Principles of Innate Immunity

How do sensor cells distinguish "self" from "nonself"?

Innate recognition is mediated by Pattern Recognition Receptors (PRRs) expressed on sensor cells like macrophages and dendritic cells. These receptors are germline-encoded and detect Pathogen-Associated Molecular Patterns (PAMPs)—repetitive molecular structures essential to microbes but absent in the host (e.g., bacterial lipopolysaccharides or unmethylated CpG DNA)

What are "DAMPs," and why are they significant?

Damage-Associated Molecular Patterns (DAMPs) are self-derived molecules (like ATP or urate crystals) released during cellular stress or damage. Recognition of DAMPs allows the innate system to respond to "sterile" injury or tissue damage even in the absence of a live infection

What are the four major families of signaling PRRs?

1. Toll-like Receptors (TLRs): Transmembrane sensors for extracellular or endosomal PAMPs (e.g., TLR-4 for LPS).

2. NOD-like Receptors (NLRs): Cytoplasmic sensors for bacterial peptidoglycans (NOD1/2) or cellular stress (NLRP3), the latter forming the inflammasome.

3. RIG-I-like Receptors (RLRs): Cytoplasmic sensors that detect viral RNA.

4. cGAS/STING: A cytoplasmic pathway dedicated to sensing double-stranded DNA

How do anatomic and chemical barriers work together?

The first line of defense consists of epithelial surfaces (skin, gut, lungs) providing a mechanical seal via tight junctions. This is augmented by chemical defenses: antimicrobial enzymes like lysozyme (which digests bacterial cell walls) and antimicrobial peptides like defensins (which disrupt microbial membranes)

What is the role of the Complement System in innate defense?

Complement is a system of ~30 plasma proteins acting as a "humoral" innate barrier. Three pathways (Classical, Lectin, and Alternative) converge to form a C3 convertase, which deposits C3b on the pathogen surface. This results in three outcomes: opsonization (marking for phagocytosis), inflammation (via C3a and C5a), and lysis (via the membrane-attack complex)

How do the primary phagocytes differ?

• Macrophages: Long-lived residents in almost all tissues; they kill microbes and orchestrate the inflammatory response by releasing cytokines.

• Neutrophils: Short-lived "professional" killers recruited from the blood in large numbers; they use a "respiratory burst" of reactive oxygen species to destroy pathogens in intracellular vesicles

What are Innate Lymphoid Cells (ILCs) and NK cells?

These cells arise from the common lymphoid progenitor but lack antigen-specific receptors. Natural Killer (NK) cells kill virus-infected or stressed cells directly. Other ILCs act as "innate homologs" to helper T cells, producing cytokines that amplify specific types of immune responses (Effector Modules)

What drives the four signs of inflammation (heat, pain, redness, swelling)?

Activated macrophages and neutrophils release cytokines (e.g., TNF-α, IL-1, IL-6) and chemokines (e.g., CXCL8). These cause vasodilation (redness/heat), increased vascular permeability (swelling/edema), and endothelial activation, allowing leukocytes to squeeze out of blood vessels (extravasation) and migrate toward the infection

What are "Effector Modules"?

The system organizes its response based on the pathogen type:

• Type 1 (Intracellular): Driven by ILC1/TH1 and IFN-γ to activate macrophage killing.

• Type 2 (Parasites): Driven by ILC2/TH2 to recruit eosinophils and mast cells.

• Type 3 (Extracellular Bacteria/Fungi): Driven by ILC3/TH17 to recruit neutrophils

How does the innate system "hand off" to the adaptive system?

Dendritic cells (DCs) are the crucial link. Upon sensing a pathogen via PRRs, they migrate to secondary lymphoid organs (like lymph nodes) where they present antigen pieces on MHC molecules to T cells. Importantly, innate recognition induces co-stimulatory molecules (like B7.1/B7.2) on the DC surface, which are required to fully activate naive T cells—a process Janeway called the "dirty little secret" of immunology