Innate Immunity: Principles and Mechanisms

Innate Immunity

Overview of Immune Responses

The immune response is a physiological process coordinated by the immune system to eliminate antigens. Immunity refers to specific protection conferred by immune responses, while susceptibility indicates a lack of immunity to a given pathogen, increasing the risk of infection. The immune system is divided into innate and adaptive immunity, both of which recognize diverse pathogens, eliminate invaders, and discriminate between self and foreign antigens.

Types of Immunity

• Innate Immunity: Inborn, generalized, and non-specific responses present in all individuals from birth.

• Adaptive Immunity: Found only in vertebrates, matures over time, tailored to specific pathogens, requires 4–7 days to fully activate, and exhibits memory.

Role of Normal Microbiota

Normal microbiota play a central role in inducing, training, and calibrating immune responses. The good hygiene hypothesis suggests that reduced diversity and levels of microbes in our microbiota may negatively affect immune responses. Studies in germ-free animals show that microbe-free environments lead to underdeveloped immune systems, highlighting the importance of normal microbiota in immune system development.

Lines of Defense

First-line Defenses

First-line defenses prevent pathogen entry and are categorized as mechanical, chemical, and physical barriers.

• Mechanical Barriers: Rinse, flush, or trap pathogens (e.g., tears, urine, saliva, mucus membranes, mucociliary escalator).

• Chemical Barriers: Directly attack invaders or create hostile environments (e.g., lysozyme in secretions, hydrochloric acid in the stomach, fatty acids in sweat and earwax, antimicrobial peptides such as defensins).

• Physical Barriers: Structures that physically block pathogen entry (e.g., skin, tightly packed epithelial cells of the epidermis).

Second-line and Third-line Defenses

When pathogens bypass first-line defenses, they encounter second-line defenses (molecular factors and leukocytes) and third-line defenses (T and B lymphocytes of the adaptive immune response).

Organs, Tissues, Cells, and Molecules of the Immune System

Lymphatic System

The immune system is interconnected with the lymphatic system, which collects, circulates, and filters fluid in body tissues before returning it to the blood.

Primary and Secondary Lymphoid Tissues

• Primary Lymphoid Tissues: Sites of leukocyte production and maturation (thymus for T cells, bone marrow for red and white blood cells).

• Secondary Lymphoid Tissues: Filter lymph and include lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT).

Blood Cells and Leukocytes

Blood contains erythrocytes (oxygen delivery), platelets (clotting), and leukocytes (immune defense). Leukocytes are classified as granulocytes (with cytoplasmic granules) and agranulocytes (without granules).

Granulocytes

• Neutrophils: Most numerous, first responders, phagocytic, release antimicrobial peptides (AMPs).

• Eosinophils: Bilobed nucleus, moderate phagocytic activity, combat parasites, involved in allergies.

• Basophils: Least numerous, granules contain histamine, involved in allergic responses and parasitic infections.

• Mast Cells: Reside in tissues, release histamine, involved in allergies and parasite defense, capable of phagocytosis.

Agranulocytes

• Monocytes: Largest agranular WBCs, mature into macrophages in tissues, elevated in chronic infections and inflammation.

• Macrophages: Highly phagocytic, can be fixed (in tissues) or wandering (move through tissues).

• Dendritic Cells: Highly phagocytic, patrol tissues, present antigens to adaptive immune cells.

• Lymphocytes: Include natural killer (NK) cells (innate immunity), B cells, and T cells (adaptive immunity).

White Blood Cell Counts in Clinical Diagnosis

Differential white blood cell (WBC) counts are rapid, inexpensive tests used to diagnose infections and immune disorders. Leukocytosis is an increase in leukocytes, while leukopenia is a decrease.

Immune System Molecules

• Cytokines: Signaling proteins for cell communication, initiating and coordinating immune actions.

• Chemokines: Induce chemotaxis, aid in wound healing, blood vessel formation, and immune cell recruitment.

• Interleukins (ILs): Activate immune responses, stimulate hematopoiesis, regulate inflammation, and fever.

• Interferons (IFNs): Signal presence of pathogens or tumor cells, induce antiviral defenses.

• Tumor Necrosis Factors (TNFs): Stimulate inflammation and fever, kill tumor cells.

Iron-Binding Proteins and Pathogen Strategies

Iron-binding proteins (hemoglobin, ferritin, lactoferrin, transferrin) limit iron availability to microbes. Some pathogens produce siderophores to steal iron or break down red blood cells to access hemoglobin.

Complement System

The complement system consists of over 30 proteins that work in a cascade to enhance immune defenses. Activation leads to:

• Opsonization: Tagging invaders for phagocytosis.

• Membrane Attack Complex (MAC) Formation: Causes cytolysis of pathogens.

• Inflammation: Promotes recruitment of immune cells and pathogen clearance.

Inflammation

Mechanisms and Phases

Inflammation is a key innate immune defense triggered by tissue damage or infection. It recruits immune defenses, limits pathogen spread, and promotes tissue repair. The three phases are:

1. Vascular Changes: Vasodilation and increased vessel permeability allow immune cells and proteins to access tissues.

2. Leukocyte Recruitment: Chemoattractants guide leukocytes to the site; cells exit blood vessels via margination and diapedesis.

3. Resolution: Signals tone down inflammation, swelling decreases, and tissue repair begins.

Cardinal Signs of Inflammation

• Redness

• Pain

• Localized heat

• Swelling

• Loss of function

Inflammatory Mediators

• Histamine: Increases vasodilation and vessel permeability.

• Kinins: Induce vascular changes and pain, assist in clotting.

• Eicosanoids: Prostaglandins, leukotrienes, and thromboxanes; induce vascular changes and pain. NSAIDs and SAIDs reduce eicosanoid production.

Chronic Inflammation

Chronic inflammation results from prolonged immune responses, causing tissue injury and contributing to diseases such as atherosclerosis, certain cancers, and neurodegenerative disorders.

Fever

Mechanisms and Effects

Fever (pyrexia) is an abnormally high systemic body temperature induced by pyrogens (e.g., bacterial toxins, cytokines). Pyrogens signal the hypothalamus to raise body temperature. Low-grade fever (37.5°C to 38.3°C) is considered protective, enhancing interferon effects, phagocyte efficiency, leukocyte production, and tissue repair, while limiting pathogen growth.

Clinical Management of Fever

Antipyretics (aspirin, ibuprofen, acetaminophen) are used to treat fever by limiting prostaglandin production in the hypothalamus. High fever (≥40.5°C) is life-threatening and requires immediate medical attention, as essential enzymes and proteins may denature above 43°C, leading to fatal outcomes.

Summary Table: Leukocyte Types and Functions

Cell Type	Appearance	Function
Neutrophil	Multi-lobed nucleus, granules	Phagocytosis, first responder to infection
Eosinophil	Bilobed nucleus, red-orange granules	Combat parasites, moderate phagocytosis
Basophil	Double-lobed nucleus, dark granules	Release histamine, allergic responses
Mast Cell	Granular, tissue-resident	Release histamine, allergies, parasite defense
Monocyte	Large, horseshoe-shaped nucleus	Mature into macrophages, phagocytosis
Macrophage	Large, variable	Phagocytosis, antigen presentation
Dendritic Cell	Star-shaped	Phagocytosis, antigen presentation
Lymphocyte (NK, B, T)	Large nucleus, little cytoplasm	NK: innate defense; B/T: adaptive immunity

Key Terms and Concepts

• Antigen: Any substance that can induce an immune response.

• Phagocytosis: The process by which cells engulf and digest pathogens and debris.

• Cytokine: Protein mediators that regulate immune responses.

• Opsonization: The process of tagging pathogens for destruction by phagocytes.

• Pyrogen: Substance that induces fever.