Pathogen Recognition Receptors & Innate immune Response || Toll-like Receptors

Introduction to the Immune Response

The immune system is crucial for protecting the body against pathogens. It comprises two primary components: the innate immune system and the acquired immune system. The innate immune system is the first line of defense and responds to pathogens upon detection.

The Role of Dendritic Cells in Immune Response

  • Detection of Pathogens: Dendritic cells circulate throughout tissues and detect pathogens via pathogen-associated molecular patterns (PAMPs).

  • What are PAMPs?: PAMPs are conserved pathogen traits, such as lipopolysaccharides (LPS) found in the cell membranes of all gram-negative bacteria.

Recognition of PAMPs

  • Toll-Like Receptors (TLRs): Dendritic cells express TLRs, which recognize PAMPs.

    • TLR-4: Specifically recognizes LPS.

    • Mechanism:

      • LPS is carried by LPS-binding protein (LBP) and deposited on CD14 on dendritic cells.

      • TLR-4 detects LPS bound to CD14, leading to dendritic cell maturation.

  • Activation of Acquired Immune Response: Mature dendritic cells migrate to regional lymph nodes to activate acquired immunity.

Immune Cells and PAMP Recognition

  • Key Immune Cells:

    • Macrophages and dendritic cells identify diverse pathogen types.

  • Receptor Diversity:

    • Cells have evolved various receptors for different PAMPs, primarily using TLRs.

Structure of TLRs

  • Composed of leucine-rich repeats, TLRs are membrane-associated proteins located on cell surfaces or endocytic vesicles.

  • Function: TLRs inspect degraded contents of pathogens to recognize PAMPs.

Types of TLRs and Their Targets

  • Each TLR recognizes specific PAMPs, for example:

    • TLR-5: Identifies flagellin (bacterial flagellum component).

    • TLR-9: Recognizes methylated CpG oligonucleotide patterns in bacterial genomes post-lysosomal degradation.

    • TLR-6 and TLR-2: Form a dimer to detect diacyl lipopeptides.

    • TLR-1 and TLR-2: Recognize triacyl lipopeptides.

    • TLR-3 and TLR-7: Identify double-stranded and single-stranded RNA, respectively, in endocytic vesicles.

Activation of Signaling Pathways

When a TLR is activated:

  • Transcription factors are stimulated, sending signals to the nucleus for further immune response action.

  • It’s important to note that certain pathogens (e.g., viruses) reside in the cytosol rather than the extracellular space.

Cytosolic Pathogen Detection

NOD Proteins

  • Nucleotide Oligomerization Domain (NOD) Proteins: A family of receptors that detect cytosolic infections.

    • NOD2: Recognizes bacterial proteoglycans, sending signals to the nucleus upon detection of muramyl dipeptide.

RNA Helicase and CARD Domain Proteins

  • A distinct class of proteins containing RNA helicase and caspase recruitment domains (CARD).

    • Example: RIG-I: Recognizes double-stranded RNAs associated with RNA viruses, signaling Type-1 interferons synthesis.

Conclusion

Toll-like receptors, NOD proteins, and RNA helicases play critical roles in the innate immune system, allowing it to identify and respond to both extracellular and intracellular pathogens efficiently. These mechanisms form the foundation of the body’s initial defense strategy.