The Innate Immune Response
Innate vs. Adaptive Immunity
Innate Immunity
Definition: Non-specific alarm system to pathogens and stressed or damaged cells.
Characteristics:
First responders, clinically observed as acute inflammatory response.
Duration: dissipates within 2 to 14 days.
Cell Types:
Macrophage
Natural killer cell
Dendritic cell
Mast cell
Basophil
Adaptive Immunity
Definition: Lag time occurs between exposure and maximal response.
Characteristics:
Immunological memory, which allows for a longer response duration (can persist for years).
Cell Types:
B cells
Eosinophils
Cytotoxic T cells
Natural killer T cells
CD4+ and CD8+ T cells
Time Frame: Comparison of resolved innate immune responses to adaptive immune responses (e.g., T cells, neutralizing antibodies).
Pathogens and Immune Barriers
Barriers to Pathogens:
Physical and Physiological Barriers:
Skin and mucous membranes act as the first line of defense.
Other defenses:
Basophils
Cilia
Macrophages
Body Temperature (pyrexia as a defense mechanism)
Dendritic cells
Neutrophils
Plasma cells
Analogy:
Security walls (prevent entry) - Innate Immune Defenses
Security cameras (detect invaders) - Sensor systems
Security teams (eliminate threat) - Innate effector actions including phagocytosis and inflammatory response.
First Line of Defense: Physical Barrier
Skin:
Provides a difficult barrier for microbes due to its structure.
Epidermis: Multiple layers of epithelial cells, outermost layers are dead and keratinized.
Described as a water-repellent surface maintaining a dry environment and shedding constantly.
Mucosal Membranes:
Located within digestive, respiratory, and urogenital tracts.
Constantly bathed in secretions that help in clearing microbes from surfaces.
Immune System Cells
Hematopoiesis:
Production of blood cells within the bone marrow.
Hematopoietic Stem Cells: Immature cells that differentiate into various blood cells.
Colony-Stimulating Factors (CSFs):
Secreted by the bone marrow to promote cell growth and differentiation.
Types of Blood Cells:
Red Blood Cells (Erythrocytes): Transport oxygen.
Platelets (From Megakaryocytes): Involved in clotting mechanisms.
White Blood Cells (Leukocytes): Crucial for host defense, comprising granulocytes, mononuclear phagocytes, and lymphocytes.
White Blood Cells: Granulocytes
Granulocytes:
Characterized by cytoplasmic granules.
Mechanism: Degranulation to release mediators.
Types of Granulocytes:
Basophils: Involved in allergic reactions; contain histamine.
Mast Cells: Similar functions to basophils; typically found in tissues.
Eosinophils: Combat parasitic infections; contain antimicrobials and histaminase.
Neutrophils: Primary phagocytes for bacteria; increase in numbers during infections.
White Blood Cells: Mononuclear Phagocytes
Monocytes: Circulate in the blood, then differentiate into:
Macrophages:
Perform phagocytosis, removing dead cells and debris and activating other immune cells.
Dendritic Cells: Process antigens and present to the adaptive immune system.
Cell Communication in the Immune System
Surface Receptors:
Mechanism allows for environmental sensing and inducing changes upon binding specific ligands.
Cytokines:
Secreted substances that induce changes like growth and differentiation in immune cells.
Cytokine Storm
Definition:
A potentially lethal overproduction of cytokines during immune responses, leading to significant tissue damage.
Pattern Recognition Receptors (PRRs)
Function:
Recognize distinctive patterns on pathogens, leading to cytokine secretion.
Microbe-Associated Molecular Patterns (MAMPs):
Include cellular components and microbial nucleic acids.
Pathogen-Associated Molecular Patterns (PAMPs):
Specific to pathogens.
Damage-Associated Molecular Patterns (DAMPs):
Indicate cell damage and stress.
PRR Locations:
Presented on cell surfaces, within endosomes/phagosomes, or free in cytoplasm.
Innate Immune Proteins
Defensins:
Induced by TLRs and anti-viral signals; block viral entry, integration, and transcription.
Cellular Proteins:
SAMHD1: Depletes dNTP pools for DNA synthesis.
Tetherin: Inhibits budding of enveloped viruses.
RIG-I & MDA5: Recognize dsRNA within the cytoplasm.
Protein Kinase R: Potentially inhibits protein synthesis upon dsRNA recognition.
The Complement System
Overview: Enhances adaptive immune system activities.
Components: Small proteins (C1–C9) circulate in inactive form.
Activation Process: Involves cleavage of proteins and formation of complexes.
Main Steps: C3 splits into C3a and C3b through three pathways leading to complement activation.
Complex Pathways of the Complement System
Activation Pathways:
Alternative Pathway: Initiated when C3b binds to foreign cell surfaces.
Lectin Pathway: Triggered by pattern recognition molecules binding to mannose on microbial cells.
Classical Pathway: Activated by antibodies bound to antigens.
Results of Activation:
Opsonization: C3b promotes phagocytosis by binding to microbial cells.
Cell Lysis: Formed membrane attack complexes (MAC) target and lyse foreign cells.
Inflammatory Response: C3a and C5a increase local vascular permeability and attract phagocytes.
Regulation of the Complement System
Mechanism:
Host cell membranes bind regulatory proteins that inactivate C3b, preventing unregulated complement activation and opsonization.
Interferon Response
Definition: Anti-viral cytokine produced upon PRR detection of viral RNA.
Mechanism: Causes neighboring cells to express inactive antiviral proteins that degrade mRNA and halt protein synthesis, resulting in apoptosis of infected cells.
Phagocytosis
Definition: Process through which phagocytes internalize and digest pathogens.
Steps in Phagocytosis:
Chemotaxis: Recruitment of phagocytes due to chemoattractants.
Recognition and Attachment: Binding directly via receptors or indirectly via opsonins.
Engulfment: Formation of phagosome through pseudopodia.
Phagosome Maturation: Fusion with lysosomes to form a phagolysosome.
Destruction and Digestion: Enzymatic degradation and ROS production.
Exocytosis: Expulsion of digested remains.
Characteristics of Immune Cells
Macrophages:
Central to alerting other immune cells, can be activated to M1 (greater killing) or M2 (anti-inflammatory) phenotypes.
Can cluster into granulomas when faced with resistant organisms.
Neutrophils:
First responders in inflammation, capable of forming neutrophil extracellular traps (NETs) that capture microbes.
The Inflammatory Response
Trigger: Infection or tissue damage prompts an inflammatory response.
Purpose: Contains damage, localizes the immune response, eliminates invaders, and aids in the restoration of tissue function.
Symptoms: Characterized by swelling, redness, heat, and pain.
Mechanism: Host cells release mediators (cytokines, histamines) which induce vascular changes and recruiting of additional immune cells.
Inflammation Mechanisms
Vasodilation: Increased blood vessel diameter enhances tissue perfusion, creating characteristic heat and redness.
Exudate Formation: Leakage of protein-rich fluid into tissue increases swelling.
Cellular Changes:
Diapedesis: Phagocytes migrate from vessels into tissues.
Pus formation from accumulated neutrophils and tissue debris; abscess as localized pus.
Kinds of Effects Caused by Inflammation
Cytotoxic Effects: Enzymatic damage to host tissues along with pathogens.
Situations Causing Significant Damage:
Delicate systems (e.g., neurological tissues), cytokine storms, prolonged autoimmune diseases.
Cell Death Types Related to Inflammation
Necrosis: Traumatic or accidental cell death.
Apoptosis: Non-inflammatory programmed cell death.
Pyroptosis and Necroptosis: Forms of inflammatory cell death.
Fever
Definition: Temporary rise in body temperature as a response to illness or infection.
Regulation: Controlled by the hypothalamus in the brain; normally maintains a temperature of 37 °C (98.6 °F).
Fever Inducers: Classified as pyrogens, substances stimulating hypothalamic temperature increase.
Pathogen Growth Effect: Growth rate of pathogens is greatly reduced at temperatures above optimal thus allowing more time for immune defense mechanisms.