Resistance of the Body to Infection PDF

 UNIT VI Chapter 34: Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte- Macrophage System, and Inflammation Ebaa M Alzayadneh, BDS, PhD, Associate Professor of Physiology...

 UNIT VI Chapter 34: Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte- Macrophage System, and Inflammation Ebaa M Alzayadneh, BDS, PhD, Associate Professor of Physiology 1  Defense Against Infection Leukocytes Microorganisms coexist with us and within us , which can be beneficial or harmful. Phagocytes can ingest and destroy invading organisms and participate in tissue reactions that “wall off” infection. Other white cells (lymphocytes, chapter 35) mediate responses that destroy or neutralize specific microorganisms. 2  White Blood Cells Circulate in blood and may enter the tissues Are of six types: - Polymorphonuclear neutrophils - “ eosinophils - “ basophils - Monocytes - Lymphocytes (plasma cells) - Platelets (from megakaryocytes) 3  White Blood Cell Counts Total WBC ~ 7,000 / mm3 (almost 1,000-fold fewer than RBCs) Proportions: - Neutrophils 62% - Eosinophils 2.3% - Basophils 0.4% - Monocytes 5.3% - Lymphocytes 30% Platelets ~ 300,000 / mm3 4  Leukopoiesis Bone marrow myeloblast only megakaryocy te Monocyte genesis promyelocyt e neutrophil myelocyte eosinophilbasophil myelocyte myelocyte Young Mainly in neutrophil lymphogenous metamyelocyte tissues, Polymorph band neutrophil eosinophil lypmp glands, -nuclear metamyelocyte Meta thumus….. basophil -myelocyte Polymorph -nuclear neutrophil polymorphnuclea 5 r eosinophil  Genesis of White Blood Cells Granulocytes and monocytes develop in the bone marrow, and most remain there until needed peripherally (number in marrow ~3x blood; 6-day supply) Lymphocytes complete development mostly in the peripheral lymphoid organs (thymus, spleen, tonsils, lymph nodes, Peyer’s patches), less found in blood Megakaryocytes develop and reside in the marrow, fragment to release platelets 6  Life Span of White Blood Cells Granulocytes: Circulating, 4 – 8 hours In the tissues, 4 – 5 days (shorter timelines with infection, inflammation) Monocytes / Macrophages: Circulating, 10 – 20 hours As tissue macrophages, months or longer Lymphocytes: Continuously re-circulate: lymph…nodes…blood.. tissues (diapedesis) Long-lived… weeks, months, longer Platelets: ~ Replaced every ten days~ 30K each day 7  Neutrophils and Macrophages Neutrophils are mature cells that can respond immediately to infection Monocytes mature in the tissues to become macrophages (monocytes in blood little ability) Both exhibit motility: Diapedesis Diapedesis - Medical Animation by Arc Solutions - YouTube Ameboid motion Chemotaxis (Chemoattractants: bacterial or tissue degradation products, complement fragments, other chemical mediators) 8 Neutrophil Margination & Migration 9  Phagocytosis “Phagocytosis” is the ingestion of particles Phagocytes must distinguish foreign particles from host tissues Appropriate phagocytic targets: May have rough surfaces Lack protective protein coats May be immunologically marked for phagocytosis by antibodies or complement components that are recognized by receptors on the phagocytes … this immunologic marking is called “opsonization” 10 Phagocytosis Neutrophils: can ingest 3-20 bacteria Macrophages: After being activated in the tissues, are extremely effective phagocytes (up to ~100 bacteria) Macrophages can ingest larger particles… Damaged RBCs Malarial parasites Macrophages can extrude digestion products and survive and function for many months 11  Digestion of Ingested Particles In both neutrophils and macrophages, phagosomes fuse with lysosomes and other granules to form phagolysosomes (digestive vesicles) These contain proteolytic enzymes, and in macrophages, lipases (important in killing tuberculosis bacillus and some other bacteria) 12  Bactericidal Agents Bacteria may be killed even if they are not digested Enzymes in the phagosome or in peroxisomes generate strongly bactericidal reactive oxygen species… Superoxide (O2-) Hydrogen peroxide (H2O2) Hydroxyl ions (OH-) Myeloperoxidase catalyzes H2O2 + 2 Cl- 2 H+ + 2 ClO- 13  The Reticuloendothelial System After entering the tissues, macrophages become fixed and may be resident for years When appropriately stimulated they can break away and move to sites of inflammation Circulating monocytes, mobile macrophages, fixed tissue macrophages, and some specialized endothelial cells form the reticuloendothelial system, almost all derived from monocytes, comprising a phagocytic system located in all tissues 14  Specialized Macrophages Skin, subcutaneous (histiocytes) Lymph nodes Ingest / sample particles arriving through the lymph Alveolar macrophages Digest or entrap inhaled particles and microorganisms like silica, tuberculosis bacilli. Kupffer cells Lining sinusoids, Surveillance of the portal circulation. Macrophages in the spleen and bone marrow Surveillance of the general circulation 15 Structure of a Lymph Node 16 Kupffer Cells in the Liver Sinusoids 17 Structure of the Spleen 18  Neutrophils, Macrophages & Inflammation Inflammation is driven by chemical mediators and characterized by heat, redness, swelling, and pain Physiologically, it involves… Vasodilatation and increased blood flow Increased capillary permeability Coagulation of interstitial fluids Accumulation of granulocytes and monocytes Swelling of tissue cells Mediators: histamine, bradykinin, serotonin, prostaglandins, complement products, clotting components, lymphokines 19  “Walling Off” Sites of Inflammation Fibrinogen clots minimize fluid flow in and out of the inflamed area Staphylococci cause intense inflammation and are effectively “walled off” Streptococci induce less intense inflammation and may be more likely to spread than staphylococci, and cause death 20  Neutrophils and Macrophages in Inflammation Tissue macrophages that encounter foreign particles enlarge and become mobile to provide a first line of defense (min) Within an hour neutrophils migrate to the area in response to inflammatory cytokines (TNF, IL-1) 2nd line of defense Upregulated selectins and ICAM-1 on endothelial cells Bind to integrins on neutrophils, leading to margination, followed by diapedesis, and chemotaxis directing neutrophils into the inflamed tissues, to kill bacteria and scavenge 21 Neutrophil Migration to an Inflamed Site 22  Neutrophilia With intense inflammation neutrophil count can increase dramatically… 4,000-5,000 15,000-25,000 Results from mobilization of mature neutrophils from the bone marrow by inflammatory mediators 23 Secondary Macrophage Invasion In response to chemoattractants, monocytes gradually accumulate (slowly) and become macrophages (after ~ 8 hours mature) In part due to increased bone marrow production (store is low), macrophages become the dominant inflammatory cell over several weeks, cleaning up remaining bacteria, necrotic tissue, and directing tissue remodeling. Third line of defense 24  Bone Marrow Responses Growth factors produced in response to infection and inflammation drive proliferation and differentiation of leukocyte precursors in the marrow First mature cells released after 3 – 4 days The bone marrow can increase production of granulocytes and monocytes by 20 – 50- fold and maintain this for months or years Fourth line of defense 25 Bone Marrow Response to Inflammation 26  Formation of Pus Pus is composed of dead bacteria and neutrophils, many dead macrophages, necrotic tissue that has been degraded by proteases, and tissue fluid, often in a cavity formed at the inflammatory site Over days and weeks it is absorbed into the surrounding tissue and lymph and disappears 27  Eosinophils Eosinophils are weak phagocytes and exhibit chemotaxis Particularly important in defense against parasites, Ex: schistosomiases and trichinosis Can adhere to parasites and release substances that kill them (hydrolases, reactive oxygen species, major basic protein(larvacidal). Also accumulate in tissues affected by allergies, perhaps in response to eosinophil chemotactic factor from basophils (eosinophils may detoxify some products of basophils) 28  Basophils Similar to mast cells adjacent to Capillaries, both cell types release heparin Basophils and mast cells both release histamine, bradykinin, and serotonin When IgE bound to receptors on their surfaces is cross-linked by its specific antigen, mast cells and basophils degranulate, releasing… histamine, bradykinin, serotonin, heparin, leukotrienes, and several lysosomal enzymes 29  Clinical Leukopenia Perspective Leukopenia, or low white blood cell count, is usually the result of reduced production of cells by the bone marrow It can allow clinically severe infections with organisms that are not usually pathogenic Within two days of bone marrow shutdown mucous membrane ulcers or respiratory infection may occur Causes: radiation, chemical toxins, some medicines In most cases marrow precursors can reconstitute normal blood cell counts with proper support 30  Leukemias Clinical Perspective Uncontrolled production of abnormal white blood cells due to a genetic mutation Clonal, lineage-specific, often immature cells Leukemias are… Lymphocytic vs. myelogenous Acute vs. chronic (sometimes up to 10-20 years) Leukemias with partially differentiated cells may be classified as neutrophilic, eosinophilic, basophilic, or monocytic leukemias 31  Clinical Clinical Effects of Leukemias Perspective Growth of leukemic cells in abnormal sites Invasion of bone from the marrow, with pathologic fractures Eventually spreads to vascular and lymphatic “filters”… spleen, lymph nodes, liver, other organs Replacement of normal bone marrow, resulting in infection, and bleeding Wasting because of metabolic demands 32 UNIT VI Chapter 35: Resistance of the Body to Infection: II. Immunity and Allergy; Innate Immunity Ebaa M Alzayadneh, PhD Associate Professor of Physiology  Immunity Innate - inborn ability to resist damaging organisms and toxins: skin, gastric acids, tissue neutrophils and macrophages, complement, microbicidal and lytic chemicals in blood and blood cells Acquired = specific humoral circulating antibodies cellular activated cells  Acquired Immunity Antibodies or activated cells that specifically target and destroy invading organisms and toxins Powerful: can neutralize 100,000 x lethal dose of some toxins Two types of acquired immunity: Humoral ( B cell ) Cell-mediated ( T cell )  Antigen A substance that can elicit an immune response Unique to each invading organism Usually proteins or large polysaccharides Most are large (MW > 8,000) and have recurring molecular groups on their surfaces The molecular structures that are specifically recognized in acquired immunity are called “epitopes”  Lymphocytes Mediate acquired immunity Develop in lymphoid tissues Tonsils / adenoids, Peyer’s patches (GI), lymph nodes, spleen, thymus, marrow Are strategically positioned Two types of lymphocytes  Rapid expansion Maturation Each clone is specific of T cells for a single antigen in the Self-reactive clones are deleted (up to 90%) Thymus Migrate to peripheral lymphoid organs Much of the above occurs just before and shortly after birth  B cell Development Initial growth and differentiation in the liver (fetal) and bone marrow (after birth) Migrate to the peripheral lymphoid organs Each clone is specific for a single antigen Clonal development provides almost limitless antibody specificity Secreted antibodies destroy or neutralize molecules or organisms bearing their cognate antigen B cell proliferation in response to antigen  Immunologic Specificity Each B or T cell clone is specific for a single epitope of a single antigen The genes for B cell receptors (immuno-globulins) and T cell receptors have hundreds of “gene segments” that are used in varying combinations Permutations (arrangements) of these cassettes allow specificity for millions of distinct epitopes  Macrophages in lymphoid organs… ingest antigen and present antigenic peptides to “helper” T cells Secrete IL-1, other cytokines that promote T Helper lymphocyte growth and cells produce Lymphocyte differentiation additional cytokines that Activation stimulate B and T cell proliferation and differentiation Both B and T cells require antigenic stimulation to proliferate  Antibody Production B cells bind intact antigen T cells bind presented antigenic peptides B cells proliferate (with T cell help), developing lymphoblasts and plasmablasts Up to 500 antigen-specific progeny in 4 days, each producing as many as 2,000 Ig molecules/sec Can persist for many weeks, if antigenic stimulation persists Memory B cells and secondary responses Structure of Immunoglobulins  Antibody Specificity Each antibody has a steric configuration specific to its antigen Multiple prosthetic groups of each antigen interact with complementary structures of the antibody, through… hydrophobic bonding hydrogen bonding ionic interactions van der Waals forces Antibodies are at least bivalent  Antibody classes (isotypes) IgM (earliestproduced, five pairs of heavy chains and light chains) IgG (75% of all immunoglobulins) IgA IgD IgE (critically involved in allergic reactions) Immunoglobulins make up about 20% of all plasma proteins  Agglutination Precipitation Antibodies: mechanisms Neutralization of action Lysis Complement activation Agglutination  The Complement System C3a, C4a, and C5a activate mast cells and basophils,  T cell activation Binds to cognate antigen presented by antigen-presenting cell Rapid expansion of T helper (CD4) cells T helper cells produce cytokines Drives expansion of both T helper (CD4) and cytotoxic (CD8) T cells Both types of cells also generate clonal memory T cells  MHC Proteins B cell surface and secreted antibodies recognize intact antigen However, T cells only recognize antigen fragments that are presented by MHC molecules of antigen presenting cells… macrophages B lymphocytes dendritic cells Antigen Presentation  Helper (CD4) T cells ~ 75% of all T cells Regulate functions of other immunologic cells by producing cytokines… Interleukin (IL-) 2, 3, 4, 5, 6, GM-CSF, Interferon-gamma  T cell help for immune response Positive feedback for helper T cells (IL-2) Stimulation of cytotoxic T cells (IL-2, other cytokines) Stimulation of B cells (IL- 4, 5, 6 (BCGFs) ) Macrophage accumulation, activation, enhanced killing  Killing by cytotoxic T cells Virus-infected cells Cancer cells Transplanted organs and tissues  Immunologic Tolerance Host defense employs powerful destructive mechanisms These must be directed at pathogens while protecting host tissues from damage “Tolerance” in acquired immunity is achieved mainly by clonal selection of T cells in the thymus and B cells in the bone marrow clones that bind host antigens with high affinity are induced to undergo apoptosis, and are deleted  Failure of tolerance produces autoimmunity Rheumatic fever (cross-reactivity with streptococcal antigens) Post-streptococcal glomerulonephritis Myasthenia gravis (antibodies to acetylcholine receptors) Systemic lupus erythematosis (auto-immunity to multiple tissues)  Clinical Allergic manifestations Perspective Anaphylaxis systemic, potentially fatal widespread vasodilatation ↑↑ capillary permeability, volume loss leukotrienes → bronchospasm and wheezing Treatment: epinephrine and antihistamines Urticaria localized vasodilatation and red flare Increased permeability and swelling (“hives”) Treatment: antihistamines