Innate Immunity: Active
Introduction to Innate Immunity
Focus on Active (or Cellular) components of the immune system.
Learning Objectives
Vocabulary:
Granulocyte: A type of white blood cell characterized by the presence of granules in its cytoplasm.
Basophil: A type of granulocyte that releases histamine and other substances during inflammatory reactions.
Eosinophil: A white blood cell involved in combating multicellular parasites and certain infections.
Mast Cell: A type of immune cell that contains granules rich in histamine and plays a role in allergic responses.
Neutrophil: The most abundant type of white blood cell, acting primarily against bacterial infection.
Macrophage: A type of phagocyte that ingests foreign material and helps initiate the immune response.
Monocyte: A large white blood cell that differentiates into macrophages and dendritic cells.
Leukocyte: A general term for white blood cells involved in protecting the body against disease.
Lymphocyte: A subtype of white blood cells which includes T cells and B cells that are key to adaptive immunity.
Diapedesis: The process through which leukocytes pass through the endothelial cells of blood vessel walls to reach the site of injury or infection.
Phagocyte: A cell that engulfs and digests cellular debris and pathogens.
Phagosome: A vesicle formed around a particle absorbed by phagocytosis.
PAMPs (Pathogen-Associated Molecular Patterns): Molecules associated with groups of pathogens that are recognized by cells of the innate immune system.
TLRs (Toll-Like Receptors): A class of proteins that play a key role in the innate immune system by recognizing PAMPs.
Describe the basic functional characteristics of the granulocytes, including their location and the types of molecules present in their granules.
Identify the primary characteristics of the non-specific agranulocytes (such as monocytes and macrophages) and how they activate.
Describe the types of target PAMPs recognized by TLRs.
Outline the basic processes of acute inflammation.
Concept Map of the Immune System
Innate Immunity:
Physical: Mechanical barriers like skin and mucosal layers.
Microbiome: Commensal microbes that provide barrier and immune benefits.
Barrier Functions: Mechanisms that prevent pathogen entry.
Non-specific Cells: Cells that respond to general pathogens, such as granulocytes and agranulocytes.
Systemic Responses: Widespread effects of immune activation throughout the body.
Hematopoiesis and Formed Elements
“Formed Elements”:
Named because they originate from a single population of bone marrow stem cells.
Development involves ongoing differentiation and maturation processes that occur daily in individuals with a functioning immune system.
Granulocytes: Overview
Also known as leukocytes, characterized by the presence of granules that stain variably with histological dyes.
Types of granulocytes include basophils, eosinophils, neutrophils, and mast cells.
Basophils
Granules take up the basic dye methylene blue, mainly consisting of:
Histamine: Increases vascular permeability.
Heparin: Delays blood clotting.
Activation Occurs:
Only within tissues, not in blood vessels.
In response to specific stimuli.
Function:
Attracts further immune cells through the creation of leaky blood vessels.
Eosinophils
Granules stain with the acidic dye eosin, involved as primary effector cells against helminths and parasites.
Key Components in Granules:
Histamine: Facilitates recruitment of other immune cells.
Major Basic Protein: Binds to surface structures of parasites.
Degrading enzymes: Includes proteases, lipases, amylases, etc.
Additional Role:
Eosinophils are implicated in atopic asthma and respiratory distress.
Neutrophils
Granules can stain with both acidic and basic dyes, making them appear neutral.
Primary Effector Cells Against:
Extracellular bacteria.
Granule Contents:
Defensins: Antimicrobial peptides effective at killing bacteria.
Hydrolytic enzymes: Aid in the digestion of engulfed microorganisms.
Phagocytic Activity:
Can engulf and digest bacteria; a process known as phagocytosis.
Extreme Response:
In severe cases, neutrophils can extrude their chromosomal DNA to form Neutrophil Extracellular Traps (NETs).
Neutrophil Extracellular Traps (NETs)
Composition and Function:
NETs are composed of enzymes like lactoferrin, myeloperoxidase, cathepsin G, etc.
Serve as sticky traps for bacteria, focusing their antimicrobial efforts.
Phagocytosis
Defined as a highly ordered series of events that phagocytes undergo.
Targets for Phagocytosis Include:
Bacteria, viruses, yeasts, dead host cells, and damaged tissue.
Outcome:
Most phagocytes destroy the engulfed material; others facilitate communication with the adaptive immune response.
Mast Cells
Classified with granulocytes due to shared progenitor cell type but diverge during development.
Granules primarily contain:
Histamine: Released in response to certain antibody types.
Location:
Typically located deep within tissues, especially in epithelial layers and close to nerves.
Relation to Allergies:
Degranulation of mast cells is a major factor in allergic reactions, such as sinusitis and skin allergies.
Agranulocytes
Also referred to as lymphocytes.
Circulating Agranulocytes:
Includes monocytes, NK cells, B cells, and T cells.
Important Note:
This classification is based on histology; it does not determine functional capabilities.
Monocytes, Macrophages & Dendritic Cells
Monocytes: The circulating form of immune cells that can exit the bloodstream and mature into functional cells.
Macrophages: Specialized cells that play critical roles in attacking pathogens and clearing dead cells.
Dendritic Cells: Found adjacent to epithelial barriers; responsible for antigen processing and presentation to adaptive immune cells in lymph nodes.
Pathogen Associated Molecular Patterns (PAMPs)
Recognition Mechanism for Innate Immune Cells Includes:
Peptidoglycan: A major component of bacterial cell walls.
LPS (Lipopolysaccharides): Found in the outer membrane of Gram-negative bacteria.
dsRNA (Double-stranded RNA): Associated with viral infections.
Flagellin: A structural protein of bacterial flagella.
Recognition is facilitated through Toll-Like Receptors (TLRs), which activate innate immune responses upon PAMP detection.
Acute Inflammation
At the core is cell-to-cell signaling facilitated by various chemical mediators:
C3a and C5a: Byproducts from the complement cascade.
Histamine: A small, diffusible organic molecule playing a significant role in inflammation.
Cytokines, leukotrienes, prostaglandins, and interleukins: Signaling proteins that orchestrate inflammatory events.
Clinical Presentation of Inflammation:
Characterized by rubor (redness), tumor (swelling), dolor (pain), and calor (heat).
Diapedesis - Leaving the Bloodstream
Process involves:
Chemical signals secreted by injured/infected cells alert leukocytes in the bloodstream.
Leukocytes respond to chemotactic signals, migrate towards the injury site in a process known as positive chemotaxis.
They traverse the capillary wall by squeezing between endothelial cells.
Results in up to 200 leukocytes migrating to the site of injury or infection.
Resident macrophages engulf pathogens and release pro-inflammatory, chemotactic cytokines to further recruit immune cells.
Immune Action, Resolution, and Healing
The sequence of immune response activities is roughly as follows:
Complement/Mast Cells: Initial responders to infection.
Tissue Macrophages/Dendritic Cells: Present antigens and activate further immune responses.
Neutrophils: Act as the frontline defense against infection.
Monocytes → Macrophages: Enter and differentiate to enhance phagocytic capacity and clear debris.
Fibroblasts: Involved in tissue healing and repair following an immune response.
Other granulocytes may become involved depending on specific signaling from cytokines and TLR pathways.