Focus on Immunology Relates to Chapter 14 Genetics

Focus on Immunology (Relates to Chapter 14, “Genetics, Altered Immune Responses, and Transplantation, ” in the textbook) Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response • Immunity serves three functions • • • Defense Homeostasis Surveillance Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Lymphoid Organs • Central (primary) lymphoid organs • Thymus gland shrinks with age • Important in the differentiation and maturation of T lymphocytes Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Lymphoid Organs • Central (primary) lymphoid organs • Bone marrow • Produces red blood cells, white blood cells, and platelets Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Lymphoid Organs • Peripheral lymphoid organs • • Tonsils Gut-associated lymphoid tissues Genital-associated lymphoid tissues Bronchial-associated lymphoid tissues Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Lymphoid Organs • Peripheral lymphoid organs • • • Skin-associated lymphoid tissues Lymph nodes Spleen Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Organs of the Immune System Fig. 14 -5 Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Lymphoid Organs • Lymphoid tissue • Found in the submucosa of the respiratory, genitourinary, GI tracts • Skin-associated lymph tissue Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Lymphoid Organs • Spleen • Primary site for filtering foreign substances from blood • Major site of immune responses to bloodborne antigens Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • Lymphocytes • Mononuclear phagocytes • Dendritic cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Immune Response to a Virus Fig. 14 -6 Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • Lymphocytes • • • Produced in the bone marrow Eventually migrate to peripheral organs Differentiate into B and T lymphocytes Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Types of Lymphocytes T cells B cells Natural Killer (NK) cells 70%– 80% 10%– 20% < 10% Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • B lymphocytes • Differentiate into plasma cells when activated • Plasma cells produce antibodies (immunoglobulins) Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • T lymphocytes • Cells that migrate from bone marrow to thymus differentiate into T lymphocytes • Compose 70% to 80% of circulating lymphocytes • Responsible for immunity to intracellular viruses, tumor cells, and fungi Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • T lymphocyte subsets • T cytotoxic cells (CD 8) • Attack antigens on cell membrane of foreign pathogens • Release cytotoxic substances that destroy pathogen Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • T lymphocyte subsets • T helper cells (CD 4) • Regulate cell-mediated immunity and the humoral antibody response Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Macrophage, B Lymphocytes, and T Lymphocytes in the Immune Response Fig. 14 -7 Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • Natural killer (NK) cells • Involved in cell-mediated immunity • Large lymphocytes, not T or B cells • Do not require prior sensitization for activation • Recognize and kill virus-infected cells, tumor cells, and transplanted grafts Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune System Cells of Immune Response • Mononuclear phagocytes • Includes monocytes in the blood and macrophages found throughout the body • Capture, process, and present antigens to lymphocytes to initiate humoral or cytotoxic response • Capture antigens by phagocytosis Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response • Antigens • Substances the body recognizes as foreign that elicit an immune response • Most are composed of protein • Antibodies • Immunoglobulins produced by lymphocytes in response to antigens Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response • Cytokines • Soluble factors secreted by WBCs and a variety of other cells in the body • Act as messengers between the cell types • Instruct cells to alter their proliferation, differentiation, secretion, or activity Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response • Cytokines • Currently at least 100 different cytokines • Have a beneficial role in hematopoiesis and immune function Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response • Cytokines categories • • • Interleukins Interferons Tumor necrosis factor Colony-stimulating factors Erythropoietin Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-1 • • • Augments immune response Inflammatory mediator Promotes maturation and clonal expansion of B cells • Enhances activity of natural killer cells • Activates T cells and macrophages Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-2 • Induces proliferation and differentiation of T cells • Activates of T cells, NK cells, and macrophages • Stimulates release of other cytokines Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-3 (multicolony-stimulating factor) • Hematopoietic growth factor for hematopoietic precursor cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-4 • B cell growth factor • Stimulates proliferation and differentiation of B cells • Induces differentiation into TH 2 cells • Stimulates growth of mast cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-5 • B cell growth and differentiation • Promotes growth and differentiation of eosinophils Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-6 • • T- and B-cell growth factor Enhances inflammatory response Stimulates antibody secretion Promotes differentiation of B cells into plasma cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • IL-6 • Induces fever • Synergistic effects with IL-1 and TNF Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • -Interferon ( -IFN) and β-Interferon (β-INF) • Inhibit viral replication • Activate NK cells and macrophages • Antiproliferative effects on tumor cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • γ-Interferon (γ-IFN) • Activates macrophages, neutrophils, and NK cells • Promotes B-cell differentiation • Inhibits viral replication Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Mechanism of Action of Interferon Fig. 14 - 8 Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • Tumor necrosis factor (TNF) • Activates macrophages and granulocytes • Promotes the immune and inflammatory responses • Kills tumor cells • Responsible for extensive weight loss • Associated with chronic inflammation and cancer Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • Colony-stimulating factors (CSFs) • Granulocyte colony-stimulating factor (G -CSF) • Stimulates proliferation and differentiation of neutrophils • Enhances functional activity of mature PMN Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • CSFs • Granulocyte-macrophage colonystimulating factor (GM-CSF) • Stimulates proliferation and differentiation of PMNs and monocytes Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cytokines • CSFs • Macrophage colony-stimulating factor (M -CSF) • Promotes proliferation, differentiation, and activation of monocytes and macrophages Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • α-Interferon (Roferon-A, Intron A) • • • Hairy cell leukemia Chronic myelogenous leukemia Malignant melanoma Renal cell carcinoma Lymphomas Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • α-Interferon (Roferon-A, Intron A) • • Ovarian cancer Hepatitis B and C Kaposi sarcoma Multiple myeloma Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • -Interferon (Betaseron, Avonex, Rebif) • Multiple sclerosis Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • Colony-stimulating factors • G-CSF (Neupogen, Neulasta) • Chemotherapy-induced neutropenia • GM-CSF (Leukine) • Neutropenia, myeloid recovery after bone marrow transplantation Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • Soluble TNF receptor (Enbrel) • Rheumatoid arthritis Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • IL-2 (Proleukin) • • • Metastatic renal cell carcinoma Metastatic melanoma Stimulate hematopoiesis in bone marrow and extramedullary sites Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • Erythropoietin (Epogen, Procrit, Aranesp) • Anemia of chronic cancer and chemotherapy Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Clinical Uses of Cytokines • IL-1 receptor antagonist (Kineret) • Rheumatoid arthritis Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Comparison of Humoral and Cell-Mediated Immunity Humoral Cell involved B lymphocytes Products Antibodies Memory cells Present Cellular • T lymphocytes • Macrophages • Sensitized T cells • Cytokines Present Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Comparison of Humoral and Cell-Mediated Immunity Humoral Protection • Bacteria • Viruses (extracellular) • Respiratory pathogens • Gastrointestinal pathogens Cellular • Fungus • Viruses (intracellular) • Chronic infectious agents • Tumor cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • Antibody-mediated immunity • Antibodies produced by plasma cells (differentiated B lymphocytes) • Primary immune response is evident 4 to 8 days after initial exposure to antigen Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • Ig. G • Largest component of total immunoglobulins • Found in plasma and interstitial fluid • Only Ig to cross placenta and provide newborn with passive acquired immunity Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • Ig. A • Found in body secretions • Saliva • Tears • Breast milk • Colostrum • Lines mucous membranes Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • Ig. M • Largest of immunoglobulins is found in plasma • Responsible for primary immune response • Forms antibodies to ABO blood antigens Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • Ig. D • Found in plasma • Present on lymphocyte surface • Assists in differentiation of B lymphocytes Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • Ig. E • Found in plasma and interstitial fluids • Causes symptoms of allergic reaction Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Humoral Immunity • When an individual is exposed to an antigen for a second time, the response is faster (1 to 3 days) and lasts longer • Main product of secondary response is Ig. G rather than Ig. M • Memory cells account for more rapid production of Ig. G Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Log of antibody titer Normal Immune Response Humoral Immunity Secondary response Primary response Ig. M First exposure to antigen Ig. G Subsequent exposure to same antigen Relative time after exposure Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved. FIG. 14 - 9

Normal Immune Response Cell-Mediated Immunity • Immune responses initiated through specific antigen recognition by T cells • Several cell types involved in cellmediated immunity • T lymphocytes • Macrophages • NK cells Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response Cell-Mediated Immunity • Important roles • Immunity against pathogens that survive inside cells (viruses, some bacteria) • Fungal infections • Rejection of transplanted tissues • Contact hypersensitivity reactions • Tumor immunity Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Normal Immune Response to a Virus Fig. 14 -6 Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Effects of Aging on the Immune System • Decline in immune system • • • ↑ Incidences of tumors Greater susceptibility to infections Thymic involution ↓ Cell-mediated immunity ↓ Delayed hypersensitivity reaction ↓ IL-1 and IL-2 synthesis Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Effects of Aging on the Immune System • Decline in immune system • • • ↓ Expression of IL-2 receptors ↓ Proliferation response of T and B cells ↓ Primary and secondary antibody responses • ↓ Autoantibodies Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.

Effects of Aging on the Immune System • Bone marrow function is relatively unaffected by increasing age • ↓ In size and activity of thymus is mostly cause of immunosenescence • Both T and B cells show deficiencies in activation with increasing age Copyright © 2007, 2004, 2000, Mosby, Inc. , an affiliate of Elsevier Inc. All Rights Reserved.