4 - Hema Physiology Part 1 of 2 - BANZUELA - SY 2015-2016

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SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGYRBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY Page 1 of 9RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

RBCs, WBCs and IMMUNITY

SBCM PHYSIOLOGYMODULE 1, LECTURE 3:RBCs, WBCs and IMMUNITY

By Enrico Paolo C. Banzuela, MDAteneo de Manila High School 1998

UP College of Medicine Class 2005

Course Coordinator for Physiology, San Beda College of Medicine

Year Level I Coordinator, San Beda College of Medicine

Faculty (Physiology, Biochemistry) San Beda College of Medicine

Faculty (Biochemistry) Ateneo School of Medicine & Public Health

Program Director, Topnotch Medical Board Prep

Lecturer (Physiology, Pathology), Topnotch Medical Board Prep

Former Researcher, UP-NIH

Co-Author, IM Platinum

EDUCATIONAL OBJECTIVESAt the end of the 4-hour lecture, the future Bedan Doctor must be

able to:

Enumerate the general functions of blood.

Give the composition of whole blood.

Differentiate plasma from serum.

Give the composition of plasma.

Trace the steps in hematopoiesis.

Identify the locations of hematopoiesis from embryogenesis to

adulthood.

Describe the morphology of Red Blood Cells (RBCs).

Explain the functions of erythrocytes, their destruction and

recycling.

Differentiate hemoglobin from hematocrit.

Discuss hemoglobin formation and iron metabolism.

Give the role of hemoglobin in gas transport.

Discuss the mechanism of erythopoiesis before and after birth.

Describe the role of vitamin B12 and folic acid in hematopoiesis.

Organize the white blood cells into granulocytes and

agranulocytes.

Give the functions and characteristics of each.

Discuss the mechanism of leukocytic reaction during infection.

Define the differences between innate and adaptive

immunity.

Illustrate the general structure of immunoglobulins.

Enumerate and give the roles of each type of immunoglobulins.

Give the ways how antibodies work to destroy the antigen.

Stage the sequence of events in immune responses.

Enumerate the types of T lymphocytes and the characteristics of

each.

Differentiate natural from artificial immunity.

BLOOD

General Functions of Blood

Vehicle of transportfor gases, nutrients, Hormones and

metabolic wastes

Regulation of pH and ion compositionof interstitial

fluids

Defenseagainst toxins and pathogens

Stabilizationof body temperature

Composition of Whole Blood

Plasma

Fluid medium of the blood/non cellular part of the blood

It is where the cells are suspended

Serum

Plasma minus clotting proteins

QUESTION:

Because Plasma is FLUID, how much PLASMA comprises

TOTAL BODY weight?

ANSWER:

Composition of Plasma

Plasma Proteins

Collectively, plasma proteins exert a colloidal osmotic

pressure (oncotic pressure)within the circulatory

system

are nearly derived from the liver(primary source of

plasma proteins)

with the exception of immunoglobulins(which are derived from

plasma cells)

Clinical Correlation

liver disorders can alter the composition and functionalproperties of blood

some forms of liver disease can lead to uncontrolledbleeding

this is due to inadequate synthesis of proteins involved

in clotting


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Cellular Elements of the Blood

QUESTION:

Where are the formed blood elements made?

ANSWER

Formed Elements are made in the ___________________ via the

process called______________________________________

Blood Cells: From Womb To Tomb

Yolk Sac / Aorta Gonad Mesonephros (AGM) Region

1stsite of blood cell production during 3rdweek of fetal

embryologic development

Liver

Chief site of blood cell formation until shortly after birth

begins during the 3rdmonth of embryogenesis

with minorcontribution fromspleen and lymph nodes

Bone Marrow

only source of hematopoiesispostnatally

begins during the 4thmonth of development

Birth to Puberty

marrow throughout the skeleton remains red and

hematopoietically active

Age 20 and Above

only vertebrae, ribs, sternum, skull, pelvis & proximal

epiphyseal regions of the humerus retain red marrow

remaining marrow becomes YELLOW, FATTY &

INACTIVE

Blood cells: from womb to tomb

YOUNGLIVERSYNTHESIZESBLOOD.

Yolk Sac Liver, Spleen Bone Marrow

Points of Emphasis

Chief Site of Blood Formation PRE-NATALLY:

_________________

Chief Site of Blood Formation POST-NATALLY:

__________________________________

Therefore, postembryonic extramedullary hematopoiesis is

_________________ in a full-term infant

Clinical Correlations

Clinical conditions that causes hemolytic anemia

(premature destruction of RBCs) maxes out bone

marrow compensatory mechanismsextramedullary

hematopoiesishappens in thespleen, liver, lymph

nodes

Differentiation of Hematopoietic Cells

Difference of Progenitors (Committed Cell Types) from Hsc

(Parent Cell)

loss of pluripotency

lack of capacity for self-renewal

higher fraction of cells traversing the cell cyle

reduced ability to efflux foreign substances

change in their surface protein profile

Genetic Basis for Transition of HSC to Committed

Progenitors

marked downregulation of large number of hsc-

associated genes

progressive upregulation of limited number of lineage-

specific genes


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Cytokines and Hormones Active on Stem Cells andProgenitors

Cytokine Principal activities

IL-1 Induces production of other cytokines from

many cells, works in synergy with other

cytokines on primitive hematopoietic cells

IL-2 T-cell growth factor

IL-3 Stimulates the growth of multiple myeloid cell

types, involved in delayed type hypersensitivity

IL-5* Eosinophil growth factor and affects mature cell

function

IL-6 Stimulates B lymphocyte growth; works in

syngery with other cytokines on megakaryocytic

progenitors

IL-7* Principal regulator of early lymphocyte growth

IL-9 Produced by Th2 lymphocytes; cotimulates thegrowth of multiple myeloid cell types

IL-11 Stimulate growth of multiple lymphoid and

myeloid cells

IL-15* Modulates T-lymphocyte activity and stimulates

natural killer cell proliferation

IL-21 Affects growth and maturation of B,T & natural

killer cells

Cytokine Principal activities

SCF* Induces production of other cytokines frommany cells, works in synergy with other

cytokines on primitive hematopoietic cells

EPO* Stimulates proliferation of erythroid

progenitors

M-CSF* Promotes proliferation of monocytic

progenitors

G-CSF* Stimulates proliferation of neutrophilic

progenitors, acts in synergy with IL-3 on

primitive myeloid cells and activates mature

neutrophils

GM-CSF Affects granulocyte and macrophageprogenitors and activates macrophages

TPO* Affects hematopoietic stem cells and

megakaryocytic progenitors

RED BLOOD CELLS

Red Blood Cells (Erythrocyte)

_________________________ of blood cells

it gives the whole blood its characteristic

functions

1.

it transports ____________________(carries oxygen)

from lungs to tissues for use2.

it transports ____________________ (in the form of

bicarbonate ion or HCO3-) from tissues to

lungs for expulsion

3.

it acts as an acid-base buffer for whole blood

(contains ________________________, an enzyme

that catalyzes the reaction between co2and

h20 to form carbonic acid or h2co3)

Structure of RBCs

normal resting shape: ______________________ disc

central 1/3 is appears relatively pale compared to the

periphery

Implications of RBC structure

Large ratio of SA to volume

Enables RBCs to form stacks for smoother blood flow

Allows large reversible elastic deformation as it passes through

microcirculation (i.e. small capillaries around 2-3 m in

diameter)

Hemoglobin vs Hematocrit

Hemoglobinis the protein inside the RBC that binds

with oxygen

Normal Hemoglobin values:

Males: 14-18 g/dl

Females: 12-18 g/dl

Hematocritis the % of whole blood occupied by

cellular elements

Normal Hematocrit values:

Males: 46 (40-54)

Females: 42 (37-47)

Hemoglobin Structure Adult Hemoglobin (HbA) is composed of a 4

polypeptide subunits (2 alpha units and 2 beta units)

97% of oxygen transported from the lungs is carried by

hemoglobin in RBC

Formation of Hemoglobin


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QUESTION:

How many oxygen molecules can 1 hemoglobinmolecule

bind?

ANSWER:

QUESTION:

How many oxygen molecules can 1 myoglobinmolecule

bind?

ANSWER:

Variations in Hemoglobulin Sub-Units

Adult Hemoglobin (__________________) (2 Alpha & 2 Beta

Chains) is most common form of hemoglobulin in adults

Fetal Hemoglobin (__________________)(2 Alpha & 2Gamma chains) ist most common form of hemoglobin

during fetal life

has a higher affinity for oxygen compared to Hgb A

Binds less to2,3 BPG(an enzyme that causes Shift to the Right of

the O2-HgB dissociation curve or increased unloading of O2)

compared to HbA

Iron Metabolism

iron is an essential metallic component of heme

total iron in the body is 4-5 g

65% hemoglobin (majority)

4% myoglobin

1% in various heme compounds that promote

intracellular oxidation

RBC Formation (Erythropoiesis)

Hormone responsible for RBC production and

maturation:_____________________ (Erythropoietin)

Stimulus for EPO production:_____________________

RBC Formation (Erythropoiesis)

Orthochromatic Erythroblast

(+) Nucleus, ER reabsorbed

Reticulocytes

NO nucleus

(+) Remnants of Golgi, mitochondria and other organelles

QUESTION

What is the average lifespan of your red blood cell?

ANSWER:

Adult:

Fetal:

RBC Destruction

INTRAVASCULAR

DESTRUCTIONEXTRAVASCULAR

DESTRUCTION

RBC membrane is

breeched becomes

fragile self destruct in

the red pulp of SPLEEN

Ingestion by a macrophage

(Kuppfer cells of liver/

macrophages in spleen and blood)

2 signals that differentiate young

from OLD RBC:

1.

Decreased deformability

2.

Altered surface

properties

RBC Destruction

INTRAVASCULARDESTRUCTION

EXTRAVASCULARDESTRUCTION

RBC is destroyed Hgb

that escapes is bound to

haptoglobin

Hgb:haptoglobin complexgoes to the liver

Ingestion by a macrophage

degraded within lysosomes

lipid, protein and heme

Heme (in hemoglobin) is converted to iron and biliverdin by

heme oxygenasebiliverdin is converted to Bilirubin(finalproduct of hemoglobin metabolism) excreted into BILE in

GIT


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Role of Vitamin B12 and Folic Acid in RBC Formation

Both are essential for thesynthesis of DNA

formation of thymidine triphosphate, building block of DNA

Vitamin B12or Folic Acid deficiency causes:

Abnormal or diminished DNA

Failure of nuclear maturation and cell division in a developing

RBC

_______________________________________________________ (macrocytes with

flimsy membranes that are oval in shape and irregular)

Vitamin B12 Deficiency: will also cause

___________________________________

Folic Acid Deficiency: will also cause

___________________________________

SOURCES:

VITAMIN B12

Baboy

FOLIC ACID

Froccoli, cauliFlower

WHITE BLOOD CELLS & IMMUNITYImmunity

Immunityis the capability of the body to resist almost

all types of organisms or toxins that tend to damage

tissues and organs

Types of Immunity

Innate Immunity Acquired Immunity

Pre-existing (skin, mucous

membranes, phagocytic

cells, inflammatory

mediators, complement

system)

Antibody

mediated/lymphoid cells

Not acquired through

contact with a non-self

(antigen)

Occurs after exposure to

an antigen

Non specific Specific

Quick Delayed response

1stline of defense 2ndline of defense

White Blood Cells


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Members of the White blood cell Family

CELL TYPE %

NEUTROPHILS 62%

EOSINOPHILS 2.3%

BASOPHILS 0.4%

MONOCYTES 5.3%

LYMPHOCYTES 30%

Members of the White blood cell Family

Neutrophils

Most common type

Acute inflammatory response to tissue injury (degrade

tissue components, destroy damaged tissue and kills

bacteria)

Prominent feature: Highly lobulated nucleus

Eosinophils

Weak phagocytes

Parasitic infections

Hydrolysis, reactive Oxygen, major basic protein

Allergic reactions

Eosinophilic chemotactic factor: released by mast cells and

basophils causes eosinophils to migrate to inflammed allergic

tissue

Prominent feature: bilobed nucleus, stain bright redwith eosin dye

Basophils

Least common type

Share functional similarities with Mast Cells

Produces histamine, heparin, bradykinin, serotonin

Allergic reactions: IgE

Prominent feature: bilobed/trilobed nucleus, largely

densely basophilic (blue) granules

Monocytes

Largest of WBC

Tissue: macrophages

Resident phagocytes

Prominent feature: eccentrically placed nucleus

Platelets

Small, non-nucleated cells from megakaryocytes

Not part of WBC, not involved in immunity

Involved in Hemostasis

Life span: 7-10 days

Lymphocytes

2ndmost common type

Cells of adaptive immunity

T cell (thymus) or B cell (bone marrow)

Smallest of WBC

Prominent feature: round, densely stained nucleus

with a pale basophilic, non-granular cytoplasm

White Blood CellsWhat is the largest WBC?

_______________________

What is the most numerous, least numerous WBC?

Most numerous: _______________________

Least numerous: _______________________

What are the cells involved in adaptive immunity and parasitic

infections?

Adaptive Immunity: ______________________

Parasitic Infections: ______________________

Neutrophils vs Macrophages

Neutrophils Macrophages

Released as Mature Cells Released as Immature Cells

ATTRACTED TO THE SITE OF INJURY VIA CHEMOTAXIS

ENTER THE TISSUE VIA DIAPEDESISMOVE THROUGH THE TISSUE VIAAMEBOID MOVEMENT

Can phagocytize 3-20 bacteria

before dying

Can phagocytize up to 100

bacteria; can engulf larger

particles (e.g. RBCs,

Plasmodium); can extrude

these particles and survive

after for months

LYSOSOMES: PROTEASES, HYPOCHLORITE and LIPASES(in

macrophages only)

PEROXISOMES: FREE RADICALS LIKE SUPEROXIDE(O2-),

HYDROGEN PEROXIDE(H2O2), HYDROXYL IONS(OH-)

Question

Movement of neutrophils and macrophages towards aCHEMICAL SIGNAL (bacterial toxins, products ofinflammation, complement cascade, products from clotting)?A:

Movement out of the circulatory system and into the site of

injury?A:

Mechanisms of INNATE IMMUNITY


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Splinter in your finger Break in the skin

pathogen will enter the break

Tissue injury occurs

Mast Cells: will release histamine causing vasodilation and

increased vascular permeability

Tissue Macrophages

- 1stline of defense

- Present within minutes

- identifies the pathogen phagocytosis

Neutrophils

- 2ndline of defense

- Will start migrating in response to inflammatory cytokines

- Cause Phagocytosis

Monocytes

3rdline of defense

- Blood monocytes (inactive) are converted to tissues:

macrophage (active)

- This response takes time (at least 8 hours)

Inc Monocytes & Granulocyte production by BM

- 4th line of defense

- Takes 3-4 days

- Mediated by TNF, IL-1, GM-CSF,M-CSF

PUS = battlefield of dead cells and pathogens

Adaptive Immunity

is caused by a special immune system that forms

Antibodiesand/or activated lymphocytes that attack

and destroy the specific invading organism or toxin

Antibodies

Are gamma globulins called immunoglobulins

Constitute 20% of plasma proteins

Formed by Plasma Cells (activated B-Cells)

Variable Portion: determines specificity to antigen

Constant Protion:determines other properties of

antibodies

Immunoglobulin Classes

Class FUNCTION

IgG Divalent antibody,75% of antibodies (most

abundant); predominant antibody in

secondary responses;smallest(only one

able to cross the placenta)

IgM Main immunoglobulin concerned with

primary immune response; present on all

uncommitted B cells; largest

IgA Main immunoglobulin in secretions (milk,

saliva, tears, respiratory, intestinal and genital

tract)

IgE Antibody mediated allergies and

hypersensitivity

IgD Acts as an antigen receptor when present on

the surface of certain B lymphocytes

Mechanisms of Action of Antibodies

Can either act DIRECTLY or INDIRECTLY

DIRECT MEANS INDIRECT MEANS

Agglutination: clumping

Precipitation: insoluble

antigen-antibody complex

Neutralization: AB covers the

toxic sites of the antigenic

agent

Lysis: rupture of the agent

Via complement system

Complement System

Part of your innate and adaptive immunity

Complement proteins are soluble proteins in the blood

stream

Responsible for 3 things

Opsonization: serve as marker that makes it easier to

phagocytize foreign bodies

Membrane Attack Complex: perforate foreign organisms

Stimulate Inflammation

http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57

Complement SystemWhich complement is responsible for opsonization?

________

Which complement is an anaphylatoxin(induces inflammation)?

________, ________, ________

Which complement is chemotacticto WBCs?

________

Which complement is part of the Membrane Attach Complex

(MAC)?

________________
http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57http://www.youtube.com/watch?v=2-57bqFSJ1E&list=PLAB2FC119A2CA3C57


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Adaptive Immunity

Types of T cells

T- Helper Cells (CD4, MHC II)

Cytotoxic T Cells (CD8, MHC I)

Suppressor T Cells

Helper T cell

Most numerous of T cells

Various helper functions

Regulatory function of lymphokines (IL-2, IL-3, IL-4, IL-5, IL-6, G-

CSF, Interferon gamma)

Stimulation of growth and proliferation of Cytotoxic T cells &Suppressor T cells

Stimulation of growth and differentiation of B-cell & antibody

formation (IL-4,IL-5&IL-6)

Activation of macrophage system

Cytotoxic T cell

Direct attack cell capable of killing microorganisms

Create holes (perforins)

Targets virally infected cells, cancer cells,

transplanted cells

Suppressor T cells

Regulatory function by suppressing action of Helper T

cells and Cytotoxic T cells

Plays an important role in limiting the ability of the

immune system to attack a persons own body tissue

Artificial Immunity

Could either be passive or active immunity

Active immunity

Induced after contact with foreign antigen (usually killed or live

attenuated infectious agents)

Advantage: long term protection

Disadvantage:slow onset of action

Passive immunity

Administration of antibody (in antisera) in a vaccine

Advantage:prompt availability of large amount of antibodies

Disadvantage:short life span of antibodies, hypersenstivity

reaction

Development of B-Cell and T-Cell


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SOURCES:1.

Guyton & Hall Textbook of Medical Physiology 12th

Edition by Hall, John &, Guyton, Arthur C. , , Published in

Philadelphia, Pensylvania: Saunders/Elsevier, 20112.

Williams Hematology 8thedition by Kaushansky,

Lichtman, Beutler, Kipps, Seligsohn & Prchal. 2011.

3.

Jawetz, Melnick & Aldelbergs Medical Microbiology,24thedition, 2007

4.

Robbin and Cotran Pathologic Basis of disease, 7 th

edition, 2007

5. Wheaters Functional Histology: A text and Colour Atlas,

2006

6.

Various Internet Websites

4 - Hema Physiology Part 1 of 2 - BANZUELA - SY 2015-2016

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