BIO 580 - Medical Microbiology - Introduction - The Dynamic
Nature of Infectious Disease
BIO 580 Medical Microbiology Unit 1 The Adversaries 50
The Dynamic Nature of Infectious Disease
Lecture 1 Objectives:
Understand that infectious disease is dynamic; diseases emerge
and disappear, and perhaps re-emerge over time. The major diseases
of our past may not be the major diseases of today. New diseases
will continue to emerge in the future. Understand the major factors
that influence why a new disease emerges, especially factors that
can be influenced by human activity.
Overview of human history with infectious disease:
Year
Event
Homework ID microbial agent of disease as virus (V), bacterium
(B), protozoa (P), Fungi (F)
1876
Koch proves that a specific microbe (Bacillus anthracis) causes
a specific disease (Anthrax)
1885
Pasteur treats a boy post-exposure, with attenuated rabies
1918-19
Pandemic of Influenza A H1N1 (Spanish Flu) kills 500,000
Americans, 50 million worldwide
1928
Penicillium discovered to kill Staphylococcus
1944
Penicillin introduced into general clinical practice
1952
Staphylococcal strains demonstrate resistance to penicillin
1962
Machupo emerges in Bolivia
1967
Marburg terrorizes Germany
1969
Emergence of Lassa in Nigeria
1975
Global vaccination campaign eradicates smallpox
1976
Emergence of Ebola in Zaire
Emergence of Lyme disease (Borrelia bergdorferi)
182 American Legionnaires get sick in Philadelphia, 29 die
(Legionella pneumophilia)
Emergence of penicillin resistant Neisseria gonorrhoea
1977
Gonorrhea triple antibiotic resistant
June 1981
CDCs Morbidity and Mortality Weekly Report describes a curious
new health problem in American homosexuals
1983
1,000th official AIDS case documented
1984
Causative agent of AIDS identified - HIV
1990
Jim Henson is killed by a new stain of Streptococcus
1991
Drug resistant tuberculosis surfaces in the US
1993
4 children die of E. coli hemorrhagic syndrome
Sin Nombre emerges in the Four Corners area
1996
Recognition of BSE and nvCJD
Vancomycin-resistant S. aureus reported in Japan
1997
Vancomycin-resistant S. aureus reaches Michigan
Bird flu(Influenza A H5N1) in Hong Kong
1999
West Nile seen in U.S. for first time
2002
West Nile reaches west coast
2003
SARS-CoV emerges
2009
Influenza A (H1N1) first Influenza pandemic in 40 yrs
Preparation for next class meeting:
Write the take home message from today in a single sentence in
the space below:
Read in the text Introduction and Chapters 1, 2, and 3 (We will
discuss the info in order Ch. 1, 3, 2).
Terminology Find definitions for these terms. You may use one of
the on-line medical dictionaries on our course web site
http://www.cst.cmich.edu/users/alm1ew/MM%20Index%20Page.html
Used in Lecture 1
Infectious disease - any change from a state of health in which
part or all of the host body is not capable of carrying on its
normal functions due to the presence of a parasite or its
products.
Parasite -
Attenuated
Pandemic
Eradicate -
Unit One - The Adversaries
Unit One - Outline of Topics
1. Review of Microbes (viruses, bacteria, fungi, protozoa,
helminths, arthropods, normal microbiota)
1. Host Defenses
1. Nonspecific Defenses
1. Defenses against entry
1. Physical
1. Chemical
b. Biological
1. Defenses of the interior
1. Complement cascade
1. Acute phase proteins
1. Interferons
1. Phagocytic cells
1. polymorphonuclear leukocytes
1. monomorphonuclear leukocytes
1. Nonspecific cytolytic cells
1. Specific Defenses
1.T lymphocytes
1. Recognition of specific antigen (TCR and MHC)
1. Activation against a specific antigen (role of APC and
TH)
1. Response to specific antigen
1. T helpers
1. T cytotoxic
1. T regs
2.B lymphocytes
1. Recognition of specific antigen (BCR)
1. Activation against a specific antigen (role of APC and
TH)
1. Response to a specific antigen
i.Plasma cells
3. Memory cells (primary vs secondary response)
Unit One - Background Terminology/Concepts will not be covered
in lecture
Obligatory Steps For Infectious Microbes:
Phenomenon
Step
How
1. Entry
attach and enter into body
evade host's natural protective and cleansing mechanisms
2. Spread
local or general spread in body
evade natural barriers and immediate local defenses
3. Multiplication
multiply
but many offspring will die in host
4. Evasion
evade host defenses
evade phagocytic and immune defenses long enough for full cycle
in host to be completed
5. Transmission
exit from body
leave body at a site and on a scale that ensures spread to fresh
host
6. Pathology
cause damage in host
not strictly necessary but often occurs
Pathogen - agent capable of causing disease
Pathogenicity ability to cause disease
Frank pathogen= obligate pathogen causes disease in a healthy
host by direct interaction
Opportunistic pathogen- may cause disease under the right
conditions
Virulence degree or intensity of pathogenicity.
Dependent on:
1. Invasiveness ability of organism to spread
1. Infectivity ability of organism to leave point of entry
1. Pathogenic potential degree pathogen causes damage
Virulence factors individual characteristics of a specific
strain of microbe that confer virulence
Colonization (esp. by bacteria/yeast) establishment of a site of
replication dependent on attachment
Symbiosis - an association of two different species of
organisms.
Commensalism - one species uses the body of another species as a
habitat and possibly as a source of nutrition.
Mutualism - a reciprocal relationship between two species.
Parasitism - one species in a relationship benefits and the
other does not.
------
Respiration - use electron transport chain with an external e-
acceptor (like O2 or NO3) as the terminal e- acceptor
Fermentation - no external e- acceptor, one of the substrates
involved accepts the e-
Facultative fermenter will respire in the presence of external
electron acceptors and ferment in their absence (Ex. Escherichia
coli)
Obligate aerobe - must have O2 because only O2 can serve as the
terminal e- acceptor (Ex. Bacillus spp.)
Facultative anaerobe - will use O2 for aerobic respiration if
its present but will switch to fermentation or anaerobic
respiration if no O2 (Ex. E. coli)
Aerotolerant anaerobe - can't use O2 as an external e- acceptor,
but not killed by it.
Strict or obligate anaerobe - killed by exposure to O2 (Ex.
Bacteroides fragilis)
BIO 580 Medical Microbiology Unit 1 The Adversaries 4
Microaerophilic - grows optimally in presence of oxygen
concentrations that are below atmospheric concentrations (ex. the
streptococci)
UNIT ONE THE ADVERSARIES
I. The Microbes
Objectives:
To Review:
1. important structural features of viruses
1. sequence of steps during viral infection
1. consequences of viral infections at a cellular level
1. important structural features of bacteria
1. key differences between Gram positive and Gram negative cell
walls
1. clinical significance of LPS, capsules, flagella, fimbriae,
and pili
1. important features of eukaryotic pathogens: fungi, protozoa,
helminths, arthropods
1. distribution and significance of normal microbiota by way of
clinical cases
A. VIRUSES - Obligate intracellular parasites
Common structural features
1. Genetic material - DNA or RNA, ss or ds
2. Outer coat - capsid - composed of subunits called
capsomers
Nucleic acid + capsid = nucleocapsid
Only nucleocapsid = naked
Nucleocapsid surrounded by a lipid and protein envelope =
enveloped
*Outer surfaces (capsids or envelopes) impt cause they 1st make
contact w/ host cells.
Viral infection of host proceeds through several steps:
1. Entry into body of host - 4 routes
1) inhalation of droplets -
2) ingestion -
3) direct transfer -
4) bites of arthropod vectors -
2. Adsorption to target cell(s) in host specific interaction
between virus surface molecules and receptors on target cells
***
3. Entry into target cell - 3 mechanisms
1) Fusion (enveloped)
2) Receptor-mediated endocytosis (RME)
(naked & enveloped)
Entry step ends with release of viral nucleic acid inside host
target cell.
4. Multiplication w/in the target cell (obligate intracellular)
complex process
1) synthesis of viral mRNA
DNA viruses may use host RNA polymerase -- viral DNA viral
mRNA
RNA viruses have to use viral RNA polymerases
1. translation of viral proteins in host cytoplasm using host
ribosomes viral mRNA can displace host mRNA
1. replication of viral nucleic acid
1. assembly of nucleic acid & capsomers into new
nucleocapsids (= viral progeny)
5. Release from host cell (immediate or delayed) 2
mechanisms
1) lysis -
2) budding (acquisition of envelope)
Pathology - effects of viral infection on the targeted cell
1. lysis
1. persistence
1. latency ( lytic)
1. transformation
CONCEPT CHECK - Viruses
In the space below, in your own words, describe in complete
detail:
1) the significance of surface projection target cell receptor
interactions in viral infections
2) the two mechanisms by which an enveloped virus may enter into
a target host cell
B. BACTERIA - prokaryotes
Common structural features
1. Genetic material ds, circular DNA = chromosome
2. Ribosomes are only organelle 70S (30S + 50S)
3. Cell membrane site of many metabolic functions (e.g.,
respiration)
4. Cell wall shape, rigidity, strength; impt in virulence and
immunity
Compound responsible for strength of cell wall is peptidoglycan
(hexose sugars + amino acids) unique to bacteria
Differences in cell wall structure - Gram positive vs. Gram
negative
Gram positive
peptidoglycan layer is thick
1. highly polar hydrophilic surface
1. Lipoteichoic acids = LTA
1. resists activity of bile
1. digested by lysozyme
1. synthesis is disrupted by penicillin and cephalosporin
antibiotics (more in Unit 4)
Gram negative
peptidoglycan layer is thin, overlaid by outer membrane that
contains lipopolysaccharide and lipoprotein
1. outer membrane is polar, but lipids are hydrophilic
1. Lipopolysaccharide = LPS
0. carbohydrates antigenicity
0. lipid A is toxic = endotoxin induces fever, increases
vascular permeability, may result in shock. etc. (more Units 2
& 3)
5. Structures exterior to the cell wall in some bacteria (more
common in pathogens)
a. Capsule high molecular weight polysaccharides slimy and
sticky
clinically relevant for 2 reasons
1) attach to a wide variety of surfaces *
2) more resistant to engulfment by host defense cells **
b. Flagella
1) allow bacteria to move
2) proteins are strongly antigenic/immune stimulating
c. Fimbriae (aka common pili, esp. in the Neisseria)
1) attachment (fimbriae adhesins to target cell membranes)
2) evading engulfment
d. Pili (aka sex pili)
1) exchange of genetic info, incl. antibiotic resistance (more
in Unit 4)
Bacterial infection of host proceeds through several steps:
0. Entry into body of host 3 routes
1) direct contact
2) ingestion
3) fomites (inanimate objects)
0. Adhere to, colonize, (and possibly invade) host tissues or
cells (infection may be extracellular or intracellular)
0. Evasion of host defenses (more in Unit 2)
0. Multiplication in the host (extracellular or
intracellular)
0. Pathology (more in Units 2 and 3)
1) toxins
2) host immune response
0. Transmission to new hosts usually passive in body fluids
EUKARYOTIC PATHOGENS
C. FUNGI
1. Morphology
1. cell wall contains chitin; plasma membrane contains
ergosterol
1. yeastvsmold
hyphae mycelium
Dimorphic - 2 forms yeast and mold
2. Reproduction moldvsyeast
sporesdivision
budding
3 types of fungal infections = mycoses
1) superficial
2) subcutaneous
3) systemic or deep -
Infections are most serious in immunocompromised.
D. PROTOZOA
0. Infection
may be extracellular or intracellular
2. Evasion of host defenses
3. Reproduction
asexual in humans, sexual absent or in insect vector.
4. Transmission
bites of insects
ingestion
sexually transmitted
E. HELMINTHS multicellular worms
1. Exs. tapeworms, flukes, nematodes
2. Have complex life cycles
3. Transmission
fecal-oral
ingestion of larvae in tissues
active penetration by larvae
bites of insects
F. ARTHROPODS
1. Exs. mosquitoes, biting flies, fleas, ticks, lice
1. increases potential for infection with viruses and
protozoa
NORMAL MICROBIOTA = Indigenous microbiota (= Normal flora)
1. 1012 eukaryotic cells in adult human - 1013 prokaryotic
Clinical significance
1. common contaminants of clinical specimens
Fig 8.1 and Fig 8.2
2. opportunistic pathogens
In class mini clinical cases
Objectives:
1. understand the multiple lines of defenses against microbial
infection
1. recognize the signs of acute inflammation when presented in a
clinical context and describe how each sign of acute inflammation
is generated at a cellular/tissue level
1. know why/how the alternate complement cascade is activated,
what the important molecules formed are, what their function is,
and what the consequences of complement activation are
1. understand how complement and phagocytosis are integrated
processes
1. compare and contrast PMNs and macrophages
1. understand the importance of direct cell-cell contact in
phagocytosis and the relationships between capsules, opsonins, and
phagocytosis
Terminology:
Inflammation - the bodys response to injury or infection, which
may be acute or chronic.
Acute inflammation - the immediate defensive reactions to any
injury. It involves swelling, redness, heat, and pain.
Edema - excessive accumulation of fluid in the tissues.
Erythema - abnormal flushing of the skin caused by dilation of
the blood capillaries.
BIO 580 Medical Microbiology Unit 1 The Adversaries 17
Opsonin - a molecule that attaches to cells, provides a bridge
to receptors on phagocytic cells, and enhances the rate of
phagocytosi
Cells of the Immune System
(White Blood Cells = WBC = leukocytes)
MonocytesMononuclear
Macrophages (differentiated monocytes, found in
tissues)leukocytes
(agranulocytes)
Phagocytes
Neutrophils
EosinophilsPolymorphonuclear
Basophilsleukocytes
Mast cells (differentiated basophils, found in
tissues)(granulocytes)
Natural Killer (NK) cellsLarge Granular Lymphocytes (LGL)
Killer (K) cells
Cytotoxic T cell (TC)
LymphocytesHelper T cell (TH)T lymphocytes (T cells)
Regulatory T cell (Tregs)
Effector B cells/ Plasma cellsB lymphocytes (B cells)
Origins of Cells of the Immune System
II. HOST DEFENSES
The immune system is composed of 2 arms
1. innate = nonspecific already in place, response is rapid, not
as efficient
1. adaptive = specific must be induced, response is slower,
highly efficient, enhances nonspecific. Has memory
A. Nonspecific Defenses
1. Defenses against entry into the host (1st line defenses)
1. Physical defenses (examples)
1. epithelial cells
2. turbulence
3. shedding, scraping, flushing (saliva, urine)
4. muco-ciliary clearance (1-3 cm/hr)
1. Chemical defenses (exs)
1. acids (e.g. gastric, fatty acids)
2. enzymes (e.g. lysozyme in saliva, tears, perspiration,
urine)
3. other microbicidal chemicals (e.g. zinc, dermicidin)
1. Biological defenses (exs)
1. normal microbiota physical, competition, inhibitory
substances
2. immune defense cells and molecules
2. Defenses of the interior of the host (2nd line defenses)
Inflammation
a. phagocytic cells
b. cytolytic cells
c. acute phase proteins
i. CRP
ii. interferon
iii. complement
Inflammation - a process that coordinates and regulates all
aspects of non-specific interior defense.
Acute inflammation is characterized by:
1. increased blood supply to the area
2. increased capillary permeability
3. accumulation of neutrophils
Signs of acute inflammation 4 signs
1.
2.
3.
4.
Triggers of acute inflammation 2 triggers
1. cell/tissue damage/injury chemical alarms
2. cell wall components of bacteria (peptidoglycan, LTA,
LPS)
How Signs of Acute Inflammation are Produced
1. release of Inflammatory Mediators (=IM; see table 9.3)
2. vaso-dilation & blood flow
2. endothelial cells of vessels contract
3. plasma leaks out of vessels & into tissues =
exudation
4. swelling pressure on nerve endings
bradykinin
***Increased blood flow & capillary permeability - a
mechanism for white blood cells and critical soluble factors to
enter the tissues to combat microbial invaders.
The Critical White Blood Cells (WBC = leukocytes)
a. Phagocytes professional engulfing cells
2 main roles for phagocytes
1. engulf and destroy foreign matter
2. secrete chemicals (esp. cytokines)
Cytokines: (see table 11.2)
0. small secreted proteins that mediate and regulate
inflammation, immunity, and hematopoiesis
0. act over short distances, short duration, and low conc.
0. receptor binding induces signal transduction and
transcription and translation
2 main kinds of professional phagocytic cells
1. polymorphonuclear leukocytes (= PMN = polymorph =
neutrophils) are granulocytes -
2. mononuclear leukocytes - monocytes & macrophages are
agranulocytes -
1. polymorphonuclear leukocyte
dominant cell type in early stages acute inflammatory
response
made in the bone marrow - 80 mil/min
dominant WBC, ~5,000/ul of blood - 15,000-20,000/ul
live for 2-3 days - function in anaerobic environments
abundant cytoplasmic granules contain loads of antimicrobial
enzymes and chemicals, esp. lysozyme
best with extracellular pathogens, esp. bacteria
2. mononuclear leukocyte
majors players later in inflammatory process
made in bone marrow
in the blood - monocytes (~600/ul); in tissues - macrophages
(~60,000)
conc. in lung, liver, lymph nodes, spleen
live for months-years
fewer granules (acid hydrolases, peroxidase)
one of the antigen presenting cells
secrete lots of different proteins (incl. lysozyme, nitric
oxide, cytokines, complement factors)
BIO 580 Medical Microbiology Unit 1 The Adversaries 30
best with intracellular pathogens
Process of Phagocytosis 6 steps
1. Activation phagocytes are circulating with the bloodstream,
need to move to the site of inflammation.
1. margination
1. pavementing
1. diapedesis
1. Migration via chemotaxis phagocytes have receptors for
chemoattractant molecules, will track a concentration gradient of
these molecules to the site where they are being produced.
3-6. illustrated in diagram
1. Attachment phagocytosis cannot happen until the phagocyte
makes direct contact with the surface of the microbe. That direct
contact is mediated by receptors on the surface of the
phagocyte.
Pathogen-Associated Molecular Patterns
Microbe - PAMP PRR phagocyte
Pattern Recognition Receptors
PAMP incl. LTA & LPS (table 9.2)
After PAMP-PRR interaction, macrophages secrete pro-inflammatory
cytokines (TNF, IL-1)
enhance antigen-presentation leads to activation of Th1. Well
talk about this later.
1. Engulfment
1. Phagosome-lysosome fusion and intracellular killing
1. Expulsion of debris
Phagocytosis - Diagram
Role of Opsonins in Process of Phagocytosis - Diagram
(review definition of opsonin)
Opsonin
Interaction
Rate of Phagocytosis
Microbe
+phagocyte
none
present
Phagocyte Intracellular Killing Mechanisms
1. Oxygen-dependent killing (see box 9.2, p. 83) PMN and
macrophages
oxidative burst
Reductionsuperoxide anionO2-
O2hydrogen peroxideH2O2 Reactive Oxygen
NADPHNADPsinglet oxygen1O2 Intermediates (ROI)
hydroxyl radicalsOH
(phagosome membrane)Other reactive intermediates
1. reactive nitrogen (nitric oxide = NO) (macrophages)
1. reactive chlorine (OCl) + myeloperoxidase (PMN)
2. Oxygen-independent killing compounds contained in cytoplasmic
granules (see Table 14.2, p. 153)
1. acid hydrolases (PMN)
1. cathepsin G (PMN)
1. cationic proteins (PMN, eosinophils)
1. defensins (PMN)
1. lactoferrin (PMN) -
1. lysozyme (PMN, macrophage)
1. peroxidase (eosinophils)
b. Cytolytic Cells
1. natural killer cells (NK)(LGL)
target - intracellular pathogens, primarily viruses
attach by way of receptors to glycoproteins on infected
cells
release - perforins (membrane channels) granzyme (apoptosis)
also secrete TNF
also secrete -IFN, impt early source, can activate
macrophages
2. basophils and mast cells
target parasites
can be triggered to discharge cytoplasmic granules
release histamine, heparin, anaphylactic factors
3. eosinophils
target - large parasites (e.g. helminthes)
can be triggered to discharge cytoplasmic granules
release basic proteins, perforins, ROI chemical burns
c. The Critical Soluble Factors
Acute Phase Proteins
Plasma proteins proteins that increase in concentration 2-100X
during the acute phase of an infection, in response to cytokines
(IL-1, TNF).
i.. C-reactive protein (CRP) produced by liver - uses pattern
recognition to bind to bacteria
1. acts as an opsonin
1. activates complement cascade
1. often used to monitor inflammation
ii. Interferons
Interferons first recognized because they interfere w/ viral
replication
3 classes of Interferons:
1. - produced by leukocytes (WBC) anti-viral - prod w/in 24h
2. - produced by fibroblasts and other cells anti-viral - prod
w/in 24 h
3. - produced by NK and esp. T lymphocytes anti-viral and
involved in cell-cell communication.
iii. Complement - activation of the alternate cascade (=
properdin pathway) - A group of 20 serum proteins form an enzymatic
cascade
C3 (most abundant, prod. by liver cells)
C3aC3b
Factor B
C3bB
Factor D
C3bBb = C3 convertase
---------------------------------------------------------------------------------------------------------------------
C3C3
C3aC3b C3aC3b
C5 (prod by macrophages)
C5aC5b
C5b678 multiple C9
cell lysis
Opsonin
Interaction
Rate of Phagocytosis
Microbe
+phagocyte
none
C3b
CRP
Integration of Nonspecific Defenses
1. Stimulus
1. cell/tissue injury
inflammatory mediators released
1. microbial surface polysaccharides
1. Within seconds to minutes
1. acute inflammation begins
1. vaso-dilation of capillaries increases blood flow to/volume
at the site
1. increased vascular permeability exudation of plasma, cells,
and proteins
1. acute phase proteins increase in concentration
1. alternate complement cascade is activated
1. C3a and C5a mast cell degranulation
maintains vaso-dilation/vascular permeability
1. C5a attracts phagocytes from vasculature
1. C3b and C5b bind to cell surfaces
1. C3b opsonin
1. Minutes to hours
1. PMNs arrive in huge number and encounter cells opsonized by
C3b and CRP phagocytosis is enhanced.
1. Hours to days
1. Interferons are produced
1. NK arrive
1. Macrophages arrive
SUMMARIZE Nonspecific Defenses
List the Nonspecific Interior Defenses important against
Bacteria
List the Nonspecific Interior Defenses important against
Viruses
CONCEPT CHECK Nonspecific defenses
Bubble Map
Characteristics unique to PMNShared
characteristicsCharacteristics unique to macrophages
(MacrophagePMN)
CONCEPT CHECK Nonspecific defenses
Draw a concept map that illustrates the integration of
complement and phagocytosis
CONCEPT CHECK - Nonspecific Host Defenses
Steve, a college student, was backpacking in a remote wilderness
region with some friends. While pitching a tent, he tripped and
fell. In an attempt to break his fall, he extended his arms and
sustained a puncture wound to his right palm. Although the wound
was painful and bled for a short time, it didnt appear to be
serious, and Steve fell asleep that night unconcerned.
By the next morning, however, Steve noticed that the tissues
immediately surrounding his wound were red, swollen, and warm. A
round area about 1 inch in diameter really looked abnormal compared
to the rest of his hand. The affected area was also painful,
especially when he touched it or bumped it. After hiking all day,
the sore hand was even more painful, and a thick yellow discharge
oozed from the open wound. Steve felt unusually tired, his body
ached, and a brief chill made him aware that he was getting a
fever. His friends helped him elevate his arm and applied warm
compresses to his palm, hoping that he would feel better in the
morning.
1. List the nonspecific defenses against entry that are relevant
to skin.
2. How were Steves skins defenses against entry overcome?
3. List the nonspecific interior defenses that would become
activated in this case of bacterial invasion.
4. What are the signs in the case history that Steve is
experiencing an inflammatory process? List them.
5. Describe the mechanisms at the cellular/tissue level that
cause each of the signs of inflammation listed in 4 above?
Supplemental information FYI
Blood (modified from Wikipedia)
Blood accounts for 8% of the human body weight. The average
adult has a blood volume of roughly 5 liters (1.3 gal), composed of
plasma and several kinds of cells; these formed elements of the
blood are erythrocytes (red blood cells; RBC), leukoytes (white
blood cells; WBC), and thrombocytes (platelets). By volume, the red
blood cells constitute about 45% of whole blood, the plasma about
54.3%, and white cells about 0.7%.
Cells:
One microliter of blood contains:
1. 4.7 to 6.1 million (male), 4.2 to 5.4 million (female)
erythrocytes. The proportion of blood occupied by red blood cells
is referred to as the hematocrit, and is normally about 45%.
1. 4,00011,000 leukocytes. White blood cells are part of the
immune system; they destroy and remove old or aberrant cells and
cellular debris, as well as attack infectious agents and foreign
substances.
1. 200,000500,000 thrombocytes: Platelets are responsible for
blood clotting (coagulation). They change fibrinogen into fibrin.
This fibrin creates a mesh onto which red blood cells collect and
clot, which then stops more blood from leaving the body and also
helps to prevent bacteria from entering the body.
Plasma:
About 55% of whole blood is blood plasma, a fluid that is the
blood's liquid medium, which by itself is straw-yellow in color.
The blood plasma volume totals of 2.73.0 liters (2.83.2 quarts) in
an average human. It is an aqueous solution containing 92% water,
8% blood plasma proteins, and trace amounts of other materials.
Plasma circulates dissolved nutrients, such as glucose, amino
acids, and fatty acids (dissolved in the blood or bound to plasma
proteins), and removes waste products, such as carbon dioxide,
urea, and lactic acid.
Other important components include:
1. Serum albumin
1. Blood-clotting factors (to facilitate coagulation)
1. Immunoglobulins (antibodies)
1. lipoprotein particles
1. Various other proteins
1. Various electrolytes (mainly sodium and chloride)
The term serum refers to plasma from which the clotting proteins
have been removed. Most of the proteins remaining are albumin and
immunoglobulins.
Constitution of normal blood
Parameter
Value
hematocrit
45 7 (3852%) for males
42 5 (3747%) for females
pH
7.357.45
base excess
3 to +3
PO2
1013 kPa (80100 mm Hg)
PCO2
4.85.8 kPa (3545 mm Hg)
HCO3
2127 mM
oxygen saturation
Oxygenated: 9899%
Deoxygenated: 75%
Saliva (modified from Wikipedia) - Produced in salivary glands,
human saliva is 98% water, but it contains many important
substances, including electrolytes, mucus, antibacterial compounds
and various enzymes
It is a fluid containing:
1. Water
1. Electrolytes: (sodium, potassium, calcium, magnesium,
chloride, bicarbonate, phosphate, iodine)
1. Mucus. Mucus in saliva mainly consists of mucopolysaccharides
and glycoproteins;
1. Antibacterial compounds (thiocyanate, hydrogen peroxide, and
secretory IgA)
1. Epidermal growth factor or EGF
1. Various enzymes. There are three major enzymes found in
saliva.
5. -amylase - starts the digestion of starch and lipase fat.
5.
5. s that kill bacteria: **
2.
2. Salivary
2.
5. -rich proteins (function in formation, Ca2+-binding, microbe
killing and lubrication)
5. Minor enzymes
1. Cells: Possibly as much as 8 million human and 500 million
bacterial cells per mL. The presence of bacterial products (small
organic acids, amines, and thiols) causes saliva to sometimes
exhibit foul odor.
1. , a newly researched pain-killing substance found in human
saliva.
Lysozyme, also known as muramidase or N-acetylmuramide
glycanhydrolase, are a family of that damage bacterial cell walls
by catalyzing of 1,4-beta-linkages between and residues in a and
between residues in . Lysozyme is abundant in a number of
secretions, such as , , , and . It is also present in granules of
the (PMN).
Urine is approximately 95% water. The other components of normal
urine are the solutes that are dissolved in the water component of
the urine. These solutes can be divided into two categories
according to their chemical structure (e.g. size and electrical
charge).
Organic molecules These include:
1. Urea Makes up 2% of urine. Urea is an organic compound
derived from ammonia and produced by the deamination of amino
acids. The amount of urea in urine is related to quantity of
dietary protein.
1. Creatinine - Creatinine is a normal constituent of blood. It
is produced mainly as a result of the breakdown of creatine
phosphate in muscle tissue. It is usually produced by the body at a
fairly constant rate (which depends on the muscle mass of the
body).
1. Uric acid - Due to its insolubility, uric acid has a tendency
to crystallize, and is a common part of kidney stones.
1. Other substances/molecules - Example of other substances that
may be found in small amounts in normal urine include
carbohydrates, enzymes, fatty acids, hormones, pigments, and mucins
(a group of large, heavily glycosylated proteins found in the
body).
Ions These include:
1. Sodium
1. Potassium
1. Chloride
1. Magnesium
Calcium
1. Ammonium
1. Sulfates
Phosphates
Objectives:
1. understand how the appropriate lymphocytes are selected and
activated and amplified
2. understand how immune cells talk with each other via
cytokines
3. compare and contrast activation and response of T and B
lymphocytes
4. compare and contrast the activation and response of Th1, Th2,
and TC
5. understand the interactions between nonspecific and specific
host defenses
6. understand how the specific immune response focuses the
nonspecific response
7. understand the power of the secondary (anamnestic) immune
response
B. Specific Defenses
1. = adaptive = acquired
1. 3rd line of defense only one with antigenic memory
1. based on lymphocytes
1. feedback into the nonspecific defenses enhance the
effectiveness of the non-specific defenses
Specific immune system has to:
1. recognize
1. activate
1. respond
1. Overview
a. Recognition of antigen
A specific interaction between an antigen and a receptor
Anti gen
Antigens incl:
***proteins (incl. proteins + carbos or lipids) (T and B)
***complex polysaccharides (B only)
***nucleic acids (B only)
Full activation of the specific defenses involves several
different types of immune cells working in concert:
1. non-specific cells (antigen-presenting cells)
1. specific cells (lymphocytes)
Antigen-Presenting Cell (APC)
Specialized cells that present microbial peptides (antigenic
determinants) in a way that can be recognized by lymphocyte
receptors.
Most significant: dendritic cells (tissues) > macrophages
> B cells
Antigenic determinant (= epitope) a certain stretch of peptides
from a larger microbial antigen
1. linear or conformational
1. small in size
2 main types of Lymphocytes
1. T lymphocytes (T cells)
1. B lymphocytes (B cells
Lymphocyte receptors (R)
1. constant region transmembrane
1. variable region interacts with microbial peptide
General Overview of Antigen Presentation - Diagram
Presentation of antigenic determinant by an APC to a lymphocyte
occurs in draining lymph nodes (surfaces, tissues) or spleen
(blood)
Initiates a chain of events that transforms a small, resting,
nave lymphocyte into a highly active, functional lymphocyte (more
later)
b. Activation from all the antigen nave lymphocytes,
selection of lymphocytes with complementary receptor that
matches
specific microbial antigenic determinant
1. receive and secrete cytokines
2. undergo proliferation = clonal expansion
1104 105 - occurs in lymphoid organs
Results in an expanded population of immature effector
lymphocytes
3. differentiate into functional sub-types
effectors fight this time
memory reserves, to be deployed in the future
c. Response of activated effector sub-types
activated (= primed) effector T lymphocytes either:
1. kill infected cells
2. coordinate and regulate immune response
activated effector B lymphocytes (called plasma cells)
secrete antibodies
2. Add in specifics
T Lymphocytes
2 categories of T cells by surface marker called Cluster
Determinant
1. CD4 - 2 functional types
1) T helper cells = TH - regulate the immune system by
increasing the response ( by activating other immune cells).
a) Subset Th1
b) Subset Th2
2) T regulatory cells (=Tregs) - regulate the immune system by
the response
2. CD8 =T cytotoxic cells =TC = CTL- kill cells infected w/
intracellular pathogens
a. Antigen Recognition by Antigen-Nave, Resting T
lymphocytes
*T cell receptor interacts with microbial (foreign) antigenic
determinant complexed with a self antigen
Self antigens Major Histocompatibility Complex (MHC) proteins
protein molecules on the surface of cells that mark them as
cells.
2 classes of MHC
Class I - on the surface of all nucleated host cells
Class II on the surface of APC
THR - recog. antigenic determinant complexed w/ Class II MHC +
co-stimulatory interactions (depend on who the APC is)
TCR - recog. antigenic determinant complexed w/ Class I MHC +
co-stimulatory interactions
b. Activation of T lymphocytes 3 steps
1. Receive cytokines from APC
ex. IL-1 from macrophage
1. # of IL-2R and secrete/receive IL-2 proliferation
Results in an expanded set of immature effector lymphocytes,
all with same receptor for antigenic determinant complexed
to MHC II (will all recognize the same microbial threat)
1. Differentiation into effector and memory T cells
(Tc, and NK)
c. Response of Effector T Lymphocytes
Each category of effector T cell has a unique response:
regulating the immune response = immunoregulation
enhance response - TH
subset Th1 secretes IL-2 stimulates Tc proliferation &
maturation. Secretes -IFN activates effector TC , activates
macrophages and NK to kill their intracellular pathogens; (down
regulates Th2)
subset Th2 secretes IL-4 stimulates B cell proliferation &
differentiation into plasma cells; (down regulates Th1)
suppress response - Tregs
OR
direct cell killing = cytotoxicity TC
secrete perforin transmembrane channels
secrete granzyme apoptosis
also secrete TNF
also secrete -IFN (activates NK and macrophages)
Integration via Lymphocyte Recognition, Activation, and Response
- Diagram
B Lymphocytes
a. Antigen Recognition by B Lymphocytes
Receptor interacts with microbial (foreign) antigen alone
receptor does not interact with MHC.
Can present antigen to Th2
b. Activation of B Lymphocytes
1. IL-2 from subset Th2 clonal expansion (= proliferation)
1. IL-4 from subset Th2 differentiation into effector (= plasma)
and memory B cells
c. Response of Effector B lymphocytes (=Plasma Cells)
Secrete Antibody (Ab) at the rate of 1,000 molecules/min.
Antibody Structure - Diagram
Actions of Antibody Molecules focus the non-specific
1. bind to microbial antigen interfere with receptor interaction
for any microbe that uses specific attachment sites =
neutralizing
***2linking a bacterium to a phagocyte = opsonization (followed
by phagocytosis)
Opsonin
Rate of Phagocytosis
Microbe
+phagocyte
none
-/+
C3b
+
CRP
+
Ab
C3b + Ab
3. linking many small antigens together = agglutination
(followed by phagocytosis)
4. complement activation - classical pathway (followed by either
opsonization and phagocytosis or lysis) (notes p.45)
5. ADCC - antibody dependent cellular cytotoxicity (notes p.
47)
Activation of Classical Complement Cascade - Diagram
C1
C2C4
C2bC2aC4bC4a
C2a4b
C3C3
C3aC3b C3aC3b
C5
C5aC5b
C5b678 multiple C9 (MAC)
Fill in:
Triggers
Important molecules
Consequences -
Timing
Complement activation enhances phagocytosis and inflammation and
leads to cell lysis.
Classes of Antibody Molecules
Antibody = Immunoglobulin (Ig) proteins found in fluids in the
body
5 Classes:
Class
Structure
%
Location
Roles
IgG
monomer
75-80
serum, extra vascular spaces, crosses placenta
fix complement
opsonin
IgA
monomer
dimer
15-21
serum, tears, saliva, mucus, colostrum
neutralizing
IgM
pentamer
6-7
serum, 1st made by virgin B cells, 1st made by fetus
fix complement
agglutinating
IgD
monomer