Transcript Lecture 18

Chapter 16
Nonspecific Defenses of the Host
Immunity
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Immunity - The ability to ward off disease through body defenses
1. Innate immunity or “nonspecific resistance”
• Defenses against any pathogen.
• Refers to defenses that are present at birth
2. Adaptive immunity or “specific resistance” :
• Defenses to a specific pathogen.
• Acquired during the lifetime.
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Lack of immunity is called susceptibility.
Host Defenses
Figure 16.1
First line of defense
1. Mechanical Factors
• Skin
– Epidermis consists of tightly packed cells – keratinocytes.
– Keratin is a protective protein.
• Mucous membranes
– Ciliary escalator:
Microbes trapped in mucus are transported away from the lungs.
• Lacrimal apparatus:
Figure 16.4 (3 of 3)
– Washes eye
• Saliva: Washes microbes off.
• Urine: Flows out.
• Vaginal secretions: Flow out.
Figure 16.3
First line of defense
2. Chemical Factors
– Fungistatic fatty acid in sebum
– Low pH (3-5) of skin
– Lysozyme in perspiration, tears, saliva, and tissue fluids
– Low pH (1.2-3.0) of gastric juice
– Low pH (3–5) of vaginal secretions
– Transferrins in blood find iron.
First line of defense
3. Normal Microbiota
– We have about 1013 cells in our bodies and 1014 bacteria, most of which live in
the large intestine.
– There are 103–104 microbes per cm2 on the skin (Staphylococcus aureus, Staph.
epidermidis, Corynebacteria (diphteroids), Streptococci, Candida, etc.).
– Fill almost all of the available ecological niches in the body.
– Produce factors all of which work to destroy other bacteria that compete for
their niche in the body.
– Microbial antagonism/competitive exclusion: Normal microbiota compete
with pathogens.
• The resident bacteria can become problematic when they invade
spaces in which they were not meant to be.
– Staphylococcus living on the skin can gain entry to the body through small
cuts/nicks.
– Clostridium difficile, - Some antibiotics, in particular clindamycin, kill some of
the bacteria in our intestinal tract. This causes an overgrowth of
C. difficile, which results in pseudomembranous colitis, a rather painful
condition wherein the inner lining of the intestine cracks and bleeds.
Second line of defense
1. Defensive cells
– Phagocytic white blood cells
– Natural killer (NK)cells
2. Inflammation
3. Fiver
4. Antimicrobial substances in blood
– Complement system
– Interferons
– Transferins
– Antimicrobial peptides
Fluid Systems of the Body
• There are two main fluid
systems in the body:
– Blood
– Lymph.
• The blood and lymph systems
are intertwined throughout
the body
• They are responsible for
transporting the agents of the
immune system.
Human blood cells
• Erythrocytes - red blood cells
– Transport O2 and CO2
• Platelets
– Blood clotting
• White Blood Cells - Leukocytes
– Granulocytes
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Neutrophils - phagocytic
Basophils ( Mast cells in tissues) – Histamine
Eosinophils – Kill parasites
Dendritic cells - antigen-presenting cells
– Agranulocytes
• Monocytes - Phagocytic as mature macrophages
• Lymphocytes:
– Natural killer cells
– T cells
– B cells (plasma cells)
White Blood Cells - Leukocytes
• Granulocytes
• Neutrophils - phagocytic
– Nondividing, short-lived (half-life of 6–8 hours, 1–4 day lifespan), and have a
segmented nucleus.
– First on the scene to fight infection.
– Chemotaxis (IL-8, INF-γ, C5a).
• Basophils ( Mast cells in tissues) – Histamine
– Circulating, store histamine granules.
– Active against parasites, participate in allergic reaction
• Eosinophils – Kill parasites
– Granules containing chemical mediators, such as histamine and proteins such as
eosinophil peroxidase, RNase, DNases, lipase, plasminogen, and Major Basic Protein
– Some phagocytic
• Dendritic cells
– Their main function is to process antigen material and present it on the surface
to other cells of the immune system, thus functioning as antigen-presenting cells
» Initiation of adaptive immune response
White Blood Cells - Leukocytes
• Agranulocytes
• Monocytes - Phagocytic as mature macrophages
– Promonocytes are made in the bone marrow, after which they are
released into the blood and called circulating monocytes, which
eventually mature into macrophages (meaning "big eaters", see
below).
– Long-lived, depend on mitochondria for energy, and are best at
attacking dead cells and pathogens capable of living within cells.
– Fixed macrophages in lungs, liver, and bronchi
– The non-fixed macrophages roam the blood vessels and can even
leave them to go to an infection site where they destroy dead tissue
and pathogens.
• Lymphocytes:
– Natural killer cells move in the blood and lymph to lyses (cause to
burst) cancer cells and virus-infected body cells.
» They attach to the glycoproteins on the surfaces of infected cells
and kill them
– T cells - Cell- mediated immunity
– B cells (plasma cells) - Produce antibodies
Differential White Cell Count
• Percentage of each type of white cell in a sample of 100 white
blood cells (Leukocytes)
Neutrophils
Basophils
60-70%
0.5-1%
Eosinophils
2-4%
Monocytes
3-8%
Lymphocytes
20-25%
The Concept of Immunity- Recognition
• Host Toll-like receptors (TLRs) - a class of proteins that play a key
role in the innate immune system
• Membrane-spanning receptors that recognize structurally conserved molecules
derived from microbes
– Localized on cell surface
Monocytes/macrophages
B lymphocytes
Dendritic cells
Mast cells
Intestinal epithelium
• These receptors are encoded in the germ line of each person.
– Once microbes have breached physical barriers such as the skin or intestinal tract
mucosa, they are recognized by TLRs which activates immune cell responses.
– TLRs induce cytokines that regulate the intensity and duration of immune responses
• This immunity is passed from generation to generation.
– They are set to target both Gram-negative and Gram-positive bacteria.
Second line of defense
1. Phagocytosis
• Phago: eat; Cyte: cell
• Ingestion of microbes or particles by a cell, performed by phagocytes
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Adherence
Ingestion
Formation of a phagosome
Phagosome-Lysosome fusion
Digestion
Formation of a residual body
Discharge
• Once a macrophage phagocytizes a cell, it places some of its
proteins, called epitopes, on its surface—much like a fighter plane
displaying its hits.
– These surface markers serve as an alarm to other immune cells.
Microbial Evasion of Phagocytosis
• Inhibit adherence: M protein, Streptococcus pyogenes,
capsules
S. pneumoniae
• Kill phagocytes:
Leukocidins
Staphylococcus aureus
• Lyse phagocytes:
Membrane attack
complex
Listeria monocytogenes
• Escape phagosome
Shigella
• Prevent phagosomelysosome fusion
HIV
• Survive in phagolysosome Coxiella burnetti
Second line of defense
2. Inflammation
• Inflammation is the process by which the body responds to injury or
an infection
– It is characterized by:
– Redness
– Pain
– Heat
– Swelling (edema)
– Sometimes the loss of function.
• Chemicals Released by Damaged Cells
• Histamine
Vasodilation, increased permeability of blood
vessels
• Kinins
Vasodilation, increased permeability of blood
vessels
• Prostaglandins
Intensity histamine and kinins effect
• Leukotrienes
Increased permeability of blood vessels,
phagocytic attachment
Inflammation
- Acute inflammation is a short, intense response to infection.
1. Tissue damage
2. Vasodilation
and increased
permeability
of blood vessel
3. Phagocytes
migration and
phagocytosis
4. Tissue repair
- Chronic inflammation is a prolonged response (it is a disease)
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It is associated with a broad spectrum of neurodegenerative diseases of aging - Alzheimer's
disease, Parkinson's disease, amyotrophic lateral sclerosis, and also included are such
peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial
infarction.
Second line of defense
3. Fever
• Abnormally High Body Temperature
– Hypothalamus normally set at 37°C
– Gram-negative endotoxin cause phagocytes to release interleukin1
• Hypothalamus releases prostaglandins that reset the hypothalamus to a
high temperature
• Body increases rate of metabolism and shivering to raise temperature
• When IL-1 is eliminated, body temperature falls.
• Disadvantages of fiver
– Tachycardia
– Acidosis
– Dehydration
Second line of defense
4. Antimicrobial substances
• The Complement system
– Helps or “complements” the ability of antibodies and phagocytic cells to clear
pathogens from an organism
– It is part of the innate immune system that is not adaptable and does not
change over the course of an individual's lifetime.
– However, it can be recruited and brought into action by the adaptive immune
system.
– It consist of over 25 proteins and protein fragments, produced by liver.
– Account for about 5% of the globulin fraction of blood serum.
– Complement protein are usually designated by letter C, C1- C9
– The fragments are activated proteins and are indicated by the lower letters a
and b – C3a and C3b.
– Complement proteins act as a cascade
– Once is activated, its destructive capabilities usually cease very quickly
– Inherited deficiencies of complement component causing disease
The Complement System
• C serum proteins constantly present in the blood
• Serum proteins activated in a cascade.
Membrane Attack Complex (MAC)
Figure 16.9
Three biochemical pathways activate the complement system:
Complement proteins – factors B, D, and P
Lectines - proteins that bind to carbohydrates. (When macrophages ingest
bacteria, viruses, and other foreign matter by phagosytosis, they release chemicals
that stimulate the liver to produce lectins).
1.Classical Pathway
2. Alternative Pathway
3. Lectin Pathway
Some bacteria evade complement
• Capsules prevent C activation
• Surface lipid-carbohydrates prevent membrane attack
complex formation
• Enzymatic digestion of C5a
Second line of defense
4. Antimicrobial substances
• Interferons (IFNs) - proteins made and released by lymphocytes in
response to the presence of pathogens
– alpha-IFN,
– beta-IFN
– gamma-IFN
• The mode of action of -IFN
and -IFN is to induce uninfected
cells to produce antiviral proteins
(AVPs) that prevent viral replication.
• Interferons are host-cell–specific but not virus-specific.
• Gamma-interferon activates neutrophils and macrophages to kill
bacteria.
Second line of defense
4. Antimicrobial substances
• Transferrins are iron-binding proteins found in blood, milk, saliva,
and tears.
– Inhibit bacterial growth by reducing the amounts of available iron.
– Iron also suppress chemotaxis and phagocytosis
• Antimicrobial peptides (also called host defense peptides) are an
evolutionarily conserved component of the innate immune response
and are found among all classes of life.
– These peptides are potent, broad spectrum antibiotics which demonstrate
potential as novel therapeutic agents.
– Antimicrobial peptides may also have the ability to enhance immunity by
functioning as immunomodulators.
Learning objectives
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Differentiate between innate and adaptive immunity.
Describe the role of the skin and mucous membranes in innate immunity.
Differentiate physical from chemical factors, and list five examples of each.
Describe the role of normal microbiota in innate resistance.
Classify phagocytic cells, and describe the roles of granulocytes and monocytes.
Define differential white blood cell count.
Define phagocyte and phagocytosis.
Describe the process of phagocytosis, and include the stages of adherence and ingestion.
Identify methods of avoiding destruction by phagocytes.
List the stages of inflammation.
Describe the roles of vasodilation, kinins, prostaglandins, and leukotrienes in
inflammation.
Describe phagocyte migration.
Describe the cause and effects of fever.
List the components of the complement system.
Describe three pathways of activating complement.
Describe three consequences of complement activation.
Define interferons.
Compare and contrast the actions of a-IFN and b-IFN with g-IFN.
Describe the role of transferrins in innate immunity.
Describe the role of antimicrobial peptides in innate immunity.