Non-specific Host Defense Mechanisms

Lecture 8

Non-specific Host Defense Mechanisms

NORBEL A. TABO, RM, SM

Learning Objectives

1. Briefly describe the three lines of defenses2. Differentiate non-specific from specific host defense

mechanism3. Identify three ways by which the digestive system is

protected from pathogens4. Name three cellular and chemical responses to microbial

invasion5. Describe the benefits of complement activation6. List the cardinal signs and symptoms associated with

inflammation7. Outline the four steps in phagocytosis.8. Cite ways in which pathogens escape destruction by

phagocytes9. Categorize the disorders and conditions that affect the

body’s non-specific host mechanisms

Overview of the Immune SystemImmune System

Innate(Nonspecific)

Adaptive(Specific)

Anatomical Barriers

Humoral Components

Cellular Components

Mechanical

Chemical

Biological

Complement

Coagulation

Cytokines

Neutrophils

Eosinophils

Monocytes and Macrophages

Anatomical Barriers - Mechanical Factors

System or Organ Cell type Mechanism

Skin Squamous epithelium Physical barrierDesquamation

Mucous Membranes

Non-ciliated epithelium (e.g. GI tract)

Peristalsis

Ciliated epithelium (e.g. respiratory tract)

Mucociliary elevator

Epithelium (e.g. nasopharynx)

Flushing action of tears, saliva, mucus, urine

Anatomical Barriers - Chemical Factors

System or Organ Component Mechanism

Skin Sweat Anti-microbial fatty acids

Mucous Membranes

HCl (parietal cells)Tears and saliva

Low pHLysozyme and phospholipase A

Defensins (respiratory & GI tract)

Antimicrobial

Sufactants (lung) Opsonin

Anatomical Barriers - Biological Factors

System or Organ Component Mechanism

Skin and mucous membranes

Normal flora Antimicrobial substancesCompetition for nutrients and colonization

Microbial antagonism

Inhibitory capability of normal flora Competition for colonization sites Competition for nutrients Production of substance that kill other bacteria

The effectiveness of this antagonism is frequently decreased after prolonged administration of broad spectrum antibiotics

Superinfection of Candida albicans

Pseudo-membraneous colitis

Humoral Components

1. Complement system2. Coagulation system3. Lactoferrin and transferrin4. Interferons5. Lysozymes6. Cytokines

Complement System

The major humoral non-specific defense mechanism.

Once activated, complement can lead to increased vascular permeability, recruitment of phagocytic cells, and lysis of bacteria

Coagulation system

Some products of coagulation system are directly antimicrobial

Example: Beta lysin

Protein produced by platelets can lyse G+ bacteria by acting as a cationic detergent

Lactoferrin and Transferrin

Proteins that can limit bacterial growth.

Interferons

protect cells from viral attack (among other functions).

alpha, beta, and gamma interferon produced by virus-infected cells and also by

macrophages and some lymphocytes, which are stimulated to produce interferon via activation by antigens.

the effect of interferon on healthy cells is to stimulate them to produce antiviral proteins (AVP) which protects them from viral infection.

Lysozymes

Breaks down the cell wall of bacteria

Interleukin I

Induces fever and production of acute phase proteins (C-reactive proteins which is a laboratory marker for inflammation)

Cytokines

Chemical mediators that are released from different types of cells.

They enable cells to communicate with each other.

Cellular Components

Cell Functions

Neutrophils Phagocytosis and intracellular killingInflammation and tissue damage

Macrophages Phagocytosis and intracellular killingExtracellular killing of infected or altered self targetsTissue repairAntigen presentation for specific immune response

NK and LAK cells Killing of virus-infected and altered self targets

Eosinophils Killing of certain parasites

Leukocytes

There are typically 5,000 to 10,000 of these per cubic millimeter of human blood ( 5-10 billion per liter ).

The white cell count typically increases in response to infection.

Leucocytes play a role in both specific (antibody-based) and non-specific host defense mechanisms.

Polymorphonuclear neutrophils (PMNs) about 55-70% of circulating wbc's are PMNs. These are phagocytic cells that play an important role in

the defense against bacterial pathogens. Eosinophils

represent about 5 % of circulating wbc's. These are capable of phagocytosis under some

conditions, but are more directly concerned with the extracellular destruction of invading organisms, particularly parasites such as helminths.

High eosinophil numbers are typically associated with helminth infections.

Types of Leukocytes

Basophils constitute 1% or less of circulating wbc's. Basophils produce a variety of biologically active chemicals

including histamine (involved in allergic response) and heparin (an anticoagulant).

Monocytes Constitute about 5-8 % of circulating wbc's. Like, PMNs, these cells are capable of phagocytosis. In the tissues, these cells can be transformed into

macrophages which phagocytize invading cells and process and "present" antigens to B-lymphocytes, stimulating them to produce antibodies.

Types of Leukocytes…..

Lymphocytes about 20% of circulating wbc's are lymphocytes. These cells are largely responsible for both humoral and

cellular immunity. There are two general types of lymphocytes,

B cells (plasma cells) that produce soluble (humoral) antibodies, and

T cells which are responsible for cellular immunity. There are 5 different types of T-cells, each with its own set of functions (discussed later):

Helper cells (Th) Suppressor cells (Ts) Delayed hypersensitivity cells (Td) Cytoxic [killer] cells (Tc)

Types of Leukocytes…..

Natural killer cells (Nk) - destroy tumor cells, transplanted tissue, and cells infected with intracellular bacteria such as the Rickettsia and Chlamydias.

Both Tc and Nk cells produce a protein called perforin which bores a hole in the membrane of the attacked cell, much like the membrane attack complex( MAC) of complement.

While lymphocytes are generally considered to be part of the "specific" immunity system (involving antigens and antibodies), the Nk cells do not require an antigen to activate them, and so are perhaps best considered to be part of the body's non-specific defense system.

Lymphocytes

Phagocytosis and Inflammatory Response

Phagocytosis able to engulf and destroy bacteria and some

other invading organisms polymorphonuclear neutrophils and

monocytes and other cells called macrophages (tissue cells derived from monocytes)

Phagocytosis

1. Chemotaxis2. Attachment3. Ingestion4. Digestion

Inflammation a complex interwoven series of processes

that increase the blood supply to an infected site.

The symptoms of inflammation: swelling, warming, reddening, and pain are all the result of the increased blood supply brought about by capillary dilation.

A series of chemical mediators including histamine and the prostaglandins are also involved in inflammatory processes.

Inflammatory Response Large number of

phagocytes are attracted to the wound area

Blood vessels dilate Phagocytes move out

from the blood Phagocytes engulf the

pathogen

Classical signs and symptoms

1. Calor - heat2. Dolor - pain3. Rubor - redness4. Tumor – swelling5. Fluor - secretions

Importance of Inflammation

1. To localize infection2. To prevent spread of pathogens3. To destroy and detoxify pathogens4. To aid in repair and healing

fever

Creates an unfavorable thermal environment for bacteria whose thermal optimum is 37o C.

Speeds-up chemical reactions that are part of the chemical defense mechanism

Mechanisms by which pathogens escape destruction by phagocytes1. Production of capsules2. Secretion of leukocidins3. Presence of waxes in the cell wall (M.

tuberculosis)4. Growth within the phagocytes (Rickettsia,

Legionella, Brucella, Coxiella, Listeria)5. Growth within the leukocytes (Ehrlichia,

Anaplasma)

Disorders and conditions that adversely affect phagocytic and inflammatory processes

Leukopenia Low number of circulating leukocytes

Chediak-Higashi Syndrome Inability of leukocytes to migrate in response

to chemotactic agents Chronic Granulomatous Disease

Incapability of phagocytes to kill the pathogens

Factors that can impair host defense mechanisms1. Nutritional status2. Increased iron levels3. Stress4. Age5. Cancer and Cancer chemotherapy6. AIDS7. Drugs8. B-cell and T-cell deficiency