt Schäfer Faculty of chemistry and biochemistry Molecular Immunology 2016 Date: Wed 29th June, 2016 1
Overview classification involved components chronic autoimmune diseases mechanisms of tissue/cell damage autoantibodies T cells Treatment of unwanted immune responses drugs biologics 2
general information loss of self tolerance autoimmunity can be provoked: proved by mouse models self proteins are hard to eliminate Picture source: http://histohal.unihalle.de/histopatho/histopics/s639.jpg (28.06.2016) 3
Classification Organ-specific autoimmune diseases Organ-specfic: few organs are targeted Systemic: many tissues effected both can become chronical clustering of autoimmune diseases classification into subtypes Type 1 diabetes mellitus Goodpasture s syndrom Multiple sclerosis Crohn s disease Psoriasis Graves disease Hashimoto s thyroiditis Autoimmune hemolytic anemia Autoimmune Addison s disease Vitiligo Myasthenia gravis Systemic autoimmune diseases Rheumatoid arthritis Scleroderma Systemic lupus erythematosus Primary Sjögren s syndrome Polymyositis Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.623 4
Classification Organ-specific autoimmune diseases Organ-specfic: few organs are targeted Systemic: many tissues effected both can become chronical clustering of autoimmune diseases classification into subtypes exceptions: inflamatory bowel disease (IBD) autoimmune hemolytic anemia Type 1 diabetes mellitus Goodpasture s syndrom Multiple sclerosis Crohn s disease Psoriasis Graves disease Hashimoto s thyroiditis Autoimmune hemolytic anemia Autoimmune Addison s disease Vitiligo Myasthenia gravis Systemic autoimmune diseases Rheumatoid arthritis Scleroderma Systemic lupus erythematosus Primary Sjögren s syndrome Polymyositis Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.623 5
involved components autoantibodies (e.g. myastenia gravis) recognize: acetylcholine receptors damage: muscle weakness Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.625 6
involved components autoantibodies (e.g. myastenia gravis) antibodies as immune complexes complement activation and ligation of Fc-receptors damage: inflammation of tissue Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.625 7
involved components effector T cells (e.g. type 1 diabetes) recognize: self peptides of commensal microbiota with self-mhc damage: local inflammation or dircet tissue damage Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.626 8
involved components pregnancy IgG can cross placenta maternal IgG is catabolized can cause chronic organ injury Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.626 9
involved components Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.627 10
involved components Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.627 11
chronic autoimmune diseases high number of self antigen limiting of immune response is hardly possible broken sequestration Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.628 12
chronic autoimmune diseases autoimmune response lead to production of epitopes reveal cryptic epitopes epitope of antigen can be completly different e.g. SLE can be linked to the progress of a disease e.g. pemphigus vulgaris Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.628 13
Mechanisms of tissue/cell damage Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.572 14
Mechanisms of tissue/cell damage Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.630 15
Mechanisms of tissue/cell damage Type III are systemic diseases Type IV are mainly organ-specific diseases most diseases have a more complex response e.g. type 1 diabetes Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.630 16
Autoantibodies against blood cells self antigens on blood cells trigger destruction e.g. autoimmune hemolytic anemia destruction of blood cell in MPS or through lysis lysis of nucleated cells is rare but possible e.g. Hashimoto s thyroiditis treatment: removal of spleen administration of lgg Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.631 17
Autoantibodies against receptors stimulation of receptor through antibody binding e.g. Graves disease Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.633 18
Autoantibodies against receptors inhibition of receptor through antibody binding e.g. myasthenia gravis autoantibodies against α-chain of nicotinic acetylcholine receptors progressive muscle weakness Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.633 19
Autoantibodies against extracellular antigens is rare but harmful Goodpasture s disease: antibodies against α 3 chain of basement membrane collagen ligate Fcγ receptor activation of monocytes, neutrophils, tissue basophils and mast cells release of chemokines influx of neutrophils Picture source: http://library.med.utah.edu/webpath/jpeg2/renal093.jpg (25.06.2016) 20
Autoantibodies against extracellular antigens 3 failures in immune complex clearance 1. injection of large amounts of antigens large amounts of immune complexes overwhelming system (serum sickness) 2. chronic infections incapability of clearing infection bacterial endocarditis: widespread immune complex injury mixed essential cryoglobulinemia: deposite immune complexes in joint and tissues 21
Autoantibodies against extracellular antigens 3. part of the pathogenesis of SLE 3 types of antigens: nucleosome subunit of chromatin, spliceosome and small cytoplasmatic ribonucleoprotein complex autoantigens are exposed by dying cells large amounts of immune complexes are produced activation of phagocytic cells more nucleoprotein complexes 22
T cells specific for self antigens difficult to prove existence of autoreactive T cells: T cells recognition is MHC restricted difficult to identify targeted antigen antigens recognized by CD4 T cells are easier to identify than those that are recognized by CD8 T cells evidence through diseases like Typ 1 diabetes 23
T cells specific for self antigens evidence through diseases like Typ 1 diabetes Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.636 24
T cells Multiple sclerosis T cell mediated chronic neurological disease affected antigens: - myelin basic protein (MBP) - proteolipid protein (PLP) - myelin oligodendrocyte glycoprotein (MOG) development of plaques demyelination of nerve cells inflammatrory infiltration along blood vessels Picture source: https://indianmedtrip.com/wpcontent/uploads/2016/02/multiple-sclerosis.jpg (25.06.2016) variety of neurological symptoms 25
T cells Multiple sclerosis autoreactive B cells produce with help of T cells autoantibodies against myelin antigens demyelination Picture source: Murphy, Kenneth; Janeway; 8th Edition; p.637 26
T cells Rheumatoid arthritis progressive chronic disease affected tissues: synovium, cartilage and bone Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.638 27
Overview classification involved components chronic autoimmune diseases mechanisms of tissue/cell damage autoantibodies T cells Treatment of unwanted immune responses drugs biologics 28
Treatment of unwanted immune responses general information occur in autoimmune disease, transplant rejection and allergy aim: avoid tissue damage and prevent disruption of tissue function Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.670 29
Treatment of unwanted immune responses drugs - corticosteroids cross plasma membranes bind intercellular receptors of nuclear receptor family regulate approximately 20% of genes expressed in leukocytes side effects: toxic and develop tolerance Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.670 30
Treatment of unwanted immune responses drugs cytotoxic drugs most commen: azathioprine, mycophenolate and cyclophosphamide azathioprine target: DNA synthesis side effects: toxic to all tissues azathioprine: block de novo synthesis of AMP and GMP cyclophsphamide mycophenolate: block de novo synthesis of GMP cyclophosphamide: alkylates DNA Picture source: sigma aldrich 31
Treatment of unwanted immune responses drugs non cytotoxic drugs most commen: cyclosporin A, tacrolimus (FK506) and rapamycin interfere with T cell signaling Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.672 32
Treatment of unwanted immune responses drugs non cytotoxic drugs cyclosporin A and tacrolimus inhibit calcineurin T cells are sensitve to calcineurin side effects: affect all immune responses effect several tissues fine tuning of drug dosis is neccessary Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.673 33
Treatment of unwanted immune responses drugs non cytotoxic drugs rapamycin immunophilin complex inhibits mtor reduces cell growth and proliferation increase number of regulatory T cells fingolimod: inhibits migration of dendritic cells causes retention of effector lymphocytes Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.674 34
Treatment of unwanted immune responses biologics monoclonal antibodies new class of therapeutic compounds act by two general mechanisms: depleting antibodies (trigger destruction of lymphocytes) non depleting antibodies (blocking function of their target protein) various approches to make them more compatible Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.675 35
Treatment of unwanted immune responses biologics monoclonal antibodies Monoclonal antibodies developed for Immunotherapy Generic name Specifity Mechanism of action Approved indication Rituximab Anti-CD20 Eliminates B cells Alemtuzumab Muromonab Daclizumab Basiliximab Infliximab Anti-CD52 Anti-CD3 Anti-IL2R Eliminates lymphocytes Inhibits T cell activation Reduces T cell activation Non-Hodgkin s lymphoma Chronic myeloid leukemia Kidney transplantation Crohn s disease Certolizumab Adalimumab Golimumab Anti-TNF-α Inhibit inflamation induced by TNF-α Rheumatoid arthritis Source: Murphy, Kenneth; Janeway; 8 th Edition; p.67600 36
Treatment of unwanted immune responses biologic agents immunomodulatory therapy: aim is to reduce tissue damage antibodies against activity of cytokines like TNF-α and IL-1 anti-tnf-α antibodies are used in rheumatoid arthritis block TNF- α activity neutralize TNF- α activity problem: higher risk of infections e.g tubercolosis 37
Treatment of unwanted immune responses biologics natalizumba is specific for α 4 integrin subunit blockade of α 4 :β 1 integrin is not specific side effect: reduced defence against infections Picture source: Murphy, Kenneth; Janeway; 8 th Edition; p.680 38
Treatment of unwanted immune responses biologics - antigens change of immune response and reduction or elimination of pathogenic features by antigen presentation for example: peptides given orally can effect regulator T cells without activating other T cells peptide drugs (e.g. glatiramer acetat) altered peptide ligands can be designed to be an antagonist, agonist or induce differentiation of regulatory T cells 39
take home messages : classification of diseases in organ-specific and systemic classification of tissue injury by scheme of hypersensitivity reactions multiple components are involved inducement of autoimmune response remains unclear Treatment of unwanted immune responses: conventional drugs: anti-inflammatory have a wide range cytotoxic kill all dividing cells immunosupressant drug intervene in intracellular signaling pathways biologics: reduce, inhibit or prevent lymphocyte actions inhibition TNF-α 40
Thank you for your attention 41
List of sources M. KENNETH, Janeway s Immunobiology, 8 th Edition http://www.niddk.nih.gov/pages/default.aspx http://www.mayoclinic.org 42