Towne Lecture 2

INNATE IMMUNOLOGY LECTURE NOTES

Course Information

  • Course: IHL Course

  • Target Audience: Class of 2029

  • Instructor: Dr. Francina Towne

PURPOSE OF THIS LECTURE

  • Goals:

    • Learn how the innate immune system:

    • Recognizes pathogens

    • Fights pathogens once recognized

    • Aids and stimulates the adaptive immune system

READING MATERIALS

  • Before Class:

    • "Basic Immunology: Functions & Disorders of the Immune System" by Abbas & Lichtman

    • Chapter 2: Components of Innate Immunity (excluding the Complement System)

  • After Class:

    • Enhance understanding of concepts with:

    • DSA: Leukocyte Migration

    • Zoom Lect: Complement

    • Review connections with COVID-19 and the innate immune response

OBJECTIVES OF THE LECTURE

  • Describe physiological functions of innate immunity

  • Identify four principal cellular and molecular components:

    1. Epithelium/Mucosal Surfaces

    2. Pattern Recognition Receptors (TLR/NLR, PRR/PAMP, DAMP)

    3. Cells (Macrophages, Neutrophils, DCs, Mast cells, Eosinophils, NK cells)

    4. Secreted Products (Histamine, Lipids, Cytokines/Chemokines, PR-molecules, Complement)

COMPONENTS OF INNATE IMMUNITY

1. Epithelium/Mucosal Surfaces

  • Physical Barriers:

    • Tight junctions

    • Cilia

  • Chemical Barriers:

    • Rapid pH changes

    • Mucus

    • Fatty Acids

    • Produces antimicrobials:

    • Defensins

    • Cathelicidins

  • Normal Flora: Necessary for overall immunity

  • Specific Cells:

    • Intraepithelial Lymphocytes (Skin: 2 m², Airways: 100 m², Gut: 300 m²)

2. Pattern Recognition Receptors (PRRs)

  • Function: Detect pathogens via pathogen-specific components

  • Locations of PRRs:

    • Surface of cell membrane (TLRs)

    • Inside endosomes in cell (TLRs)

    • Cytosol (NLRs)

  • Key Characteristics:

    • Recognize approximately 1000 patterns

    • Unable to react against self

Pathogen-Associated Molecular Patterns (PAMPs)


  • Definition:

    • Molecules/structures shared by various microbes not present in self.


  • Role: Recognize essential structures for microbial survival and infectivity.


  • PRRs connect with PAMPs examples:

    Microbe Type

    PAMP Example


    Nucleic acids

    ssRNA (Virus)


    dsRNA (Virus)


    CpG (Virus/Bacteria)


    Proteins

    Pilin (Bacteria)


    Flagellin (Bacteria)


    Cell wall lipids

    LPS (Gram-negative)


    Lipoteichoic acid (Gram-positive)


    Carbohydrates

    Mannan (Fungi/Bacteria)


    Glucans (Fungi)

    3. Cells of Innate Immunity

    • Macrophages:

      • Receptors: TLRs, Complement, Mannose binding, IFN-γ, Chemokines

      • Functions upon Activation:

      • Phagocytosis

      • Opsonization

      • Reactive Oxygen Species (ROS) production

      • Cytokines and Growth factor release

    • Neutrophils:

      • Receptors: IFN-γ, Chemokines, TLRs, Complement, Mannose binding

      • Activation Functions:

      • Phagocytosis

      • Opsonization

      • Produce ROS and iNOS

      • Secrete various cytokines and growth factors

      • Genetic defects can lead to Chronic Granulomatous Disease

      • Lifespan in circulation: ~24 hours

      • Form sticky neutrophil extracellular traps (NETs) to capture pathogens

    • Dendritic Cells:

      • Receptors: TLRs, NLRs

      • Primary Functions:

      • Phagocytosis

      • Antigen presentation

      • Cytokine release

      • Serve as a bridge between innate and adaptive immunity

    • Eosinophils:

      • Primarily fight against parasites

      • Involved in Th2 inflammation

    • Mast Cells:

      • Release histamine

      • Play a significant role in allergic responses

    • Natural Killer Cells:

      • Characteristics:

      • Lymphocytes that do not express clonally diverse receptors

      • Comprise about 10% of total lymphocytes

      • Activation:

      • Produced by IL-12 (from macrophages), IL-15, Type I Interferons (IFNs)

      • Secrete IFN-γ, activating macrophages

    4. Secreted Products of Innate Immunity

    • Components:

      • Mast Cells, Dendritic Cells, Macrophages: Produce mediators like histamine, cytokines, prostaglandins.

      • Polymorphonuclear Leukocytes: Elimination of microbial threats

      • Plasma Proteins: Supplementary role in immune response, particularly the complement.

    • Detailed Secreted Products:

      • Histamine: Vasodilator released from mast cells

      • Lipid Mediators: Derived from membrane phospholipids; includes leukotrienes, prostaglandins, thromboxane

      • Chemokines: Proteins that mediate attraction of other cells to infection sites

      • Cytokines: Support growth and differentiation of lymphoid cells, can act on endothelial cells.

      • Types include Interleukins, Interferons (α, β, γ), and Tumor Necrosis Factors (α, β).

      • Pattern Recognition Molecules: Proteins like Mannose Binding Lectin or C-reactive protein bind to unique microbe structures.

      • Complement: A cascade of serum proteins; activates inflammation and eliminates microbes. (Detailed coverage in next week's Zoom Lecture)

    ACUTE INFLAMMATION

    • Definition:

    • The innate immune system addresses infections and tissue injury through acute inflammation which involves accumulation of leukocytes, plasma proteins, and fluid from blood.

    • Key Cytokines in Acute Inflammation:

      • TNF, IL-1, and IL-6 have local/systemic inflammatory effects.

      • Induce fever, acute-phase protein synthesis (liver), and increased leukocyte production (bone marrow).

      • Can lead to septic shock through pathologic mechanisms if systemic.

    • Phases in Inflammatory Response:

      1. Initial recruitment of leukocytes led by TNF and IL-1, which increases P & E selectins on endothelium.

      2. Process involves multiple phases including rolling, adhesion, and extravasation of leukocytes.

      3. Cytokines from macrophages correlate with activating and regulating immune functions.

    CLINICAL CASE STUDY: LUISA

    • Presentation:

      • Newborn with omphalitis showing elevated WBC count, treated for infections.

      • Family history of severe infections led to further evaluation.

    • Lab Findings:

      • Pertinent values indicating leukocyte adhesion deficiency (LAD) type I due to defective integrins
        detection of CD18 in leukocytes leading to impaired migration.

    LEUKOCYTE ADHESION DEFICIENCY (LAD)

    • Definition: Condition restricting leukocyte migration to infection sites leading to clinically significant implications.

    • LAD Type I:

      • Autosomal recessive disorder characterized by defects in the β2 chain of integrins (CD18) leading to clinical manifestations such as recurrent infections and impaired wound healing.

    IMPACT OF ACUTE INFLAMMATION IN COVID-19

    • Acute inflammation plays a crucial role in exacerbating or mitigating lung injury during viral infections due to:

      1. Increased permeability leading to fluid exudation.

      2. Recruitment and activation of macrophages and neutrophils, often leading to collateral damage of normal lung cells.

    3. Impaired gas exchange due to inflammation and resultant damage to alveolar cells

    SELF-QUIZ

    1. What is an antimicrobial peptide that protects epithelial surfaces?

    2. What cytokines activate NK cells?

    3. Define PAMP and PRR.

    CONCLUSION

    • Reiterate the significance of understanding innate immunity with regard to disease prevention and management, especially in light of infectious diseases impacting public health today (e.g., COVID-19).

    • Encourage students to explore content connections across various biological and clinical frameworks.