Transcript chapter15

The Innate Immune
Response
Chapter 15
The “Good” Immune Response
The immune response’s principal objective is the
containment of infectious threats
Most of the time, containment requires
elimination of the microbe (sterilizing)
But sometimes it is sequestration of a pathogen
These objectives are accomplished by a highly
coordinated series of events
Many types of cells
Many soluble molecules
It also provides long-term memory
The “Bad” Immune Response
The immune response is inherently dangerous
Its job is to kill infectious agents
Sometimes it kills the body’s own cells in
doing so
If sufficient damage is done by the immune
response, it can cause the death of the
patient
Disease and death caused by the immune
response is immunopathology
The Phases of the Immune Response
The innate phase
Considered “nonspecific” (a misnomer)
because it recognizes common molecules of
microbes
Pattern recognition receptors (PRR) are
proteins that bind to a broad-spectrum of
microbial products
Lipopolysaccharide
Double-stranded RNA
Molecules of the innate phase are everpresent, thus act immediately upon a danger
signal
The Phases of the Immune Response
The adaptive phase
Becomes apparent within a few days after infection
Principally mediated by two types of cells
T cells that secrete cytokines (which are proteins) that mediate
local immune responses
B cells that secrete high affinity antibodies that noncovalently
bind to microbes and their products
Together, these cells control the great majority of
infections
It also provide long-term memory to infectious
agents, such that disease rarely recurs
It also is responsible for immunopathology
15.1 Overview of Innate Defenses
Portals of entry are those where microbes
have an opportunity to access the body
First-line defenses
Skin
Mucosa
PRR, including Toll-like receptors (TLRs)
found on phagocytic cells
Complement proteins
Inflammation
Fever
15.2 First-Line
Physical barriers
Defenses
The mucosa contain many substances that are
toxic to microbes
Defensins are antimicrobial peptides about 30 amino acids in
length
Peroxidase is an enzyme that causes oxidation of microbial
products
Lysozyme degrades peptidoglycan
The skin possesses the water-tight protein polymer
keratin that is resistant to penetration
Normal flora are the bacteria that inhabit the body
and protect against other infectious agents
Staph epidermidis outcompetes Staph aureus
15.3 The Cells of the Immune System
All cells of the immune system arise in the bone
marrow
Stem cells of various developmental maturity exist
in the bone marrow and are precursor cells for
immune and blood cells
Hematopoiesis is the process of generating and
maintaining immune and blood cells
The process of immune and blood cell formation is mostly
unknown and considered the Holy Grail of immunology
Special cytokines, termed colony stimulating factors (CSF)
play a prominent role in hematopoiesis, but bone marrow
stromal cells are also required
15.3 The Cells of the Immune System
15.3 The Cells of the Immune System
Granulocytes
The granules are toxic substances, such as histamine
Neutrophils are highly phagocytic and produce
oxidative substances
Basophils and mast cells contribute to inflammation
Eosinophils are thought to play a role in containing
parasitic infections
Mononuclear phagocytes
Circulating monocytes exit the blood vessel into a
tissue and differentiate into macrophages
These macrophages play a prominent role in
constraining microbes to the infected tissue
Dendritic
cells
15.3
The
Cells of the Immune System
Extremely rare
Reside in all tissues
Provide a link between the innate response and
the adaptive response by stimulating naive T
cells
Lymphocytes (Adaptive Response)
T cells
Helper T cells secrete cytokines
Cytotoxic T cells kill other cells that harbor pathogens
B cells secrete antibodies (aka,
immunoglobulins)
Natural killer (NK) cells kill infected cells (and
cause collateral damage by killing adjacent,
15.4 Cell Communication
Cytokines are secreted by all cells of the body
There are more than 60 known cytokines in
vertebrates
They have a dramatic impact on immune
responses
Can be secreted in large amounts
Are not restricted to the tissue
Functional at very low concentrations
They bind to specific cytokine receptors, which
results in a physiologic change in the recipient
cell
Alterations in gene expression
DNA synthesis
15.4 Cell Communication
Classes of cytokines
Chemokines
Recruit immune cells into infected tissues (”help!”)
Participate in inflammation
Interferons - confer antiviral status upon
cells
Interleukins
Largest group
Mediate immune responses
Tumor necrosis factors
Initiate inflammation
Induce programed cell death of infected cells
15.5 Sensor Systems
Vertebrates are under constant microbial
threat
Evolution has provided a number of sensing
systems capable of recognized these threats
Some complement proteins recognize
bacterial cell walls and perforate them
Other complement proteins bind to bacteria
and facilitate their phagocytosis
Interferons induce the expression of RNase
L, which digests double-stranded RNA
15.5 Sensor Systems
15.6 Phagocytosis
Phagocytic (”to eat”) cells have receptors on their
surfaces that bind to bacterial products and
complement proteins
They are recruited to sites of infection by
chemokines
After engulfment of microbes into a phagosome,
the cells are killed by fusion of the phagosome
with a lysosome (termed phagolysosome), which
contains toxic compounds
Some microbes have evolved mechanisms for
evading phagocytosis
15.6 Phagocytosis
15.7 Inflammation
Inflammation is mechanism for containment of
microbes in the infected tissue
It is a double-edged sword:
Too little and the microbes can go systemic
Too much and it can lead to cardiovascular
shock
The process
15.7 Inflammation
Infected or traumatized tissues secrete
chemokines
Circulating leukocytes (white blood cells) exit the
blood vessel (diapedesis) by squeezing between
capillary endothelial cells
Once in the tissue, the cells secrete inflammatory
proteins that augment capillary leakage
The tight junctions between capillary cells loosen
The blood plasma, which is under high pressure relative to
the tissue, leaks from the vessel and into the tissue
If the gaps between capillary cells are large enough, red
blood cells will also leak into the tissue (hemorrhage)
15.7 Inflammation
15.7 Inflammation
Bacterial Endotoxins (e.g., LPS)
Potent inducers of inflammation
Bind directly to macrophages and elicit TNF
production
If enough macrophages are stimulated, as in
septicemia, then septic shock can occur
In septic shock, so much plasma leaks from the capillaries
that the circulatory system collapses
Disseminated intravascular coagulation (DIC) ensues,
causing systemic blood clots
The heart cannot continue to pump and the patient dies
15.9 Fever
Fever is caused by the production of interleukin-1
IL-1, a pyrogen, travels through the blood to the
brain, where it acts upon the hypothalamus to
increase body temperature
Many bacteria are killed or retarded by high
temperatures
Some immune molecules work at higher
temperatures
Moderate fever is good for the immune
response