Pattern Recognition Receptors Lecture Notes

Pattern Recognition Receptors in the Innate Immune System

Overview

  • Innate Immune System: Represents the body's first line of defense against pathogens, providing immediate responses upon infection.

  • Key Components: Contains preformed soluble effector molecules (e.g., complement) and effector cells (e.g., macrophages, natural killer cells) that act against infections.

    • Immediate Response: Initiation of the immune response occurs as soon as a pathogen invades.

Key Objectives of the Lecture

  • Familiarization with terminology related to Pattern Recognition Receptors (PRR) including:

    • PAMPs (Pathogen-Associated Molecular Patterns)

    • PRR (Pattern Recognition Receptors)

    • TLR (Toll-Like Receptors)

    • NOD (Nucleotide-binding Oligomerization Domain)

    • Inflammasomes

  • Understanding the history and discovery of TLRs.

  • Exploring ligand specificities of TLRs and their cellular localization.

  • Learning about TLR-mediated signaling and its significance.

  • Discussing consequences of excessive inflammation in conditions like sepsis.

The Induced Immune Response

  • Induction of Response:

    • Triggered by pathogen components or signs of inflammation recognized through receptors on innate immune cells.

    • Involves activation of host cells to enhance pathogen elimination.

  • Mechanisms:

    • If initial control is insufficient, an adaptive immune response may occur, typically beginning 4 to 5 days post-infection.

    • The adaptive response leads to proliferation of T and B cells, generating immunological memory for quicker future responses.

    • If control fails, chronic conditions or overwhelming infections may develop, potentially resulting in death.

Pattern Recognition Receptors (PRRs)

  • Recognize PAMPs and initiate immune responses.

  • Types of PRRs include:

    • Toll-like receptors (TLRs): Large family of receptors mostly found in membranes.

    • NOD-like receptors (NLRs): Located in the cytoplasm.

    • RIG-I-like receptors (RLRs): Also localized in the cytoplasm, recognizing viral components.

  • Other receptors (scavenger, complement, and lectin receptors) aid in pathogen uptake rather than signaling.

    • Uptake Receptors: Bind pathogen patterns to facilitate cellular uptake.

    • Signaling Receptors: Recognize PAMPs, initiate signaling cascades, and influence gene expression.

Pathogen-Associated Molecular Patterns (PAMPs)

  • Definition: Molecular structures found on pathogens.

    • Gram-Positive Bacteria: May express peptidoglycan and lipoteichoic acid as PAMPs.

    • Gram-Negative Bacteria: Express lipopolysaccharide (LPS).

    • Flagellin: A protein component of flagella from motile bacteria recognized by TLR5.

    • Bacterial DNA: Characterized as hypomethylated CpG DNA, recognized by certain TLRs.

  • PAMPs are generally shared among broad classes of organisms, facilitating recognition across different species.

Toll-Like Receptors (TLRs)

  • Membrane-bound receptors essential for pathogen recognition.

  • TLRs activate signaling pathways leading to innate immune responses.

  • Key TLRs and their Specificities:

    • TLR 2: Recognizes lipoteichoic acid from gram-positive bacteria.

    • TLR 4: Recognizes lipopolysaccharide from gram-negative bacteria, requiring several accessory proteins (LBP, MD2, CD14).

    • TLR 3, 7, 8, 9: Recognize viral RNA and specific unmethylated DNA.

    • TLR 5: Unique as it recognizes flagellin protein.

  • TLRs have distinct localization:

    • Some reside on the plasma membrane; others are found within endosomes to recognize nucleic acids.

Signaling Mechanisms of TLR Activation

  • Upon ligand binding, TLRs initiate signaling cascades through interaction with adapter proteins like MYD88, leading to activation of kinases.

  • The result is activation of transcription factors, notably NF-kappa B, which leads to:

    • Expression of various inflammatory cytokines (e.g., IL-1, IL-6, TNF-alpha).

    • Induction of innate immune responses.

Inflammation and Cytokine Production

  • Inflammatory cytokines are crucial mediators in the immune response.

  • Major pro-inflammatory cytokines include:

    • Interleukin-1 (IL-1)

    • Interleukin-6 (IL-6)

    • Tumor Necrosis Factor-alpha (TNF-alpha)

  • Functions:

    • Induce acute phase response, mobilize neutrophils, and raise body temperature (fever) to inhibit pathogen growth.

  • Mediate dendritic cell maturation and enhance antigen presentation.

    • Dendritic cells transition from an immature to a mature state, enhancing their ability to activate T cells and initiate adaptive responses.

Consequences of Excessive Inflammation

  • Sepsis: Systemic infection leading to widespread inflammation and consequences like septic shock due to excessive TNF-alpha release. This results in:

    • Increased vascular permeability, leading to fluid loss and potentially fatal low blood pressure (disseminated intravascular coagulation).

    • Urgent medical interventions required to restore homeostasis (e.g., rehydration therapies, antibiotics).

Conclusion

  • Pattern recognition receptors play a vital role in the innate immune response, providing rapid detection and signaling pathways against pathogens. Understanding their mechanisms helps to comprehend the complexities of immune system functioning and its implications in health and disease.