Host Defenses: Overview

Three Lines of Host Defense

The human body employs a multilevel network of defenses to protect against microbial invasion. These defenses are categorized into three lines: the first and second lines are innate (nonspecific), while the third line is adaptive (specific).

• First Line of Defense: Physical and chemical barriers that prevent pathogen entry at portals of entry. These are general and nonspecific.

• Second Line of Defense: Internalized system involving protective cells and fluids, including inflammation and phagocytosis. Acts rapidly after the first line is breached.

• Third Line of Defense: Adaptive immunity acquired through exposure to specific pathogens, involving lymphocytes and the production of unique protective substances. Provides long-term immunity.

Additional info: The three lines of defense work together, often overlapping and providing redundancy to maximize protection.

Immunology and the Immune System

Definition and Mandate

Immunology is the study of the body's second and third lines of defense, including responses to infectious agents, allergies, and cancer. The immune system is responsible for:

• Surveillance of the body

• Recognition of foreign material

• Destruction of entities deemed foreign

Markers and Antigens

Cells are evaluated by the immune system through markers (also called antigens), which are molecules on cell surfaces composed of proteins and/or sugars. These markers help immune cells distinguish between self and nonself, a process central to immune function. Errors in this process can lead to autoimmune disorders.

PAMPs and PRRs

• Pathogen-Associated Molecular Patterns (PAMPs): Common molecular signatures found on many microbes but not on mammalian cells. Examples include peptidoglycan and lipopolysaccharide (bacteria), and double-stranded RNA (viruses).

• Pattern Recognition Receptors (PRRs): Host cell receptors (on phagocytes, dendritic cells, etc.) that recognize PAMPs and trigger innate immune responses.

Body Systems in Immunity

Major Participating Systems

• Mononuclear Phagocyte System (MPS): Network of connective tissue fibers and phagocytic cells in direct contact with tissue cells and extracellular fluid.

• Blood: Contains plasma, serum, and formed elements (red blood cells, white blood cells, platelets).

• Lymphatic System: Closely connected with the circulatory system, facilitating the movement of immune cells and molecules throughout the body.

Blood Cells in Immunity

Blood cells originate from stem cells in the bone marrow through hematopoiesis. White blood cells (leukocytes) are divided into granulocytes and agranulocytes, both essential for nonspecific and specific immunity.

Key Blood Cells in Innate Immunity

• Neutrophils: General-purpose phagocytes, first responders to infection, and primary component of pus.

• Monocytes: Differentiate into macrophages and dendritic cells in tissues.

• Macrophages: Engulf and destroy pathogens, present antigens, and regulate immune responses.

Cytokines: Cell Communication Molecules

Cytokines are small, active molecules secreted by various cells (monocytes, macrophages, lymphocytes, etc.) to regulate, stimulate, or suppress immune responses, inflammation, and cell development. Examples include pro-inflammatory cytokines (e.g., interleukin-1) and anti-inflammatory cytokines.

First Line of Defense: Physical and Chemical Barriers

Skin and Mucous Membranes

The first line of defense consists of inborn, nonspecific barriers that impede the entry of microbes. These include:

• Skin: The stratum corneum is a tough, waterproof outer layer. Shedding of skin and hair, as well as sweat, helps remove microbes.

• Mucous Membranes: Found in the digestive, urinary, respiratory tracts, and eyes. Mucus impedes entry and attachment of microbes, while blinking, tears, saliva, vomiting, and defecation help flush out pathogens.

Respiratory Tract Defenses

• Nasal hair traps particles.

• Mucus and ciliated epithelium move trapped particles toward the pharynx.

• Sneezing and coughing expel irritants.

Genitourinary Tract Defenses

• Continuous urine flow and periodic bladder emptying flush the urethra.

• Vaginal secretions cleanse the lower reproductive tract.

Human Microbiome

The normal microbiota forms a structural barrier, competes with pathogens for nutrients, and alters local pH to inhibit pathogen growth. Disruption of the microbiome can contribute to diseases such as Crohn’s disease and ulcerative colitis.

Second Line of Defense: Cellular and Chemical Systems

Phagocytosis

Phagocytosis is a cornerstone of inflammation and specific immunity. Phagocytes survey tissues, ingest and eliminate microbes, and process antigens. Main phagocytes include neutrophils, monocytes, and macrophages.

• Histiocytes: Tissue-resident macrophages (e.g., alveolar macrophages in the lungs, Kupffer cells in the liver).

Steps of Phagocytosis

1. Chemotaxis: Movement toward chemical signals.

2. Ingestion: Engulfment of the microbe.

3. Phagolysosome Formation: Fusion of phagosome with lysosome.

4. Destruction: Enzymatic and chemical killing of the microbe.

5. Excretion: Removal of debris.

Recognition of Microbes

• PAMPs: Signal molecules on microbes recognized as 'red flags' by phagocytes.

• PRRs: Host receptors that bind PAMPs and trigger immune responses.

• Inflammasomes: Cytoplasmic PRRs in phagocytes that regulate inflammation upon PAMP recognition.

Inflammatory Response

Signs and Symptoms

• Rubor: Redness

• Calor: Warmth

• Tumor: Swelling

• Dolor: Pain

• Loss of function

Inflammation can be local or systemic, acute or chronic. It is triggered by infection, tissue injury, or immune reactions.

Functions of Inflammation

• Mobilize and attract immune components to injury site

• Repair tissue damage and localize harmful substances

• Destroy microbes and block further invasion

Stages of Inflammation

1. Vasoconstriction and release of chemical mediators

2. Vasodilation, increased permeability, and migration of white blood cells

3. Formation of pus and tissue repair

4. Resolution and scar formation

Diapedesis and Chemotaxis

• Diapedesis: Migration of white blood cells out of blood vessels into tissues.

• Chemotaxis: Movement of cells toward chemical signals at infection sites.

Benefits of Edema and Leaky Vessels

• Dilution of toxins

• Fibrin clots trap microbes

• Neutrophils destroy bacteria and debris

• Pus formation (pyogenic bacteria attract neutrophils)

Fever

Definition and Types

Fever is an abnormally elevated body temperature, commonly associated with infection. The hypothalamus maintains body temperature around 37°C (98.6°F).

• Low-grade fever: 37.7–38.3°C (100–101°F)

• High-grade fever: 40.0–41.4°C (104–106°F)

Pyrogens

• Exogenous pyrogens: Derived from outside the body (e.g., microbial products, vaccines).

• Endogenous pyrogens: Released by immune cells during phagocytosis (e.g., interleukin-1, tumor necrosis factor).

Benefits and Treatment of Fever

• Inhibits growth of temperature-sensitive microbes

• Reduces iron availability for bacteria

• Increases metabolism and immune activity

• Treatment is recommended for high, prolonged fevers or in vulnerable individuals

Antimicrobial Products

Interferons

Interferons (IFNs) are small proteins produced by white blood and tissue cells. They regulate immune responses and have antiviral and antitumor effects.

• IFN-α and IFN-β: Produced by lymphocytes, fibroblasts, and macrophages; stimulate phagocytes.

• IFN-γ: Produced by T cells; regulates macrophages and lymphocytes.

Interferons bind to cell surfaces, induce antiviral proteins, degrade viral RNA, and block viral protein synthesis. They are not microbe-specific and are used therapeutically for some viral infections.

Complement System

The complement system consists of over 30 blood proteins that work in a cascade to destroy bacteria, viruses, and infected cells. The cascade involves:

1. Initiation: C3 hydrolysis

2. Activation and cascade: C3b cleaves C5

3. Polymerization: Formation of membrane attack complex (MAC)

4. Membrane attack: MAC forms pores, leading to cell lysis

There are two main pathways:

• Classical pathway: Initiated by antibodies bound to microbes.

• Alternative pathway: Initiated by foreign antigens, faster response.

Antimicrobial Peptides

Short proteins (12–50 amino acids) such as defensins can insert into bacterial membranes, forming pores that lead to cell lysis. They also modulate immune responses and are being explored as therapeutic agents.