1. The Innate Immune Response
Chapter 15

2. 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

3. 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

4. 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 ever- present, thus act immediately upon a danger signal

5. 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

6. 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

7. 15.2 First-Line Defenses Physical barriers
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

8. 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

9. 15.3 The Cells of the Immune System

10. 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

11. 15.3 The Cells of the Immune System
Dendritic cells
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, uninfected cells)

12. 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

13. 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

14. 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. 15.5 Sensor Systems

16. 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

17. 15.6 Phagocytosis

18. 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

19. 15.7 Inflammation The process
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)

20. 15.7 Inflammation

21. 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

22. 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