Immunology: Toll-like Receptors and Phagocytosis

Innate Immunity Lecture Notes

• Learning Objectives:
  • Characteristics of the innate immune system
  • Pathogen recognition by innate immune cells
  • Functions of the innate immune system (phagocytosis, complement, natural killer cells)

Innate Defenses

• Physical Barriers:
  • Tight junctions at epithelial cells
  • Mucous membranes
  • pH
  • Antimicrobial secretions (e.g., lysozyme in tears)
• Internal Defenses:
  • Phagocytosis
  • Complement
  • Natural Killer Cells
  • Cytokine secretion

Adaptive Defenses

• Humoral Immunity:
  • B cells
  • Antibodies
• Cell-Mediated Immunity:
  • T cells
  • Cell killing
  • Cytokine secretion

Cells Involved in Innate and Adaptive Immunity

• Innate Immunity (Hours):

  • Basophils
  • Eosinophils
  • Neutrophils
  • Macrophages
  • Mast cells
  • Natural killer cells
  • Dendritic cells

• Adaptive Immunity (Days):

  • Antibodies
  • B cells
  • Cytokines
  • Cytotoxic molecules
  • T cells

Features of Innate/Natural Immunity

• Innate immunity is present from birth and is always functional.
• It can respond immediately to pathogens.
• It instructs the adaptive immune system.
• It recognizes non-self (foreign) structures in a non-specific way.
• It has no memory of previous infections and cannot improve its response with experience.

Pathogen Recognition by Innate System Cells

• Proposed by Janeway (1989).
• Innate cells have pattern recognition receptors (PRRs).
• PRRs are encoded in germline cells and have limited diversity.
• Toll-like receptors (TLRs) and NOD-like receptors are examples of PRRs.
• PRRs recognize pathogen-associated molecular patterns (PAMPs) -shared by different classes of microbes.
  • Examples of PAMPs include peptidoglycan, lipopolysaccharide (LPS).

Innate Immune Recognition of Bacterial Cell Wall Components

• Gram-negative bacteria: have lipopolysaccharide in outer membrane, porins.
• Gram-positive bacteria: have teichoic acid and peptidoglycan.

Identical Toll-like Receptors

• Recognize common structures on different microbes.

More on Toll-like Receptors (TLRs)

• Jules Hoffman and others discovered the role of Toll receptors in invertebrates.
• Beutler discovered mammalian TLR4 (responds to LPS).
• Humans have ten different TLRs.
• TLRs are expressed on various cells (e.g., macrophages, dendritic cells).
• TLRs are found on cell surfaces and intracellular vesicles.

Complement

• 30 plasma proteins in an inactive state.
• Become active at infection sites, triggering inflammatory events.
• C3 is a central component in the complement cascade.
• Three pathways activate complement:
  • Classical pathway
  • Alternative pathway
  • Lectin pathway
• A "membrane attack complex" (MAC) forms to lyse pathogens.

Classical Pathway Activation

• Activated by immune complexes containing IgM or IgG.
• Other activators include C-reactive protein, lipopolysaccharide, bacterial porins.

Safety Checks of Classical Pathway

• Covalent binding of C4b and C3b to the activator ensures the reaction stays on the pathogen surface.
• Plasma and host cell inhibitors prevent activation in the absence of a pathogen.

Membrane Attack Complex (MAC)

• Disrupts fluid balance, leading to lysis of pathogens.
• Composed of C5b, C6, C7, C8, and multiple C9 molecules.

Functions of Complement

• Opsonization:

  • C3b binds to complement receptor type I (CR1 or CD35) on phagocytes.
  • C5a activates phagocytosis when C3b is bound to CR1.

• Cell Lysis: Through the membrane attack complex.

• Inflammation: C3a, C4a, and C5a are inflammatory mediators that activate cells.

• Recruits adaptive immunity: Some components stimulate B-cell activation.

Deficiencies of Complement

• Deficiency in the classical pathway (especially C1q) increases susceptibility to autoimmune diseases like SLE.
• Can also increase susceptibility to some bacterial infections (e.g., Streptococcus pneumoniae, Haemophilus influenzae).

Natural Killer (NK) Cells

• Lymphoid lineage (10-15% of blood lymphocytes).
• Recognize if a cell has a viral infection or is cancerous.
• Kill infected cells by releasing perforin.
• Perforin creates holes in the target cell membrane.
• Granzyme enters the target cell through the perforin pore
• Induces apoptosis (programmed cell death).

Summary of Main Points

• Innate immunity responds quickly but is non-specific.
• Innate cells do not have memory.
• Innate cells distinguish self from non-self using pattern recognition receptors (PRRs).
• They bind to pathogen-associated molecular patterns (PAMPs).
• Innate functions include phagocytosis, complement activation, NK cell killing.
• Facilitate the killing of pathogens and activate the adaptive immune response.

This quiz explores the roles of Toll-like receptors (TLRs) and the process of phagocytosis within the immune system. It covers important concepts such as innate immunity, complement function, and key cell types involved in these processes. Test your knowledge on the fundamentals of immunology!