Introduction to Host Defenses and Immunity
Susceptibility and the Nature of Host Resistance
Susceptibility refers to an individual's lack of resistance to a disease. When susceptibility is high, the ability to ward off a disease is absent.
COVID- serves as a relevant example where natural resistance was initially nonexistent in the population, rendering everyone susceptible upon exposure.
Resistance is the innate or acquired ability of an organism to ward off disease. This can be categorized into two main types:
Inborn or Innate Resistance: Non-specific defenses present from birth.
Adaptive or Acquired Resistance: Specific defenses developed through life experiences and exposure to antigens.
The host-pathogen relationship is conceptually viewed as a battle; the host must win the battle to ensure the infection does not develop into a fatal disease.
The defensive strategy of the host is organized into three distinct lines of defense:
First Line of Defense: Consists of physical and chemical barriers designed to block portals of entry (Inborn/Nonspecific).
Second Line of Defense: Comprises internal mechanisms such as inflammation, fever, and cellular defenses that protect against a wide variety of pathogens (Inborn/Nonspecific).
Third Line of Defense: involves specific internal responses requiring B and T lymphocytes, initiated by exposure to foreign antigens (Adaptive/Specific).
These lines of defense do not act in isolation. For instance, components of the first line of defense help bolster the second, and phagocytosis within the second line is enhanced by B and T cells from the third line.
The First Line of Defense: Physical Barriers and Secretions
The primary goal of the first line of defense is to keep pathogens out by blocking physical entry.
The Skin: This is the body’s largest physical barrier to infection.
It consists of multiple layers of epithelial cells (epidermis) rather than a single layer, making it difficult to penetrate.
Cells are packed tightly together and held by the extracellular matrix.
The skin is a dry environment. Since microorganisms require water for growth and metabolism, this dryness inhibits bacterial expansion.
Epidermal cells are continually shed and rapidly replaced. If a microorganism resides on a surface cell that is shed, it is removed from the host before it can infect.
Keratin is a protective protein found in the skin that adds structural integrity to epithelial layers.
Mucus Membranes: These membranes protect holes in the epidermis (portals of entry) such as the nares.
They secrete mucus, a thick, sticky glycoprotein. Much like the La Brea Tar Pits trap animals, mucus acts as a sticky trap for pathogens.
In the respiratory tract, mucus traps organisms. If this material is dislodged by coughing, the microorganism can be expelled from the body or swallowed into the acidic environment of the stomach.
Ciliary Escalator: Cilia in the lungs move trapped material up and out of the lower respiratory tract. In smokers, this escalator is often coated with tar, making them more predisposed to lung infections.
Lacrimal Apparatus: Produces tears to wash the surface of the eye. Blinking helps flush microorganisms away from this portal of entry and down the face.
Saliva: Constantly washes the mouth to dislodge microorganisms. When swallowed, saliva carries pathogens into the stomach acid.
Urine: The flow of urine through the urethra acts with high force, similar to a fire hose, to dislodge organisms. It typically has a low $pH$ which inhibits bacteria but is less effective against fungi.
Vaginal and Seminal Secretions: These fluids flow out of the body, removing organisms. While this protects the host, seminal fluids may introduce pathogens to a new host. Both fluids contain antimicrobial compounds.
The First Line of Defense: Chemical Barriers and the Microbiota
Chemicals are added to physical barriers to increase their effectiveness.
Sebum: Produced by the skin to keep it soft and supple, preventing it from drying and cracking, which would create a portal of entry.
Sebum contains fungistatic fatty acids that prevent fungal colonization.
It lowers the $pH$ of the skin to an acidic level, which inhibits bacterial growth.
Lysozymes: Digestive enzymes found in perspiration, tears, and saliva. They hydrolyze (break down) the carbohydrate components of the peptidoglycan cell wall, making them particularly effective against Gram-positive bacteria.
Stomach Acid: The extremely low $pH$ of gastric juice is an inhospitable environment that destroys many pathogens and denatures exotoxins.
Normal Microbiota: Resident microorganisms serve as a first line of defense by:
Outcompeting pathogens for nutrients and attachment sites.
Altering the environment (e.g., fermenting and producing acids) to favor their own growth while inhibiting pathogens.
Producing bacteriocins, which are toxins that kill or inhibit foreign bacteria.
The Second Line of Defense: The Complement System
The complement system consists of a cascade of blood proteins that work together to prevent bacterial and viral infections.
Activation functions like a series of tipping dominoes; the stimulation of one protein initiates the synthesis of the next.
There are three activation pathways:
Classical Pathway: Initiated when antibodies bind to microorganisms.
Lectin Pathway: Initiated when blood proteins bind to mannan, a carbohydrate foreign to the host found on certain pathogens.
Alternative Pathway: Initiated when complement proteins naturally circulating in the serum bind directly to the surface of a microorganism.
Outcomes of Complement Activation:
Opsonization: Coating a pathogen with complement proteins to make it more visible to phagocytes. This is compared to putting ‐hunter's orange‐ on a deer to make it easier to find.
Inflammation: Complement proteins can initiate the inflammatory response and vasodilation.
Chemotaxis: Proteins create a chemical ‐breadcrumb trail‐ that attracts leukocytes to the site of infection.
Membrane Attack Complex (MAC): Complement proteins associate within the pathogen’s plasma membrane to create holes, leading to lysis and cell death.
The Second Line of Defense: Classification of Leukocytes
Leukocytes (white blood cells) are divided into two categories based on their appearance under a microscope:
Granulocytes: Characterized by visible granules in the cytoplasm and a lobed nucleus.
Neutrophils: Also known as polymorphonucleatids. They constitute the majority of circulating leukocytes, are highly phagocytic, and are modal. They are the primary responders in the initial stages of infection.
Eosinophils: Located primarily in the bone marrow and spleen. They are essential for destroying eukaryotic parasites that are too large for phagocytosis by releasing compounds that cause lysis. They also produce histamines.
Basophils: The least numerous granulocytes. They are critical for the inflammation and allergic responses, producing histamines that cause swelling.
Mast Cells: Functionally similar to basophils but found within tissues; they also produce histamines.
Agranulocytes: Lack visible granules and have an unlobed nucleus.
Monocytes: These mature into either macrophages or dendritic cells.
Macrophages: Can be ‐fixed‐ (remaining in the lungs, liver, bronchi, or lymph nodes) or ‐wandering‐ (modal in tissues). They act as Antigen Presenting Cells (APCs), which are necessary to stimulate the third line of defense, specifically T cells.
Dendritic Cells: Phagocytic cells often associated with the epidermis, mucosal membranes, and lymph nodes.
Natural Killer (NK) Cells: Found in the spleen, lymph nodes, and bone marrow. They destroy the host’s own infected or cancerous cells by recognizing a missing or altered Major Histocompatibility Complex ($MHC$). They release perforins for lysis or induce apoptosis (programmed cell death).
Lymphocytes: B and T cells, which are discussed in the context of the third line of defense (Chapter ).
Mechanisms of Leukocyte Action: Diapedesis and Chemotaxis
Diapedesis (Transmigration): The process by which modal leukocytes change their shape to ‐weasel‐ through fissures in the vessel wall to reach surrounding tissues. This is facilitated by vasodilation.
Positive Chemotaxis: Once in the tissues, leukocytes move toward the site of injury or infection by following a concentration gradient of chemical messengers called cytokines.
Phagocytosis: The Process of Cellular Destruction
Phagocytosis is the process of ‐cell feeding‐ used to destroy invading particles. The process follows several steps:
Adherence: The phagocyte must make direct contact and attach to the pathogen. If it cannot adhere, phagocytosis cannot occur.
Ingestion: The pathogen is taken into the cell within a vesicle called a phagosome.
Fusion: A lysosome containing digestive enzymes fuses with the phagosome to create a phagolysosome.
Digestion: The enzymes break down the microorganism within the phagolysosome.
Exocytosis: Undigestible material, held in a residual body, is discharged from the cell.
Pathogenic Evasion of Phagocytosis
Pathogens have evolved several ways to avoid destruction by phagocytes:
Capsules: Prevent the phagocyte from adhering to the cell (e.g., Streptococcus pyogenes, Streptococcus pneumoniae, and Neisseria).
Leukocidins: Compounds produced by pathogens like Staphylococcus aureus that kill the phagocyte.
Membrane Attack: Listeria monocytogenes produces complexes that embed in and lyse the phagocyte's membrane.
Phagosome Escape: Shigella escapes the phagosome before fusion with the lysosome occurs.
Prevention of Fusion: HIV prevented the creation of the phagolysosome.
Replication within the Phagolysosome: Coxiella is an obligate intracellular parasite that requires the acidic environment of the phagolysosome to complete its life cycle.
Inflammation: Signs, Symptoms, and Biological Stages
Inflammation recruits cells to an infection site, removes damaged cells, dilutes toxins, and initiates repair.
The Classic Signs and Symptoms of Inflammation:
Erythema (Redness): Caused by increased blood flow to the site.
Heat: Localized increase in temperature due to blood flow.
Edema (Swelling): Accumulation of fluids which act like a dam to prevent the spread of the pathogen.
Pain: The only symptom listed (cannot be directly measured), caused by swelling stimulating nerve endings.
Altered Function: Impairment at the site of infection.
The Process of Inflammation:
It begins with vasodilation, which increases vessel size and permeability.
Cytokines such as histamines, kinins, leukotrienes, and prostaglandins are released.
Clots are formed by fibrinogen in the fluids to trap microorganisms and prevent focal infections from spreading.
Pus forms as a collection of dead microorganisms, dead white blood cells, and cellular debris.
Fever: The Systemic Response and Pyrogenic Activity
A fever is a systemic response involving an abnormally elevated body temperature, regulated by the hypothalamus.
Pyrogens: Compounds that reset the hypothalamus to a higher temperature.
Endogenous Pyrogens: Originate from the host (e.g., Interleukin- and Tumor Necrosis Factor/TNF).
Exogenous Pyrogens: Stimulated by the pathogen (e.g., Lipid A, which is an endotoxin, or superantigen exotoxins).
Mechanism: Unlike inflammation, pyrogens cause vasoconstriction to prevent heat loss, raising the overall body temperature.
Benefits of Fever:
Inhibits the growth of certain viruses such as poliovirus, herpes virus, and cold viruses.
May exceed the pathogen's optimal growth temperature.
Increases host metabolism and speeds up the immune response.
Inhibits hydrophores, which are used by bacteria to steal iron from the host.
Treatment: Antipyretic drugs like aspirin or acetaminophen block pyrogen activity. Once the drug wears off, if the pyrogen is still present, the fever will return.
Fevers in specific populations, such as a fever of in an adult, may not be a problem, but the same temperature in an infant can be fatal.
The Lymphatic System and Secondary Defensive Organs
The lymphatic system acts as a drain-off for the inflammation response. Fluids that leak out of the circulatory system during inflammation enter the lymphatic system to be filtered before returning to the blood.
Flow is unidirectional from extremities toward the heart and is moved via peristalsis of surrounding tissues, as the vessels are not pressurized by the heart.
Lymph Nodes: These filter lymphatic fluids and contain fixed macrophages and white blood cells that destroy pathogens.
Spleen: Filters the blood (rather than lymph) to remove dead red blood cells, toxins, viruses, and cellular debris using phagocytes.
Thymus Gland: The site where T cells mature.
Cytokines: The Chemical Messengers of the Immune Response
Cells communicate chemically via cytokines to coordinate the immune response.
Tumor Necrosis Factor (TNF): Produced by macrophages and natural killer cells; increases chemotaxis and phagocytosis.
Interferons: Possess antiviral properties. They are produced by viral-infected cells or leukocytes and bind to the surface of neighboring cells to induce the production of antiviral proteins, making those cells less susceptible to infection. They can also inhibit gene expression in certain cancers.
Histamines: Produced by basophils, eosinophils, and mast cells to facilitate vasodilation and vessel permeability.