* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download The Immune System
Survey
Document related concepts
Rheumatic fever wikipedia , lookup
DNA vaccination wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Rheumatoid arthritis wikipedia , lookup
Immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Autoimmunity wikipedia , lookup
Adaptive immune system wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Innate immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Transcript
Disorder of immune system Yeong-Wook Song, MD Division of Rheumatology Seoul National University The Immune System Objectives 1 2 3 4 5 Define the terms infection, pathogen, and antigen, tolerance, autoimmunity, rheumatic disease. List and describe mechanism of the nonspecific and specific body defense mechanisms. Explain the signs and causes of inflammation. Define B cells and T cells and describe their locations and functions. Explain the importance of MHC proteins. 2 The Immune System Objectives (cont.) 6 7 8 9 10 List the different types of T cells and describe their functions. List the different types of antibodies and explain how they differ and how they fight infection. Define complement and give its functions. Explain the difference between innate and adaptive immunity. Describe the signs and symptoms of common immune disorders (rheumatoid arthritis, lupus, ankylosing spondylitis scleroderma, myositis). 3 What does the immune system do? • Normal (physiologic) functions: – Immunity = protection against infection – Defense against some tumors • Roles in disease: – Cause of many immunological diseases (allergies, autoimmune diseases) – Suspected role in many diseases thought to be non-immune (atherosclerosis, Alzheimer’s disease, type 2 diabetes) 4 Innate and adaptive immunity Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier Innate immunity: always present (ready to attack); many pathogenic 5 microbes have evolved to resist innate immunity Adaptive immunity: stimulated by exposure to microbe; more potent Cells of the immune system • Lymphocytes: the cells of adaptive immunity; recognize antigens and develop (differentiate) into cells that perform the defense functions • Antigen-presenting cells: cells that capture antigens and display them to lymphocytes • Effector cells: leukocytes (white blood cells) that eliminate microbes (the “effect” of the immune response); may be lymphocytes, but are often other leukocytes 6 Classes of lymphocytes Excluding NK cells and other innate lymphoid cells 7 Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier Lymphocyte diversity and clonal selection Lymphocyte precursor Generation of mature lymphocytes with many different antigen receptors Naïve lymphocytes circulate through lymphoid organs Antigen X Antigen Y Specific lymphocytes recognize antigens Lymphocytes are activated to proliferate and to differentiate into effector cells Anti-X Anti-Y antibody antibody Lymphocytes with highly specific and diverse antigen receptors develop prior to exposure to antigens Adaptive immune responses 9 Stages in the life history of lymphocytes Proliferation: expands number of antigen-specific cells Differentiation: converts lymphocytes into effective defenders The immune system can cause disease • Excessive, uncontrolled responses against infectious pathogens (collateral damage) • Inappropriate responses against self antigens may cause injury to normal tissues, resulting in disease • Fundamental defect is failure of control mechanisms in the immune system The significance of recent advances Provides a solid foundation of basic principles Improved understanding of disease mechanisms Development of novel therapies Appreciation of the role of the immune system in non-immune diseases Inflammation Causes: Injured or infected with a pathogen, inflammation can result Signs: Redness Heat Swelling Pain 13 Major Immune System Disorders Diseases and disorders that challenge the immune system: (the following are the most significant) HIV/AIDS Infections Autoimmune disease Cancer Allergies 14 Acquired Immune Deficiency Syndrome (AIDS) Caused by human immunodeficiency virus (HIV) infection Most common routes of transmission are through sexual contact, blood, or from mother to child during pregnancy or breast-feeding. Can have infection for years before developing any symptoms of this disease Less common routes of transmission are through accidental needle sticks, artificial insemination, and organ transplants. 15 Acquired Immune Deficiency Syndrome (AIDS) (cont.) AIDS virus affects the immune system Counts of CD4 cells are used to diagnose the stage of HIV infection. If below 200 patient has AIDS CD4 cells are types of T cells and are important for the functions of other components of the immune system. 16 Acquired Immune Deficiency Syndrome (AIDS) (cont.) Signs and Symptoms of AIDS: Low T cell counts Frequent infections Fever Some rare forms of cancer Profuse sweating A common form of Weakness cancer is called Weight loss “Kaposi’s” sarcoma. Swollen glands 17 Allergies Allergic reaction is an immune response to a substance Allergens - trigger of allergic responses Anaphylaxis - blood vessels dilate quickly causing blood pressure to drop too quickly for organs to adjust. This condition is life threatening. 18 Allergies (cont.) Allergic reactions involve IgE antibodies and mast cells. IgE antibodies bind to allergens, they cause mast cells to release histamine and heparin These chemicals trigger allergic reactions. If a person is receiving allergy shots, he is being injected with tiny amounts of the allergen and reduces symptoms 19 Immunology in Rheumatic Diseases Toll like receptors (TLRs) Value of the Immune System Macrophages & toll-like receptors (TLRs) 10-12 different TLRs can (collectively) bind a wide range of pathogens Each macrophage has all of the set of TLRs Toll-like receptors recognize a variety of PAMPs. Gene duplication of the TLR precursor and divergence of function has led to a family of molecules capable of recognizing different types of pathogen. TLRs and Autoimmunity Clear evidence they play a role in SLE and RA Clear evidence that intrinsic molecules trigger TLRs in RA and SLE Targeted inhibitors of TLRs are in Phase II trials Agonists of TLRs are being used as vaccine and tumor adjuvants Antigen Presenting Cells Unlike the other cells, TH cells only recognize antigen that is properly presented with MHC by other cells These specialized cells are called antigen presenting cells They include macrophages, B cells, fibroblasts & dendritic cells Major Histocompatibility Complex (MHC) Antigen is ingested by the antigen presenting cell then presented on its surface in molecules called major histocompatibility complex MHC are also the molecules responsible for rejection in transplant organs Major Histocompatibility Complex MHC proteins =HLA(Human Leucocyte Antigen) in humans Molecules on cell surfaces which can display antigen Products of a region of highly polymorphogenic genes on chromosome 6 2 types : Class I & Class II Comparison of MHC Class I & II Molecules Class I Class II Genes HLA A/B/C HLA D Expressed on All nucleated cells APCs – B cells, macrophages & dendritic cells Size 9 to 10 amino acids (smaller) 12 to 28 amino acids (larger) Intracellular eg viral infections Extracellular eg bacterial infections Source of antigen displayed Antigen presented to CD8+ T cells CD4+ cells ( APC = Antigen presenting cell) Activation of the Adaptive Immune System Antigens that escape the innate immune system encounter the adaptive system Adaptive immune system – powerful must be activated Activation of the Adaptive Immune System In this diagram, the macrophage represents the innate system & the TH cell, the adaptive system 3. T cell recognizes its cognate Ag 2. Ag presented on cell surface with MHC 1. 4. 2nd signal required = protein on APC + a TH cell receptor APC eg Macrophage ingests Ag 5. ACTIVATION & 6. Cytokine production Cytokines Cells of the immune system communicate with each other using cytokines Protein hormones Mediate the effect of the innate & specific immunity Autocrine/ paracrine/endocrine Effects include cell activation, division, apoptosis, movement Cytokine types Interleukins – – produced by leucocytes & have effects mainly on WBC Chemokines – – chemoattractants Colony stimulating factors – – differentiation & proliferation of stem cells Interferons – – interfere with viral replication Eg. Il-2 = a growth factor that stimulates CTLs & NK cells to proliferate TNF activates primed macrophages & NK cells Cells & cytokine production Cells produce different subgroups of cytokines which will instruct the innate & adaptive systems to produce cells & antibodies against specific antigens. Here is an example Cells TH1 (CD4) Cytokines IL2 IFN TNF TH2 (CD4) IL 4 IL 5 IL10 Antigen Viruses Bacteria TH0 Parasites T Cell Subsets – the Family Grows 10 < CCR7 > 10 10 10 5 44 28.2 4 CM Naive EM TEM 3 2 0 23.1 4.73 0 10 2 10 3 < CD45RA> 10 4 10 5 Naïve (CD45RA+CCR7+) CM: central memory (CD45RA-CCR7+) EM: effector memory (CD45RA-CCR7-) TEM: terminal effector memory (CD45RA+CCR7-) IL-12 IL-23 p40 IL-12Rβ1 p35 p19 p40 IL-12Rβ2 IL-23R NK or T cell membrane Signal Signal IL-1 IL-6 INF Th1 cell proliferation Th17 cell proliferation IL-22 2. Tolerance Is……………. the immunologic unresponsiveness to self antigens It allows the immune system to protect the body without turning against itself The focus is on the adaptive immune system T & B cells must be able to discriminate self from non self This occurs centrally & peripherally Central T Cell Tolerance NEJM 2001;344(9): 655 – 664. T cells are produced in the bone marrow & migrate to the thymus. Here they go through a rigorous selections process. Only T cells that react to antigen but not self exit. The rest die by apoptosis. Peripheral T Cell Tolerance If autoreactive T cells enter the circulation, there are several mechanisms that can prevent an autoimmune reaction. NEJM 2001;344(9): 655 – 664. B Cell Tolerance CENTRAL –Clonal deletion of autoreactive B cells in the bone marrow, spleen & lymph nodes. PERIPHERAL –Lack of help from T cells is the predominant factor. Breakdown in peripheral tolerance 3. Autoimmunity Breakdown in mechanisms preserving tolerance to self Severe enough to cause a pathological condition Autoimmune diseases Organ specific e.g. – Insulin dependant diabetes – Myasthenia gravis Multisystem e.g. – Rheumatoid arthritis – SLE Mechanisms GENETIC FACTORS Aberant MHC/HLA present self peptide Autoreactive T & B cells ENVIRONMENTAL FACTORS Infectious/ noninfectious triggers Hypothesis : Molecular mimicry AUTOIMMUNE DISEASE Molecular mimicry : The antigen looks similar to a self-peptide. As a result, the body produces an immune response to the trigger factor as well as to self. The Major Theories in the Development of Autoimmune Diseases Release of the normally sequestered antigens Increased expression of autoantigen/cryptic epitope/MHC II Molecular mimicry, Epitope spreading Defects in apoptosis Decreased cell numbers or function of suppressor and/or regulatory cells Altered Th1 and Th2 cytokine pattern Increased expression of costimulatory molecules Release of inflammatory mediators Autoantibodies in Connective Tissue Diseases Produced by B cells May be pathogenic eg. – Form immune complexes in lupus nephritis Markers of certain diseases May not be diagnostic – Apart from rheumatic disorders, they may be found in normal population & with other conditions – Therefore only test when clinically indicated. Autoantibodies associated with disease DISEASE AUTOANTIBODY Rheumatoid Arthritis Rheumatoid factor SLE ANA,dsDNA, Smith Scleroderma ANA,centromere, topoisomerase Antiphospholipid Syndrome Sjogren’s syndrome Anticardiolipin (ACLA) Polymyositis Jo-1 Dermatomyositis Mi-2 Wegener’s granulomatosis c-ANCA Ro, La Cellular Targets for autoantibodies Ab to intracellular proteins -proteinase 3 •cANCA Ab to cell membrane Proteins •ACLA Ab to IgG •Rheumatoid factor Antinuclear antibodies (ANA) •dsDNA •ENA – Smith, Ro , La, RNP •Centromere, topoisomerase Ribosomal & lysosomal components -t RNA synthetase • AntiJo 1 This diagram depicts the autoantibodies & their respective target antigens 1. 2. 3. Immune Mechanisms Tolerance Autoimmunity 4. Rheumatologic conditions – – – – – Rheumatoid arthritis Systemic Lupus Erythematosis Spondarthropathies Inflammatory myopathies Systemic sclerosis The above disease will be used to highlight some of the concepts of Immunology in Rheumatology. Note that the details of each pathway does NOT have to be memorized. Rheumatoid Arthritis Chronic autoimmune disorder Affects 1% of population A symmetrical peripheral polyarthritis of unknown etiology that leads to joint deformity & destruction due to erosion of cartilage & bone Inflammation Drives Arthritis The inflammatory process results in damage to cartilage & bone NEJM 2001; 344 (12): 907 – 916. Rheumatoid Factor Rheumatoid Factor is an autoantibody produced in RA It is however produced in several other conditions Clinical features are important in making the diagnosis Anti-CCP Ab Rheumatoid Arthritis Current therapies – Nonsteroidal anti-inflammatory drugs (NSAIDs) – Oral corticosteroids – Disease-modifying antirheumatic drugs (DMARDs) D-penicillamine, auranofin, hydroxychloroquine, azathioprine, MTX MTX has the most rapid onset of action and is well tolerated with long-term use Many patients receiving DMARD therapy show only partial symptom relief and still exhibit features of active disease New Agents for the Treatment of RA Cytokine inhibitors – – – – Human monoclonal Ab to TNFα PEGylated anti-TNFα Monoclonal antibody to IL-6 receptor JAK3 inhibition Co-stimulatory molecule blockers-abatacept Targeted B-cell therapy- anti-CD20 yOther unique mechanisms of action Systemic Lupus Erythematosus A generalized connective tissue disorder affecting many organs and characterized by the production of many autoantibodies Signs: Arthritis “Butterfly” rash on face Sensitivity to sunlight Renal failure Headaches Mental disorders Systemic lupus erythematosus classification criteria (SOAP BRAIN MD) 1. Serositis: (a) pleuritis, or (b) pericarditis 2. Oral ulcers 3. Arthritis 4. Photosensitivity 10. Malar rash 11. Discoid rash ". ..A person shall be said to have SLE if four or more of the 11 criteria are present, serially or simultaneously, during any interval of observation." 5. Blood/Hematologic disorder: (a) hemolytic anemia or (b) leukopenia of < 4.0 x 109 (c) lymphopenia of < 1.5 x 109 (d) thrombocytopenia < 100 X 9 10 6. Renal disorder: (a) proteinuria > 0.5 gm/24 h or 3+ dipstick or (b) cellular casts 7. Antinuclear antibody (positive ANA) 8. Immunologic disorders: (a) raised anti-native DNA antibody binding or (b) anti-Sm antibody or (c) positive anti-phospholipid antibody work-up 9. Neurological disorder: (a) seizures or (b) psychosis Lupus Nephritis The kidney biopsy on the right is from a patient with diffuse proliferative lupus nephritis shows massive deposits of IgG on immunofluorescence Ankylosing Spondylitis AS is a chronic inflammatory disease of the axial skeleton manifested by back pain & progressive stiffness of the spine Ankylosing Spondylitis The prevalence of the MHC,HLA-B27 is high in Caucasians but rare in Black populations with Ankylosing Spondylitis Dermatomyositis An idiopathic inflammatory myopathy associated with certain characteristic cutaneous manifestations Note: the inflammatory infiltrate in the muscle biopsy of this patient with Dermatomyositis Scleroderma The term encompasses a heterogeneous group of conditions linked by the presence of thickened sclerotic skin lesions The inflammatory process in Scleroderma results a marked fibrotic precess responsible for many of the clinical features Scleroderma Lung Disease 2 important lung diseases which occur due to the inflammatory process in Scleroderma Summary Medical Assistant Knowledge of the immune system forms the basis of understanding many of the diseases and disorders of the immune system and has become the focus of many exciting new treatment strategies. You must have knowledge of this system when assisting the physician during the examination of a patient who is having problems with their immune system. 86 Apply Your Knowledge Your 18-year-old patient states that he thinks his right big toe is inflamed. What symptoms would you expect to see? 87 Apply Your Knowledge Answer - Your 18-year-old patient states that he thinks his right big toe is inflamed. What symptoms would you expect to see? Redness, heat, swelling, and pain 88 Apply Your Knowledge How can a patient contract HIV? 89 Apply Your Knowledge Answer - How can a patient contract HIV? Most common routes of transmission are through sexual contact, blood, or from mother to child during pregnancy or breast-feeding 90 Apply Your Knowledge As you are taking your patient to the exam room, you notice that she has “Butterfly” rash on her face. What disorder exhibits this sign? 91 Apply Your Knowledge Answer - As you are taking your patient to the exam room, you notice that she has “Butterfly” rash on her face. What disorder exhibits this sign? Lupus 92 References 1. 2. 3. 4. 5. Sompayrac L. How the Immune System works. Blackwell Science, Inc. 1999 Roitt IM. Roitt’s Essential Immunology 10th ed. Blackwell Science 2001 Hochburg et al. Rheumatology 3rd ed. Mosby 2003 UpToDate 12.3 Kalla AA. Rheumatology Handbook. Rheumatic Diseases Unit Univrersity of Cape Town. 2003 References (cont) 6. 7. 8. 9. 10. Parkin J, Cohen B. An overview of the immune system. Lancet 2001;357: 17771789. Mackay IR, Rosen FS. Tolerance and Autoimmunity. NEJM 2001;344(9): 655 – 664. Mackay IR, Rosen FS. Autoimmune diseases. NEJM 2001; 345(5): 340-350. Epstein FH. Cytokine pathway and Joint Inflammation in Rheumatoid Arthritis. NEJM 2001; 344 (12): 907 – 916. Yuan G et al. Immunologic Intervention in the Pathogenesis of Osteoarthritis. Arthritis & Rheumatism 2003; 48(3) 602- 611. 감사합니다