From Blood to Host Defense: Components and Function
The relationship between blood and host defense is explored in this comprehensive study by Gregory J. Bagby, Ph.D. The immune system's innate and adaptive responses, as well as the role of cellular elements in blood, are detailed. Learn about hemostasis, pathogen recognition, inflammatory responses, and more essential functions of blood in defending the body.
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From Blood to Host Defense Gregory J. Bagby, Ph.D. gbagby@lsuhsc.edu Office: 310 (CSRB)
From Blood to Host Defense Blood Components and function Hemostasis and clotting The host defense system Innate immune system Pathogen recognition Inflammatory response Local to systemic responses and integration Adaptive immune system Humoral immune system and antibodies Cell-mediated immune system
The Relationship between Blood and Host Defense Liver Bone marrow Vascular system Lymphoid system Lymph node
The Relationship between Blood and Host Defense Cellular elements of blood and the immune system produced and/or originate in bone marrow via hematopoiesis Red blood cells (erythrocytes) important in O2 and CO2 transport. White blood cells (leukocytes) key roles in host defense. Platelets perform role in hemostasis and clotting Plasma proteins many produced in liver or by cells of the host defense system
From Blood to Host Defense Blood Components and Function Gregory J. Bagby, Ph.D. gbagby@lsuhsc.edu Office: 310 (CSRB)
The components of blood Assessment of Cell Numbers and Types Regulation of hematopoiesis Regulation of erythrocyte production
What is blood? Blood is a fluid that normally circulates through the lumen of the cardiovascular system (heart, arteries, capillaries, and veins) Two major components Plasma liquid (a complex solution) Formed elements (cells and cell fragments)
What are the main functions of blood? Transport water, ions, nutrients and waste products to and from tissues Ions sodium, chloride, calcium, bicarbonate, etc Nutrients glucose, amino acids, lipids, oxygen Waste products urea, lactic acid, carbon dioxide Transport signaling molecules (hormones) from cells of origin to target cells Defending or protecting the blood and extravascular compartments Hemostasis and clotting Role in host defense - means by which elements of the host defense system travel to the thymus, mucosal tissues, liver, lymphoid tissue, and sites of tissue injury or infection.
The Components of Blood Plasma liquid component Formed elements 1. Erythrocytes 2. Leukocytes 3. Platelets Regulation of Blood Cell Production These components are maintained within a narrow range (concentration or counts/ml), but new replace old. Production and/or removal of each constituent if regulated to maintain homeostasis.
Hematocrit or PCV Plasma includes water, ions, proteins, nutrients, hormones, wastes, etc. Normal values Men = 45% Women = 42% Buffy coat of leukocytes separates RBC from plasma. The hematocrit is a rapid assessment of blood composition. It is the percent of the blood volume that is composed of RBCs (red blood cells).
How Much Blood Is in the Body? Blood volume normally 8% of body weight Blood volume = 5.6 L in 70 kg man Erythrocyte Volume (45% hematocrit): 0.45 x 5.6 L = 2.5 L Plasma Volume: 5.6 L 2.5 L = 3.1 L
Constituents of Plasma Constituents Amount/Concentration Water 93% Electrolytes Total < 1% plasma weight Na+ 145 mM K+ 4 mM Ca+2 2.5 mM Mg+2 1.5 mM H+ 0.0004 mM Cl- 103 mM HCO3- 25 mM Phosphate 1 mM SO4-2 0.5 mM Function Solvent Osmotic balance; buffers; membrane excitability; clotting Proteins Albumins Globulins Fibrinogen Total = 7.3% plasma weight 4.2% 2.8% 0.3% Lumen confined solutes - osmotic balance; buffers; transporters of lipids, etc; clotting; enzymes, antibodies; hormones (Liver) (Immune) (Liver)
Constituents of Plasma (continued) Constituents Amount/Concentration Function Gases CO2 O2 N2 1 mM 0.1 mM 0.5 mM Waste product; pH buffer Oxidative metabolism No function Nutrients Glucose Amino acids Lipids Cholesterol Fatty acids Triglycerides Vitamins Hormones 5.6 mM Sum = 2 mM 500 mg/dl Energy metabolism Back bone of proteins Energy metabolism; Hormone precursors; Involved in metabolic pathway control and ion homeostasis Bound to albumin or in lipoproteins
Constituents of Plasma (continued) Constituents Vitamins Amount/Concentration 0.00005-0.1 mM Function Co-enzymes, pre- hormones, other Co-factors, other Trace elements (Cu, Zn) Waste products Urea Creatinine Uric acid Bilirubin Individual hormones 0.003-0.018 mM 5.7 mM 0.09 mM 0.3 mM 0.003 0.018 mM 10-12-10-7 M) Breakdown from proteins From creatine From nucleic acids From heme Messengers
Serum and Plasma Serum is plasma with fibrinogen and other proteins involved in clotting removed as a result of clotting. Serum is often used for analysis instead of plasma Need anticoagulant to obtain plasma Fewer interfering substances in serum (less protein)
Suspended Formed Elements 5,000,000/mm3 250,000/mm3 7,000/mm3 The major forms of cells in the blood. Among these, only the leukocytes are true cells with nuclei.
Normal Range of Blood Cell Numbers (counts/liter) Cell Type Erythrocytes Adult women 3.8 to 5.0 x 1012 Adult men 4.5 to 6.5 x 1012 Leukocytes 4 to 11 x 109 4 to 11 x 109 Granulocytes (neutrophils) 2.0 to 7.5 x 109 2.0 to 7.5 x 109 Lymphocytes 1.3 to 4.0 x 109 1.3 to 4.0 x 109 Platelets 150 to 440 x 109 150 to 440 x 109 Oxford Handbook of Clin Med and Anatomy & Physiology in Health and Illness (Ross and Wilson)
Red Blood Cells: Erythrocytes Carry O2 from the lungs / CO2 to the lungs Contain large amounts of hemoglobin (35% of mass) Men: 16 g / 100 ml Women: 14 g / 100 ml Biconcaved discs (high surface:volume ratio to maximize diffusion capacity. Aids in flow through small vessels.)
Leukocytes and Platelets Cells of the Immune System Small percentage of total blood cells Types: Neutrophils (50-70%) Eosinophils (1-4%) Basophils (0.1%) Monocytes (2-8%) Lymphocytes (20-40%) Platelets (250,000 per mm3 of blood) Polymorphonuclear (PMN) leukocytes (granulocytes)
The components of blood Assessment of Cell Numbers and Types Regulation of hematopoiesis Regulation of erythrocyte production
Assessment of Cell Numbers and Types Manual counts using a microscope Morphology/staining Auto analyzers such as a Coulter Counter Morphology Flow cytometry Morphology/Specific Antibody binding to antigens on/in cells (proteins)
Manual Blood Cell Count Determination Using a Light Microscope, Hemacytometer and Blood Smear
Auto Analyzyer Coulter Counter RBC red blood cell (count 10^6 cell/microliter) Hgb hemaglobin (gm/dl) Hct hematocrit (%) Rtc reticulocytes Mcv mean corpuscular volume (fl) (femtoliters) -- normal R.m indoor adult males 72-76 --- normal adult humans 86-98 Mch mean cell hemaglobin (pg) - normal R.m. indoor adult males 21.8-24.6 -- - normal adult humans 27-32 Mchc mean cell hemaglobin concentration(%) - normal R.m. indoor adult males 29.6-31.2 --- normal adult humans 32-36 Rdw red cell distibution width --- normal adult males 11-15 WBC white blood cell (count 10^3/microcliiter) Sgs segmented neutrophils (%) Bnd banded neutrophils (%) Eos eosenophils (%) Bso basophils (%) Mno moncytes (%) Lym lymphocytes (%) Plt platelets (count/microliter)
Flow Cytometry of Fluorescence Activated Cell Sorting (FACS) Detection Laser FALS Sensor Fluorescence detector Scattered light detector - + Fluorescence labeled antibodies against specific proteins Charged Plates Single cells sorted into test tubes Modified from Purdue University Cytometry Laboratories
Forward Angle Light Scatter (Forward Scatter) When a cell intercepts the laser beam, the light scattered in the forward direction (along the same axis that the laser light is traveling) is detected in the forward scatter channel. Laser FALS Sensor Forward scatter Size and shape of cell bigger the shadow the bigger the cell
90 Degree Light Scatter (Side Scatter) The amount of light scattered to the side (perpendicular to the axis that the laser light is traveling) is detected in the side or 90o scatter channel. Laser FALS Sensor Forward scatter Reflected light Shape (irregular) and optical heterogeneity of cells granulation (# of organelles increases side scatter) 90LS Sensor Side scatter
Light Scatter Gating Neutrophils Scale associated with # of events or cells 1000 1000 800 Forward scatter 200 100 600 50 40 Monocytes 30 400 20 15 Lymphocytes 8 0 200 200 400 600 800 1000 0 Side Scatter Modified from Purdue University Cytometry Laboratories
Detection of Fluorescence The amount of fluorescence is detected in the side or 90o scatter channel. Laser Excitation FALS Sensor Forward scatter Emission intensity Fluorescence detector Detection of protein on surface or inside cell by binding of fluorochrome-conjugated antibody (Phenotype or function).
Light Scatter Gating Neutrophils Scale associated with # of events or cells 1000 1000 800 Forward scatter 200 100 600 50 40 Monocytes 30 400 20 15 Lymphocytes 8 0 200 200 400 600 800 1000 0 Side Scatter Modified from Purdue University Cytometry Laboratories
Gating on Lymphocytes and Detecting CD3+ Cells that are either CD4+ or CD8+ CD3+ (T lymphocytes) 1 2 Log PE Fluorescence (CD4) 45% 2% 10 1 3 4 27% 26% .1 .1 1 10 100 1000 Log FITC Fluorescence (CD8)
Immunophenotyping of Lymphocytes CD # = cluster designation number CD4 CD3 CD8 CD3 IFNgamma IFNgamma CD20 T helper cell Cytotoxic T cell CD3+CD4+ CD3+CD8+ (Th1 cell) (Antigen specific CTL) B cell CD3-CD20+
Stem cells in the bone marrow constitute an important precursor of many of the formed components in the blood.
Hematopoietic Growth Factors HGF:receptor binding activates intracellular signaling cascades
Major Hematopoietic Growth Factors: (Derived from Table 14-4) Name: Product: Erythropoietin Colony-Stimulating Factors Interleukins Thrombopoietin Stem Cell Factor Others (TNF, Interferons) Erythrocytes Granulocytes and monocytes Various Leukocytes Platelets Many Blood types
Erythrocytes Produced in the bone marrow Lose nuclei and organelles Life-span = 120 days 250 billion cells made per day Destroyed in liver and spleen Bilirubin is the breakdown product (gives plasma its color) Erythrocyte production tightly regulated by hormones.
Erythropoiesis is hormonally regulated: decreased oxygen delivery to the kidney causes the secretion of erythropoietin, which activates receptors in bone marrow, leading to an increase in the rate of erythropoiesis. Erythropoietin Used Clinically: Blood loss Renal failure In conjunction with chemotherapy
Erythrocytes Produced in the bone marrow Lose nuclei and organelles Life-span = 120 days 250 billion cells made per day Destroyed in liver and spleen Bilirubin is the breakdown product (gives plasma its color) Erythrocyte production tightly regulated by hormones. Erythrocyte production dependent on folic acid, vitamin B12 and iron
Folic Acid and Vitamin B12 Folic acid A vitamin found in leafy plants, yeast, and liver Is required for synthesis of the nucleotide base thymine Essential for the formation of DNA and normal cell division Vitamin B12 Is found only in animal products- Strict vegetarian diets are often deficient in B12 Absorption in GI tract requires intrinsic factor Is required for the action of folic acid (DNA replication)
Iron Metabolism 50% The availability of dietary iron can be a limiting factor in rbc production, so storage and recycling mechanisms are highly developed in humans as a protection from anemia. 25% Balance input vs output (95% recycled). Transferrin Maintaining iron balance important for adequate hemoglobin/rbc production. Iron deficiency anemia Hemochromatosis iron toxicity 25% Ferritin
Anemia and Polycythemia Anemia: Decreased ability of blood to carry oxygen - Decreased # erythrocytes - Decreased concentration or performance of hemoglobin within erythrocytes - Combination of both Polycythemia: More erythrocytes than normal (opposite of anemia) - Increased viscosity of blood - altitude
Sickle-cell anemia Genetic mutation alters one amino acid in hemoglobin Fiber-like structures form during low [O2], distorting erythrocyte into sickle shape Capillary blockage Tissue damage Destruction of deformed erythrocyte Anemia
Regulation of Total Blood Cell production All blood cells are derived from multipotent/pluripotent hematopoietic stem cells Differentiation and proliferation of stem cells (the path taken) is stimulated by hematopoietic growth factors(HGF s).
