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Autoimmune Diseases SS 2006 Adelheid Cerwenka, PhD Innate Immunity German Cancer Research Center The dark and the bright side of the Immune system First Observations on Tolerance I: Early 1900: • Paul Ehrlich: Horror autotoxicus Effector mechanisms used in host defense may be turned against the host and cause severe tissue damage (Horror autotoxicus). However, animals avoid self-destructive processes. The dark and the bright side of the Immune system Autoimmunity Loss of tolerance towards self-antigens. Autoimmune Diseases Loss of tolerance leads to autoimmunity towards self-antigens and consequently to pathological damage of one organ or several tissues within the body. Autoimmune Diseases “ Over the past century, there have been almost as many theories about the origins of autoimmunity as there are autoimmune diseases.” Yehuda Shoenfeld Nat. Med. 10, 2004 Mechanisms of Tolerance Central Tolerance: • negative selection in thymus (apoptosis) Peripheral Tolerance: • Indifference • Deletion • Immuno Modulation: – Regulatory T cells – Cytokine Micromilieu • Immune-priviledged sites Thymus CD4-8TCRCD4+8+ TCR+ CD4+8or CD4-8+ TCR+ “foreign” Absent “self” Present “self” Absent Negative Selection Periphery CD4+8or - + CD4 8 TCR+ “foreign” (e.g., virus) Activation “self” Tolerance/Autoimmunity Loss of Tolerance? Autoimmune Diseases Risk Factors: Hormons genetic environment Genetic Risk Factors: Major Histocompatibility complex (MHC) MHC genes are polygenic: several MHC class I and class II genes exist: MHC genes are polymorphic: each gene consists of several allels: MHC molecules are highly variable and each MHC protein binds a different set of antigens: Population studies show association of susceptibility to IDDM with HLA genotype Affected siblings share 2 HLA haplotypes much more frequently than expected Certain HLA genotype are frequently found in diabetic patients DR3/4 tight linkage to DQb, MHC Risk Factors for Diabetes Juvenile Diabetes (IDDM): MHC class II: e.g., HLA DQß position 57 IDDM risk IDDM resistence Ala, Ser, Val Asp Additional 19 non MHC genetic regions determine IDDM susceptibility! Genetic Risk Factors: Non-MHC A Role for Non-MHC Genetic Polymorphism in Susceptibility to Spontaneous Autoimmunity B. Scott, R Liblau, S. Degermann, L. A. Marconi, L. Ogata, A. J. Caton, H.O. McDevitt, D. Lo Immunity 1994, volume 1,p 73-82. T cells HASpecific TCR X HA: influenza hemagglutinin RIP-HA Balb/c B10.D2 T cell activation yes yes Diabetes no yes Th2 Phenotype yes no IL-4! Cytokines play a critical role in autoimmunity! TH1 and TH2 Cytokine-Profiles TH1 IL-2, IFN-, TNF- reciprocal control TH2 mediate cellular immunity IL-4, IL-10, TGF-b mediate humoral immunity Functional Imbalance BetweenTH1 and TH2 Cytokine Levels Example: autoantibodymediated autoimmune desease Normal homeostasis Prone to autoimmunity Autoimmunity Autoimmune Diseases Risk Factors: hormones genetic environment Example environmental factors: Goodpasture s disease • Autoantibodies against type 4 IV collagen (distibuted widely in basement membranes) • Manifeestation: often glomerulonephritis, and pulmonary hemorrhage • pulmonary hemorrhage: ofen found in smokers: inflammation of alveoli Environmental Risk Factors for Autoimmune Diseases Ref.: Conrad et al. Nature, 1994, 371, P. 351 Infections can break self-tolerance! Molecular Mimicry Reactivity towards pathogens can cause autoreactivity. Epitopes derived from the pathogen are sufficiently homolog with host self-epitopes to cause cross-reactivity, but different enough to break tolerance. Example: Juvenile Diabetes (IDDM) Summary: Risk Factors for Autoimmune Diseases • Genetic Factors: MHC • Genetic Factors: non-MHC Hormones/sex Th1 versus Th2 cytokine production Regulatory T cells • Environmental Factors: Infections „Molecular Mimicry“ Superantigens Disruption of tissue barriers Group Work Discuss the following questions within your group: Which autoimmune diseases do your know? What mechanisms might cause autoimmunity? Use the scheme of a human body to indicate diseased organs Examples for Autoimmune Diseases Autoimmune Disease Frequency [%] Insulin-Dependent Diabetes Mellitus (IDDM) Multiple Sclerosis (MS) 0.4 0.1 Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE) 1.0 0.1 Insulin-Dependent Diabetes Mellitus (IDDM): Selective Destruction of b Cells Imbalance in glucose metabolism: blindness, renal failure Insulin-Dependent Diabetes Mellitus: Mechanism? T cell-mediated, Autoantigens: autoantibodies Insulin: early antigen, insulin-specific CD4+ T cells transfer diabetes in NODScid mice, in humans: anti-insulin antibodies found in 50 % of patients just diagnosed with IDDM. GAD: glutamic acid decarboxylase, catalyses synthesis of the neurotransmitter GABA in the brain, function in b cells unclear, in humans: anti-GAD Ig serum levels are markers for IDDM Transgenic Diabetes Mouse Model: RIP-NP Mice Develop Diabetes after Viral Infection Spontaneous Diabetes Mouse Model: Nonobese Diabetic Mouse (NOD) Spontaneous, accumulating b-cell damage results in overt diabetes, origins of autoreactivity not identified. Phenotype Age Peri-Insulitis 4-6 weeks limited number of primary antigens Islet infiltration, increasing -cell damage 12 weeks recruitment of T cells with different specificities 18-20 weeks “epitope-spreading” observed Diabetes increase of blood glucose levels due to massive -cell damage (>90%) Antigen Multiple Sclerosis (MS): Selective Destruction of the Myelin Sheath in the Central Nerveous System T cell-mediated, autoantibodies Motory and sensory disturbances, Episodes of relapse followed by remission. Antigens: MBP: myelin basic protein PLP: proteo lipid protein Transfer Model for MS: Experimental-Autoimmune Encephalomyelitis (EAE) Epitope Spreading I Spontaneous Regression of Primary Autoreactivity during Chronic Progression of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis By Vincent K. Tuohy, Min Yu, Julie. A. Kawczak, and R. Philip Kinkel J. Exp. Med., Volume 189, Number 7, 1999, 1033-1042. Induction of EAE in mice via injection of PLP: PLP peptide recognition early late late early: EAE NH2 104-117 139-151 late MBP NH2 87-99 178-191 COOH late: symptom-free period, followed by chronic EAE COOH Epitope Spreading II A) Epitope-spreading can enhance clinical symptoms by inducing autoreactive T cells, which recognize novel self-peptides. OR B) Epitope-spreading leads to regression of clinical symptoms by inducing regulatory T cells, which suppress autoreactive T cells by a mechanism called: “Bystander Suppression”. Systemic Lupus Erythematosus: SLE Systemic Autoimmune Disease Autoantibodies CD4+ T cells complement Heterogeneous clinical symptomes: – skin rash – joint pain – disturbances of the central nerveous system – renal disfunction (Glomerulonephritis) Structures recognized by autoantibodies: – double stranded DNA – nuclear constituents Antibody Deposition Causes Systemic Injuries Animal Models for SLE Spontaneous animal models: Lpr and gld mice: –lpr: mutation of Fas –gld: mutation of FasL - - Defect in apoptosis leads to accumulation of CD4 /CD8 T cells and production of autoantibodies. Symptomes: glomerulonephritis, vasculitis Experimental animal models: Knock-out mice: e.g., TGF-ß, CTLA4 Molecules involved in T cell priming. Therapy in Autoimmune diseases • Unspecific suppression of the immune system. • Monoclonal antibodies, specific for effector cells, e.g., anti-CD4, anti-VLA, anti-IFN-g • Modified peptides: blocking of peptide presentation by MHC molecules or blocking of TCR signaling. Most autoimmune diseases show reactivity towards multiple antigens, which is enhanced by epitope spreading. It is therefore unlikely that blocking of only one T cell population is therapeutically successful. Oral Tolerance Oral uptake of antigen leads to immune suppression: Induction of regulatory T cells, which migrate to the attacked organ and secrete inhibitory cytokines. The inhibitory cytokine milieu down-modulates the activity of T cells with the same or diverse antigen specifity. “Bystander Suppression” Oral Administration of MBP Protects from Experimentally Induced EAE Conclusion: Autoimmune Diseases Risk factors Autoimmune Diseases Insulin-Dependent Diabetes Mellitus (IDDM) Multiple Sclerosis (MS) Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE) Therapy