Innate Immunity Overview

Innate Immunity

• Innate immunity is a body's first line of defence against pathogens
• It's a rapid response system
• It involves a wide variety of cells and proteins
• The cells work together to recognise and eliminate threats
• This system is non-specific, meaning it responds to a broad range of pathogens

Immune System

• A collection of cells and tissues working to protect against disease
• Leukocytes (white blood cells) are produced in bone marrow
• Some leukocytes circulate in blood, most reside in tissues/organs

Immune Cells

• Monocytes: Precursors to dendritic cells and macrophages
• Macrophages: Tissue-resident, phagocytic, antigen-presenting cells
• Dendritic Cells: Differentiate in tissues, phagocytic and antigen-presenting. Travel to lymph nodes to activate T cells
• Granulocytes:
  • Neutrophils: Circulating, highly phagocytic
  • Eosinophils: Circulate, respond to IgE, degranulate to remove parasites
  • Basophils: Circulating, very low numbers
  • Mast Cells: Tissue resident, source of cytokines, can degranulate
• Lymphocytes:
  • T lymphocytes: Helper and cytotoxic cells, recirculate through lymph nodes, activated by dendritic cells
  • B lymphocytes: Produce antibodies
  • Natural Killer Cells: Innate immune cells killing infected cells

Physical Barriers

• Protect entrances to body
• Respiratory tract, skin, gastrointestinal tract, genitourinary tract, and eyes
• Tight epithelial layer, fluids, and secretions to protect these entrances

Defenses at Barriers

• Tight Epithelial Layers: Restrict movement of materials between cells
• Fatty Acids: Destabilise bacterial cell membranes
• Defensins: Antimicrobial peptides disrupting cell membranes
• Enzymes: e.g., lysozyme in tears, reduce chance for microbial settlement
• Normal Microbiota: Outcompete harmful organisms
• Low pH: Restricts pathogen survival

Inflammation

• A body's response to damage
• Characterized by redness (rubor), heat (calor), swelling (tumor), and pain (dolor)
• Part of the body's defense mechanisms
• Initiated without pathogen presence by cell fragments or other damage

Pro-inflammatory cytokines

• Small proteins released by immune cells to communicate
• Trigger inflammatory reactions
• IL-1β, TNF-α, IL-6: Key pro-inflammatory cytokines released in response to damage

Cytokine Effects on Tissue

• Pro-inflammatory cytokines act on endothelial cells to increase permeability
• Causes fluid to leak into tissues (edema)
• Causes increased blood vessel diameter, resulting in redness and heat
• Release of bradykinins sensitizes nerve endings, causing pain

Pathogen Recognition

• Pathogen-associated molecular patterns (PAMPs) distinguish pathogen surfaces/nuclear material
• Recognized by pattern-recognition receptors (PRRs) on tissue and immune cells

Pattern Recognition Receptors (PRRs)

• Same shape on various microbes
• Innate immune system, evolved alongside pathogens
• Responses are similar for different pathogens

Cell Receptors

• External Receptors: (Toll-like Receptors) result in changes to transcription and cytokine release
• Cytoplasmic Receptors: (NOD and RIG-like receptors) result in changes to transcription and cytokine release
• Endosomal Receptors (Toll-like Receptors) result in changes to transcription and type I interferon release

Toll-Like Receptors (TLRs)

• Recognize various pathogen components
• Signal transduction activates transcription of pro-inflammatory cytokines

Phagocytic Receptors

• Important for engulfing and destroying pathogens
• Examples include C-type lectin receptors (e.g., Dectin-1), scavenger receptors, and mannose receptors
• Recognize specific pathogen components

Macrophages Killing Pathogens

• Pathogens recognized by receptors
• Phagocytosis is induced
• Phagosome fuses with lysosome
• Pathogen broken down and destroyed
• Lysosome contains antimicrobial peptides, lysozyme, and nitric oxide

Complement Proteins

• Small proteins produced by the liver
• Become active when they enter tissues
• Binding to pathogen surfaces makes them visible to phagocytic receptors

Chemotaxis

• Process of cell recruitment to infection site
• Induced by chemokines
• Chemokines attract leukocytes to the site of infection

Neutrophil Function

• Granules contain antimicrobial proteins and peptides
• Produce superoxide radicals
• Lower pH and activate peptides within 3 minutes of phagocytosis

Neutrophil Apoptosis and Netosis

• Respiratory burst produces toxic oxygen species
• Eventually, neutrophils die (apoptosis or netosis)
• During netosis, chromatin and granule contents are released (Neutrophil Extracellular Traps (NETs))

Systemic Effects of Pro-inflammatory Cytokines

• Liver: Induces acute phase protein production
• Fat and Muscle: Protein and energy mobilization, increased body temperature
• Hypothalamus: Increases body temperature
• Bone Marrow & Epithelium: Neutrophil mobilization

Incomplete Pathogen Clearance

• Continued cytokine release can damage tissues
• Damaged blood vessels and bradykinin release contribute to pain and swelling

Summary

• Barriers try to prevent injury or infection
• If breached, damage/pathogens induce inflammation
• Cytokines have local and systemic effects to enhance immune responses
• Tissue resident cells, like macrophages, act early to phagocytose pathogens; neutrophils are recruited