Immune System Effector Functions

Immune System Functions: How Immune Cells and Molecules Eliminate Microbes

Traditional Owners Acknowledgment

• Acknowledgement of the traditional owners of the lands.

References

• Same references as the first lecture can be used.

Lecture Objectives

• Outline the effector modules of immunity and list the class of pathogens for which they provide protection.
• Discuss key effector mechanisms of the innate immune system.
• Describe the activation of B and T cells.
• Explain key effector mechanisms of the humoral and cell-mediated adaptive immune systems.

Immune Effector Modules

• The immune system needs to recognize and combat potential pathogens of different:
  • Sizes (viruses to parasites).
  • Locations (extracellular, intracellular in cytosol or vesicles).
  • Life cycles (viral vs. bacterial).
  • Mechanisms of disease (toxins).
• Innate Immunity: Broadly specific, quick response.
• Adaptive Immunity: Highly specific, slower response, more effective, provides memory.
• Classification of the immune system:
  • Innate vs. Adaptive.
  • Immune effector modules (integrated innate and adaptive).

Cytotoxicity Effector Module

• Targets cytosolic pathogens (e.g., viruses) and cancerous cells.
• Involves:
  • NK cells (innate).
  • CD8 T cells (adaptive).

Type One Immunity

• Targets intracellular pathogens in vesicles.
• Involves:
  • Macrophages (innate).
  • Th1 helper cells (adaptive).

Type Two Immunity

• Targets macroscopic pathogens.
• Involves:
  • Granulocytes (eosinophils, basophils, mast cells - innate).
  • Th2 cells (adaptive).
  • B cells (adaptive - not explicitly listed but important).

Type Three Immunity

• Targets extracellular pathogens (bacteria, fungi).
• Involves:
  • Neutrophils (innate).
  • Th17 cells (adaptive).

Layers of Defense in the Immune System

• Pathogens encounter a series of barriers upon exposure.
• Defense mechanisms:
  • Nonspecific.
  • Broadly specific.
  • Highly specific.
• Layers:
  • Anatomic barriers.
  • Complement and antimicrobial proteins.
  • Innate immune cells.
  • Adaptive immune cells.
• First three layers comprise the innate immune system.
• Last layer is the adaptive immune system.
• Pathogens face increasingly sophisticated mechanisms as they breach each layer.

Innate Immune System

Barrier Defenses

• Prevent infection.
• Contain pathogens via anatomical barriers.
• Mechanisms at different barrier types (skin, gut, lungs, eyes, nose, mouth).
• Mechanical barriers:
  • Epithelial cells with tight junctions.
  • Mucus.
  • Cilia.
• Chemical barriers:
  • Low pH.
  • Defensins.
  • Lysozyme.
• Normal microbiota (commensals):
  • Non-pathogenic.
  • Shape the immune system.
  • Provide protection from pathogenic microorganisms.

Complement System

• Part of the innate immune system, also used in adaptive (humoral) immunity.
• Soluble proteins in circulation (serum and plasma).
• Circulate in an inactive form.
• Activation:
  • Recognition of pathogen surface directly.
  • Recognition of antibody bound to a pathogen (link to humoral immunity).
• Proteolytic enzyme cascade.
• Three outcomes for the elimination of microbes:
  • Inflammatory response.
  • Phagocytic response.
  • Lysis.
• Complement proteins as inflammatory mediators recruit innate cells to the site of infection.
• Opsonization: coating pathogens for phagocytosis.
• Lysis: membrane attack complex forms a pore in the bacteria membrane.

Cells of the Innate Immune Response

• Cells recognize pathogen-associated molecular patterns (PAMPs) on microbes using pattern recognition receptors (PRRs).
• Response to damaged host cells (DAMPs) also occurs, important for tissue repair.
• Recognition results in signaling and activation of innate immune cells.
• Cells produce mediators and enact effector responses.
• Key innate immune cells: macrophages, neutrophils, and dendritic cells.
• Bacterial LPS recognized by Toll-like receptor.
• Signaling cascade leads to mediators (cytokines) production.
• Acute inflammation and activation of adaptive immune response.
• Type one interferons for antiviral response.

Cytokines

• Produced by immune (and non-immune) cells in response to pathogen or antigen recognition.
• Soluble signaling molecules that orchestrate the immune response.
• Produced in response to pathogen or antigen recognition, danger signals, or cytokine receptor engagement.
• Functions:
  • Communication between cells.
  • Cell survival, proliferation, and differentiation.
  • Cell migration (chemokines).
  • Inflammatory mediators.
• Act in autocrine, paracrine, or endocrine manners.
• Act locally or have systemic effects (e.g., fever).

Inflammation

• Innate immune response that brings cells and molecules to the site of infection or tissue damage.
• Contain and eliminate microbes, also important for tissue repair.
• Signs: Redness, heat, swelling, pain, loss of function.
• Process:
  • Bacteria enters through a cut in the skin.
  • Innate immune cells (sentinels) are activated through pattern recognition receptors.
  • Production of inflammatory mediators.
  • Vasculature becomes permeable: gaps in endothelial cells form.
  • Proteins and fluid exit into the site of infection.
  • Recruitment of neutrophils to phagocytose microbes.
  • Monocytes enter the tissue and differentiate into macrophages.
  • Macrophages are important for phagocytosis and tissue repair.
  • Neutrophils respond quickly (minutes to hours), macrophages respond later (hours to days).

Phagocytosis

• Process of engulfing microscopic extracellular pathogens.
• Microbes recognized by pattern recognition receptors and complement receptors.
• Phagocyte engulfs microbe into a phagosome.
• Phagosome fuses with lysosome to form phagolysosome.
• Activation of the phagocyte and "oxidative burst".
• Enhanced when microbes are flagged with complement and antibodies (opsonization).
• The principal function of neutrophils and macrophages.
• Dendritic cells phagocytose for antigen presentation.

Degranulation

• Method for both microscopic and macroscopic pathogens.
• Neutrophils: Target extracellular bacteria and fungi.
• Eosinophils, basophils, and mast cells: Target large parasites such as worms. Associated with allergic responses.
• Granule contents:
  • Preformed toxic substances that kill bacteria, fungi, or worms.
• Activated by various methods (not detailed in the lecture).
• Quick release of substances leads to pathogen killing.

Natural Killer (NK) Cells

• Function through cytotoxicity (killing of other cells).
• Important for virally infected cells and cancer cells.
• Mediated through:
  • Receptors that recognize molecules expressed on infected or stressed cells.
  • Antibodies.
• Activating and inhibitory receptors:
  • If both engaged, the cell is not killed.
  • Virus-infected cells may downregulate MHC, leading to NK cell activation and killing.
  • Antibody-coated cells can also activate NK cells.
• Activation leads to the release of granules:
  • Induce apoptosis of the target cell.