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Introduction to the Immune System

• Professor: Kevin Maloy (kevin.maloy@glasgow.ac.uk)

Key Learning Objectives

• Understand how microbes are sensed by immune cells.

• Explore mechanisms used by microbes to evade immune detection.

Immune System Decision-Making

• The immune system differentiates between:

  • Foreign & Dangerous: Pathogens

  • Self or Innocuous Substances: Body's own cells, allergens (e.g., pollen)

• Examples to differentiate:

  • Self epithelial cells

  • Common pathogens (Virus, Bacteria)

Discussion Questions for the Lecture

• What microbial substances activate the immune system?

• How does the immune system recognize damage caused by pathogens?

• Which cells and receptors respond to microbial products?

• What are the consequences of microbial sensing for the host?

• How do microbes evade detection?

Overview of Initial Immune Response

• Key Immune Cells Involved:

  • Mast cells

  • Dendritic cells

  • Macrophages

  • Neutrophils

• Events During Infection:

  • Activation of local innate immune cells

  • Increased blood vessel permeability

  • Migration of immune cells and plasma proteins (acute inflammation)

Historical Insights

• Charles Janeway: Predicted host receptors recognize conserved patterns on pathogenic molecules.

• Timeline:

  • Life: 1943-2003

  • Contribution: Cold Spring Harbor 1989, Nobel Prize in Physiology and Medicine 2011

Microbial Recognition: PAMPs & DAMPs

• PAMPs (Pathogen Associated Molecular Patterns):

  • What distinguishes microbes from host cells:

    • Viruses: Viral nucleic acids, glycoproteins

    • Bacteria: Bacterial DNA, cell wall components

    • Fungi: Polysaccharides

    • Protozoa: Glycolipids

• DAMPs (Damage Associated Molecular Patterns):

  • Indicators of tissue damage:

    • Nuclear and cytoplasmic proteins

    • Nucleic acids

    • Metabolites from dying cells

Immune Response Cascade

• Information from pathogens is conveyed to adaptive immune cells:

  • Pathway: Pathogens → Dendritic Cells (DCs) & Innate Cells → Adaptive Immune Cells (B cells, CD8+ T cells, CD4+ T cells)

  • Roles of Adaptive Immune Cells:

    • Kill infected cells

    • Coordinate immune responses

    • Produce antibodies

Immune Cell Variations

• Cells involved in pathogen detection at infection sites:

  • Mast Cells: Release toxins to kill pathogens

  • Neutrophils: Engulf and destroy pathogens

  • Macrophages & Monocytes: Engulf pathogens

  • Dendritic Cells: Activate adaptive immune cells

  • Tissue Cells: Epithelial cells, fibroblasts release inflammatory mediators

Host Defense Mechanisms

• Various soluble and cell surface molecules assist in sensing pathogens:

  • Pathogens evading these molecules can cause higher disease severity.

Complement System Overview

• Function: Series of plasma proteins acting in an enzymatic cascade impacting pathogen control

  • Consequences:

    • Enhances acute inflammation

    • Soluble factors (C3a, C5a) increase immune cell influx

    • Improved phagocytosis and pathogen clearance

    • Kill pathogens through Membrane Attack Complex (MAC) formation (C5-C9 components)

Evasion of the Complement System

• Pathogens and host cells utilize mechanisms to evade the complement response:

  • Examples:

    • CD46 (inactivates C3b)

    • CD59 (prevents MAC formation)

    • C1 inhibitor (regulates early complement components)

    • Smallpox virus protein (SPICE) inactivates C3b

Recognizing PAMPs with PRRs

• Pattern Recognition Receptors (PRRs): Detect PAMPs and DAMPs

  • Types of PRRs:

    • Toll-Like Receptors (TLRs): Primarily recognize PAMPs

    • Nucleotide-binding Oligomerization Domain-Like Receptors (NLRs): Recognize diverse PAMPs and DAMPs

    • C-type Lectin-Like Receptors (CLRs): Target pathogen carbohydrates

    • Absent in Melanoma 2-Like Receptors (ALRs): Recognize bacterial or viral DNA

    • Retinoic Acid-Inducible Gene-I-Like Receptors (RLRs): Detect RNA from pathogens

Role of PRRs in Immune Cells

• PRR Thematic Distribution:

  • TLRs are located in endosomes

  • NLRs, RLRs, CLRs primarily in cytoplasm

  • Specific receptors for pathogens located on cell membrane

Subversion of PRR Recognition by Pathogens

• Pathogens evolve mechanisms to avoid detection:

  • Examples:

    • Helicobacter pylori flagellin reducing TLR5 recognition

    • Polio virus masking RNA caps from NLRs

    • Listeria monocytogenes altering cell wall to evade NLR recognition

Activation Outcomes from PRRs

• Consequences upon PRR activation:

  • Notify neighboring cells of threats

  • Produce inflammatory cytokines

  • Engage adaptive immune system

  • Phagocytosis of invading microbes

  • Regulation of microbial replication

Connection Between PRR Activation and Immune Response Modulation

• PRR activation leads to changes in gene transcription via NF-κB:

  • TLR activation initiates pathway leading to NF-κB translocation into the nucleus.

  • This process aids in conveying infection alerts to the immune system.

Pathogen Strategies to Limit Immune Activation

• Some pathogens diminish NF-κB activation:

  • E.coli and Shigella: Secrete factors that degrade NF-κB, reducing immune signaling.

Inflammasomes and Cytokine Release

• Certain NLRs form inflammasomes to activate Caspase-1:

  • Produces pro-inflammatory cytokines (IL-1β, IL-18)

Influenza Virus Response Mechanisms

• Infection Outcomes:

  • Induces inflammatory cytokine release and cell death:

    • Warns neighboring cells through Type I interferons.

    • Promotes apoptosis & immune response activation.

Viral Evasion of Immune Activation

• Influenza can restrict PRR activation, leading to unchecked spread.

  • NS1 protein inhibits RIG-I and NF-κB pathways to evade detection.

Summary of Immune System Lectures

• Core Topics:

  • Pathogen-triggered innate immune responses

  • Adaptive immunity and its mechanisms

  • Strategies pathogens use to evade immunity

  • Misactivation of immune system can lead to conditions such as allergies and autoimmunity.

Introduction to Microbial Sensing in the Immune System

Microbial Substances Activating Innate Immune Cells

• Pathogen-Associated Molecular Patterns (PAMPs): Distinguish microbes from host cells and can include:

  • Viruses: Viral nucleic acids, glycoproteins

  • Bacteria: Bacterial DNA, cell wall components

  • Fungi: Polysaccharides

  • Protozoa: Glycolipids

• Damage-Associated Molecular Patterns (DAMPs): Indicators of tissue damage which can involve:

  • Nuclear and cytoplasmic proteins

  • Nucleic acids

  • Metabolites from dying cells

Recognition of Damage Caused by Pathogens

• Immune cells recognize damage via the following mechanisms:

  • Detection of PAMPs and DAMPs activates innate immune responses.

  • Specific receptors on immune cells respond to microbial products and recognize damage.

Receptors Used by Immune Cells

• Pattern Recognition Receptors (PRRs): Detect PAMPs and DAMPs.

  • Toll-Like Receptors (TLRs): Primarily recognize PAMPs.

  • Nucleotide-binding Oligomerization Domain-Like Receptors (NLRs): Recognize diverse PAMPs and DAMPs.

  • C-type Lectin-Like Receptors (CLRs): Target pathogen carbohydrates.

  • Absent in Melanoma 2-Like Receptors (ALRs): Recognize bacterial or viral DNA.

  • Retinoic Acid-Inducible Gene-I-Like Receptors (RLRs): Detect RNA from pathogens.

Consequences of Microbial Sensing for the Host

• Activation Outcomes from PRR activation include:

  • Notify neighboring cells of threats.

  • Produce inflammatory cytokines.

  • Engage the adaptive immune system.

  • Regulate microbial replication.

  • Phagocytosis of invading microbes.

Microbial Evasion of Immune Detection

• Pathogens have evolved mechanisms to evade detection by the immune system, such as:

  • Helicobacter pylori: Reduces TLR5 recognition.

  • Polio virus: Masks RNA caps from NLRs.

  • Listeria monocytogenes: Alters cell wall structure to evade NLR recognition.

  • Degrading NF-κB to diminish immune signaling (e.g., by E.coli and Shigella).