When the immune system goes wrong - Mark Peakman.pdf

When the Immune system goes wrong Professor Mark Peakman Department of Immunobiology Faculty of Life Sciences & Medicine Immunology Roadmap Innate immunity Adaptive immunity Microbes B lymphocytes Antibodies Epithelial...

When the Immune system goes wrong Professor Mark Peakman Department of Immunobiology Faculty of Life Sciences & Medicine Immunology Roadmap Innate immunity Adaptive immunity Microbes B lymphocytes Antibodies Epithelial barriers T lymphocytes Phagocytes C3a C3b Effector T cells NK cells Complement Viruses The immune system Bacteria protects us from Parasites Topics Hypersensitivity Autoimmunity Immunodeficiency Cancer Hypersensitivity Immune response to a harmless molecule, ignored by the immune systems of the majority but initiating in some people a response that leads to tissue damage and even death. Immediate hypersensitivity = Allergy. It is mediated by IgE, mast cells and Th2 responses Harmless molecule is called an “ aller gen”: it “ gen”erates “ aller”gic response Atopy is an inherited tendency to make immediate hypersensitivity responses 30-50% of the population suffer The immediate hypersensitivity response is due to mast cell degranulation and histamine release and when it happens in the skin there is a wheal and flare. Wheal = raised lesion Flare = surrounding redness Th2 responses direct allergic disease CD4 CD4 Th2 Th2 cytokines Class switch to IgE and Interleukin-4, IL-5, IL-13 B cell Differentiate to plasma cell Th2 responses direct allergic disease Symptoms of allergy or atopy: Sneezing CD4 Wheal and flare CD4 Th2 Th2 cytokines Class switch to IgE and Interleukin-4, IL-5, IL-13 B cell Differentiate to plasma cell Immediate hypersensitivity / Allergy Common diseases: Common therapies: Asthma Anti-histamines Perennial rhinitis 2-adrenoceptor agonist (“hay fever”) Corticosteroids Allergic eczema More rare: More rare: Desensitization Anaphylaxis Monoclonal antibody (60-80 deaths per year from bee/wasp against IgE stings in America, and 5-10 in the UK ) (Omalizumab)  Inflammatory T cell response to Desensitization Bee stings/month bee sting allergen In the clinic: “Desensitization” Autoimmunity Immunological self tolerance Controlled failure to respond to self …despite having the capability to do so Autoimmunity Loss of immunological tolerance to self components Autoimmune disease Loss of immunological tolerance to self components, associated with pathology Disease accompanied by one or more manifestations of autoimmunity (ie T or B cell) Prevalence of autoimmune disease Disease Female:male Ratio Prevalence Addison’s disease 12.3 13,335 Chronic active hepatitis 7.5 1,156 Glomerulonephritis 0.8 167,325 Graves’ thyroiditis 7.3 3,089,841 Type 1 diabetes 0.9 1,146,892 Multiple sclerosis 1.8 154,278 Myasthenia gravis 2.6 13,589 Pernicious anaemia 2.0 399,455 Myositis 2.0 13,462 Primary biliary cirrhosis 8.1 9,232 Rheumatoid arthritis 3.0 1,736,099 Scleroderma 11.8 8,922 Sjogren’s syndrome 15.0 38,108 Systemic lupus erythematosus 7.4 63,052 Thyroiditis/hypothyroidism 13.7 1,695,530 Uveitis 1.0 4,637 Vitiligo 1.1 1,059,560 9,511,845 (~5%) Spectrum of autoimmune disease Non-organ specific Organ specific Type I Systemic lupus diabetes erythematosus Grave’s Rheumatoid disease arthritis Serum autoantibodies: examples of breakage of self tolerance Usually IgG class Important diagnostic tools Useful for monitoring disease activity Useful for predicting future disease May be pathogenic (ie cause disease) Autoantibodies are often used diagnostically. It is often not obvious what links antibody specificity with pathology: Rheumatoid factors (anti-IgG) Rheumatoid arthritis Anti-citrullinated peptide Anti-DNA and nucleoprotein SLE Anti-myeloperoxidase or proteinase 3 Autoimmune vasculitis (neutrophil proteins) Anti-islet cell antibodies and antibodies to Type I diabetes Insulin, GAD65, IA-2, ZnT8 More obvious links: Anti-myelin basic protein Multiple sclerosis Anti-thyroid stimulating hormone receptor Graves’ disease Anti-acetylcholine receptor Myasthenia gravis Proof of autoimmunity? Passive transfer of disease by immune effectors (eg T cells, antibodies) Examples IgG mediated pathology in Grave’s disease and myasthenia gravis: transfer of disease to fetus via placental IgG Clinical responsiveness to immune suppression, or to re- establishment of tolerance Examples rheumatoid arthritis and Type I diabetes Autoimmunity examples Graves’ thyroiditis Myasthenia Gravis 1. Autoimmune thyroid disease Graves’ Disease The first disorder to be associated with autoimmunity: Anti-thyroid autoantibodies discovered in 1950s  Health Grave’s Disease Anti-TSH receptor Pituitary Pituitary Negative feedback by throxine prevents excess TSH production by the pituitary gland Thyroid Thyrocyte Thyrocyte Production of thyroxine by the thyroid gland is regulated by thyroid stimulating hormone (TSH) Constant stimulation of the thyroid and produced by pituitary gland. pituitary with no feedback loop = Fast heartbeat, hyperactivity, Binding of TSH to the TSH receptor stimulates the production of thyroxine. weight loss, bulging eyes, goitre Healthy neuronal Myasthenia Gravis stimulation Neuronal Neuronal stimulus stimulus Neuron Acetylcholine Muscle No or poor muscle contraction contraction Acetylcholine receptor Antibody to the = Muscular weakness acetylcholine receptor and fatigue Maternal IgG is transported across the placenta to protect the baby during the first weeks of life until the baby’s own antibody response develops Mother with Grave’s disease has IgG antibodies Cross placental transfer of disease to thyroid stimulating manifestations from mother to fetus by IgG hormone (TSH) receptor proves that antibody causes pathology in Grave’s Disease and Myasthenia Gravis Plasmapheresis T cell mediated autoimmune disease pathology: symptoms and/ or progression reduced by immunosuppression Rheumatoid arthritis Type 1 diabetes is a progressive loss of the insulin producing beta cells of the pancreas resulting in failure to regulate blood sugar levels This is T cell mediated. How do I know? Success of humanized monoclonal antibody against T cells as therapy for Type 1 diabetes Herold et al, NEJM 2002 Chatenoud et al, NEJM, 200 Type 1 diabetes is T cell mediated. How? 1. CD8 T cell mediated killing of  cells Supported by 2. CD4 T cell mediated inflammation 3. Failure of Treg to suppress   CD4+ Treg CD8 CD4+ Th1 CD4+ Th17 CD4 CD4+ Th2 Immunodeficiency Immunodeficiencies PRIMARY = inherited defect = rare SECONDARY = acquired defect = common.  Cells of the immune system – primary immune deficiencies Bone marrow Erythrocytes precursors Platelets Granulocyte/ monocyte Pluripotent (myeloid) lineage stem cell Lymphocyte (lymphoid) precursor ? Granulocyte precursor Dendritic cell Monoblast precursor Pre-B cell Pre-T cell Pre-NK cell Mature blood Thymus ? forms ? Neutrophil Eosinophil Monocyte Immature Di George Basophil dendritic cell B cell Syndrome T cell NK cell Mature tissue Often abnormalities of heart forms and facial features in addition Macrophage to immunodeficiency Mast cell Dendritic cell Plasma cell  Cells of the immune system – primary immune deficiencies Bone marrow Erythrocytes precursors Platelets Granulocyte/ monocyte Pluripotent (myeloid) lineage stem cell Lymphocyte (lymphoid) precursor ? Granulocyte precursor Dendritic cell Monoblast precursor Pre-B cell Pre-T cell Pre-NK cell Mature SCID blood Thymus ? forms Severe ? Neutrophil Eosinophil Combined Monocyte Immature Immune dendritic cell Basophil deficiency B cell T cell NK cell Mature tissue The Boy in the Bubble forms Macrophage Mast cell Dendritic cell Plasma cell  Cells of the immune system – primary immune deficiencies Bone marrow Erythrocytes precursors Platelets Granulocyte/ monocyte Pluripotent (myeloid) lineage stem cell Lymphocyte (lymphoid) precursor ? Granulocyte precursor Dendritic cell Monoblast precursor Pre-B cell Pre-T cell Pre-NK cell Mature blood Thymus ? forms ? Neutrophil Eosinophil Chronic Granulomatous Monocyte Immature Disease Basophil dendritic cell B cell T cell NK cell Mature tissue forms Macrophage Mast cell Dendritic cell Plasma cell  Cells of the immune system – primary immune deficiencies Bone marrow Erythrocytes precursors Platelets Granulocyte/ monocyte Pluripotent (myeloid) lineage stem cell Lymphocyte (lymphoid) precursor ? Granulocyte precursor Dendritic cell Monoblast precursor Pre-B cell Pre-T cell Pre-NK cell Mature blood Thymus ? forms ? Neutrophil Eosinophil Monocyte Immature Basophil dendritic cell B cell T cell NK cell Mature tissue forms Hypergammaglobulinemia Macrophage eg Hyper IgM syndrome Mast cell Dendritic cell Plasma cell Secondary immune deficiencies Human Immunodeficiency virus HIV 36.9 million people were living with HIV globally at the end of 2014 HIV infection to acquired immune deficiency syndrome (AIDS) Concentration in blood CD4 Highly Active Antiretroviral Therapy Number in blood HAART Iatrogenic immune deficiency Increasing numbers of patients being treated with immune based therapies. These may cause highly focused secondary immune abnormalities. Examples: Monoclonal anti-TNF-α therapy for rheumatoid arthritis results in unusual opportunistic infections including mycobacterial infections. Monocloncal anti-IL-17 therapy for infammatory diseases such as psoriasis can give rise to severe systemic fungal infections; telling us that IL-17 is a key component of protection from fungi Cancer Cancer – failure of immune surveillance CD4+ Treg Cancer – failure of immune surveillance Cancer – failure of immune surveillance Programmed death-1 and Programmed death- ligand 1 Interaction blocked PD-L1 PD-1 Antibody to PD-1 or PD-L1 Summary Hypersensitivity Autoimmunity Immunodeficiency Cancer Post transplant lymphoproliferative disease- PTLD In healthy individuals B cells may be infected with Epstein Barr virus (EBV). This is normally controlled by cytotoxic T cells. T cells may be suppressed, for example by drugs to prevent rejection of a transplant In this case the cytotoxic T cell response may longer be able to control infected B cells and they undergo malignant transformation and form a B cell lymphoma