Host defenses are composed of two complementary, frequently interacting systems: (1)innate...

Host defenses are composed of two complementary, frequently interacting systems:

(1)innate (nonspecific) defenses, which protect against microorganisms in general, and

(2) acquired (specific) immunity, which protects against a particular microorganism.

TWO TYPES OF IMMUNITY

Nonspecific (innate)•Physical and chemical agents•Lysozyme•Acute phase proteins•Complement system•Cytokines (chemokines)•Phagocytes (granulocytes, macrophages)•Natural killer (NK) cells•Dendritic cells•Toll-like receptors

Specific (adaptive)•Antibodies (B lymphocytes)•T lymphocytes

Present at birth

Immediate protection against variety of pathogens and foreign substances

Immunity signifies all those properties of the host that confer resistance to a specific infectious agent.

Immunity

Natural Acquired or adaptive (specific)

(Innate, nonspecific)

Passive Active

Acquired ( Adaptive) Immunity

Active Passive

Natural Artificial Natural Artificial (Infection)

(Immunizing agents)

Clinical Subclinical (Placental transfer,

colostrum)

(administration of immune sera)

First Line of Defense Epidermis Mucous membranes

Mucous Cilia Lacrimal apparatus of

eyes Saliva Urine flow Vaginal secretions Defecation and vomiting

Sebum Perspiration Lysozyme Gastric juice

Intact skin is the first line of defense against many organisms. In addition to the physical barrier presented by skin, the fatty acids secreted by sebaceous glands in the skin have antibacterial and antifungal activity.

Innate (nonspecific) defenses

Skin and Mucous Membranes

Mucous membranesMucous membranes protective covering in intestine, lungs, eyes

etc., that resists penetration and traps many microbes

antimicrobial secretions

Lysozyme Lactoferrin: macrophages and PMNs, sequesters

iron Lactoperoxidase: produces superoxide radicals mucosal-associated lymphoid tissue (MALT)

MUCOSAL MUCOSAL SURFACESSURFACES

•Gastrointestinal tract

•Respiratory tract

•Urinary tract

•Reproductive tract

Respiratory System- The mucociliary blanket of the respiratory epithelium traps microorganisms less than 10 ㎛ diameter - The bronchial-Associated Lymphoid Tissue (BALT)

Gastrointestinal Tract - In the stomach : lower pH, enzymes - In the intestine : enzymes - In the large intestine : the normal microbiota ⇒ preventing the establishment of pahtogens

⇒ destroy microorganisms

Genitourinary Tract - Urine kills some bacteria due to its low pH and the presence of urea and other metabolic end products

The Eye - Tears contain large amount of lysozyme, lactoferrin and sIgA

A second important defense

is the mucous membrane of the respiratory tract,

which is lined with cilia and covered with mucus. The

coordinated beating of the cilia drives the

mucus up to the nose and mouth,

where the trapped bacteria can be expelled.

In lacrimal fluid, sputum, saliva, blood, milk, tissues and organs lysozyme is found. It is found in some bacterial cells. Nasal mucus is bactericidal for many microbes and viruses of influenza, herpes, poliomyelitis, etc.

Second Line of Defense

Antimicrobial proteins

1. Interferons (IFNs) Antivirals that prevent replication of virus

2. Complement system Enhance immune reactions

3. Transferrins Inhibit bacterial growth by reducing available

iron

Interferons (IFNs) are antiviral proteins produced in response to viral infection.

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.

Interferons (IFNs)

Complement System Summary

Series of 30 plasma (serum) proteins, activated in a cascade

Three effects of complement system:

1. Enhances inflammatory response, e.g.: attracts phagocytes

2. Increases phagocytosis through opsonization or immune adherence

3. Creates Membrane Attack Complexes (MACs) Cytolysis

Classical Pathway of Complement ActivationClassical Pathway of Complement Activation

IgA and IgE cannot activate complement

Alternative Pathway of Complement ActivationAlternative Pathway of Complement Activation

Lectin Pathway of Complement ActivationLectin Pathway of Complement Activation

Late Steps of Complement Activation

Inflammation Stimulated by ComplementInflammation Stimulated by Complement

TransferrinsTransferrins

Transferrins are iron-binding proteins. Inhibit bacterial growth by reducing the amounts of available iron.

Transferrin transports iron from the small intestine, where the iron is absorbed, to the tissues, where the iron is used. Transferrin and lactoferrin bind iron, limiting the growth of pathogens in the blood.

Lactoferrin is present in tears, semen, breast milk, bile, and nasopharyngeal, bronchial, cervical, and intestinal mucosal secretions. Transferrin is present in serum and the intercellular spaces of many tissues and organs.

Innate Immunity Depends on Receptor-Recognition of Common Pathogen-Associated

Molecules Pathogen-associated molecular patterns (PAMPs)

help the innate immune system recognize pathogens

Toll-like receptors (TLRs) are signaling receptors on: macrophages dendritic cells endothelial cells

TLRs on TLRs on MPhs, MPhs, dendritic dendritic cells, cells, epithelial epithelial cellscells

Cytokines!

PAMPs recognition

Second Line of Defense Natural killer (NK) cells

~ 5 – 10% of lymphocytes In spleen, lymph nodes and red bone marrow Attack body cells displaying abnormal plasma membrane

proteins Perforin perforates cell membranes Granzymes destroy cell proteins

Phagocytes Phagocytosis

Neutrophils Macrophages

Develop from monocytes Wandering Fixed

Figure 21.8a

Phagocytosis

Killing mechanisms of phagocytes

SEM of macrophage engulfing E. coli cells on the surface of a blood vessel

PhagocytosisPhagocytes recognize the enemy

either directly, by binding to components on

the surface of the organism or

indirectly, by binding to a foreign entity that has antibody bound to it.

Inhibit adherence: M protein, capsules

Streptococcus pyogenes, S. pneumoniae

Kill phagocytes: Leukocidins

Staphylococcus aureus

Lyse phagocytes: Membrane attack complex

Listeriamonocytogenes

Escape phagosome Shigella

Prevent phagosome-lysosome fusion

HIV

Survive in phagolysosome Coxiella burnetti

Microbial Evasion of Phagocytosis

Natural Killer Cells Recognize and Kill Abnormal Cells NK cells are formed in the bone marrow, and

migrate to: tonsils lymph nodes spleen

When activated, they produce cytokines that trigger response by macrophages and other cells

Then they move into blood and lymph where they kill: cancer cells virus-infected cells

When an NK cell recognizes a cell as “non-self” it releases cytotoxic perforins and granzymes

ADCC by NK Cells

Destruction of Virus-Infected Cells by NK Cells through Antibody-Dependent Cellular Cytotoxicity

(ADCC)

Tissue damage triggers the inflammatory response

The inflammatory response mobilizes nonspecific defense forces

Tissue injury; release ofchemical signals such ashistamine

1 2 3Dilation and increased leakinessof local blood vessels; migrationof phagocytes to the area

Phagocytes (macrophages andneutrophils) consume bacteriaand cell debris; tissue heals

Pin

Skin surface

Bacteria

Chemicalsignals

Whiteblood cell

Swelling

Phagocytes andfluid moveinto area

Phagocytes

Red, swell, warm

Non-specific defense system

The inflammatory response can disinfect tissues limit further infection

CytokinesCytokines

•“Cytokines” are soluble protein mediators secreted by immune cells (mostly) that act on other cells to regulate their activity; many are called “interleukins” (IL-1, IL-2, etc.)

•Cytokines have many functions, we’ll focus on a few central functions of a few key cytokines

•A subfamily of cytokines primarily functions in directing migration of cells, these are called “chemotactic cytokines” or “chemokines”

- monokines, lymphokines, interleukines

colony stimulating factors, chemokines,

interferon - The four cytokine families

Function : • autocrine • paracrine • endocrine

A summary of innate and acquired immunity

INNATE IMMUNITY Rapid responses to a

broad range of microbes

ACQUIRED IMMUNITYSlower responses to

specific microbes

External defenses Internal defenses

Skin

Mucous membranes

Secretions

Phagocytic cells

Antimicrobial proteins

Inflammatory response

Natural killer cells

Humoral response(antibodies)

Cell-mediated response(cytotoxic lymphocytes)

Invadingmicrobes

(pathogens)

Break !