3. Innate Immunity: Phagocytes (and other innate immune cells)

What are words used to describe the innate immune system?

• Rapid (minutes to hours)

• Evolutionarily old

• Relatively non-specific

• No specific memory

• Mostly driven by myeloid cells

What are words used to describe the adaptive immune system?

• Slower (days)

• Found only in vertebrates

• Highly specific

• Highly specific memory

• Driven by lymphoid cells

What are the key innate cells?

• NK cells

• Neutrophil

• Eosinophil

• Basophil

• Mature dendritic cell

• Mast cell

• Macrophage

Describe the characteristics and functions of macrophages involved in immunity.

• Professional phagocyte.

• Has an active, patrolling mechanism thus is more likely to encounter a pathogen.

• Tissue-resident and specialised to different tissues.

• Function: tackle primary infection by recognising foreign material, phagocytosing it and alerting other cells of the infection.

How do macrophages recognise foreign particles?

• Endogenous ligands on the pathogen surface, unique to the pathogen (PAMPs).

• Host factors that are deposited onto the surface (opsonins).

How do macrophages alert other immune cells of the infection?

Following phagocytosis, alarm molecules are released:

• Cytokines

• Chemokines

What are cytokines?

Cytokines are signalling proteins involved in immune system regulation and communication.

• Modulate immune responses (both pro-inflammatory and anti-inflammatory)

• Regulate cell proliferation, differentiation, and apoptosis

• Promote tissue repair and wound healing

What are chemokines?

Specialised subclass of cytokines that primarily guide the migration (chemotaxis) of immune cells to sites of infection, inflammation, or injury.

• Direct the movement of immune cells to affected tissues during inflammation or infection.

• Help in the development and maintenance of lymphoid tissues.

What physiological responses do cytokines and chemokines bring about following an infection?

Vasodilation and increased vascular permeability:

• Redness

• Heat

• Swelling

• Pain- inflammatory cells migrate into the tissue, releasing inflammatory mediators that cause pain

Describe the characteristics and functions of dendritic cells involved in innate immunity.

• Professional phagocyte.

• Has a continual sampling mechanism with erratic membrane movement, responding early to invasion

• Tissue-resident, specialised in different tissues

• Phagocytose and destroy pathogens

• Constitutively macropinocytose and use the pathogenic material to activate T-lymphocytes

• Antigen-presenting cell

What is macropinocytosis?

The process of taking up large amounts of extracellular fluid, nutrients, or soluble compounds.

Give some examples of dendritic cell subsets and their functions.

• CD103+ dendritic cells migrate to lymph nodes for antigen presentation.

  • CD103- dendritic cells remain tissue-based and promote local T-cell and inflammatory responses.

Describe the characteristics and functions of neutrophils involved in immunity.

• Professional phagocyte.

• Respond rapidly to cytokines and chemokines.

• Migrate rapidly to the site of infection, phagocytose and kill pathogens.

• There is growing evidence of a complex role in resolving immunity.

• Attracted to a range of chemoattractants e.g. C5a, IL-8 and IFNgamma.

List the professional phagocytes involved in innate immunity.

• Neutrophils

• Dendritic cells

• Macrophages

List the non-phagocytic cells involved in innate immunity.

• Eosinophils

• Basophils

• Mast cells

• Natural killer cells

Give examples of immune cells that are capable of phagocytosis but are not commonly known to carry it out.

• Gamma-delta T-cell (humans)

  • B-cells (bony fish and Xenopus)

Give an example of a phagocyte defect.

Chronic granulomatous disease (CGD)

• Defect in the oxidative burst, used by phagocytes to kill pathogens.

• Highly susceptible to infection (including organisms usually considered non-infectious).

Describe the characteristics and functions of eosinophils in innate immunity.

• Non-phagocytic.

• Deals with large pathogens (e.g. parasitic worms) that are too big to phagocytose.

• Contains a range of toxins/enzymes that are released in response to antibody-coated pathogens, particularly IgE-coated.

• Also found in invertebrates but their function is unclear.

Describe the characteristics and function of basophils in innate immunity.

• Non-phagocytic.

• General functions are unknown but are known to be involved in allergic responses.

• Contains a range of enzymes/toxins and is frequently found close to internal parasites (e.g. worms) or exoparasites (e.g. tick bites).

Describe the characteristics and functions of mast cells in innate immunity.

• Non-phagocytic.

• Major inflammation orchestrator.

• Degranulates in response to IgE (within seconds).

• Releases inflammatory mediators e.g. enzymes, toxic mediators, cytokines, chemokines and lipid mediators.

What are the incurred biological effects of the release of enzymes from mast cells?

Biological effects: remodelling the connective tissue matrix.

• Facilitates immune cell recruitment as immune cell pathways are created for easy migration to the site of injury or infection.

• Clearing damaged tissue to facilitate repair.

• Modulating inflammation via ECM fragments becoming signalling molecules from enzymatic cleavage.

• Angiogenesis and wound healing.

What are some enzymes are released by mast cells?

• Tryptase

• Chymase

What are the incurred biological effects of the release of toxic mediators from mast cells?

• Toxic to parasites.

• Increases vascular permeability.

• Causes smooth muscle contraction.

What are the incurred biological effects of the release of cytokines from mast cells?

• Stimulates and amplifies TH2-cell responses (IL-4, IL13).

• Promotes eosinophil production and activation (IL-3, IL-5, GM-CSF).

• Promotes inflammation, stimulates cytokine production by many cell types, and activates endothelium (TNF-alpha).

What are the incurred biological effects of the release of chemokines from mast cells?

Attracts monocytes, macrophages and neutrophils.

What are the incurred biological effects of the release of lipid mediators from mast cells?

Prostaglandins D2, E2

• Smooth muscle contraction.

• Increases vascular permeability.

• Stimulates mucus secretion.

Platelet-activating factor

• Attracts leukocytes.

• Amplifies lipid mediator production.

• Activates neutrophils, eosinophils and platelets.

State the toxic mediators that mast cells release.

• Histamine

• Heparin

State the chemokine that mast cells release.

CCL3

How are mast cells involved in local responses to infection?

• Present on all body surfaces.

• Consecutively bind IgE on their surface.

• Binding of cognate antigen triggers cytokines and chemokine release.

What immune cells play a role in allergic reactions?

• Mast cells

• Eosinophils

• Basophils

Describe the characteristics and functions of NK (natural killer) cells in innate immunity.

• Non-phagocytic

• Lymphoid-derived but still a major player in innate immunity.

• Acts early in infection to kill infected host cells.

• Killing is mediated by the release of toxic granules & the induction of apoptosis in the target cell.

Describe the mechanism NK cells perform in immunity.

Natural Killer (NK) cells scan cells for MHC class I molecules.

• Normal cells express MHC I, which engages inhibitory receptors on NK cells, preventing activation.

• Infected, stressed, or tumor cells often have reduced or absent MHC I, failing to trigger inhibitory signals.

• In this case, activating receptors dominate, and the NK cell becomes activated.

• Activated NK cells release perforin and granzymes, inducing apoptosis in the abnormal cell.

Generally speaking, how is infection detected?

1. The first line of defence (e.g. skin, AMPs ect.) is constitutively active. Once bypassed, the tissue macrophage is activated:

• Inflammatory signals are released.

• Pathogen is phagocytosed and destroyed.

• Acts as an antigen-presenting cell to trigger adaptive responses locally.

What do inflammatory cytokines induce?

• Increase in vascular diameter.

• Activation of endothelial cells.

• Attract leukocytes.

How is adaptive immunity activated?

Dendritic cells capture antigens at the infection site, migrate to draining lymph nodes, and present processed antigens on MHC molecules to naïve T cells, providing both antigen-specific (signal 1) and co-stimulatory (signal 2) signals, thereby activating them and initiating the adaptive immune response.