Nutrition, Metabolism &

Energy Balance Pt II

Chapter 24
p. 955- 968
Chapter 16
p. 630 – 634 (The Pancreas)
p. 617 - 621 (The Thyroid) http://2012books.lardbucket.org/books/an-introduction-to-
nutrition/section_14/162d91c78c4bfdaeade6c0c77d0b9ee5.jpg
Objectives for Part 2
2.4 Describe the metabolic consequences of the two types of
Diabetes Mellitus
2.5 List the various hepatic functions associated with
metabolism
2.6 List and describe the 4 major types of lipoproteins
2.7 Describe the synthesis of thyroid hormones & its regulation
2.8 List the metabolic processes regulated by thyroid hormones
2.9 Define basal metabolism and total metabolism and identify
the factors that influence them
2.10 Discuss the mechanisms of appetite regulation
2.11 Describe and explain the mechanisms of heat exchange
2.12 Explain the mechanisms for the control of body
temperature
Regulating
Blood
Glucose
Levels
https://yegfitness.ca/wp-content/uploads/2021/01/diabetes.jpeg
Insulin and
glucagon from
the pancreas
regulate blood
glucose levels
Triangular gland located partially behind stomach
Has both exocrine and endocrine cells
Acinar cells (exocrine) produce enzyme-rich juice for digestion
Pancreatic islets (islets of Langerhans) contain endocrine cells
Alpha (α) cells produce glucagon (hyperglycemic hormone)
Beta (β) cells produce insulin (hypoglycemic hormone)
Delta (D) cells secrete somatostatin
F cells produce pancreatic polypeptide
 Effects of Insulin on Metabolism
Secreted when
blood glucose levels increase
blood levels of amino acids and fatty
acids increase
acetylcholine is released by
parasympathetic nerve fibers
Synthesized as proinsulin that is then
modified
Insulin lowers blood glucose levels in
three ways:
Enhances membrane transport of
glucose into fat and muscle cells
Inhibits breakdown of glycogen to
glucose
Inhibits conversion of amino acids or Net Effect of Insulin
fats to glucose ↓ Blood glucose / ↑ glycogen storage
↓ Blood amino acids & FFA
Effects of Glucagon on Metabolism
Extremely potent hyperglycemic agent
Triggered by decreased blood glucose
levels, rising amino acid levels, or
sympathetic nervous system
Raises blood glucose levels by targeting
liver to:
Break down glycogen into glucose
Synthesize glucose from lactic acid
and other noncarbohydrates
Release glucose into blood

Net Effect of Glucagon

↑ Blood glucose / ↓ glycogen storage
↑ Blood amino acids & FFA
Diabetes
Mellitus
Diabetes mellitus (DM) is a
group of metabolic diseases
characterized by
high levels of blood
glucose resulting from
defects in insulin
production, insulin action,
or both.
Complex disorders of
CHO, fat and protein
metabolism

https://diabetespharmacist.lexblogplatformthree.com/wp-content/
uploads/sites/346/2009/11/diabetes-symptoms21.jpg
 Diabetes Mellitus
Type 1 DM

autoimmune destruction of pancreatic β-cell

absolute insulin deficiency (Why?)

Type 2 DM
insulin resistance =
relative insulin
deficiency
e.g. interference
with insulin
binding to target https://www.researchgate.net/publication/293637004/figure/fig1/
AS:391399162826753@1470328240924/Major-types-of-diabetes-condition-Picture-showing-blood-

tissue
stream-having-high-levels-of.png
Insulin Mechanism of Action
 Figure 16.18 Consequences of Insulin Deficiency (Diabetes Mellitus)

o
↓ uptake of glucose by peripheral tissue / ↑ glucose production (gluconeogenesis) / ↑ release
of glucose from the liver (glycogenolysis)
 Type I DM: Metabolic Consequences cont.

When sugars cannot be used as fuel, as in DM, fats are used, causing lipidemia
(high levels of fatty acids in blood)
Fatty acid metabolism (lipolysis) results in formation of ketones (ketone bodies)
Ketones are acidic, and their build-up in blood can cause ketoacidosis
Also causes ketonuria
Untreated ketoacidosis causes hyperpnea, disrupted heart activity and O 2 transport, and severe
depression of nervous system that can possibly lead to coma and death

Hyperinsulinism
Excessive insulin secretion
Causes hypoglycemia: low blood glucose levels
Symptoms: anxiety, nervousness, disorientation, unconsciousness, even
death
Treatment: sugar ingestion
 Type 2 DM

Risk factors: age, obesity, hypertension, physical inactivity, and

family history.
Consequences of obesity
adipose tissue secrete hormone that decrease insulin sensitivity
increased FFAs/ TGs and cholesterol:
interfere with intracellular insulin signalling
decrease tissue responses to insulin
alter incretin actions
promote inflammation
increase inflammatory cytokines that cause insulin
resistance and are toxic to beta cells
BioFlix Video: Homeostasis

Copyright © 2019, 2016, 2013 Pearson Education, Inc. All Rights Reserved
 Hepatocytes carry out ~500 metabolic functions
Metabolic Process nearly every class of nutrient
Role of the Play major role in regulating plasma cholesterol
Liver levels
Store vitamins and minerals
Metabolize alcohol, drugs, hormones, and bilirubin
Cholesterol Metabolism and Regulationof
Blood Cholesterol Levels

Not used as an energy

source
Structural basis of bile
salts, steroid hormones, and
vitamin D
Major component of
plasma membranes
15% is ingested, the rest
made in body, primarily by
liver
Lost from body when
catabolized or secreted in
bile salts that are lost in
feces
 Cholesterol Metabolism and Regulationof
Blood Cholesterol Levels
Cholesterol Transport
Transport of exogenous & de novo cholesterol requires a diversity of lipoproteins
complexes containing triglycerides, phospholipids, cholesterol, and protein
Lipoproteins
transport water-insoluble cholesterol and TGs through blood
Regulate lipid entry/exit at target cells
All contain triglycerides, phospholipids, cholesterol, and protein
The higher the percentage of lipids, the lower the density

Types of transport lipoproteins

HDLs (high-density lipoproteins): highest protein content
LDLs (low-density lipoproteins): highest cholesterol content
VLDLs (very low-density lipoproteins): contents are more than half triglycerides, with low density
of proteins
Chylomicrons: transported from; have lowest density and consist almost entirely of triglycerides
Composition and Function of Lipoproteins
 Cholesterol Metabolism and Regulationof
Blood Cholesterol Levels
Cholesterol Transport

VLDLs: transport triglycerides from liver to peripheral tissues (mostly adipose)

LDLs: transport cholesterol to peripheral tissues for membranes, storage, or
hormone synthesis
HDLs: transport excess cholesterol from peripheral tissues to liver to be broken
down and secreted into bile
Also provide cholesterol to steroid-producing organs
Factors Regulating Blood Cholesterol levels
The liver produces cholesterol at a basal level regardless of dietary cholesterol
intake
Restricting dietary cholesterol does not markedly reduce blood cholesterol levels

More important effect is relative amounts of saturated and unsaturated fatty acids
Saturated vs Unsaturated fats

Saturated fatty acids stimulate liver synthesis of cholesterol & inhibit

cholesterol excretion from body
Unsaturated fatty acids enhance excretion of cholesterol into bile salts

Trans fats

Worse effect on cholesterol levels than saturated fats; increase LDL &
reduce HDL
Factors Regulating Blood Cholesterol levels

Unsaturated omega-3 fatty acids (found in cold-water fish) have lower

proportions of saturated fats and cholesterol
Make platelets less sticky and help prevent spontaneous clotting
Have antiarrhythmic effects on heart
Can lower blood pressure

Stress & cigarette smoking

lowers HDL levels

Aerobic exercise & estrogen

↑ HDL levels & ↓ LDL levels
Body shape
“Apple”: fat carried on upper body is correlated
with high cholesterol and LDL levels
“Pear”: fat carried on hips and thighs is
correlated with lower cholesterol and LDL
levels
https://s-media-cache-ak0.pinimg.com/564x/b8/3b/79/
b83b7979447638c0eddb35dc3739aabc.jpg
 The Thyroid gland

Chapter 16: pp 617-621

 The Thyroid gland
Location and Structure
Butterfly-shaped gland in anterior neck on the trachea, just inferior to larynx, that
consists of:

Isthmus: median mass connecting two lateral lobes

Follicles: hollow sphere of epithelial follicular cells that produce glycoprotein
thyroglobulin

Colloid: fluid of follicle

lumen containing
thyroglobulin & iodine
(precursor to thyroid
hormone)
Parafollicular cells: produce
hormone calcitonin
 Thyroid Hormone
o The body’s major metabolic
hormone
Tyrosin
o Found in two forms e

T4 (thyroxine): major form that

consists of two tyrosine molecules
with four bound iodine atoms
Most converted to T3 at tissue
level
T3 (triiodothyronine): form that
has two tyrosines with three bound
iodine atoms
o Both are iodine-containing
amine hormones

https://ljkboerner.files.wordpress.com/2011/03/t3-and-t4.jpg
 Thyroid hormone
TH affects virtually every cell in body
Enters target cell and binds to intracellular receptors within nucleus
Triggers transcription of various metabolic genes
Effects of thyroid hormone include:
Increases basal metabolic rate and heat production
Referred to as calorigenic effect
Regulates tissue growth and development
Critical for normal skeletal and nervous system development and
reproductive capabilities
Maintains blood pressure
Increases adrenergic receptors in blood vessels
 Thyroid hormone cont.
Synthesis
T3 and T4 are stored in the follicles lumen until triggered for release by TSH
amounts sufficient for 2-3 months

Role of iodine
Iodine - ingested in the form of
iodides is necessary for the formation
of T3/T4
Iodide from the GI → the blood and is
trapped in the thyroid follicles that
actively pump iodide from the blood
into the interior of the cells
The rate of iodide trapping is
influenced by TSH
Thyroid Hormone Synthesis
 Thyroid hormone cont.
Transport and regulation

T4 & T3 transported by thyroxine-binding globulins (TBGs)

Both bind to target receptors, but T3 is 10 times more active than T4
Peripheral tissues have enzyme that to convert T4 to T3 (- 1 iodine)

Negative feedback regulation of TH release

Falling TH levels stimulate release of thyroid-stimulating hormone (TSH)

Rising TH levels provide negative feedback inhibition on TSH
TSH can also be inhibited by GHIH, dopamine, and increased levels of
cortisol and iodide
Hypothalamic thyrotropin-releasing hormone (TRH) can overcome the negative
feedback during pregnancy or exposure to cold
Regulation of Thyroid Hormone secretion

Figure 16.12
 Chapter 24 p.945-957

Energy
Balance

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 Energy Balance
Energy Balance = energy released from food (intake) must equal total energy output

Energy intake
energy derived from absorbable foods =
energy liberated during food oxidation
Energy output
Immediately lost as heat (~60%) https://static1.squarespace.com/static/
Used to do work (driven by ATP) 53c14549e4b055ae0c76a5c7/t/
53ceef94e4b0602f13f978c5/1406070676762/calorie-
balance.jpg
Stored as fat or glycogen

Nearly all energy from food is eventually converted to heat, which cannot be
used to do work, but it

Warms tissues and blood

Helps maintain homeostatic body temperature
Allows metabolic reactions to occur efficiently
 Energy balance
Body mass (BM) is maintained when energy intake (consumed) = energy expenditure (used)

Body mass index (BMI) is a formula used to determine obesity based on a

person’s weight relative to height
To calculate: BMI = wt (kg) /height in (m)2
Example: A person is 175 cm tall and has a weight of 70 kg.

BMI = 70 = 70 = 70
= 22. 86 ( normal body weight)
(1.75)2 (1.75 X 1.75) 3.0625

https://www.1mg.com/articles/wp-content/uploads/2018/07/BMI.jpg
 Obesity

Current statistics:
2 out of 3 adults are overweight
1 out of 3 is obese
1 in 10 has diabetes
17% of children are obese (compared
with only 5% 40 years ago)

Obese people have higher incidence of

atherosclerosis
Diabetes mellitus
hypertension
heart disease
osteoarthritis
 Metabolic
Syndrome
cluster of five risk factors
Presence of these factors can:
Double chance of heart disease
Increase risk of diabetes five times
Five factors seen in metabolic syndrome:
↑ Waist circumference
↑ Blood pressure
↑ Blood glucose
↑ Blood triglycerides
↓ Blood HDL cholesterol
Regulation of
Food Intake
 Regulation of Food Intake

Areas of
hypothalamus release
peptides that
influence feeding
behavior
Arcuate nucleus
(ARC)
lateral hypothalamic
area (LHA),
Ventromedial nucleus
(VMN)
 Regulation of Food Intake
Arcuate nucleus (ARC)

Some ARC neurons release neuropeptide Y

(NPY) and agouti-related peptides that enhance
appetite
Other ARC neurons release pro-opiomelanocortin
(POMC) and cocaine-/amphetamine-regulated
transcript (CART), which suppress appetite

Lateral hypothalamic area (LHA)

promote hunger when stimulated by neuropeptides
(e.g., NPY)

Ventromedial neurons (VMN)

cause satiety through release of corticotropin-releasing hormone (CRH) when stimulated by
appetite-suppressing peptides (e.g., POMC and CART)
 Regulation of Food Intake
Feeding behavior and hunger regulated by:

Neural signals from digestive

tract
Bloodborne signals related to
body energy stores
Hormones
To lesser extent, body
temperature and psychological
factors
Operate through brain
thermoreceptors, chemoreceptors,
and others https://www.gemhospitals.com/wp-content/uploads/2019/07/45154185_xl-
1024x1024.jpg

Food intake is subject to both short-

and long-term controls
 Regulation of Food Intake
Short-term regulation of food intake

Neural signals from digestive tract

High protein content of meal increases and prolongs
afferent vagal signals
Distension sends signals along vagus nerve that suppress
hunger center

Nutrient signals related to energy stores

Increased nutrient levels in blood depress eating
Rising blood glucose levels
Elevated blood amino acid levels
Blood levels of fatty acids
Hormones
Gut hormones (e.g., insulin and CCK) depress hunger
Glucagon and epinephrine stimulate hunger
Ghrelin (Ghr) from stomach stimulates appetite; levels peak
prior to mealtime
 Regulation of Food Intake
Long-term regulation of food intake

Leptin
Hormone secreted by fat cells in response to increased body fat mass
Indicator of total energy stores in fat tissue
Protects against weight loss in times of nutritional deprivation
Acts on ARC neurons in hypothalamus
Suppresses secretion of NPY—potent appetite stimulant
Stimulates expression of appetite suppressants (e.g., CART peptides)

Rising leptin level causes some weight loss but is no “magic bullet” for obese
patients
Obese people have high leptin levels but seem to be resistant to its action
Theory on function of leptin is that it helps prevent weight loss during times of
nutritional deficiency
Regulation of Food Intake
 Regulation of Food Intake
Additional factors in regulation of food intake

Temperature: cold activates hunger

Stress: depends on individual
Psychological factors
Adenovirus infections
Sleep deprivation
Composition of gut bacteria
Metaboli
c Rate

https://i.ytimg.com/vi/68zJ6jqtgfU/hqdefault.jpg
 Metabolic Rate
total heat produced by chemical reactions and mechanical work
of body

Can be measured:
Directly: calorimeter measures heat liberated into water chamber
Indirectly: respirometer measures oxygen consumption (directly proportional
to heat production)
 Basal Metabolic Rate (BMR)

BMR: energy body needs to

perform its most essential activities

Measured in postabsorptive state

(12-hour fast)
reclining position
relaxed mentally & physically http://upload.wikimedia.org/wikipedia/commons/b/b0/
Indirect_calorimetry_laboratory_with_canopy_hood.jpg

room temperature 20–25°C

Recorded as kilocalories per square meter of body surface per hour

(kcal/m2/h)

Example: 70 kg adult BMR = 66 kcal/h

 Basal Metabolic Rate (BMR)
BMR is influenced by:

Age and gender: BMR decreases

with age
Males have disproportionately
higher BMR
Body temperature: BMR increases
with temperature
Stress: BMR increases with stress
Thyroxine: increases oxygen
consumption, cellular respiration,
and BMR
 Total Metabolic Rate (TMR)
Total metabolic rate (TMR)

Rate of energy consumption to fuel all ongoing activities

Increases with skeletal muscle activity and food ingestion (food-induced
thermogenesis)
Greatest with protein ingestion

Can be considered as daily energy expenditure

Components are

Basal energy expenditure (BMR)

The thermic effect of food (TEF)
Energy expended on physical activity (thermic effect of activity = TEA)
Total metabolic rate (TMR) = Total daily energy expenditure (TDEE)
 Regulation of Body Temperature

Only ~ 40% of energy released by catabolism can be captured by ATP; the rest is lost as heat

Cannot be used to do work

Warms the tissues and blood
Helps maintain the homeostatic body temp.

Body temperature reflects the balance between heat production

and heat loss
At rest, the liver, heart, brain, kidneys & endocrine organs generate most heat
During exercise, heat production from skeletal muscles increases
dramatically
 Regulation of Body Temperature
Normal body temperature =
37°C ± 5°C (98.6°F)
Optimal enzyme activity at this
temperature
Increased temperature denatures
proteins and depresses neurons
In children under 5, temperature of 41°C
(106°F) can lead to convulsions
~43°C (109°F) is the limit for life
Tissues can tolerate low body
temperatures better
 Core and Shell Temperature

Core (organs within skull and

thoracic and abdominal cavities) has
highest temperature
Rectal temperature is best
clinical indicator
Core temperature is regulated and is
fairly constant
Blood is major agent of heat
exchange between core and shell
Shell (skin) has lowest temperature
Fluctuates between 20°C and
40°C

http://www.frca.co.uk/images/insulating_shell.jpg
 Mechanisms of Heat Exchange

Four mechanisms of heat transfer:

Radiation: loss of heat by infrared rays ; objects are not in contact
Conduction: heat transfer between molecules of objects in direct contact

Convection: heat transfer to

surrounding air
Evaporation: heat loss due to
evaporation of water from body
surfaces; heat absorbed by water
during evaporation is known as heat https://lh3.googleusercontent.com/

of vaporization
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bcW5_B2P6bZWnpjcJCMsrh9mG36gOlRDED51HIFdg

Insensible heat loss accompanies insensible water loss from lungs, oral mucosa, and skin
Loss ~ 10% of basal heat production
Sensible heat loss – when body temperature rises and sweating increases water vaporization
Factors contributing to heat balance
 Role of the Hypothalamus

Thermoregulatory centers: preoptic region

of hypothalamus is main integrating center
for thermoregulation

Two thermoregulatory centers

Heat-loss center
Heat-promoting center
Hypothalamus receives afferent input from:

Peripheral thermoreceptors in shell (skin)

Central thermoreceptors in core (some in
hypothalamus)

Initiates appropriate heat-loss and heat-

promoting activities
 Heat-Promoting Mechanisms

Behavioral modifications
(voluntary) measures include:

Putting on more clothing

Drinking hot fluids
Changing posture (clasping
arms across chest)
Increasing physical activity
(jumping up and down)
 Heat-Promoting Mechanisms
Constriction of cutaneous blood vessels
Regulated by sympathetic nervous system

Shivering
Heat from skeletal muscle activity

Increases in metabolic rate

Chemical (non-shivering) thermogenesis: via epinephrine and
norepinephrine stimulated by cold temperatures
Mechanism seen in infants
Brown adipose tissue in infants and adults

Enhanced release of thyroxine

Seen only infants
 Heat-Loss Mechanisms

Voluntary measures include:

Wearing light-colored, loose-fitting clothing

take off a sweater, turn on a fan, get a cold drink
Reducing activity and seeking a cooler environment
Heat-promoting center is inhibited
Dilation of cutaneous blood vessels
Enhanced sweating
Mechanisms of
body
temperature
regulation
 Homeostatic Imbalance
Hypothermia

Low body temperature where vital signs

decrease
Shivering stops at core temp of 30 - 32°C
Can progress to coma and death by cardiac
arrest at ~ 21°C
Hyperthermia

Elevated body temp depresses the hypothalamus

Positive-feedback mechanism, heat stroke begins
at core temperature of 41°C
Can be fatal if not corrected

Heat exhaustion

Also referred to as exertion-induced heat exhaustion

Heat-associated collapse after vigorous exercise
Due to dehydration and low blood pressure
Heat-loss mechanisms are still functional
May progress to heat stroke if body is not cooled and rehydrated promptly
Fever
Controlled hyperthermia mostly due to
infection, but also cancer, allergies, or CNS
injuries
Macrophages release cytokines called pyrogens
that cause release of prostaglandins from
hypothalamus, resetting thermostat higher
Triggers heat-producing mechanisms, and
temperature rises
The set-point temperature of the body will
remain elevated until
prostaglandins (PGE) are no longer present
Natural body defenses or antibiotics reverse
disease process

Cryogens (example: vasopressin) reset thermostat to

lower (normal) level, activating heat-loss
mechanisms, so temperature falls
Aspirin and other NSAIDs inhibit fever by blocking
 Clinical Note
TH hyposecretion in adults can lead to myxedema

Symptoms include low metabolic rate, thick

and/or dry skin, puffy eyes, feeling chilled,
constipation, edema, mental sluggishness,
lethargy Myxedema
If due to lack of iodine, a goiter may develop
↑ synthesize of unusable thyroglobulin
causes thyroid to enlarge

Hyposecretion in infants leads to cretinism

Symptoms include intellectual

disabilities, short and
disproportionately sized body, thick
tongue and neck
 Clinical Note
Hypersecretion of TH: most common type is Graves’ disease

Autoimmune disease: body makes abnormal antibodies directed against

thyroid follicular cells
Antibodies mimic TSH, stimulating TH
release
Symptoms include elevated metabolic
rate, sweating, rapid and irregular
heartbeats, nervousness, and weight loss
despite adequate food
Exophthalmos may result: eyes
protrude as tissue behind eyes
becomes edematous and fibrous
Treatments include surgical removal of
thyroid or radioactive iodine to destroy
active thyroid cells
 Introduction to the Immune System

Chapter 17: pp. 651-654 (Section 17.4)

Chapter 21: pp. 781- 810 (Sections 21.1 – 21.6)
Objectives

Distinguish between the non-specific (cellular & chemical) and

specific (humoral and cell-mediated immune responses) mechanisms
of defence
list the 5 different types of leucocytes and give a brief description of the
structure and function of each
in flow chart form, summarize the main steps of leukopoiesis
discuss briefly each of these leukocyte disorders in terms of causes &
consequences: leukemia, infectious mononucleosis, leukopenia
 The major components of whole blood

Pathophysiology; McCance and Hueter 7th ed 2014

 Never Let Monk
(neutrophils, lymphocytes, mon
 Chapter 17

Leukocytes
General Structure & Functional Characteristics
only formed elements that are complete cells
<1% total blood volume; usu 4800 -10,800 WBCs/μl blood

Function in defense against disease

Can leave capillaries via diapedesis → immune and/or inflammatory response

Move through tissue spaces by amoeboid motion and positive chemotaxis
Leukocytosis: WBC count > 11,000 per μl
blood
Leukocytes grouped into two major
categories:
Granulocytes: contain visible
cytoplasmic granules (neutrophils,
eosinophils, basophils)
Agranulocytes: do not contain visible
cytoplasmic granules (lymphocytes,
monocytes)

Never Let Monkeys Eat Bananas

(neutrophils, lymphocytes, monocytes, eosinophils, basophils)
 Granulocytes
neutrophils, basophils, eosinophils
spherical, larger than RBCs, lobed nuclei, cytoplasmic granules, Wright’s stain
All are phagocytic to some degree

Neutrophils

Most numerous WBCs (50–70% of WBCs)

Granules stain with both acid and basic dyes
Granules contain either hydrolytic enzymes or antimicrobial proteins,
defensins
Called polymorphonuclear leukocytes (PMNs or polys): they contain
many differently shaped nuclear lobes
Cell has anywhere from three to six lobes
Very phagocytic
Referred to as “bacteria slayers”
Kill microbes by process called respiratory burst
Cell synthesizes potent oxidizing substances (bleach or
hydrogen peroxide)
Defensin granules merge with phagosome
Form “spears” that pierce holes in membrane of ingested
microbe
 Granulocytes

Eosinophils

Account for 2–4% of all leukocytes

Nucleus has two lobes connected by a broad band; resembles ear muffs
Red-staining granules contain digestive enzymes
Release enzymes on large parasitic worms, digesting their surface
Also play role in allergies and asthma, as well as immune response
modulators

Basophils

Rarest WBCs, accounting for only 0.5–1% of leukocytes

Nucleus deep purple with one to two constrictions
Large, purplish black (basophilic) granules contain histamine
Histamine: inflammatory chemical that acts as vasodilator
and attracts WBCs to inflamed sites
Are functionally similar to mast cells
 Agranulocytes
includes lymphocytes, monocytes
no visible granules; nuclei spherical or kidney-shaped

Lymphocytes
Second most numerous WBC, accounts for 25%
Large, dark purple, circular nuclei with thin rim of blue cytoplasm
Mostly found in lymphoid tissue (example: lymph nodes, spleen), but a
few circulate in blood / Crucial to immunity
Two types of lymphocytes
T lymphocytes (T cells) act against virus-infected cells & tumor
cells
B lymphocytes (B cells) give rise to plasma cells, which produce
antibodies

Monocytes

Largest of all leukocytes; 3–8% of all WBCs

Abundant pale blue cytoplasm
Dark purple-staining, U- or kidney-shaped nuclei
Leave circulation, enter tissues, and differentiate into macrophages
Actively phagocytic cells; crucial against viruses, intracellular
bacterial parasites, and chronic infections
Activate lymphocytes to mount an immune response
 Leukopoiesis

hormonally regulated according to body’s need

Interleukins (ILs) and colony-stimulating factors
(CSFs)

All leukocytes originate from hemocytoblast

stem cell that branches into two pathways:
Lymphoid stem cells produces
lymphocytes
Myeloid stem cells produce all other
elements

bone marrow stores mature granulocytes (not

erythrocytes); usu contains 10-20X more
granulocytes than in blood
lifespan of granulocytes = 0.5-9.0 days (most Fig.
die in line of duty) 17.11
 Leukocyte Disorders
Leukemias

Cancerous condition involving overproduction of abnormal

WBCs /usually involve clones of single abnormal cell
Named according to abnormal WBC clone involved
Myeloid leukemia: myeloblast descendants Normal marrow
aspiration
Lymphocytic leukemia involves lymphocytes
Acute (quickly advancing) leukemia derives from stem cells
- primarily affects children
Chronic (slowly advancing) leukemia involves proliferation
of later cell stages -more prevalent in older people
ALL marrow
aspiration

bone marrow taken over by cancerous cells

severe anemia, clotting problems (also fever, weight loss, bone pain)
NB: WBCs numerous but non-functional - death usu from internal bleeding &
overwhelming infections
Treatment: irradiation & admin of anti-leukemic drugs; bone marrow transplant
 Leukocyte Disorders
Infectious mononucleosis

Highly contagious viral disease (“kissing disease”)

Usually seen in young adults
Caused by Epstein-Barr virus
Results in high numbers of typical agranulocytes
Involve lymphocytes that become enlarged
Originally thought cells were monocytes, so disease
named mononucleosis
Symptoms Infectious mononucleosis & production of atypical
Tired, achy, chronic sore throat, low fever lymphocytes; eduserv.hscer.washington.edu/...

Runs course with rest in 4–6 weeks

Leukopenia
abnormally low WBC count - usu due to drugs, esp.
glucocorticoids & anticancer agents

https://healthhema.com/wp-content/uploads/2017/10/leukopenia.jpg
 THE
IMMU
NE
SYSTE
M

Fig.
21.1
 THE IMMUNE
SYSTEM
Immune system provides resistance to disease
Made up of two intrinsic systems

Innate (nonspecific) defense system

Constitutes first and second lines of defense
First line of defense: external body membranes (skin and mucosae)
Second line of defense: antimicrobial proteins, phagocytes, and other cells
(inhibit spread of invaders; inflammation most important mechanism)
protect against foreign substances/abnormal cells without having to
specifically identify them

Adaptive (specific) defense system

Third line of defense attacks particular
foreign substances (takes longer to react
than innate)
subpopulations of lymphocytes recognize the
specific target (usually specific cell surface
proteins) and attack the target
https://qph.ec.quoracdn.net/main-qimg-
85b70277b6979cc1fa54b2a925d24635
 INNATE
DEFENSES
uses the first and/or second lines of defense to stop attacks by pathogens (disease-causing
microorganisms)

(see next slide)

 Innate Defense: Surface Barriers
Surface barriers are skin and mucous membranes, along with their secretions

Physical barrier to most microorganisms

Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins
Mucosae provide similar mechanical barriers
Skin and mucous membranes produce protective chemicals that inhibit or destroy microorganisms

Acid: acidity of skin and some mucous secretions inhibits growth; called acid mantle
Enzymes: lysozyme of saliva, respiratory mucus, and lacrimal fluid kills many microorganisms;
enzymes in stomach kill many microorganisms
Mucin: sticky mucus that lines digestive and respiratory tract traps microorganisms
Defensins: antimicrobial peptides that inhibit microbial growth
Other chemicals: lipids in sebum and dermicidin in sweat are toxic to some bacteria

Respiratory system also has modifications to stop pathogens

Mucus-coated hairs in nose trap inhaled particles
Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus toward mouth

Surface barriers breached by nicks or cuts trigger the internal second line of defense that
protects deeper tissues
 Innate Internal Defense: cells & chemicals
Innate internal system necessary if microorganisms invade deeper
tissues; includes:

Phagocytes; Natural killer (NK) cells; Inflammatory response; antimicrobial

proteins; fever
PHAGOCYTES
white blood cells that ingest and digest (eat) foreign invaders
Neutrophils: most abundant phagocytes, but die fighting; become
phagocytic on exposure to infectious material

Macrophages: develop from

monocytes (which leave the blood
stream) are chief and most robust
phagocytic cells
Free macrophages
Fixed macrophages
 Innate Internal Defense: cells & chemicals
Phagocytosis

Phagocyte recognizes & binds to

pathogen’s carbohydrate “signature”
Some pathogens hide their surface
carbohydrates, helping them evade
phagocytosis
Opsonization: immune sys. uses
antibodies or complement proteins
as opsonins that coat pathogens

Some pathogens are not killed with acidified lysosomal enzymes (e.g.,
tuberculosis bacteria)
Helper T cells trigger macrophage to produce respiratory burst, which kills
pathogens resistant to lysosomal enzymes by:
Releasing cell-killing free radicals /producing oxidizing chemicals (e.g., H 2O2)
/ increasing pH and osmolarity of phagolysosome
 Innate Internal Defense: cells & chemicals
NATURAL KILLER
CELLS
Nonphagocytic, large granular lymphocytes that police blood and lymph
don’t identify invaders; just
recognize abnormalities on
surface of body cells such as
loss of self-antigens –
recognize cells that are
“stressed”
contact target and inject toxins
inducing it to undergo
apoptosis
secrete potent chemicals that
enhance inflammatory response
NK population greatly reduced
in people with AIDS http://sphweb.bumc.bu.edu/otlt/MPH-Mod
ules/PH/Ph709_Defenses/PH709_Defens
es4.html
 Innate Internal Defense: cells & chemicals
INFLAMMATION: Tissue response to injury
triggered whenever body tissues are injured

Benefits of inflammation :

prevents spread of
damaging agents to nearby
tissues
disposes of cell debris &
pathogens
sets the stage for repair
processes
alerts the adaptive immune
system

Sometimes a fifth sign, impairment

of function, is seen if movement or Fig. 21.4: Events of Acute Inflammation
use of area is hampered
(see next 2 slides)
 Innate Internal Defense: cells & chemicals
STAGES OF INFLAMMATION
Inflammatory chemical release
Chemicals are released into ECF by injured tissues or immune cells
Example: histamine released by mast cells is key inflammatory chemical
Kinins, prostaglandins (PGs), cytokines and if pathogens are involved, complement
All make capillaries leaky / many attract phagocytes to area

Vasodilation & increased vascular

permeability
Vasodilation causes hyperemia—which
leads to redness and heat
Increased capillary permeability causes
exudate to leak into tissue
Results in local swelling (edema)
Swelling also pushes on nerve
endings, resulting in pain
 Innate Internal Defense: cells & chemicals
INFLAMMATI
ON
Phagocyte mobilization
Neutrophils flood area first; macrophages follow
If inflammation is due to pathogens, complement is activated; adaptive immunity elements
arrive
Steps for phagocyte mobilization
1.

1. Leukocytosis: release of neutrophils from bone marrow in

response to leukocytosis-inducing factors from injured
cells
2. Margination: endothelial cells of capillaries in inflamed
area project cell adhesion molecules (CAMs) into vessel
lumen that grab onto passing neutrophils, causing them to
slow and roll along, clinging to vessel wall
3. Diapedesis: neutrophils flatten and squeeze between
endothelial cells, moving into interstitial spaces
4. Chemotaxis: inflammatory chemicals act as chemotactic
agents that promote positive chemotaxis of neutrophils
toward injured area
 Innate Internal Defense: cells & chemicals
ANTIMICROBIAL PROTEINS
enhance innate defense by:
Attacking microorganisms directly, or
Hindering microorganisms’ ability to reproduce

Most important antimicrobial proteins

Interferons
Complement proteins

Interferon (IFN)
Family (α, β, γ) of immune modulating proteins
secreted by virus-infected cells to warn healthy
neighboring cells
enter nearby non-infected cells stimulating
production of proteins that block viral reproduction
& degrade viral RNA (α & β)
NOT virus-specific
interferons also activate macrophages & mobilize natural
killer cells (α & β), allowing for some anti-cancer effects
as well
INF-γ secreted by lymphocytes, activates macrophages,
widespread immune mobilizing effect
Fig.
21.5
 Innate Internal Defense: cells & chemicals
ANTIMICROBIAL
PROTEINS
Complement

consists of ~20 blood proteins that circulate in blood in inactive form

Includes proteins C1–C9, factors B, D, and P, and regulatory proteins
Provides major mechanism for destroying foreign substances
Activation enhances inflammation and directly destroys bacteria
Enhances both innate and adaptive defenses

COMPLEMENT SYSTEM
ACTIVATION
1. Classical pathway

Antibodies first bind to invading organisms

and then bind to complement components,
activating them
Double binding called complement
fixation Nature Reviews Immunology 2, 346-353 (May 2002)
Once initial complement proteins are
activated, an activation cascade is triggered
 Innate Internal Defense: cells & chemicals
ANTIMICROBIAL
PROTEINS
COMPLEMENT SYSTEM ACTIVATION
(cont.)

2. Lectin pathway
Lectins are produced by innate system
to recognize foreign invaders
When lectin is bound to specific sugars
on foreign invaders, it can also bind
and activate complement
3. Alternative pathway
Complement cascade is activated
spontaneously when certain
complement factors bind directly to Nature Reviews Immunology 2, 346-353 (May 2002)

foreign invader
Lack of inhibitors on
microorganism’s surface allows
process to proceed
Figure 21.6 Complement Activation

Last slide of lecture 1

Innate Internal Defense: cells & chemicals

Fever
Abnormally high body temperature
that is a systemic response to invading
microorganisms
body’s thermostat normally set at
…………
reset by pyrogens released by
leukocytes & macrophages exposed to
bacteria & other foreign substances

High fever is dangerous - Why?

Moderate fever is helpful - Why?
 ADAPTIVE IMMUNE
SYSTEM
is a specific defensive system that eliminates almost any pathogen or abnormal
cell in body
Amplifies inflammatory response & activates complement but it must be primed

Characteristics of adaptive immunity

it involves B and T lymphocytes

it is specific: recognizes and targets
specific antigens
it is systemic: not restricted to initial site
it has memory: mounts an even stronger
attack to “known” antigens (second and
subsequent exposures)
http://www.amoebasisters.com/uploads/2/1/9/0/21902384/vaccine_orig.png
 ADAPTIVE IMMUNE
SYSTEM
Two main branches of adaptive system
1.

1. Humoral immunity
Antibodies, produced by lymphocytes,
circulate freely in body fluids
Bind & temporarily inactivate target cell
Mark for destruction by phagocytes or
complement
Has extracellular targets
2. Cellular (cell-mediated) immunity
3. Lymphocytes act against target cell
Directly—by killing infected cells
Indirectly—by releasing chemicals that
enhance inflammatory response; or
activating other lymphocytes or
macrophages
Cellular immunity has cellular targets
 ADAPTIVE IMMUNE
Antigens SYSTEM
substances that can mobilize adaptive defenses and provoke an immune response
Targets of all adaptive immune responses
Most are large, complex molecules not normally found in body (non-self)
Characteristics of antigens
Can be a complete antigen or hapten (incomplete)
Contain antigentic determinants (parts of antigen that antibodies or lymphocyte
receptors bind to)
Can be a self-antigen

Fig. 21.7
 ADAPTIVE IMMUNE
Antigens (cont.) SYSTEM
Complete antigens have two important functional properties:

Immunogenicity: ability to stimulate proliferation of specific lymphocytes

Reactivity: ability to react with activated lymphocytes and antibodies released by
immunogenic reactions
eg: foreign proteins, polysaccharides, lipids, and nucleic acids; seen on many foreign invaders such as
pollen and microorganisms
Incomplete antigens (aka haptens) involve molecules too small to be seen so are not
immunogenic by themselves

eg: small peptides, nucleotides, some hormones

May become immunogenic if hapten attaches to body’s own proteins
Combination of protein + hapten is then seen as foreign
Causes immune system to mount attack that is harmful to person because it attacks self-
proteins as well as hapten
o eg: poison ivy, animal dander, detergents, and cosmetics
 ADAPTIVE IMMUNE
SYSTEM
Self-Antigens: MHC Proteins
all cells are covered with variety of proteins located on surface that are not
antigenic to self, but may be antigenic to others in transfusions or grafts
one set of important self-proteins are group of glycoproteins called MHC
proteins
Coded by genes of major histocompatibility complex (MHC) and unique
to each individual
Contain groove that can hold piece of self-antigen or foreign antigen
T lymphocytes can recognize only antigens that are presented on MHC proteins
 ADAPTIVE IMMUNE
SYSTEM
Adaptive immune system involves three types of cells
Two types of lymphocytes
B lymphocytes (B cells)—humoral immunity
T lymphocytes (T cells)—cellular immunity
Antigen-presenting cells (APCs)
Do not respond to specific antigens
Play essential auxiliary roles in immunity
 LYMPHOCYTES

“It is our genes, not antigens,

that determine what specific
foreign substances our
immune system will be able to
recognize and resist.”

∼25,000 different
genes codes proteins
in the body; up to a
billion different types
of lymphocyte antigen
receptors
Huge variety of
receptors: gene
segments are shuffled
around, resulting in
many combinations

(see next 2 slides)

 LYMPHOCYTES
Development, maturation, and activation

T and B lymphocytes share common development and steps in their life cycles
Five general steps:
1. Origin: both lymphocytes originate in red bone marrow
2. Maturation
Lymphocytes are “educated” in a 2–3-day process and mature in
primary lymphoid organs (B cells in bone marrow and thymus)
Lymphocytes are educated for 2 reasons:
1. Immunocompetence: lymphocytes must be able to recognize
only 1 specific antigen
B or T cells display only one unique type of antigen
receptor on surface when mature so bind only one specific
antigen
2. Self-tolerance: lymphocytes must be unresponsive to own
antigens
 LYMPHOCYTES
Development, maturation, and activation (cont.)
1.

1.

1. Seeding secondary lymphoid organs and circulation

Immunocompetent B and T cells not yet exposed to antigen are called naive
Exported from primary lymphoid organs (bone marrow and thymus) to “seed” (colonize)
secondary lymphoid organs (lymph nodes, spleen, etc.)
Increases chance of encounter with antigen
2. Antigen encounter and activation
Naive lymphocyte’s first encounter with antigen triggers lymphocyte to develop further
Lymphocyte is selected to differentiate into active cell by binding to its specific antigen
Referred to as clonal selection
If correct signals are present, lymphocyte will complete its differentiation into active cell
3. Proliferation and differentiation
Once selected and activated, lymphocyte proliferates
Forms army of exact copies of itself
Referred to as clones
Most clones become effector cells that fight infections
A few remain as memory cells
Able to respond to same antigen more quickly second time it is encountered
B and T memory cells and effector T cells circulate continuously
 LYMPHOCYTES
Lymphocyte Education during Maturation

T cells mature in thymus under negative and

positive selection pressures (“tests”)
Positive selection process
Selects T cells capable of recognizing self-
MHC proteins (MHC restriction); those
that can’t are destroyed by apoptosis
Negative selection
Prompts apoptosis of T cells that bind to
self-antigens displayed by self-MHC
Process, called clonal deletion, ensures
self-tolerance
 Antigen-Presenting Cells (APCs)
Engulf antigens and present fragments of antigens to T cells for recognition

Dendritic cells
Found in connective tissues & epidermis / act as mobile
sentinels of boundary tissues
Phagocytize pathogens that enter tissues, then enter lymphatics
to present antigens to T cells in lymph node
Most effective antigen presenter known / key link between
innate & adaptive immunity

Macrophages
Widely distributed in connective tissues and lymphoid organs
Present antigens to T cells, which not only activates T cell, but also further activates
macrophage
Activated macrophage becomes voracious phagocytic killer
Also trigger powerful inflammatory responses and recruit additional defenses

B cells
Do not activate naive T cells
Present antigens to helper T cell to assist their own activation
https://i.shgcdn.com/4309b351-e205-4107-81e7-016c9b81de22/-/stretch/off/-/resize/3000x/-/quality/best/
 Humoral Immune Response
When B cell encounters target antigen, it provokes humoral immune response

Antibodies specific for that particular antigen are then produced

B cells: activated when antigens
bind to surface receptors, cross-
linking them
Triggers receptor-mediated
endocytosis of cross-linked
antigen-receptor complexes (clonal
selection), leading to proliferation
and differentiation of B cell into
effector cells

Most clone cells become plasma cells,

antibody-secreting effector cells
Secrete specific antibodies at rate of 2000
molecules per second for 4 to 5 days, then
die
Antibodies circulate in blood or lymph,
binding to free antigens, marking them for
destruction by innate or other adaptive
mechanisms
 Humoral Immune Response
Clone cells that do not become plasma cells become memory cells
Provide immunological memory
Mount an immediate response to future exposures to same antigen
Humoral Immune Response

(see next slide)

 Immunological Memory
Primary immune response: cell proliferation and differentiation upon
exposure to antigen for the first time

Lag period: 3 to 6 days

Peak levels of plasma antibody are reached in 10 days
Antibody levels then decline

Secondary immune response

Re-exposure to same antigen gives faster, more prolonged, more effective

response
Sensitized memory cells provide immunological memory
Respond within hours, not days
Antibody levels peak in 2 to 3 days at much higher levels
Antibodies bind with greater affinity
Antibody level can remain high for weeks to months

Where do vaccines fit into this?

 Types of Vaccines
There are 4 main types of vaccines:
Live-attenuated vaccines
similar to the natural infection
MMR, small pox, chicken pox, yellow fever

Inactivated vaccines
the killed version of the germ that causes a disease
Hepatitis A, flu shot, polio, rabies

Subunit, recombinant, polysaccharide, and conjugate vaccines

use specific pieces of the germ — like its protein, sugar, or capsid
Hepatitis B, HPV, Shingles, Whooping cough, pneumococcal disease

Toxoid vaccines
use a toxin (harmful product) made by the germ that causes a disease
Diphtheria, tetanus
 COVID-19
Vaccines

There are three main

types of COVI-19
vaccines
mRNA vaccines
Protein subunit
vaccines
Vector vaccines

https://ichef.bbci.co.uk/news/976/cpsprodpb/10BAA/
production/_115722586_more_vaccines_compared_v6-
nc.png
Active and Passive Humoral Immunity

(see next slide)

 Active and Passive Humoral Immunity
Active humoral immunity: B cells encounter antigens and produce specific antibodies
against them

Two types of active humoral immunity

1. Naturally acquired: formed in response to actual bacterial or viral infection
2. Artificially acquired: formed in response to vaccine of dead or attenuated
pathogens
Provide antigenic determinants that are immunogenic and reactive
Spare us symptoms of primary response

Passive humoral immunity: ready-made antibodies are introduced into body

B cells are not challenged by antigens; Immunological memory does not occur
Protection ends when antibodies degrade
Two types of passive humoral immunity
1. Naturally acquired: antibodies delivered to fetus via placenta or to infant through
milk
2. Artificially acquired: injection of serum, such as gamma globulin
Protection immediate but ends when antibodies naturally degrade in body
 Antibodie
s
also called Immunoglobulins (Igs)—are proteins secreted by plasma cells / make up
gamma globulin portion of blood
Capable of binding specifically with antigen detected by B cells

Basic antibody structure

Overall T- or Y-shaped antibody monomer
consists of four looping polypeptide chains
linked by disulfide bonds
Four chains consist of:
Two identical heavy (H) chains with hinge
region at “middles”
Two identical light (L) chains
Variable (V) regions at one end of each arm
combine to form two identical antigen-binding
sites
Stems makeup constant (C) regions
Area that determines antibody class
Considered effector region of antibody

Fig.
 Antibodie
Five Ig classes s
IgM - Pentamer (larger than others); first antibody
released
IgA (secretory IgA)- Monomer or dimer; found in
mucus & other secretions
IgD - Monomer attached to surface of B cells / B-cell
receptors
IgG - Monomer; 75–85% of antibodies in plasma
IgE - Monomer active in some allergies reactions and
parasitic infections

Plasma B cells can switch from making one class of antibodies to

another

Retain specificity for same antigen

IgM is released during primary response, but plasma cell can
switch to IgG for secondary response
Almost all secondary responses are IgG
Fig. 21.15: Mechanisms of Antibody Action

(see next slides)

 Mechanisms of Antibody Action

Antibodies do not destroy antigens; they inactivate and tag them

Form antigen-antibody (immune) complexes
Neutralization
Simplest, but one of most important defensive mechanism
Antibodies block specific sites on viruses or bacterial exotoxins /Prevent antigens from
binding to receptors on tissue cells
Antigen-antibody complexes undergo phagocytosis
Agglutination
Antibodies can bind same determinant on two different antigens at the same time
Allows for antigen-antibody complexes to become cross-linked into large lattice-like clumps -
process referred to as agglutination eg clumping of mismatched blood cells

Precipitation
Soluble molecules (instead of cells) are cross-linked into complexes which precipitate out of solution
→ easier for phagocytes to engulf
Complement fixation
Main antibody defense against cellular antigens (bacteria, mismatched RBCs)
When several antibodies are bound close together on same antigen, complement-binding sites on
their stem regions are aligned → complement fixation, which leads to cell lysis, as well as other
https://i.shgcdn.com/3a964030-f8bc-41a5-8139-a40fcdb6d97e/-/stretch/off/-/resize/3000x/-/quality/best/
 CELLULAR IMMUNE
RESPONSE
antibodies can handle only obvious
antigens (outside cells) - cannot, eg, fight
TB bacillus or viruses that multiply
inside cells
cell-mediated immunity involves various
types of T-cells - don’t respond to free
antigens; « see » only processed antigen
fragments displayed on body’s own cells
https://s3-us-west-2.amazonaws.com/courses-images-archive-read-only/wp-
content/uploads/sites/
403/2015/04/21031600/2216_Antigen_Processing_and_Presentation.jpg

direct attack against body cells infected by viruses, bacteria; also abnormal or
cancerous cells, cells of infused/transplanted foreign tissues
Some T cells directly kill cells; others release chemicals that regulate immune
response
Major Types of T Cells
 Cellular Immune
Response
T cells are more complex than B cells both in classification and function
Two populations of T cells are based on which cell differentiation
glycoprotein receptors are displayed on their surface
CD4 cells usually become helper T cells (TH) that can activate B cells,
other T cells, and macrophages; direct adaptive immune response
Some become regulatory T cells, which moderate immune response
Can also become memory T cells
CD8 cells become cytotoxic T cells (TC) capable of destroying cells
harboring foreign antigens
Also become memory T cells
Helper, cytotoxic, and regulatory T cells are activated T cells
Naive T cells are simply termed CD4 or CD8 cells
 MHC Proteins and Antigen Presentation
T cells respond only to processed fragments of antigens displayed on surfaces
of cells by major histocompatibility complex (MHC) proteins
Antigen presentation is vital for activation of naive T cells and normal
functioning of effector T cells
Two classes of MHC proteins:

Class I MHC proteins: displayed by all cells except RBCs

Bind with short fragment (8–9 amino acids) of endogenous antigen
Endogenous antigen can be:

Self-antigen / non-self antigen: abnormal proteins in infected or abnormal

cell
Class I MHC crucial for CD8 cell activation
Act as antigen holders; form “self” part that T cells recognize
Inform cytotoxic T cells of microorganisms hiding in cells (cytotoxic T cells
ignore displayed self-antigens)
 MHC Proteins and Antigen
Presentation
Class II MHC proteins: displayed by APCs
Bind with longer fragments (14–17 aa) of exogenous (extracellular) antigens that have
been engulfed and broken down in a phagolysosome by APC
Class II MHC proteins recognized by helper T cells
Signal CD4 cells that help is required
Both types are synthesized in ER and bind to peptide fragments
 MHC Proteins and Antigen
Presentation
MHC restriction

CD4 and CD8 cells have different requirements for MHC protein that
presents antigens to them
CD4 cells that become TH are restricted to binding to only class II MHC
proteins typically on APC surfaces
CD8 cells that become cytotoxic T cells are restricted to binding only
class I MHC proteins found on every cell surface, including APC
surfaces
Once activated, cytotoxic T cells seek out same antigen on class I
MHC proteins on any cell
 Activation and Differentiation of T cells

T cells can be activated only when antigen is

presented to them
Activation is a two-step process
1.

1. Antigen binding
2. T cell antigen receptors (TCRs) bind to antigen-
MHC complex on APC surface
3. TCR must perform double recognition by
recognizing both MHC & foreign antigen it
displays
4. Co-stimulation
5. T cell also bind to one or more co-stimulatory
signals on surface of APC
6. Without co-stimulation, anergy occurs, in which T
cells:
Become tolerant to that antigen
Are unable to divide
Do not secrete cytokines
Both occur on surface of same APC & are
required for clonal selection of T cell
 Activation and Differentiation of T cells

Proliferation and differentiation

Activated cells enlarge, proliferate,
differentiate & perform functions according to
their T cell class / response peaks within 1 wk
Apoptosis (cell death) occurs btwn 7 – 30 d.
Memory cells remain & mediate 2o responses

Cytokines

Chemical messengers of immune system

Mediate cell development, differentiation, and
responses in immune system
Include interferons and interleukins
 Helper T Cells
(T H)
Play central role in adaptive immune response
Activate both humoral and cellular arms
Once primed by APC presentation of antigen, helper T cells:
Help activate B cells and other T cells
Induce T and B cell proliferation
Secrete cytokines that recruit other immune cells
Without TH, there is no immune response

Activation of B cells
Helper T cells interact directly with B cells displaying
antigen fragments bound to MHC II receptors
Stimulate B cells to divide more rapidly and begin
antibody formation
B cells may be activated without TH cells by binding
to T cell–independent antigens
Response is weak and short-lived
Most antigens are T cell–dependent antigens that
require TH co-stimulation to activate B cells
 Helper T Cells
(TH)
Activation of CD8 cells
CD8 cells require TH cell to become activated into
destructive cytotoxic T cells
Cause dendritic cells to express co-stimulatory
molecules required for CD8 cell activation

Amplification of innate defenses

Amplify responses of innate immune system
Activate macrophages, leading to more potent killers
Mobilize lymphocytes and macrophages and attract other types of WBCs
 Cytotoxic T (TC)
cells
Directly attack & kill other cells
Activated TC cells circulate in blood/lymph
/lymphoid organs
TC cells target:
Virus-infected/ cancer cells
Cells with intracellular bacteria or parasites
Foreign cells (transfusions or transplants)
Deliver lethal hit using two mechanisms
releases perforins & granzymes by
exocytosis
binds specific membrane receptor on target
cell and stimulates apoptosis

Natural killer cells recognize other signs of abnormality that cytotoxic T cells do not look for, such as:
Cells that lack class I MHC proteins
Antibodies coating target cell
Different surface markers seen on stressed cells
NK cells use same key mechanisms as TC cells for killing their target cells
Immune surveillance: NK and TC cells prowl body looking for markers they each recognize
 Regulatory T (TReg)
cells
Dampen immune response by direct contact or by secreting
inhibitory cytokines such as IL-10 and transforming growth factor
beta (TGF-β)
Important in preventing autoimmune reactions
Suppress self-reactive lymphocytes in periphery (outside
lymphoid organs)
Research into using them to induce tolerance to
transplanted tissue
Topic 4: Renal
System
Lecture 1

Chapters 25 and 26
Why are the Kidneys so Important?

Salt and water balance

Regulation blood ion concentrations
Acid-base balance
Excrete metabolic wastes as well as drugs and toxins
Produce EPO (RBC production) and renin (bp regulation)
Convert vitamin D to active form
 4.1 Describe the anatomy of the male & female urinary systems
4.1.1 describe the gross anatomy of the
kidneys, including the blood & nerve
supplies
• bean-shaped; retroperitoneal
• superior lumbar region: from12th thoracic
vertebra to 3rd lumbar vertebra
• some protection from rib cage; right
kidney pushed lower by liver
• ~150 g; 12 x 6 x 3 cm
• adrenal glands sit on top of kidneys

Fig. 25.1

Fig. 25.3
Fig. 25.3a

Fig. 25.2
 concave medially: renal hilum (outside cleft)
to renal sinus (internal space)
3 layers of supportive tissue
renal capsule: fibrous, adheres directly to
kidney surface, strong barrier to ?
perirenal fat capsule: cushions, helps hold
kidney in place
What is renal ptosis?
renal fascia: dense CT surrounds adrenal
gland & kidney; anchoring role

Fig. 25.3

http://biology.clc.uc.edu/fankh
auser/Labs/Anatomy_&_Physi
ology/A&P203/Urinary_Tract_
Histology/Anatomy/urinary_an
J. Carnegie, UofO
atomy.html
 INTERNAL ANATOMY
(i) cortex: What process occurs here?
(ii) medulla: darker colour; medullary or renal
pyramids; Why do they appear striped ?
separated by renal columns (indentations of
cortical tissue)
(iii) pelvis: flat, funnel-shaped tube continuous with
ureter; major & minor calices; minor calices
enclose papillae of pyramids; calices collect
urine
walls of calyces, pelvis, ureter contain smooth
muscle; propel urine by peristalsis

Fig. 25.4
What is pyelonephritis?
Circulatory Pathway through Kidney
renal artery
segmental artery
interlobar artery
arcuate artery
cortical radiate artery
afferent arteriole
efferent arteriole
peritubular capillaries
or vasa recta
cortical radiate vein
arcuate vein
interlobar vein
renal vein

Fig. 25.5
Fig. 25.5b
BLOOD & NERVE SUPPLY
• renal arteries: ~1/4 total systemic CO (~1.2 L) to kidneys/min
• arterial branches pass up between medullary pyramids to reach cortex; venous
branches drain back via same route
• nerve supply provided by renal plexus of primarily sympathetic fibers →
regulate renal blood flow by adjusting diameters of renal arterioles

http://www.merck.com/media/mmhe2/fi
gures/fg145_1.gif
4.1.2 describe the structure of a nephron; differentiate between cortical
& juxtamedullary nephrons
~106 nephrons (the structural and functional units of the kidney) &
thousands of collecting ducts/kidney
 FILTRATION COMPONENTS
glomerulus
Bowman’s capsule → renal corpuscle
fenestrated glomerular endothelium
podocytes, pedicels or foot processes
filtration slits

Fig. 25.12
J. Carnegie, UofO
 Fig. 25.6
proximal
convoluted tubule
↓
nephron loop (loop
of Henle)
↓
distal convoluted
tubule
↓
collecting duct
↓
papillary duct
↓
minor calyx

collecting duct has:

1) principal cells (lack microvilli; salt & H2O balance)
2) intercalated cells (have microvilli; acid-base balance)
 2 types of nephrons:
(i) cortical (85%)
(i) juxtamedullary (15%)
Key roles of each type
of nephron?

Fig.
25.8
What would you expect the
per cent of juxtamedullary
nephrons to be in a camel?
Why does that make
sense?

J. Carnegie, UofO
A. Microcirculation of the Nephron
glomerulus: specialized for filtration → both fed & drained by arterioles

√ arterioles are high resistance vessels

√ afferent arteriole has larger diameter

Peritubular
Capillaries:
arise from efferent
arterioles – these drain
into renal venules

What is the vasa recta and

where is it found??
Fig. 25.8
 4.1.3 describe the structural organization of the juxtaglomerular complex
at junction of early DCT and afferent/efferent arterioles; regulate renal function:
(i) arteriole walls: granular cells (JG cells) → enlarged smooth muscle cells –
mechanoreceptors; secrete renin
(ii) tubule wall: macula densa cells → chemo- or osmoreceptors – monitor filtrate
& adjust GFR accordingly

JGC regulates:
a) filtrate formation
b) systemic blood pressure

Fig. 25.10
complex
 4.1.4 differentiate between the micturition
pathways in males versus females

What is the trigone & why is it important clinically?

moderately full bladder (500 ml) ~12.5 cm long
can hold up to about double that volume
What forms the internal urethral sphincter?
What forms the external urethral sphincter?

Fig. 25.22a J. Carnegie, UofO

Fig. 25.22b
J. Carnegie, UofO
 RENAL PHYSIOLOGY

4.2 Describe the nephron as the functional unit of the kidney

4.2.1 list the 2 primary & 4 additional functions carried out by the
kidneys
• major excretory organs: perfect examples of homeostatic organs

Main function: filter several litres

of fluid from bloodstream daily
(i) toxins, metabolic wastes,
excess ions leave body in urine
(ii) materials still needed by
body returned to bloodstream

J. Carnegie, UofO
4.2.2 define glomerular filtration, tubular reabsorption, tubular secretion;
differentiate between filtrate & urine
1000-1200 ml of blood pass through gomeruli each minute; (~650 ml plasma; of this
120-125 ml plasma forced into renal tubules every minute!)
equiv to filtering entire plasma volume >60 times/day

filtrate = plasma minus proteins

urine = filtrate minus nutrients,
essential ions, most H2O
kidneys process ~180 L fluid/day;
from this, ~1% is urine (~1.5 L)
(i) glomerular filtration
(ii) tubular reabsorption
(iii) tubular secretion

J. Carnegie, UofO

Fig. 25.11
Topic 4: Renal
System

Lecture 2
4.2.2 define glomerular filtration, tubular reabsorption, tubular secretion;
differentiate between filtrate & urine
1000-1200 ml of blood pass through gomeruli each minute; (~650 ml plasma; of this
120-125 ml plasma forced into renal tubules every minute!)
equiv to filtering entire plasma volume >60 times/day

filtrate = plasma minus proteins

urine = filtrate minus nutrients,
essential ions, most H2O
kidneys process ~180 L fluid/day;
~1% is urine (~1.5 L)
(i) glomerular filtration
(ii) tubular reabsorption
(iii) tubular secretion

J. Carnegie, UofO

Fig. 25.11
Glomerular Filtration
• passive, nonselective → fluids & solutes forced thru by capillary hydrostatic
pressure
• glomerulus is a very efficient filter because:
(i) filtration membrane 1000sX more permeable than other cap membranes
(ii) glomerular bp higher than in other cap beds (55 mm Hg vs < 26 mm Hg) –
what allows this bp to be maintained at such a high level??
180 L filtrate formed by kidney caps vs 2-4 L by all other cap beds combined!

Short Video on
Glomerular Filtration
from Visible Body (45.2
Filtration Process)

Fig. 25.6
4.2.3 describe the functional anatomy of the filtration membrane
• between blood & interior of glomerular capsule - 3 layers
(i) fenestrated capillary endothelium
(ii) basement membrane
(iii) visceral membrane of glomerular capsule = foot
processes of podocytes

Fig. 25.10
 Fig. 25.12

In summary:
(i) molecules < 3 nm (water, glucose, amino acids, N-wastes) pass easily
(ii) molecules 3-5 nm pass, but with greater difficulty (meaning??)
(iii) molecules > 5 nm are usually not filtered
• basement membrane proteins, with their negative charges, restrict the passage
of most larger plasma proteins
• retention of plasma proteins maintains colloid osmotic pressure, blood flow
• presence of proteins or RBCs in urine suggests filtration membrane damage
 4.2.4 define net filtration pressure
pressure responsible for filtrate formation
NFP = HPg – (OPg + HPc)
NFP = 55 – (30 + 15)
NFP = 10 mm Hg

Fig. 25.13

HPg – pushes out of blood

OPg – pulls back into blood
HPc – pushes back into blood
 Blood cells

Electrolytes

Toxins

Large proteins

Robert Bell MD, University of Ottawa

4.2.5 define glomerular filtration rate; be aware of normal value
= total amount of filtrate formed per minute by both kidneys (~125 ml/min)
• depends on: (i) total SA for filtration
(ii) filtration membrane permeability
(iii) net filtration pressure
• glomerular caps have huge SA (= SA of skin); so even though NFP only 10 mm
Hg, get large amts of filtrate formed continuously
• BUT a decrease in glomerular bp of only ~15% completely stops filtration!
• GFR is directly proportional to NFP
What happens to GFR with an increase in bp? In case of dehydration?

http://draxe.com/wp-content/upl
http://steptohealth.com/wp-conten oads/2011/07/dehydration.jpg
 4.2.6 list & describe the 3 regulatory
influences on GFR
Why is this important?
What is the target of all regulatory
influences?
(i) renal autoregulation (intrinsic)

(ii) neural controls (extrinsic)

(iii) renin-angiotensin system (extrinsic)

1. Intrinsic Mechanisms: Renal Autoregulation:

kidney keeps GFR ~constant by determining its own rate of flow & adjusting
nephron blood flow
regulates diameter of afferent (primarily) and efferent arterioles
why is it more effective to regulate the afferent arteriole?
2 types of controls:
(i) myogenic mechanism
(ii) tubuloglomerular feedback mechanism
 1a) myogenic mechanism:
• responds to any change in the bp of blood vessels - focus = afferent arteriole
• vascular smooth muscle tends to contract when stretched – so what happens
when systemic bp increases?? decreases??
1b) tubuloglomerular feedback mechanism:
• directed by macula densa cells of JGC – monitoring NaCl content of filtrate
(i) High osmolarity of fast flowing filtrate: release vasoconstrictors (e.g. ATP)
(ii) Low osmolarity of slow flowing filtrate: allow vasodilation by releasing less ATP

renal autoregulation can maintain

~constant GFR with 80-180 mm Hg
systemic bp
If systemic bp drops below 80mm
Hg (hypovolemic shock) renal
autoregulation & filtrate formation
shut down and extrinsic regulation
kicks in

J. Carnegie, UofO
 Short Video on the Myogenic Mechanism
(Reflex) (Note: there are more details in this video
than you need to know)

Short Video on the Tubuloglomerular Feedback

Mechanism (Again, there are more details in this video than
you need to know)
2. Extrinsic Mechanisms:

2a. Neural Controls

SNS comes into play during times of extreme stress → overrides renal
autoregulation & shunts blood to the heart, brain, skeletal muscles at the expense of
the kidneys

(i) direct sympathetic-induced vasoconstriction of afferent arterioles

2b. Renin-angiotensin mechanism:

the renin-angiotensin system can be activated by:

1. direct stimulation of granular cells by the SNS to
secrete renin
2. macula densa cells stimulate granular cells to
secrete renin when they sense reduced filtrate
osmolarity, reduced flow (less ATP? More PGE2?)
3. reduced stretch of granular cells directly induces
release of renin
 angiotensinogen (from liver)
(renin)
angiotensin I
(ACE)
angiotensin II
ACE = angiotensin converting enzyme

Angiotensin II is a potent, generalized vasoconstrictor

Other effects:
(i) Angiotensin II stimulates release of aldosterone by the adrenal cortex;
aldosterone stimulates reabsorption of Na+, water follows if water channels are
open → end effect on bp??
(ii) Afferent arterioles have fewer angiotensin receptors than the efferent arterioles
– what is the effect on glomerular bp and filtration rate?
The renin-angiotensin system is involved in renal regulation, but its main
purpose is to stabilize systemic blood pressure & ECF volume
Fig. 25.14
 Fig. 25.16

4.2.7 indicate the importance of tubular reabsorption

• 45 min: total blood volume filtered by kidney; most does not become urine
• most material to be reabsorbed moves through rather than between cells
Reabsorption: general principles
• organic nutrients (glucose, amino acids) ~100% reabsorbed
• reabsorption can be active or passive
• rate/degree of reabsorption of H2O /ions hormonally adjusted J. Carnegie, UofO
 4.2.7 (cont) distinguish between active and passive tubular reabsorption; list 3
substances that are not reabsorbed & indicate why
Active tubular reabsorption
• usually substances are moved against electrical and/or chemical gradient
• active process at level of basolateral membrane: substance moves passively
into tubule cell, but only because sodium actively transported into the interstitial
space to maintain the gradient
How does material move into adjacent peritubular capillaries?
• actively reabsorbed (2o AT): glucose, amino acids, lactate, vitamins, ions
• transport? usually linked to that of Na+ (secondary active transport – so where is
ATP used?
• transport systems (carriers) fairly specific; have a transport maximum (Tm)
when carriers are saturated, excess of substance appears in urine (eg:???)
• plasma proteins: if squeeze through, taken up by tubule cells; hydrolyzed &
amino acids to blood

J. Carnegie, UofO
Topic 4: Renal
System
Lecture 3
Figure 25.15 Tubular reabsorption occurs via transcellular & paracellular routes

1. Transcellular: very similar to absorption by intestinal epithelial cells

2. Paracellular: primarily H2O and some ions (Ca++, Mg++, K+ and some Na+);
primarily in the PCT where the tight junctions are more leaky
3. 80% of ATP used for AT is to reabsorb sodium by primary AT – and this creates
gradients supporting the reabsorption of almost everything else, including water
4. 20 AT for glucose, amino acids, some ions and vitamins
 Passive tubular reabsorption
• diffusion, facilitated diffusion, osmosis
• along electrochemical gradient → no ATP required
(i) active reabsorption of Na+ pulls anions (especially Cl-)
(ii) obligatory water reabsorption due to Na+ transport (aquaporins)
(iii) As water leaves, this creates gradients for the reabsorption of other substances,
especially if they are lipid-soluble (don’t need transporters)

Fig. 25.16
 Substances that are only partially reabsorbed or not reabsorbed at all
• either no carriers, not lipid soluble and/or too large; primarily nitrogenous end
products of protein & nucleic acid metabolism
(i) urea: main nitrogen-containing end product of metabolism; small enough to diffuse
through membrane pores; 50-60% reclaimed
(ii) creatinine: large, lipid-insoluble nitrogenous waste molecule; not reabsorbed by
kidney → useful for measuring GFR because whatever gets filtered stays there
(iii) uric acid: end product of purine metabolism; some excreted & some reabsorbed;
too much uric acid can lead to

http://www.gentili.net/Han
d/gout.htm
 4.2.8 link tubular reabsorption with different
regions of the renal tubules
(1) PCT: all glucose & amino acids
65% of Na+
65% of H2O
90% of bicarbonate
50% of Cl- and K+
(2) Loop of Henle (Nephron Loop):
ascending & descending limbs different
water (not NaCl) leaves descending limb
NaCl (not water) leaves ascending limb
(3) DCT + collecting duct:
• here only 10% NaCl & 20% of water remain
(still too much)
• from here on hormonally regulated based on
body’s hydration level
Antidiuretic hormone (ADH):
Renin-angiotensin system + aldosterone:
Atrial natriuretic peptide (ANP):

Fig. 25.17
 4.2.9 list (giving examples) 4 functions associated with tubular secretion
• kidneys get rid of unwanted substances by either:
(i) not reabsorbing them
(ii) secreting them into the urine
We are usually talking about: H+, K+, creatinine, NH4+, uric acid, urea
• secretion occurs in the late DCT & early collecting ducts
4 important functions:
(i) dispose of substances not in the original filtrate
(eg: certain drugs and other metabolites bound to
plasma proteins)
(ii) dispose of substances that underwent passive
reabsorption
(eg: urea, also uric acid – almost all of the uric
acid and ~1/2 of the urea are reabsorbed in the PCT)
(iii) dispose of excess K+ ions
(iv) maintenance of blood pH (usually means getting
rid of excess H+)

J. Carnegie, UofO
 4.2.10 describe the role of the countercurrent mechanism in the regulation of urine
concentration & volume; define osmolality; define osmosis
Countercurrent mechanism & medullary osmotic gradient
• much absorption of water & salt in PCT; filtrate at top of loop still at 300 mOsm
• differing permeabilities of loops allow water, then salt to be reabsorbed

(1) Descending limb is relatively impermeable

to solutes & freely permeable to H2O:
• as filtrate moves down descending
limb, water moves freely out by osmosis
– Why?
• filtrate osmolarity can reach 1200
mOsm by “elbow” of loop of Henle (in
which nephrons?)

Focus Figure 25.1 – a juxtamedullary nephron

Fig. 25.18
 Focus Fig. 25.1

(2) Ascending limb impermeable to water & actively transports NaCl out
• Na+-K+-2Cl- cotransporter moves solute ions out; water can’t follow – why?
• positive feedback (countercurrent multiplier) → filtrate ~200 mOsm more
concentrated at each level of descending limb
• net effect is to reduce filtrate volume J. Carnegie, UofO
Focus Fig. 25.1
 Fig. 25.19
(3) Vasa recta acts as countercurrent exchanger; maintains osmotic gradient
• 15% are medullary nephrons
• blood flow is sluggish; vessel walls freely permeable to salt & water
• blood acts as exchanger --- doesn’t …………..gradient, but……………….. it
1. If the glomerular bp is 65 mm Hg, the capsular hydrostatic pressure is 12 mm Hg, and the
colloidal osmotic pressure in the glomerulus averages 28 mm Hg, what is the glomerular
net filtration pressure?
a) 93 mm Hg
b) 53 mm Hg
c) 40 mm Hg
d) 16 mm Hg
e) 25 mm Hg
2. Which of the following statements is/are true concerning the JGC?
a) the macula densa cells secrete renin
b) the granular cells are part of the distal convoluted tubule
c) the macula densa monitors filtrate concentration
d) the granular cells are mechanoreceptors
e) C and D
3. Glucose is not normally found in the urine because it:
a) does not pass through the walls of the glomerulus
b) is kept in the blood by colloid osmotic pressure
c) is reabsorbed by the tubule cells
d) is removed by tissue cells before the blood reaches the kidney

This is as far as you need to go for Midterm 2!

J. Carnegie, UofO