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SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY

RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

RBCs, WBCs and IMMUNITY


SBCM PHYSIOLOGY
MODULE 1, LECTURE 3:
RBCs, WBCs and IMMUNITY
By Enrico Paolo C. Banzuela, MD
Ateneo 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

QUESTION:
Because Plasma is FLUID, how much PLASMA comprises
TOTAL BODY weight?
ANSWER:

Composition of Plasma

EDUCATIONAL OBJECTIVES
At 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 transport for gases, nutrients, Hormones and


metabolic wastes

Regulation of pH and ion composition of interstitial


fluids

Defense against toxins and pathogens

Stabilization of 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

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 functional


properties of blood

some forms of liver disease can lead to uncontrolled


bleeding

this is due to inadequate synthesis of proteins involved


in clotting

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY Page 1 of 9


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

Cellular Elements of the Blood

Blood cells: from womb to tomb

YOUNG LIVER SYNTHESIZES BLOOD.


Yolk Sac Liver, Spleen Bone Marrow

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

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 mechanisms extramedullary
hematopoiesis happens in the spleen, liver, lymph
nodes
Differentiation of Hematopoietic Cells

Yolk Sac / Aorta Gonad Mesonephros (AGM) Region

1st site of blood cell production during 3rd week of fetal


embryologic development
Liver

Chief site of blood cell formation until shortly after birth


begins during the 3rd month of embryogenesis
with minor contribution from spleen and lymph nodes

Bone Marrow

only source of hematopoiesis postnatally

begins during the 4th month 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

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 hscassociated genes

progressive upregulation of limited number of lineagespecific genes

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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD
Cytokines and Hormones Active on Stem Cells and
Progenitors
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 the


growth 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 from


many 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 macrophage


progenitors and activates macrophages

TPO*

Affects hematopoietic stem cells and


megakaryocytic progenitors

RED BLOOD CELLS

3.

it acts as an acid-base buffer for whole blood


(contains ________________________, an enzyme
that catalyzes the reaction between co2 and
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

Hemoglobin is the protein inside the RBC that binds


with oxygen

Normal Hemoglobin values:


Males: 14-18 g/dl
Females: 12-18 g/dl

Hematocrit is 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

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 use
2. it transports ____________________ (in the form of
bicarbonate ion or HCO3-) from tissues to
lungs for expulsion

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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

QUESTION:
How many oxygen molecules can 1 hemoglobin molecule
bind?
ANSWER:
QUESTION:
How many oxygen molecules can 1 myoglobin molecule
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 & 2


Gamma chains) ist most common form of hemoglobin
during fetal life
has a higher affinity for oxygen compared to Hgb A
Binds less to 2,3 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)

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
DESTRUCTION

EXTRAVASCULAR
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

RBC Formation (Erythropoiesis)

Hormone responsible for RBC production and


maturation: _____________________ (Erythropoietin)

Stimulus for EPO production: _____________________

INTRAVASCULAR
DESTRUCTION

EXTRAVASCULAR
DESTRUCTION

RBC is destroyed Hgb


that escapes is bound to
haptoglobin
Hgb:haptoglobin complex
goes 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 oxygenase biliverdin is converted to Bilirubin (final
product of hemoglobin metabolism) excreted into BILE in
GIT

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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD
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

1st line of defense

2nd line of defense

Role of Vitamin B12 and Folic Acid in RBC Formation

Both are essential for the synthesis of DNA


formation of thymidine triphosphate, building block of DNA

Vitamin B12 or 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:

White Blood Cells

VITAMIN B12
Baboy
FOLIC ACID
Froccoli, cauliFlower

WHITE BLOOD CELLS & IMMUNITY


Immunity

Immunity is the capability of the body to resist almost


all types of organisms or toxins that tend to damage
tissues and organs

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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD
Members of the White blood cell Family
CELL TYPE
%
NEUTROPHILS

62%

EOSINOPHILS

2.3%

BASOPHILS

0.4%

MONOCYTES

5.3%

LYMPHOCYTES

30%

Smallest of WBC
Prominent feature: round, densely stained nucleus
with a pale basophilic, non-granular cytoplasm

White Blood Cells


What 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 DIAPEDESIS
MOVE THROUGH THE TISSUE VIA AMEBOID MOVEMENT
Can phagocytize 3-20 bacteria
Can phagocytize up to 100
before dying
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-)
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 red


with eosin dye

Question
Movement of neutrophils and macrophages towards a
CHEMICAL SIGNAL (bacterial toxins, products of
inflammation, complement cascade, products from clotting)?
A:
Movement out of the circulatory system and into the site of
injury?
A:

Mechanisms of INNATE IMMUNITY

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

2nd most common type

Cells of adaptive immunity

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


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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD
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
- 1st line of defense
- Present within minutes
- identifies the pathogen phagocytosis
Neutrophils
- 2nd line of defense
- Will start migrating in response to inflammatory cytokines
- Cause Phagocytosis
Monocytes
3rd line 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


Antibodies and/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

Mechanisms of Action of Antibodies

Can either act DIRECTLY or INDIRECTLY


DIRECT MEANS
Agglutination: clumping
Precipitation: insoluble
antigen-antibody complex
Neutralization: AB covers the
toxic sites of the antigenic
agent
Lysis: rupture of the agent

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=257bqFSJ1E&list=PLAB2FC119A2CA3C57
Complement System
Which complement is responsible for opsonization?

________
Which complement is an anaphylatoxin (induces inflammation)?

________, ________, ________


Which complement is chemotactic to WBCs?

________
Which complement is part of the Membrane Attach Complex
(MAC)?

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)
Main immunoglobulin concerned with
primary immune response; present on all
uncommitted B cells; largest
Main immunoglobulin in secretions (milk,
saliva, tears, respiratory, intestinal and genital
tract)
Antibody mediated allergies and
hypersensitivity
Acts as an antigen receptor when present on
the surface of certain B lymphocytes

IgM
IgA
IgE
IgD

INDIRECT MEANS
Via complement system

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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

________________

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD
Adaptive Immunity

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

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, GCSF, 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

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

Cytotoxic T cell

Direct attack cell capable of killing microorganisms

Create holes (perforins)

Targets virally infected cells, cancer cells,


transplanted cells

Development of B-Cell and T-Cell


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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SAN BEDA COLLEGE OF MEDICINE SECTION OF PHYSIOLOGY


RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD

SOURCES:
1. Guyton & Hall Textbook of Medical Physiology 12th
Edition by Hall, John &, Guyton, Arthur C. , , Published in
Philadelphia, Pensylvania: Saunders/Elsevier, 2011
2. Williams Hematology 8th edition by Kaushansky,
Lichtman, Beutler, Kipps, Seligsohn & Prchal. 2011.
3. Jawetz, Melnick & Aldelbergs Medical Microbiology,
24th edition, 2007
4. Robbin and Cotran Pathologic Basis of disease, 7th
edition, 2007
5. Wheaters Functional Histology: A text and Colour Atlas,
2006
6. Various Internet Websites

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RBCs, WBCs and IMMUNITY by Enrico Paolo C. Banzuela, MD