Chapter 1: Introduction and Natural ImmunityImmunology and Serology

1960 Cells responsible for immune response were identified and characterizedImmunity and Immunization Immunology The study of hosts reactions when foreign substances are introduced into the body Antigen Foreign substances that induces immune response Variolation (1500) Developed by Chinese Exposing individuals to material from smallpox lesions Theory: If a healthy individual was exposed as a child or young adult, effects of the disease are minimized Edward Jenner (1700) Relationship between exposure to cowpox and immunity to smallpox Vaccination From the Latin word vacca meaning cow Injecting cellular material that provide protection Cross-immunity Phenomenon in which, exposure to one agent produces protection against other agent Louis Pasteur First attenuated vaccine Attenuation Change; remains as basis for immunizations May occur through: Chemical Heat AgingCellular versus Humoral Immunity Ellie Metchnikoff Phagocytosis (cells eat cells) Foreign objects introduced to transparent starfish larvae become surrounded by motile cells Immunity to disease was based on action of scavenger cells Theory of Humoral Immunity Noncellular elements in the blood were responsible for protection from microorganisms Almoth Wright Linked 2 theories by showing that immune response involved both cellular & humoral elements Opsonins Circulating factors Coat bacteria so that they become more susceptible to phagocytosis Antibodies Serum factors Specific proteins Acute phase reactants Nonspecific factors Increase nonspecifically in any infection Natural or Innate Immunity Ability of individual to resist infection by means of normally present body function Non-adaptive/ nonspecific SAME for all pathogens NO PRIOR EXPOSURE REQUIRED

Factors that influence Mechanism of Natural Immunity1. Fatigue2. Age3. Nutrition4. Genetic Determinants5. Stress

Acquired Immunity Specific for individual pathogen REMEMBER PRIOR EXPOSURE response upon repeated exposure**Both systems (Natural and Acquired Immunity) are essential to maintain good health and are dependent on one another for maximal effectiveness Two (2) parts of Natural Defense System1. Internala. Cellular Mechanismsb. Humoral Factors2. External

External Defense System Keep microorganisms from entering the body Internal Defense System Promote phagocytosis which results in foreign cell destruction Inflammation Brings cells and humoral factors to are in need of healingExternal Defense System External Defense System Composed of structural barriers that prevent most infections from entering the bodya. Unbroken skinb. Mucosal Membrane surfaces

Skin Major structural barrier Secretions Discourages the growth of microorganisms Lactic acid Sweat Skin (pH 5.6) and Vagina (pH 5) Fatty acid Sebaceous glands Maintain pH 5.6 Mucous secretions + cilia Nasopharynx Clears 90% of deposited materials Urine Flushing action Slight acidity Genitourinary tract Hydrochloric acid Stomach pH 1, halts microbial growth Tears and Saliva Contains lysozyme that attacks cell wall of gram + bacteria Normal flora Competitive exclusion Keeps pathogens from establishing themselvesInternal Defense System Internal Defense System Second part of natural immunity Cells and soluble factors plays essential parts Recognize molecules that are unique to infectious organisms e.g. recognizing mannose which is not evident in human cells Phagocytosis Engulfment of cells or particulate matter Most important function of the internal defense system Enhanced by soluble factors/ Acute phase reactants

Acute-Phase Reactants Acute-Phase Reactants Normal serum constituents Increases rapidly by at least 25% due to:a. Infectionb. Injuryc. Trauma Produce primarily by HEPATOCYTES within 12-24 hours Cytokines Intercellular signaling polypeptides Cell messengersa. IL-1b. IL-6c. TNF- Mainly produced by MONOCYTES and MACROPHAGES at the site of inflammation

C-Reactive Protein (CRP) Trace constituent of serum Increases rapidly within 2-6 hours following infection Increase 100x-1000x Peak Value: 48 hours Member of Pentraxins Protein with 5 subunits Main substrate is phosphocholine Capable of:a. Opsonizationb. Agglutinationc. Precipitationd. Complement activation Binding is calcium-dependent and nonspecific Able to act as defense until specific antibodies can be produced (Acts before antibodies are produced) Most widely used indicator of inflammation noninvasive means of following the course of malignancy and organ transplantation Normal levels:a. Men 1.5 mg/Lb. Women 2.5 mg/L CRP Levelsa. Malignancyb. Organ rejectionc. Bacterial and viral infectiond. Tuberculosise. Myocardial infarctionf. Ischemic stroke** CRP Levels is a risk factor in Myocardial infarction and Ischemic stroke Serum Amyloid A Increase 1000x Apolipoprotein synthesized in the liver Normal levels: 30 g/L Associated with HDL; cholesterol metabolism Contributes to site if tissue injury clean up Recycles cholesterol and phospholipids for reuse un building new membranes in acute inflammation Bacterial Infection (SAA Levels) > Viral Infection (SAA Levels)

Complement Series of serum proteins Mediates inflammation Classical Cascade Nine (9) proteins activated by bound antibodies in a sequence Major functions:a. Opsonizationb. Chemotaxisc. Lysis of cells

Mannose-Binding Protein Aka Mannose-Binding Lectin A trimer that acts as a opsonin Calcium-dependent Widely distributed on mucosal suface Similar to C1q Binding activates complement cascade Normal concentrations: 10 g/ mL MBP recurrent yeast infection

Alpha1-Antitrypsin Major component of - band when serum is electrophoresed General plasma inhibitor of Elastase (Protease) Elastase Endogenous enzyme that can degrade elastin and collagen Damages lung tissue in chronic pulmonary inflammation Mop up, counteracts the effects of neutrophil invasion Regulates expression of proinflammatory cytokines AATa. Premature emphysemab. Idiopathic pulmonary fibrosis Homozygous inheritance leads to:a. Cirrhosisb. Hepatitisc. Hepatoma Can also react with any serine protease

Haptoglobin 2- globulin bind irreversibly to free hemoglobin released by intravascular hemolysis Haptoglobin + Free hemoglobin cleared by Kupffer cells and parenchymal cells plasma haptoglobin due to de novo synthesis in the liver Increases 2x-10x following:a. Inflammationb. Stressc. Tissue necrosis Normal plasma concentration: 40-290 mg/dL Functiona. Protects from kidney damageb. Prevent loss of ironc. Protection against oxidative damage by free hemoglobin Free hemoglobin Powerful oxidizing agent Generate peroxides and hydroxyl radicals

Fibrinogen Most abundant coagulation factors Forms the fibrin clot Dimer Normal levels: 100-400 mg/dL Cleaved by thrombin to form fibrils that make up the fibrin clot Clot formation:a. Increase the strength of the woundb. Stimulates endothelial cell adhesion and proliferationc. Creates a barrier that helps prevent the spread of microorganisms further into the body Promote aggregation of RBC Fibrinogen Levels risk for coronary artery disease in women

Ceruloplasmin Principal copper-transporting protein Acts as ferroxidase Feroxidase Oxidizes iron from Fe2+ to Fe3+ Means of releasing iron from ferritin for binding to transferrin

Wilsons disease Autosomal recessive genetic disorder Depletion of ceruloplasmin Massive increase of copper in tissues Copper accumulates in the liver and brain, cornea, kidneys, and bonesCellular Defense Mechanisms Five (5) Principal Types of WBC (Leukocytes)1. Neutrophil2. Eosinophil3. Basophil4. Monocyte5. Lymphocyte** Neutrophil, eosinophil, and basophil are granulocytes Myeloid line WBC that participate in phagocytosis Arise from common precursor in the marrow

Neutrophil Aka Polymorphonuclear neutrophilic leukocyte (PMN) 50-70% of total peripheral WBC 10-15 m in diameter Nucleus: 2 & 5 lobes Life span: 5 days immediately in acute infection Large number of neutral staining granulesa. Primary/ Azurophilic Granules Contains: Myeloperoxidase Elastase Proteinase 3 Lysozyme Cathepsin G defensinsb. Secondary Granules Contains: Collagenase Lactoferrin Lysozyme Reduced NADPH oxidasec. Tertiary granules Newly discovered Contains: Gelatinase Plasminogen activator Lysosomes Separate compartments that contain acid hydrolase Marginating Allow neutrophils to move from circulating blood to the tissue by diapedesis Diapedesis Movement through the blood vessel walls Selectins Receptors that make neutrophils sticky and enhance adherence to endothelial cells Chemotaxins Chemical messengers that cause cells to migrate in a particular direction

Factors that are Chemotactic to Neutrophils1. Complement2. Proteins from coagulation cascade3. Products from bacteria and virus4. Platelet activating factor5. Secretion from mast cells, lymphocyte, macrophages and other neutrophils

Eosinophils 12-15 m in diameter 1-3% of circulating WBC in parasitic infections, allergic reactions Less efficient than neutrophils in phagocytosis because of the lack of digestive enzymes Main function: Neutralize basophil and mast cell products Kill parasites Nucleus: Bilobed, ellipsoidal, eccentric Cytoplasm: Filled with large orange to red-orange granulesa. Primary Granules Contains: Acid phosphatase Arylsulfataseb. Eosinophil-Specific Granules Contains: Major basic protein Eosinophil cationic protein Eosinophil peroxidase Eosinophil-derived neurotoxin

Basophils Less than 1% of circulating WBC Smallest granulocyte (10-15 m) IgE binds to Basophil cell membranes and granules release constituents when in contact with antigen Lacks hydrolytic enzymes but contains peroxidase Contains coarse, densely staining deep-bluish-purple granules which obscure the nucleus for hypersensitivity reactionsa. Histamine Vasoactive amine that contracts smooth muscleb. Heparin anticoagulantc. Eosinophil-chemotactic factor

Mast Cells Resemble basophils but larger CT cells of mesenchymal origin Small round nucleus and more granules Life span: 9-18 months For hypersensitivity reactions Granules contain: Acid phosphatase Alkaline phosphatase Protease

Monocytes Mononuclear cells Largest cells in peripheral blood 12-20 m diameter: average diameter 18 m Irregularly folded or horseshoe-shaped nucleus that occupies one half of the cell Cytoplasm stains dull grayish blue and has a ground glass appearance containing digestive vacuoles 4-10% of total circulating WBC Stay in peripheral blood for up to 70 hours Becomes macrophages (macrophages precursors) Granules:a. 1st type Similar to lysosomes of neutrophils Contains: Peroxidase Acid phosphatase Arylsulfataseb. 2nd type Contains: - glucuronidase Lysozyme Lipase No alkaline phosphatase

Tissue Macrophages Arise from monocytes Monocyte to macrophage Enlarges between 25-80 m Contains no peroxidase Motility is slow; not as efficient as neutrophil Life span: months Macrophage + cytokines/ microorganism = macrophage becomes activated

Cytokines Chemical messengers released by T lymphocytes Monocyte-Macrophage system Initiate and regulate the immune respons

Specific names of Macrophage according to location1. Alveolar macrophage lungs2. Kupffer cells liver3. Microglial cells brain4. Histiocytes connective tissue

Function of Macrophage1. Microbial killing2. Tumoricidal activity3. Intracellular parasite eradication4. Phagocytosis5. Secretion of cell mediators6. Antigen presentation

Dendritic cells Covered with long membranous extensions Main function: Phagocytose antigen and present it to helper T lymphocyte Descendent of myeloid lines Most potent phagocytic cell

Classification based on location1. Langerhans cells - skin2. Interstital dendritic cells heart, lungs, liver, kidney, GIT3. Interdigitating dendritic cells T lymphocyte areas of secondary lymphoid tissue and thymus

Toll-like Receptors Very similar molecules with toll found on human leukocytes and some nonleukocyte cell types Highest concentration of these receptors occurs on monocytes, macrophages, and neutrophils Enhances natural immunity There are 11 slightly 11 different TLRs in humansa. TLR2 Recognizes teichoic acid and peptidoglycan (gram positive bacteria)b. TLR4 Recognizes LPS (gram negative bacteria)c. TLR1 Recognizes MycobacteriaPhagocytosis 4 Main Steps in Phagocytosis1. Physical contact between WBC and foreign particle2. Formation of phagosome3. Fusion with cytoplasmic granules to form phagolysosome4. Digestion and release of debris to the outside

Opsonins To prepare for eating Serum proteins that attach to a foreign substance and help prepare it for phagocytosis Neutralizes surface charge on foreign particle CRP Complement components Antibodies Respiratory or Oxidative Burst Occurs within the cell as the pseudopodia enclose the particle within a vacuole

Inflammation Inflammation Overall reaction of the body to injury or invasion by infectious agent

4 Cardinal Signs or Clinical Symptoms1. Redness2. Swelling3. Heat4. Pain

Major Events Associated with Inflammation1. Inc. blood supply to infected areas2. Inc. permeability caused by retraction of endothelial cells3. Migration of WBC (Neutrophils) to surrounding tissue4. Migration of macrophages to injured area

Histamine Chemical mediator Release from injured mast cell Cause dilation of blood vessels and adds blood flow to affected area

Acute-Phase Reactants Soluble mediators

Amplification Occurs through formation of clots by the coagulation system and triggering of fibrinolytic system

Neutrophils Mobilized within 30-60 minutes Major cell type in acute inflammation Emigration: 24-48 hours Proportional to level of chemotactic factors

Macrophages Peaks at 16-48 hours Clear areas by phagocytosis

Chronic Inflammation Prolonged inflammation