Innate Immune System Flashcards

Innate Immune System

Primary Protective Barriers

• Functions:

  • Prevent pathogen access (anatomical, chemical, biological barriers).
  • Recruit immune cells via chemical mediators (cytokines, chemokines).
  • Detect and remove pathogens and foreign substances.
  • Activate the Adaptive Immune System via antigen-presenting cells (APCs).

• Components:

  • Anatomical (physical) barriers.
  • Chemical defenses.
  • Commensal microflora.
  • Cells (macrophages).

Anatomical Barriers

• Skin:

  • Epidermis: Packed dead cells with keratin.
  • Dermis: Connective tissue with glands, vessels and immune cells.
  • Low pH.
  • Antimicrobial peptides (e.g., psoriasin against E. coli).
  • Fatty acids in sebum.

• Mucosal Epithelium:

  • Outer layer of epithelial cells in gastrointestinal, respiratory, and urogenital tracts.
  • Biochemical defenses:
    • Lysozyme: attacks Gram + bacteria cell walls.
    • Defensins, cathelicidins, histatins: secreted by phagocytes.
    • IgA: opsonization.

• Opsonization:

  • $Ops{\bar{o}}ne{\hat{i}}n$ (Greek): to prepare for food

  • Process to enhance phagocytosis.

  • Opsonins (antibodies, complement fragments) attach to microbes, marking them for phagocytosis. (Particular antibodies and complement fragments)

  • Lysozyme: Hydrolyzes peptidoglycan → membrane accessible for antimicrobial proteins.

Chemical Defenses

• Low pH:

  • Stomach: pH ~2.
  • Vagina: pH ~4.5.
  • Skin: pH ~5.5.

• Bile:

  • Bile acids (deoxyholic acid) effective against Helicobacter pylori.

• Pulmonary Surfactant:

  • Lipids and proteins prevent alveolar collapse.
  • Collectins opsonize pathogens; facilitate phagocytosis.

Commensal Microflora

• Compete with pathogens for nutrients and attachment sites.
• Support host by:
  • Promoting immune cell maturation.
  • Aiding digestion and nutrient absorption.
  • Antimicrobial activity.

Recognition of Pathogens

• Innate Immune System:

  • Uses a fixed pathogen recognition battery.
  • Distinguishes between self and non-self.

• Pathogen-Associated Molecular Patterns (PAMPs):

  • Unique microbial components not found in host cells.

• Pattern Recognition Receptors (PRR):

  • Detect PAMPs.
  • Types:
    • Soluble PR molecules (e.g., Mannose-binding lectin (MBL), C1q, C-reactive protein): Function as opsonins.
    • Cell membrane phagocytic receptors.
    • Cell membrane and Cytoplasmic signalling receptors.

Soluble PR Molecules: Mannose-Binding Lectin (MBL)

• Recognizes mannose, fucose, and N-acetylglucosamine residues.
• Activates the lectin complement pathway.

Phagocytic Receptors

• Stimulate phagocytosis by direct PAMP recognition.

  • C-type lectin receptors: Bind to carbohydrate residues

  • Scavenger receptors: bind to anionic polymers and lipoproteins

  • Complement receptors (CRs): bind to complement fragments

  • Fc receptors: bind to opsonizing antibodies → phagocytosis (covered in Antibodies lecture)

  • Opsonin receptors: Enhance phagocytosis by binding to opsonins on pathogens.

Mechanisms of Phagocytosis

• Main Phagocytes: Neutrophils, monocytes, macrophages, dendritic cells.
• Effector Mechanisms:
  • Oxidative Attack: Uses reactive oxygen and nitrogen species (ROS, RNS).
  • Binding of PRR to target PAMPs Activation of the membrane- associated NADPH oxidase Activation of the inducible nitric oxide synthase (iNOS)
  • Non-Oxidative Attack: Lysosomes merge with phagosome, forming phagolysosome; uses proteolytic enzymes, lysozyme, antimicrobial peptides.

Oxidative Attack

• Reactive Oxygen Species (ROS)

  • Superoxide ${O_2}^.$
    • Hydrogen peroxide $H<em>2O</em>2$

• Reactive Nitrogen Species
  * Nitric oxide $NO$

• Respiratory Burst: Transient increase of oxygen consumption.

ROS in Pathogen Elimination

• Generated continuously in small amounts during normal cell metabolism
• Generated ROS are the main mechanism for killing phagocytosed extracellular pathogens

Phagocytosis in Neutrophils: Summary

• Bacteria taken up into phagosomes
• Phagosomes fuse with primary and secondary granules.
• Rac2 induces assembly of a functional NADPH oxidase in the phagolysosome membrane, leading to generation of ${O_2}^-$.
• Acidification releases granule proteases from primary granules.

Antimicrobial mechanisms of phagocytes: Summary

• Class of mechanism
  • Acidification
  • Toxic oxygen-derived products
    • Superoxide ${O_2}^.$
    • Hydrogen peroxide $H<em>2O</em>2$
      *singlet oxygen ${1O_2}^´$
      *hydroxyl radical $´OH$
      *hypohalite $OCI^-$
  • Toxic nitrogen oxides
    • Nitric oxide $NO$

Signalling PRRs

• Cell membrane and cytoplasmic receptors that induce gene expression changes.

  • Toll-like receptors (TLR): plasma membrane and intracellular vesicles.
  • C-type lectin receptors (plasma membrane).
  • Nod-like receptors (NLR – cytosolic proteins).

• Activation induces:

  • Antimicrobial peptides
  • Production of cytokines (e.g., interferons).

Toll-Like Receptors (TLRs)

• Detect molecular carbohydrate, lipid and/or protein patterns not present in healthy vertebrate cells → Signalling → ↑ expression of Type I interferons

Definitions

• Antimicrobial peptides
• Pathogen-Associated Molecular Patterns (PAMPs)
• Pattern recognition receptors (PRR) and molecules
• Reactive Oxygen Species (ROS)
• Oxidative burst