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 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 “Bad” Immune ResponseThe “Bad” Immune Response

The Phases of the Immune Response

The Phases of the Immune ResponseThe 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

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

The Phases of the Immune Response

The Phases of the Immune Response

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 DefensesPhysical 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

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

15.3 The Cells of the Immune System

15.3 The Cells of the Immune SystemGranulocytes

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

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)

15.3 The Cells of the Immune System

15.3 The Cells of the Immune System

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 Communication15.4 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

15.4 Cell Communication15.4 Cell Communication

15.5 Sensor SystemsVertebrates 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 Systems15.5 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 Phagocytosis15.6 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

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 Inflammation15.7 Inflammation

15.7 Inflammation15.7 Inflammation

15.7 Inflammation15.7 InflammationBacterial 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 FeverFever 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